ALBERT

Description: by Valentina Cardi, Freya Corfield, Jenni Leppanen, Charlotte Rhind, Stephanie Deriziotis, Alexandra Hadjimichalis, Rebecca Hibbs, Nadia Micali, Janet Treasure Background Difficulties in social cognition have been identified in eating disorders (EDs), but the exact profile of these abnormalities is unclear. The aim of this study is to examine distinct processes of social-cognition in this patient group, including attentional processing and recognition, empathic reaction and evoked facial expression in response to discrete vignettes of others displaying positive (i.e. happiness) or negative (i.e. sadness and anger) emotions. Method One hundred and thirty-eight female participants were included in the study: 73 healthy controls (HCs) and 65 individuals with an ED (49 with Anorexia Nervosa and 16 with Bulimia Nervosa). Self-report and behavioural measures were used. Results Participants with EDs did not display specific abnormalities in emotional processing, recognition and empathic response to others’ basic discrete emotions. However, they had poorer facial expressivity and a tendency to turn away from emotional displays. Conclusion Treatments focusing on the development of non-verbal emotional communication skills might be of benefit for patients with EDs.

Description: by Laura B. Ramsey, Laura J. Janke, Monique A. Payton, Xiangjun Cai, Steven W. Paugh, Seth E. Karol, Landry Kamdem Kamdem, Cheng Cheng, Richard T. Williams, Sima Jeha, Ching-Hon Pui, William E. Evans, Mary V. Relling Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia.

Description: by Weng Yee Chin, Edmond P. H. Choi, Kit T. Y. Chan, Carlos K. H. Wong Background The Center for Epidemiologic Studies Depression Scale (CES-D) is a commonly used instrument to measure depressive symptomatology. Despite this, the evidence for its psychometric properties remains poorly established in Chinese populations. The aim of this study was to validate the use of the CES-D in Chinese primary care patients by examining factor structure, construct validity, reliability, sensitivity and responsiveness. Methods and Results The psychometric properties were assessed amongst a sample of 3686 Chinese adult primary care patients in Hong Kong. Three competing factor structure models were examined using confirmatory factor analysis. The original CES-D four-structure model had adequate fit, however the data was better fit into a bi-factor model. For the internal construct validity, corrected item-total correlations were 0.4 for most items. The convergent validity was assessed by examining the correlations between the CES-D, the Patient Health Questionnaire 9 (PHQ-9) and the Short Form-12 Health Survey (version 2) Mental Component Summary (SF-12 v2 MCS). The CES-D had a strong correlation with the PHQ-9 (coefficient: 0.78) and SF-12 v2 MCS (coefficient: -0.75). Internal consistency was assessed by McDonald’s omega hierarchical (ωH). The ωH value for the general depression factor was 0.855. The ωH values for “somatic”, “depressed affect”, “positive affect” and “interpersonal problems” were 0.434, 0.038, 0.738 and 0.730, respectively. For the two-week test-retest reliability, the intraclass correlation coefficient was 0.91. The CES-D was sensitive in detecting differences between known groups, with the AUC 〉0.7. Internal responsiveness of the CES-D to detect positive and negative changes was satisfactory (with p value 0.2). The CES-D was externally responsive, with the AUC〉0.7. Conclusions The CES-D appears to be a valid, reliable, sensitive and responsive instrument for screening and monitoring depressive symptoms in adult Chinese primary care patients. In its original four-factor and bi-factor structure, the CES-D is supported for cross-cultural comparisons of depression in multi-center studies.

Description: by Sabine Charron, François Roubertie, David Benoist, Virginie Dubes, Stephen H. Gilbert, Marion Constantin, Delphine Vieillot, Delphine Elbes, Bruno Quesson, Pierre Bordachar, Michel Haissaguerre, Olivier Bernus, Jean-Benoit Thambo, Caroline Rooryck Surgical repair of Tetralogy of Fallot (TOF) is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular or biventricular dysfunction. To better understand the molecular and cellular mechanisms of these delayed cardiac events, a chronic animal model of postoperative TOF was studied using microarrays to perform cardiac transcriptomic studies. The experimental study included 12 piglets (7 rTOF and 5 controls) that underwent surgery at age 2 months and were further studied after 23 (+/- 1) weeks of postoperative recovery. Two distinct regions (endocardium and epicardium) from both ventricles were analyzed. Expression levels from each localization were compared in order to decipher mechanisms and signaling pathways leading to ventricular dysfunction and arrhythmias in surgically repaired TOF. Several genes were confirmed to participate in ventricular remodeling and cardiac failure and some new candidate genes were described. In particular, these data pointed out FRZB as a heart failure marker. Moreover, calcium handling and contractile function genes ( SLN , ACTC1 , PLCD4 , PLCZ ), potential arrhythmia-related genes ( MYO5B , KCNA5 ), and cytoskeleton and cellular organization-related genes ( XIRP2 , COL8A1 , KCNA6 ) were among the most deregulated genes in rTOF ventricles. To our knowledge, this is the first comprehensive report on global gene expression profiling in the heart of a long-term swine model of repaired TOF.

Description: by Michael Schartner, Anil Seth, Quentin Noirhomme, Melanie Boly, Marie-Aurelie Bruno, Steven Laureys, Adam Barrett Emerging neural theories of consciousness suggest a correlation between a specific type of neural dynamical complexity and the level of consciousness: When awake and aware, causal interactions between brain regions are both integrated (all regions are to a certain extent connected) and differentiated (there is inhomogeneity and variety in the interactions). In support of this, recent work by Casali et al (2013) has shown that Lempel-Ziv complexity correlates strongly with conscious level, when computed on the EEG response to transcranial magnetic stimulation. Here we investigated complexity of spontaneous high-density EEG data during propofol-induced general anaesthesia. We consider three distinct measures: (i) Lempel-Ziv complexity, which is derived from how compressible the data are; (ii) amplitude coalition entropy, which measures the variability in the constitution of the set of active channels; and (iii) the novel synchrony coalition entropy (SCE), which measures the variability in the constitution of the set of synchronous channels. After some simulations on Kuramoto oscillator models which demonstrate that these measures capture distinct ‘flavours’ of complexity, we show that there is a robustly measurable decrease in the complexity of spontaneous EEG during general anaesthesia.

Description: by Nicola Boydell, Gillian May Fergie, Lisa Margaret McDaid, Shona Hilton An array of empirical research has emerged related to public participation in health research. To date, few studies have explored the particular perspectives of gay and bisexual men taking part in behavioural surveillance research, which includes the donation of saliva swabs to investigate HIV prevalence and rates of undiagnosed HIV. Semi-structured interviews were conducted with twenty-nine gay and bisexual men in Scotland who had participated in a bar-based survey. Thematic analysis of men’s accounts of their motives for participation and their perceptions of not receiving individual feedback on HIV status suggested a shared understanding of participation in research as a means of contributing to ‘community’ efforts to prevent the spread of HIV. Most men expressed sophisticated understandings of the purpose of behavioural research and distinguished between this and individual diagnostic testing. Despite calls for feedback on HIV results broadly, for these men feedback on HIV status was not deemed crucial.

Description: by Andre Baumann, Rüdiger Lehmann, Annika Beckert, Andreas Vilcinskas, Zdeněk Franta The larvae of the common green bottle fly Lucilia sericata (Diptera: Calliphoridae ) have been used for centuries to promote wound healing, but the molecular basis of their antimicrobial, debridement and healing functions remains largely unknown. The analysis of differential gene expression in specific larval tissues before and after immune challenge could be used to identify key molecular factors, but the most sensitive and reproducible method qRT-PCR requires validated reference genes. We therefore selected 10 candidate reference genes encoding products from different functional classes ( 18S rRNA , 28S rRNA , actin , β-tubulin , RPS3 , RPLP0 , EF1α , PKA , GAPDH and GST1 ). Two widely applied algorithms (GeNorm and Normfinder) were used to analyze reference gene candidates in different larval tissues associated with secretion, digestion, and antimicrobial activity (midgut, hindgut, salivary glands, crop and fat body). The Gram-negative bacterium Pseudomonas aeruginosa was then used to boost the larval immune system and the stability of reference gene expression was tested in comparison to three immune genes ( lucimycin , defensin-1 and attacin-2 ), which target different pathogen classes. We observed no differential expression of the antifungal peptide lucimycin , whereas the representative targeting Gram-positive bacteria ( defensin-1 ) was upregulated in salivary glands, crop, nerve ganglion and reached its maximum in fat body (up to 300-fold). The strongest upregulation in all immune challenged tissues (over 50,000-fold induction in the fat body) was monitored for attacin-2 , the representative targeting Gram-negative bacteria. Here we identified and validated a set of reference genes that allows the accurate normalization of gene expression in specific tissues of L . sericata after immune challenge.

Description: by Marika Rudler, Sarah Mouri, Frederic Charlotte, Philippe Cluzel, Yen Ngo, Mona Munteanu, Pascal Lebray, Vlad Ratziu, Dominique Thabut, Thierry Poynard Background/Aims According to guidelines, the histological diagnosis of severe alcoholic steatohepatitis (ASH) can require liver biopsy if a specific treatment is needed. The blood test AshTest (BioPredictive, Paris, France) has been initially validated for the non-invasive diagnosis of ASH in a large population of heavy drinkers. The aim was to validate the AshTest accuracy in the specific context of use of patients with suspected severe ASH, in order to reduce the need for transjugular biopsy before deciding treatment. Methods The reference was liver biopsy, performed using the transjugular route, classified according to its histological severity as none, minimal, moderate or severe. Biopsies were assessed by the same experienced pathologist, blinded to simultaneous AshTest results. Results A total of 123 patients with severe clinical ASH (recent jaundice and Maddrey function greater or equal to 32) were included, all had cirrhosis and 80% had EASL histological definition of ASH. 95% of patients received prednisolone; and the 2-year mortality was 63%. The high AshTest performance was confirmed both for the binary outcome [AUROC = 0.803 (95%CI 0.684–0.881)] significantly higher than the AST/ALT AUROC [0.603 (0.462–0.714); P

Description: by Yuri Jeong, Sang Min Yoon, Seungbong Han, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, So Yeon Kim, Jin-hong Park, Sang-wook Lee, Seung Do Ahn, Eun Kyung Choi, Jong Hoon Kim Background and Aim To investigate the value of changes in alpha-fetoprotein (AFP) levels for the prediction of radiologic response and survival outcomes in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) who received combined treatment of 3-dimensional conformal radiotherapy (3D-CRT) and transarterial chemoembolization (TACE). Methods A database of 154 HCC patients with PVTT and elevated AFP levels (〉20 ng/mL) treated with 3D-CRT and TACE as an initial treatment between August 2002 and August 2008 was retrospectively reviewed. AFP levels were determined 1 month after radiotherapy, and AFP response was defined as an AFP level reduction of 〉20% from the initial level. Radiologic response, overall survival (OS), and progression-free survival (PFS) rates were compared between AFP responders and non-responders. Propensity-score based matching analysis was performed to minimize the effect of potential confounding bias. Results The median follow-up period was 11.1 months (range, 3.1–82.7 months). In the propensity-score matching cohort (92 pairs), a best radiologic response of CR or PR occurred in more AFP responders than AFP non-responders (41.3% vs. 10.9%, p 〈 0.001). OS and PFS were also longer in AFP responders than in non-responders (median OS 13.2 months vs. 5.6 months, p 〈 0.001; median PFS 8.7 months vs. 3.5 months, p 〈 0.001). Conclusions AFP response is a significant predictive factor for radiologic response. Furthermore, AFP response is significant for OS and PFS outcomes. AFP evaluation after combined radiotherapy and TACE appears to be a useful predictor of clinical outcomes in HCC patients with PVTT.

Description: by Chao Zhang, Tyson L. Hedrick, Rajat Mittal Despite intense study by physicists and biologists, we do not fully understand the unsteady aerodynamics that relate insect wing morphology and kinematics to lift generation. Here, we formulate a force partitioning method (FPM) and implement it within a computational fluid dynamic model to provide an unambiguous and physically insightful division of aerodynamic force into components associated with wing kinematics, vorticity, and viscosity. Application of the FPM to hawkmoth and fruit fly flight shows that the leading-edge vortex is the dominant mechanism for lift generation for both these insects and contributes between 72–85% of the net lift. However, there is another, previously unidentified mechanism, the centripetal acceleration reaction, which generates up to 17% of the net lift. The centripetal acceleration reaction is similar to the classical inviscid added-mass in that it depends only on the kinematics (i.e. accelerations) of the body, but is different in that it requires the satisfaction of the no-slip condition, and a combination of tangential motion and rotation of the wing surface. Furthermore, the classical added-mass force is identically zero for cyclic motion but this is not true of the centripetal acceleration reaction. Furthermore, unlike the lift due to vorticity, centripetal acceleration reaction lift is insensitive to Reynolds number and to environmental flow perturbations, making it an important contributor to insect flight stability and miniaturization. This force mechanism also has broad implications for flow-induced deformation and vibration, underwater locomotion and flows involving bubbles and droplets.

Description: by Jeffery W. Bacher, Chelsie K. Sievers, Dawn M. Albrecht, Ian C. Grimes, Jennifer M. Weiss, Kristina A. Matkowskyj, Rashmi M. Agni, Irina Vyazunova, Linda Clipson, Douglas R. Storts, Andrew T. Thliveris, Richard B. Halberg Microsatellite instability (MSI) occurs in over 90% of Lynch syndrome cancers and is considered a hallmark of the disease. MSI is an early event in colon tumor development, but screening polyps for MSI remains controversial because of reduced sensitivity compared to more advanced neoplasms. To increase sensitivity, we investigated the use of a novel type of marker consisting of long mononucleotide repeat (LMR) tracts. Adenomas from 160 patients, ranging in age from 29–55 years old, were screened for MSI using the new markers and compared with current marker panels and immunohistochemistry standards. Overall, 15 tumors were scored as MSI-High using the LMRs compared to 9 for the NCI panel and 8 for the MSI Analysis System (Promega). This difference represents at least a 1.7-fold increase in detection of MSI-High lesions over currently available markers. Moreover, the number of MSI-positive markers per sample and the size of allelic changes were significantly greater with the LMRs (p = 0.001), which increased confidence in MSI classification. The overall sensitivity and specificity of the LMR panel for detection of mismatch repair deficient lesions were 100% and 96%, respectively. In comparison, the sensitivity and specificity of the MSI Analysis System were 67% and 100%; and for the NCI panel, 75% and 97%. The difference in sensitivity between the LMR panel and the other panels was statistically significant (p

Description: by Roland G. Roberts

Description: by Seth R. Bordenstein, Kevin R. Theis Groundbreaking research on the universality and diversity of microorganisms is now challenging the life sciences to upgrade fundamental theories that once seemed untouchable. To fully appreciate the change that the field is now undergoing, one has to place the epochs and foundational principles of Darwin, Mendel, and the modern synthesis in light of the current advances that are enabling a new vision for the central importance of microbiology. Animals and plants are no longer heralded as autonomous entities but rather as biomolecular networks composed of the host plus its associated microbes, i.e., "holobionts." As such, their collective genomes forge a "hologenome," and models of animal and plant biology that do not account for these intergenomic associations are incomplete. Here, we integrate these concepts into historical and contemporary visions of biology and summarize a predictive and refutable framework for their evaluation. Specifically, we present ten principles that clarify and append what these concepts are and are not, explain how they both support and extend existing theory in the life sciences, and discuss their potential ramifications for the multifaceted approaches of zoology and botany. We anticipate that the conceptual and evidence-based foundation provided in this essay will serve as a roadmap for hypothesis-driven, experimentally validated research on holobionts and their hologenomes, thereby catalyzing the continued fusion of biology's subdisciplines. At a time when symbiotic microbes are recognized as fundamental to all aspects of animal and plant biology, the holobiont and hologenome concepts afford a holistic view of biological complexity that is consistent with the generally reductionist approaches of biology.

Description: by Pengxing Cao, Ada W. C. Yan, Jane M. Heffernan, Stephen Petrie, Robert G. Moss, Louise A. Carolan, Teagan A. Guarnaccia, Anne Kelso, Ian G. Barr, Jodie McVernon, Karen L. Laurie, James M. McCaw Influenza is an infectious disease that primarily attacks the respiratory system. Innate immunity provides both a very early defense to influenza virus invasion and an effective control of viral growth. Previous modelling studies of virus–innate immune response interactions have focused on infection with a single virus and, while improving our understanding of viral and immune dynamics, have been unable to effectively evaluate the relative feasibility of different hypothesised mechanisms of antiviral immunity. In recent experiments, we have applied consecutive exposures to different virus strains in a ferret model, and demonstrated that viruses differed in their ability to induce a state of temporary immunity or viral interference capable of modifying the infection kinetics of the subsequent exposure. These results imply that virus-induced early immune responses may be responsible for the observed viral hierarchy. Here we introduce and analyse a family of within-host models of re-infection viral kinetics which allow for different viruses to stimulate the innate immune response to different degrees. The proposed models differ in their hypothesised mechanisms of action of the non-specific innate immune response. We compare these alternative models in terms of their abilities to reproduce the re-exposure data. Our results show that 1) a model with viral control mediated solely by a virus-resistant state, as commonly considered in the literature, is not able to reproduce the observed viral hierarchy; 2) the synchronised and desynchronised behaviour of consecutive virus infections is highly dependent upon the interval between primary virus and challenge virus exposures and is consistent with virus-dependent stimulation of the innate immune response. Our study provides the first mechanistic explanation for the recently observed influenza viral hierarchies and demonstrates the importance of understanding the host response to multi-strain viral infections. Re-exposure experiments provide a new paradigm in which to study the immune response to influenza and its role in viral control.

Description: by Shoya Umemura, Saki Imai, Ayumi Mimura, Mari Fujiwara, Shizufumi Ebihara Usp46 mutant mice (congenic strain on a B6 genetic background; MT mice) have a low weaning rate and display poor maternal behavior compared to C57BL/6J mice (B6 mice). Based on these observations, we examined how maternal behavior is shaped by cross-fostering and in-fostering MT and B6 mice. The experiments consisted of six groups: B6 mice fostered by their biological mother (B6-CO); MT mice fostered by their biological mother (MT-CO); B6 mice fostered by a different B6 mother (B6-IF); MT mice fostered by a different MT mother (MT-IF); B6 mice fostered by an MT mother (B6-CF); and MT mice fostered by a B6 mother (MT-CF). Maternal behavior was assessed using the pup-retrieval test in adult female offspring, and four parameters, time nursing pups in the nest, time sniffing or licking pups, rearing behavior, and latency to retrieve pups, were measured. Cross-fostering significantly reduced time spent nursing and sniffing/licking pup, and increased the number of instances of rearing in the B6-CF group, and improved three parameters of maternal behaviors (nursing, rearing and latency) in the MT-CF group. These results indicate that the level of maternal care is transmitted to their pups and proper maternal behaviors can be shaped if adequate postpartum maternal care is given, even in genetically vulnerable mice. However, the offspring’s genotype may also influence the development of maternal behaviors in adulthood. Thus, MT mice may prove useful as a model for trans-generational transmission of maternal care, and these findings may provide insight into the mechanisms of maltreating behaviors in human child abuse.

Description: by Oathokwa Nkomazana, Robert Mash, Sheila Shaibu, Nthabiseng Phaladze Background An adequate health workforce force is central to universal health coverage and positive public health outcomes. However many African countries have critical shortages of healthcare workers, which are worse in primary healthcare. The aim of this study was to explore the perceptions of healthcare workers, policy makers and the community on the shortage of healthcare workers in Botswana. Method Fifteen focus group discussions were conducted with three groups of policy makers, six groups of healthcare workers and six groups of community members in rural, urban and remote rural health districts of Botswana. All the participants were 18 years and older. Recruitment was purposive and the framework method was used to inductively analyse the data. Results There was a perceived shortage of healthcare workers in primary healthcare, which was believed to result from an increased need for health services, inequitable distribution of healthcare workers, migration and too few such workers being trained. Migration was mainly the result of unfavourable personal and family factors, weak and ineffective healthcare and human resources management, low salaries and inadequate incentives for rural and remote area service. Conclusions Botswana has a perceived shortage of healthcare workers, which is worse in primary healthcare and rural areas, as a result of multiple complex factors. To address the scarcity the country should train adequate numbers of healthcare workers and distribute them equitably to sufficiently resourced healthcare facilities. They should be competently managed and adequately remunerated and the living conditions and rural infrastructure should also be improved.

Description: by Julie Lebeau, Renate A. Wesselingh, Hans Van Dyck Sparing zones from mowing has been proposed, and applied, to improve local conditions for survival and reproduction of insects in hay meadows. However, little is known about the efficiency of refuge zones and the consequences for local populations. We studied population densities of butterflies before and after mowing in the refuge zone of 15 meadows in 2009 and 2011. We also studied the behaviour of the meadow brown ( Maniola jurtina ) comparing nectar use, interactions and flights in the refuge zone before and after mowing. Densities of grassland butterflies in this zone doubled on average after mowing. The density of females of M . jurtina increased on average fourfold, while males showed a more modest increase. In line with the idea of increased scramble competition in the refuge zone after mowing, M . jurtina increased the time spent on nectar feeding, the preferred nectar source was visited more frequently, and females made more use of non-preferred nectar sources. Maniola jurtina did not interact more with conspecifics after mowing, but interactions lasted longer. Flight tracks did not change in linearity, but were faster and shorter after mowing. After mowing, only a part of the local grassland butterflies moved to the uncut refuge zone. The resulting concentration effect alters the time allocated to different activities, nectar use and movements. These aspects have been largely ignored for agri-environmental schemes and grassland management in nature reserves and raise questions about optimal quantities and quality of uncut refuge sites for efficient conservation of grassland arthropods in agricultural landscapes.

Description: by Wietske van der Zwaag, Rolf Gruetter, Roberto Martuzzi Studying body representations in the brain helps us to understand how we humans relate to our own bodies. The in vivo mapping of the somatosensory cortex, where these representations are found, is greatly facilitated by the high spatial resolution and high sensitivity to brain activation available at ultra-high field. In this study, the use of different stimulus types for somatotopic mapping of the digits at ultra-high field, specifically manual stroking and mechanical stimulation, was compared in terms of sensitivity and specificity of the brain responses. Larger positive responses in digit regions of interest were found for manual stroking than for mechanical stimulation, both in terms of average and maximum t-value and in terms of number of voxels with significant responses to the tactile stimulation. Responses to manual stroking were higher throughout the entire post-central sulcus, but the difference was especially large on its posterior wall, i.e. in Brodmann area 2. During mechanical stimulation, cross-digit responses were more negative than during manual stroking, possibly caused by a faster habituation to the stimulus. These differences indicate that manual stroking is a highly suitable stimulus for fast somatotopic mapping procedures, especially if Brodmann area 2 is of interest.

Description: by Christoph Ptatscheck, Walter Traunspurger Objectives In this study we investigated the dynamics of meiofaunal and macrofaunal communities in artificial water-filled tree holes. The abundances and, for the first time, biomasses and secondary production rates of these communities were examined. The experimental set-up consisted of 300 brown plastic cups placed in temperate mixed forests and sampled five times over a period of 16 months to determine the impact of (i) seasonal events, (ii) physicochemical parameters, and (iii) food resources on the tree hole metazoans. Outcomes Metazoan organisms, especially the meiofauna (rotifers and nematodes) occupied nearly all of the cups (〉 99%) throughout the year. Between 55% and 99% of the metazoan community was represented by rotifers (max. 557,000 individuals 100 cm -2 ) and nematodes (max. 58,000 individuals 100 cm -2 ). Diptera taxa, particularly Dasyhelea sp. (max. 256 individuals 100 cm -2 ) dominated the macrofaunal community. Macrofauna accounted for the majority of the metazoan biomass, with a mean dry weight of 5,800 μg 100 cm -2 and an annual production rate of 20,400 μg C 100 cm -2 , whereas for meiofauna mean biomass and annual production were 100 μg 100 cm -2 and 5,300 μg C 100 cm -2 , respectively. The macrofaunal taxa tended to show more fluctuating population dynamic while the meiofaunal dynamic was rather low with partly asynchronous development. Seasonality (average temperature and rain intervals) had a significant impact on both meiofauna and macrofauna. Furthermore, bottom-up control (chlorophyll-a and organic carbon), mainly attributable to algae, was a significant factor that shaped the metazoan communities. In contrast, physicochemical water parameters had no evident influence. 23.7% of organism density distribution was explained by redundancy analysis (RDA) indicating a high dynamic and asynchrony of the systems.

Description: by Stephen Shannon, Connan Vaca, Dongxuan Jia, Ildiko Entersz, Andrew Schaer, Jonathan Carcione, Michael Weaver, Yoav Avidar, Ryan Pettit, Mohan Nair, Atif Khan, Ramsey A. Foty Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM) is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival. Our previous studies utilizing a series of immortalized GBM cell lines established a functional causation between activation of fibronectin matrix assembly (FNMA), increased tumor cohesion, and decreased dispersal. Activation of FNMA was accomplished by treatment with Dexamethasone (Dex), a drug routinely used to treat brain tumor related edema. Here, we utilize a broad range of qualitative and quantitative assays and the use of a human GBM tissue microarray and freshly-isolated primary human GBM cells grown both as conventional 2D cultures and as 3D spheroids to explore the role of Dex and FNMA in modulating various parameters that can significantly influence tumor cell dispersal. We show that the expression and processing of fibronectin in a human GBM tissue-microarray is variable, with 90% of tumors displaying some abnormality or lack in capacity to secrete fibronectin or assemble it into a matrix. We also show that low-passage primary GBM cells vary in their capacity for FNMA and that Dex treatment reactivates this process. Activation of FNMA effectively “glues” cells together and prevents cells from detaching from the primary mass. Dex treatment also significantly increases the strength of cell-ECM adhesion and decreases motility. The combination of increased cohesion and decreased motility discourages in vitro and ex vivo dispersal. By increasing cell-cell cohesion, Dex also decreases growth rate of 3D spheroids. These effects could all be reversed by an inhibitor of FNMA and by the glucocorticoid receptor antagonist, RU-486. Our results describe a new role for Dex as a suppressor of GBM dispersal and growth.

Description: by Chang-Hsun Hsieh, Ren-Hua Chung, Wen-Jane Lee, Ming-Wei Lin, Lee-Ming Chuang, Thomas Quertermous, Themistocles Assimes, Yi-Jen Hung, Ya-Wen Yu Objectives Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored. Materials and Methods Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years. Results The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels ( p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels ( p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development. Conclusions Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.

Description: by Eun-Jeong Yang, Sangzin Ahn, Junghwa Ryu, Moon-Seok Choi, Shinkyu Choi, Young Hae Chong, Jin-Won Hyun, Moon-Jeong Chang, Hye-Sun Kim Alzheimer’s disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5—trihydroxybenzene), a component of phlorotannins, which are plentiful in Ecklonia cava , a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ 1–42 (Aβ 1–42 ) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ 1–42 treatment in rat primary hippocampal neuron cultures . We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels.

Description: by Jian Zheng, Wai-Lan Wu, Yinping Liu, Zheng Xiang, Ming Liu, Kwok-Hung Chan, Siu-Ying Lau, Kwok-Tai Lam, Kelvin Kai-Wang To, Jasper Fuk-Woo Chan, Lanjuan Li, Honglin Chen, Yu-Lung Lau, Kwok-Yung Yuen, Wenwei Tu A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vδ2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-γ secreted from human Vδ2-T cells. Meanwhile, human Vδ2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.

Description: by Antoine Zazzo, Matthieu Lebon, Anita Quiles, Ina Reiche, Jean-Denis Vigne In the Mediterranean, the island dwarf megafaunas became extinct around the end of the Pleistocene, during a period of rapid and global climate change. In Cyprus, this coincided with the first human presence on the island, as attested by the rock shelter of Akrotiri- Aetokremnos where an Epipaleolithic anthropogenic layer (stratum 2) was found overlying a massive accumulation of pygmy hippopotamus ( Phanourios minor (Desmarest, 1822)) [Boekschoten and Sondaar, 1972] bones (stratum 4). The relationship between the two layers is highly controversial and the role played by humans in hippo extinction remains fiercely debated. Here, we provide new, direct radiocarbon and physico-chemical analyses on calcined bones which elucidates the complex depositional history of the assemblage. Bone turquoise was identified using micro-PIXE analysis and depth-profiling together with Vis spectroscopy, demonstrating that these bones were not freshly burned. Bayesian modeling of the radiocarbon dates indicates that stratum 4 accumulated during the first half of the 13 th mill cal BP and that calcination occurred several hundred years later. We conclude that accumulation occurred naturally during the beginning of the Younger Dryas and that Epipalaeolithic visitors subsequently used the bones as fuel, starting from the mid-13 th mill cal BP. At that time, dwarf hippos were probably already extinct or at least highly endangered. Our results shed new light on the possible causes of hippo extinction, on the subsequent introduction of the wild boar and on the earliest occupation of the island by humans.

Description: by Akira Yokoyama, Tetsuji Yokoyama, Toshifumi Matsui, Takeshi Mizukami, Mitsuru Kimura, Sachio Matsushita, Susumu Higuchi, Katsuya Maruyama Background Elevated serum triglyceride (TG) and high-density-lipoprotein cholesterol (HDL-C) levels are common in drinkers. The fast-metabolizing alcohol dehydrogenase-1B encoded by the ADH1B*2 allele (vs. ADH1B*1/*1 genotype) and inactive aldehyde dehydrogenase-2 encoded by the ALDH2*2 allele (vs. ALDH2*1/*1 genotype) modify ethanol metabolism and are prevalent (≈90% and ≈40%, respectively) in East Asians. We attempted to evaluate the associations between the ADH1B and ALDH2 genotypes and lipid levels in alcoholics. Methods The population consisted of 1806 Japanese alcoholic men (≥40 years) who had undergone ADH1B and ALDH2 genotyping and whose serum TG, total cholesterol, and HDL-C levels in the fasting state had been measured within 3 days after admission. Results High serum levels of TG (≥150 mg/dl), HDL-C (〉80 mg/dl), and low-density-lipoprotein cholesterol (LDL-C calculated by the Friedewald formula ≥140 mg/dl) were observed in 24.3%, 16.8%, and 15.6%, respectively, of the subjects. Diabetes, cirrhosis, smoking, and body mass index (BMI) affected the serum lipid levels. Multivariate analysis revealed that the presence of the ADH1B*2 allele and the active ALDH2*1/*1 genotype increased the odds ratio (OR; 95% confidence interval) for a high TG level (2.22 [1.67–2.94] and 1.39 [0.99–1.96], respectively), and decreased the OR for a high HDL-C level (0.37 [0.28–0.49] and 0.51 [0.37–0.69], respectively). The presence of the ADH1B*2 allele decreased the OR for a high LDL-C level (0.60 [0.45–0.80]). The ADH1B*2 plus ALDH2*1/*1 combination yielded the highest ORs for high TG levels and lowest OR for a high HDL-C level. The genotype effects were more prominent in relation to the higher levels of TG (≥220 mg/dl) and HDL-C (≥100 mg/dl). Conclusions The fast-metabolizing ADH1B and active ALDH2, and especially a combination of the two were strongly associated with higher serum TG levels and lower serum HDL-C levels of alcoholics. The fast-metabolizing ADH1B was associated with lower serum LDL-C levels.

Description: by Shuang-shuang Wang, Si-wang Hu, Qing-hua Zhang, Ai-xiang Xia, Zhi-xin Jiang, Xiao-min Chen Background and objectives Formation and progression of atherosclerotic vulnerable plaque (VP) is the primary cause of many cardio-cerebrovascular diseases such as acute coronary syndrome and stroke. It has been reported that bone marrow mesenchymal stem cells (MSC) exhibit protective effects against many kinds of diseases including myocardial infarction. Here, we examined the effects of intravenous MSC infusion on a VP model and provide novel evidence of its influence as a therapy in this animal disease model. Subjects and methods Thirty healthy male New Zealand white rabbits were randomly divided into a MSC, VP or stable plaque (SP) group (n = 10/group) and received high fat diet and cold-induced common carotid artery intimal injury with liquid nitrogen to form atherosclerotic plaques. Serum hs-CRP, TNF-α, IL-6 and IL-10 levels were measured by ELISA at 1, 2, 3, 7, 14, 21 and 28 days after MSC transplantation. The animals were sacrificed at 4 weeks after MSC transplantation. Lesions in the right common carotid were observed using H&E and Masson staining, and the fibrous cap/lipid core ratio of atherosclerotic plaques were calculated. The expression of nuclear factor κB (NF-κB) and matrix metalloproteinase 1, 2, 9 (MMP-1,2,9) in the plaque were detected using immunohistochemistry, and apoptotic cells in the plaques were detected by TUNEL. In addition, the level of TNF-α stimulated gene/protein 6 (TSG-6) mRNA and protein were measured by quantitative Real-Time PCR and Western blotting, respectively. Results Two rabbits in the VP group died of lung infection and cerebral infarction respectively at 1 week after plaque injury by liquid nitrogen. Both H&E and Masson staining revealed that the plaques from the SP and MSC groups had more stable morphological structure and a larger fibrous cap/lipid core ratio than the VP group. Serum hs-CRP, TNF-α and IL-6 were significantly down-regulated, whereas IL-10 was significantly up-regulated in the MSC group compared with the VP group. .Immunohistochemistry analysis revealed that NF-κB and MMP expression was reduced in the MSC and SP groups compared to the VP group. Cell apoptosis decreased significantly in both the MSC and SP groups in comparison to the VP group. TSG-6 mRNA and protein expression were higher in the plaques of the MSC group compared to the VP and SP groups. Conclusions Our study results suggest that MSC transplantation can effectively stabilize vulnerable plaques in atherosclerotic rabbits. This may potentially offer a new clinical application of MSC in atherosclerosis.

Description: by Uriel Alonso Hurtado Páez, Ibonne Aydee García Romero, Silvia Restrepo Restrepo, Fabio Ancizar Aristizábal Gutiérrez, Dolly Montoya Castaño Natural rubber ( Hevea brasiliensis ) is a tropical tree used commercially for the production of latex, from which 40,000 products are generated. The fungus Microcyclus ulei infects this tree, causing South American leaf blight (SALB) disease. This disease causes developmental delays and significant crop losses, thereby decreasing the production of latex. Currently several groups are working on obtaining clones of rubber tree with durable resistance to SALB through the use of extensive molecular biology techniques. In this study, we used a secondary clone that was resistant to M . ulei isolate GCL012. This clone, FX 3864 was obtained by crossing between clones PB 86 and B 38 ( H . brasiliensis x H . brasiliensis ). RNA-Seq high-throughput sequencing technology was used to analyze the differential expression of the FX 3864 clone transcriptome at 0 and 48 h post infection (hpi) with the M . ulei isolate GCL012. A total of 158,134,220 reads were assembled using the de novo assembly strategy to generate 90,775 contigs with an N50 of 1672. Using a reference-based assembly, 76,278 contigs were generated with an N50 of 1324. We identified 86 differentially expressed genes associated with the defense response of FX 3864 to GCL012. Seven putative genes members of the AP2/ERF ethylene (ET)-dependent superfamily were found to be down-regulated. An increase in salicylic acid (SA) was associated with the up-regulation of three genes involved in cell wall synthesis and remodeling, as well as in the down-regulation of the putative gene CPR5 . The defense response of FX 3864 against the GCL012 isolate was associated with the antagonistic SA, ET and jasmonic acid (JA) pathways. These responses are characteristic of plant resistance to biotrophic pathogens.

Description: by Aude Cincotta, Johan Yans, Pascal Godefroit, Géraldine Garcia, Jean Dejax, Mouloud Benammi, Sauveur Amico, Xavier Valentin The Velaux-La Bastide Neuve fossil-bearing site (Bouches-du-Rhône, France) has yielded a diverse vertebrate assemblage dominated by dinosaurs, including the titanosaur Atsinganosaurus velauciensis . We here provide a complete inventory of vertebrate fossils collected during two large-scale field campaigns. Numerous crocodilian teeth occur together with complete skulls. Pterosaur, hybodont shark and fish elements are also represented but uncommon. Magnetostratigraphic analyses associated with biostratigraphic data from dinosaur eggshell and charophytes suggest a Late Campanian age for the locality. Lithologic and taphonomic studies, associated with microfacies and palynofacies analyses, indicate a fluvial setting of moderate energy with broad floodplain. Palynomorphs are quite rare; only three taxa of pollen grains occur: a bisaccate taxon, a second form probably belonging to the Normapolles complex, and another tricolporate taxon. Despite the good state of preservation, these taxa are generally difficult to identify, since they are scarce and have a very minute size. Most of the vertebrate remains are well preserved and suggest transport of the carcasses over short distances before accumulation in channel and overbank facies, together with reworked Aptian grains of glauconite, followed by a rapid burial. The bones accumulated in three thin layers that differ by their depositional modes and their taphonomic histories. Numerous calcareous and iron oxides-rich paleosols developed on the floodplain, suggesting an alternating dry and humid climate in the region during the Late Campanian.

Description: by John W. Whitaker, David L. Boyle, Beatrix Bartok, Scott T. Ball, Steffen Gay, Wei Wang, Gary S. Firestein

Description: by Siyan Yi, Sovannary Tuot, Pheak Chhoun, Khuondyla Pal, Khimuy Tith, Carinne Brody Background Compared to the general population, men who have sex with men (MSM) are at greater risk for HIV and less understood due to their more hidden and stigmatized nature. Moreover, the discrepancy in findings in the literature merits further investigations in MSM populations from different cultures and settings. We therefore conducted this study to explore factors associated with inconsistent condom use among high-risk MSM in Cambodia. Methods This cross-sectional study was conducted in 2014 among 367 MSM randomly selected from Battembang and Siem Reap using a two-stage cluster sampling method. A structured questionnaire was used for face-to-face interviews to collect information on characteristics of respondents, HIV testing history, self-perception of HIV risk, substance use, sexual behaviors, mental disorders, and HIV knowledge. Multivariable logistic regression analysis was performed to identify factors independently associated with inconsistent condom use. Results On average, 62.3% of respondents reported that they always used condoms over the past three months. The rates varied with types of sexual partners; the proportion of respondents who reported always using condoms was 55.1%, 64.2%, 75.9%, 73.0%, 78.1%, and 70.3%, for sexual partners who were girlfriends, boyfriends, female sex workers, male sex workers, female clients, or male clients, respectively. After adjustment, inconsistent condom use was significantly associated with age of ≥25 (AOR = 1.77, 95% CI = 1.09–2.86), self-rated quality of life as good or very good (AOR = 4.37, 95% CI = 1.79–5.67), self-perception of higher HIV risk compared to the general population (AOR = 2.37, 95% CI = 1.35–4.17), illicit drug use in the past three months (AOR = 5.76, 95% CI = 1.65–10.09), and reported consistent lubricant use when selling anal sex to men in the past three months (AOR = 2.85, 95% CI = 1.07–8.12). Conclusions We found risky sexual behaviors to be considerably high among MSM in this study, especially among those who used illicit drugs or were older than 25. HIV education and social marketing should be expanded and specifically designed for MSM to better educate on the increased risk of HIV with unprotected anal sex and illicit drug use as risk factors, and the importance of the use of both condoms and lubricant during anal intercourse.

Description: by Andreas D. Meid, Renate Quinzler, Julia Freigofas, Kai-Uwe Saum, Ben Schöttker, Bernd Holleczek, Dirk Heider, Hans-Helmut König, Hermann Brenner, Walter E. Haefeli Background Cardiovascular disease is a leading cause of death in older people, and the impact of being exposed or not exposed to preventive cardiovascular medicines is accordingly high. Underutilization of beneficial drugs is common, but prevalence estimates differ across settings, knowledge on predictors is limited, and clinical consequences are rarely investigated. Methods Using data from a prospective population-based cohort study, we assessed the prevalence, determinants, and outcomes of medication underuse based on cardiovascular criteria from Screening Tool To Alert to Right Treatment (START). Results Medication underuse was present in 69.1% of 1454 included participants (mean age 71.1 ± 6.1 years) and was significantly associated with frailty (odds ratio: 2.11 [95% confidence interval: 1.24–3.63]), body mass index (1.03 [1.01–1.07] per kg/m 2 ), and inversely with the number of prescribed drugs (0.84 [0.79–0.88] per drug). Using this information for adjustment in a follow-up evaluation (mean follow-up time 2.24 years) on cardiovascular and competing outcomes, we found no association of medication underuse with cardiovascular events (fatal and non-fatal) (hazard ratio: 1.00 [0.65–1.56]), but observed a significant association of medication underuse with competing deaths from non-cardiovascular causes (2.52 [1.01–6.30]). Conclusion Medication underuse was associated with frailty and adverse non-cardiovascular clinical outcomes. This may suggest that cardiovascular drugs were withheld because of serious co-morbidity or that concurrent illness can preclude benefit from cardiovascular prevention. In the latter case, adapted prescribing criteria should be developed and evaluated in those patients.

Description: by Robert M. Dorazio, Edward F. Connor, Robert A. Askins We used repeated sightings of individual birds encountered in community-level surveys to investigate the relative roles of habitat and biological interactions in determining the distribution and abundance of each species. To analyze these data, we developed a multispecies N-mixture model that allowed estimation of both positive and negative correlations between abundances of different species while also estimating the effects of habitat and the effects of errors in detection of each species. Using a combination of single- and multispecies N-mixture modeling, we examined for each species whether our measures of habitat were sufficient to account for the variation in encounter histories of individual birds or whether other habitat variables or interactions with other species needed to be considered. In the community that we studied, habitat appeared to be more influential than biological interactions in determining the distribution and abundance of most avian species. Our results lend support to the hypothesis that abundances of forest specialists are negatively affected by forest fragmentation. Our results also suggest that many species were associated with particular types of vegetation as measured by structural attributes of the forests. The abundances of 6 of the 73 species observed in our study were strongly correlated. These species included large birds (American Crow ( Corvus brachyrhynchos ) and Red-winged Blackbird ( Agelaius phoeniceus )) that forage on the ground in open habitats and small birds (Red-eyed Vireo ( Vireo olivaceus ), House Wren ( Troglodytes aedon ), Hooded Warbler ( Setophaga citrina ), and Prairie Warbler ( Setophaga discolor )) that are associated with dense shrub cover. Species abundances were positively correlated within each size group and negatively correlated between groups. Except for the American Crow, which preys on eggs and nestlings of small song birds, none of the other 5 species is known to display direct interactions, so we suspect that the correlations may have been associated with species-specific responses to habitat components not adequately measured by our covariates.

Description: by Eric S. Michel, Stephen Demarais, Bronson K. Strickland, Jerrold L. Belant Maternal care influences offspring quality and can improve a mother’s inclusive fitness. However, improved fitness may only occur when offspring quality (i.e., offspring birth mass) persists throughout life and enhances survival and/or reproductive success. Although maternal body mass, age, and social rank have been shown to influence offspring birth mass, the inter-dependence among these variables makes identifying causation problematic. We established that fawn birth mass was related to adult body mass for captive male and female white-tailed deer ( Odocoileus virginianus ), thus maternal care should improve offspring fitness. We then used path analysis to identify which maternal characteristic(s) most influenced fawn birth mass of captive female white-tailed deer. Maternal age, body mass and social rank had varying effects on fawn birth mass. Maternal body mass displayed the strongest direct effect on fawn birth mass, followed by maternal age and social rank. Maternal body mass had a greater effect on social rank than age. The direct path between social rank and fawn birth mass may indicate dominance as an underlying mechanism. Our results suggest that heavier mothers could use dominance to improve access to resources, resulting in increased fitness through production of heavier offspring.

Description: by Claire H. den Hoedt, Muriel P. C. Grooteman, Michiel L. Bots, Peter J. Blankestijn, Ingeborg van der Tweel, Neelke C. van der Weerd, E. Lars Penne, Albert H. A. Mazairac, Renée Levesque, Piet M. ter Wee, Menso J. Nubé, Marinus A. van den Dorpel, CONTRAST investigators Background Hemodialysis (HD) patients have a high risk of infections. The uremic milieu has a negative impact on several immune responses. Online hemodiafiltration (HDF) may reduce the risk of infections by ameliorating the uremic milieu through enhanced clearance of middle molecules. Since there are few data on infectious outcomes in HDF, we compared the effects of HDF with low-flux HD on the incidence and type of infections. Patients and Methods We used data of the 714 HD patients (age 64 ±14, 62% men, 25% Diabetes Mellitus, 7% catheters) participating in the CONvective TRAnsport STudy (CONTRAST), a randomized controlled trial evaluating the effect of HDF as compared to low-flux HD. The events were adjudicated by an independent event committee. The risk of infectious events was compared with Cox regression for repeated events and Cox proportional hazard models. The distributions of types of infection were compared between the groups. Results Thirty one percent of the patients suffered from one or more infections leading to hospitalization during the study (median follow-up 1.96 years). The risk for infections during the entire follow-up did not differ significantly between treatment arms (HDF 198 and HD 169 infections in 800 and 798 person-years respectively, hazard ratio HDF vs. HD 1.09 (0.88–1.34), P = 0.42. No difference was found in the occurrence of the first infectious event (either fatal, non-fatal or type specific). Of all infections, respiratory infections (25% in HDF, 28% in HD) were most common, followed by skin/musculoskeletal infections (21% in HDF, 13% in HD). Conclusions HDF as compared to HD did not result in a reduced risk of infections, larger studies are needed to confirm our findings. Trial Registration ClinicalTrials.gov NCT00205556

Description: by Emil Schüler, Maria Larsson, Toshima Z. Parris, Martin E. Johansson, Khalil Helou, Eva Forssell-Aronsson Methods C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177 Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using 99m Tc-DTPA/ 99m Tc-DMSA scintigraphy. Results In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a , C3 , Dbp , Lcn2 , and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng , Tnf , and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99m Tc-DTPA after 150 MBq, an increased uptake of 99m Tc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months. Conclusion Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a , Dbp , Lcn2 , and Per2 genes are proposed as biomarkers for 177 Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm applicability of these genes as markers of radiation damage in kidney tissue.

Description: by Mohd Shoeb, Braj Raj Singh, Mohammad Mobin, Gul Afreen, Wasi Khan, Alim H. Naqvi The study was taken up with the objective to synthesize graphene-zinc oxide nano particles (NPs) nanocomposite (Gr@ZnO-Nc) via In-situ synthesis method. The structural, optical, thermal, electrical and photocatalytic properties of the synthesized Gr@ZnO-Nc were studied. The characterization data confirmed that the ZnO NPs were successfully incorporated into the graphene sheets. Further, TGA/DTA results exhibited an enhanced thermal stability of the Gr@ZnO-Nc compared with the graphene. The Gr@ZnO-Nc, graphene sheets were uniformly wrapped by ZnO NPs, which can protect graphene and delay their oxidation in air. The synthesized Gr@ZnO-Nc was used for the efficient photodegradation of a carcinogenic methyl orange (MO) dye. The results exhibited promising photodegradation of the MO dye under UV light irradiation through the production of reactive oxygen species (ROS). The promising effect of Gr@ZnO-Nc on the photodegradation properties was conferred by the large surface area which increased adsorption capacity, and the strong electron transfer ability. Thus, it is encouraging to conclude that the synthesized Gr@ZnO-Nc has environmental significance with its utility in remediation in the hazardous MO dye.

Description: by Paul M. Harrison, Laurent Badel, Mark J. Wall, Magnus J. E. Richardson Models of neocortical networks are increasingly including the diversity of excitatory and inhibitory neuronal classes. Significant variability in cellular properties are also seen within a nominal neuronal class and this heterogeneity can be expected to influence the population response and information processing in networks. Recent studies have examined the population and network effects of variability in a particular neuronal parameter with some plausibly chosen distribution. However, the empirical variability and covariance seen across multiple parameters are rarely included, partly due to the lack of data on parameter correlations in forms convenient for model construction. To addess this we quantify the heterogeneity within and between the neocortical pyramidal-cell classes in layers 2/3, 4, and the slender-tufted and thick-tufted pyramidal cells of layer 5 using a combination of intracellular recordings, single-neuron modelling and statistical analyses. From the response to both square-pulse and naturalistic fluctuating stimuli, we examined the class-dependent variance and covariance of electrophysiological parameters and identify the role of the h current in generating parameter correlations. A byproduct of the dynamic I-V method we employed is the straightforward extraction of reduced neuron models from experiment. Empirically these models took the refractory exponential integrate-and-fire form and provide an accurate fit to the perisomatic voltage responses of the diverse pyramidal-cell populations when the class-dependent statistics of the model parameters were respected. By quantifying the parameter statistics we obtained an algorithm which generates populations of model neurons, for each of the four pyramidal-cell classes, that adhere to experimentally observed marginal distributions and parameter correlations. As well as providing this tool, which we hope will be of use for exploring the effects of heterogeneity in neocortical networks, we also provide the code for the dynamic I-V method and make the full electrophysiological data set available.

Description: by Naomi Levy-Strumpf, Meghan Krizus, Hong Zheng, Louise Brown, Joseph G. Culotti Wnt and Netrin signaling regulate diverse essential functions. Using a genetic approach combined with temporal gene expression analysis, we found a regulatory link between the Wnt receptor MOM-5/Frizzled and the UNC-6/Netrin receptor UNC-5. These two receptors play key roles in guiding cell and axon migrations, including the migration of the C . elegans Distal Tip Cells (DTCs). DTCs migrate post-embryonically in three sequential phases: in the first phase along the Antero-Posterior (A/P) axis, in the second, along the Dorso-Ventral (D/V) axis, and in the third, along the A/P axis. Loss of MOM-5/Frizzled function causes third phase A/P polarity reversals of the migrating DTCs. We show that an over-expression of UNC-5 causes similar DTC A/P polarity reversals and that unc-5 deficits markedly suppress the A/P polarity reversals caused by mutations in mom-5/frizzled . This implicates MOM-5/Frizzled as a negative regulator of unc-5 . We provide further evidence that small GTPases mediate MOM-5’s regulation of unc-5 such that one outcome of impaired function of small GTPases like CED-10/Rac and MIG-2/RhoG is an increase in unc-5 function. The work presented here demonstrates the existence of cross talk between components of the Netrin and Wnt signaling pathways and provides further insights into the way guidance signaling mechanisms are integrated to orchestrate directed cell migration.

Description: by Hugo G. Hilton, Paul J. Norman, Neda Nemat-Gorgani, Ana Goyos, Jill A. Hollenbach, Brenna M. Henn, Christopher R. Gignoux, Lisbeth A. Guethlein, Peter Parham Modulating natural killer cell functions in human immunity and reproduction are diverse interactions between the killer cell immunoglobulin-like receptors (KIR) of Natural Killer (NK) cells and HLA class I ligands on the surface of tissue cells. Dominant interactions are between KIR2DL1 and the C2 epitope of HLA-C and between KIR2DL2/3 and the C1 epitope of HLA-C. KhoeSan hunter-gatherers of Southern Africa represent the earliest population divergence known and are the most genetically diverse indigenous people, qualities reflected in their KIR and HLA genes. Of the ten KhoeSan KIR2DL1 alleles, KIR2DL1*022 and KIR2DL1*026 likely originated in the KhoeSan, and later were transmitted at low frequency to the neighboring Zulus through gene flow. These alleles arose by point mutation from other KhoeSan KIR2DL1 alleles that are more widespread globally. Mutation of KIR2DL1*001 gave rise to KIR2DL1*022 , causing loss of C2 recognition and gain of C1 recognition. This makes KIR2DL1*022 a more avid and specific C1 receptor than any KIR2DL2/3 allotype. Mutation of KIR2DL1*012 gave rise to KIR2DL1*026 , causing premature termination of translation at the end of the transmembrane domain. This makes KIR2DL1*026 a membrane-associated receptor that lacks both a cytoplasmic tail and signaling function. At higher frequencies than their parental allotypes, the combined effect of the KhoeSan-specific KIR2DL1*022 and KIR2DL1*026 is to reduce the frequency of strong inhibitory C2 receptors and increase the frequency of strong inhibitory C1 receptors. Because interaction of KIR2DL1 with C2 is associated with risk of pregnancy disorder, these functional changes are potentially advantageous. Whereas all other KhoeSan KIR2DL1 alleles are present on a wide diversity of centromeric KIR haplotypes, KIR2DL1*026 is present on a single KIR haplotype and KIR2DL1*022 is present on two very similar haplotypes. The high linkage disequilibrium across their haplotypes is consistent with a recent emergence for these KIR2DL1 alleles that have distinctive functions.

Description: by Michael S. Behnke, Asis Khan, Elvin J. Lauron, John R. Jimah, Qiuling Wang, Niraj H. Tolia, L. David Sibley Toxoplasma gondii has evolved a number of strategies to evade immune responses in its many hosts. Previous genetic mapping of crosses between clonal type 1, 2, and 3 strains of T . gondii , which are prevalent in Europe and North America, identified two rhoptry proteins, ROP5 and ROP18, that function together to block innate immune mechanisms activated by interferon gamma (IFNg) in murine hosts. However, the contribution of these and other virulence factors in more genetically divergent South American strains is unknown. Here we utilized a cross between the intermediately virulent North American type 2 ME49 strain and the highly virulent South American type 10 VAND strain to map the genetic basis for differences in virulence in the mouse. Quantitative trait locus (QTL) analysis of this new cross identified one peak that spanned the ROP5 locus on chromosome XII. CRISPR-Cas9 mediated deletion of all copies of ROP5 in the VAND strain rendered it avirulent and complementation confirmed that ROP5 is the major virulence factor accounting for differences between type 2 and type 10 strains. To extend these observations to other virulent South American strains representing distinct genetic populations, we knocked out ROP5 in type 8 TgCtBr5 and type 4 TgCtBr18 strains, resulting in complete loss of virulence in both backgrounds. Consistent with this, polymorphisms that show strong signatures of positive selection in ROP5 were shown to correspond to regions known to interface with host immunity factors. Because ROP5 and ROP18 function together to resist innate immune mechanisms, and a significant interaction between them was identified in a two-locus scan, we also assessed the role of ROP18 in the virulence of South American strains. Deletion of ROP18 in South American type 4, 8, and 10 strains resulted in complete attenuation in contrast to a partial loss of virulence seen for ROP18 knockouts in previously described type 1 parasites. These data show that ROP5 and ROP18 are conserved virulence factors in genetically diverse strains from North and South America, suggesting they evolved to resist innate immune defenses in ancestral T . gondii strains, and they have subsequently diversified under positive selection.

Description: by Paula Breitenbach Renz, Gabriela Cavagnolli, Letícia Schwerz Weinert, Sandra Pinho Silveiro, Joíza Lins Camargo Aims Gestational diabetes mellitus (GDM) is a prevalent and potentially serious condition which may put both mothers and neonates at risk. The current recommendation for diagnosis is the oral glucose tolerance test (OGTT). This study aimed to determine the usefulness of HbA1c test as a diagnostic tool for GDM as compared to the traditional criteria based on the OGTT. Methods This was a diagnostic test accuracy study. We performed OGTT and HbA1c test in women attending prenatal visits at a tertiary hospital. GDM was defined according to WHO1999 or ADA/WHO 2013 criteria. ROC curve was used to evaluate the diagnostic performance of HbA1c. Sensitivity, specificity and likelihood ratios for different HbA1c cut-off points were calculated. Results Of the 262 women in the third trimester of gestation enrolled in the study, 86 (33%) were diagnosed with GDM. Only five of these women presented HbA1c ≥48 mmol/mol (6.5%). This cut-off point presented 100% specificity but very low sensitivity (7%). Based on ROC curve, and considering OGTT as the reference criterion, HbA1c ≥40 mmol/mol (5.8%) showed adequate specificity in diagnosing GDM (94.9%) but low sensitivity (26.4%). Unlike, HbA1c values of 31 mmol/mol (5.0%) presented adequate sensitivity (89.7%) but low specificity (32.6%) to detect GDM. For women with HbA1c ≥40 mmol/mol (5.8%), the positive and negative likelihood ratios were 5.14 (95%CI 2.49–10.63) and 0.78 (0.68–0.88), respectively. The post-test probability of GDM was about 40%, representing a 4.0-fold increase in the mean pre-test probability. This cut-off point could eliminate the need for the unpleasant and laborious OGTT tests in almost one third of cases, as 38% of patients with GDM may be diagnosable by HbA1c test alone. Conclusions Our results show that combined HbA1c and OGTT measurements may be useful in diagnosing GDM.

Description: by Antonio González-Martín, Amaya Gorostiza, Lucía Regalado-Liu, Sergio Arroyo-Peña, Sergio Tirado, Ismael Nuño-Arana, Rodrigo Rubi-Castellanos, Karla Sandoval, Michael D. Coble, Héctor Rangel-Villalobos The genetic characterization of Native American groups provides insights into their history and demographic events. We sequenced the mitochondrial D-loop region (control region) of 520 samples from eight Mexican indigenous groups. In addition to an analysis of the genetic diversity, structure and genetic relationship between 28 Native American populations, we applied Bayesian skyline methodology for a deeper insight into the history of Mesoamerica. AMOVA tests applying cultural, linguistic and geographic criteria were performed. MDS plots showed a central cluster of Oaxaca and Maya populations, whereas those from the North and West were located on the periphery. Demographic reconstruction indicates higher values of the effective number of breeding females (Nef) in Central Mesoamerica during the Preclassic period, whereas this pattern moves toward the Classic period for groups in the North and West. Conversely, Nef minimum values are distributed either in the Lithic period (i.e. founder effects) or in recent periods (i.e. population declines). The Mesomerican regions showed differences in population fluctuation as indicated by the maximum Inter-Generational Rate (IGRmax): i) Center-South from the lithic period until the Preclassic; ii) West from the beginning of the Preclassic period until early Classic; iii) North characterized by a wide range of temporal variation from the Lithic to the Preclassic. Our findings are consistent with the genetic variations observed between central, South and Southeast Mesoamerica and the North-West region that are related to differences in genetic drift, structure, and temporal survival strategies (agriculture versus hunter-gathering, respectively). Interestingly, although the European contact had a major negative demographic impact, we detect a previous decline in Mesoamerica that had begun a few hundred years before.

Description: by Luciana Kase Tanno, Daniel Shikanai Kerr, Bernardo dos Santos, Leda Leme Talib, Célia Yamaguti, Helcio Rodrigues, Wagner Farid Gattaz, Jorge Kalil Although aromatic anticonvulsants are usually well tolerated, they can cause cutaneous adverse drug reactions in up to 10% of patients. The clinical manifestations of the antiepileptics-induced hypersensitivity reactions (AHR) vary from mild skin rashes to severe cutaneous drug adverse reactions which are related to high mortality and significant morbidity. Genetic polymorphisms in cytochrome P450 genes are associated with altered enzymatic activity and may contribute to the risk of AHR. Here we present a case-control study in which we genotyped SNPs of CYP2C19, 2C9 and 3A5 of 55 individuals with varying severities of AHR, 83 tolerant, and 366 healthy control subjects from São Paulo, Brazil. Clinical characterization was based on standardized scoring systems and drug patch test. All in vivo investigation followed the ENDA (European Network of Drug Allergy) recommendations. Genotype was determined by real time PCR using peripheral blood DNA as a template. Of all 504 subjects, 65% were females, 45% self-identified as Afro-American, 38% as Caucasian and 17% as having non-African mixed ascendancy. Amongst 55 subjects with AHR, 44 had severe cutaneous drug adverse reactions. Of the 46 drug patch tests performed, 29 (63%) were positive. We found a strong association between the absence of CYP3A5*3 and tolerant subjects when compared to AHR ( p = 0 . 0002 , OR = 5 . 28 [CI95% 2 . 09–14 . 84] ). None of our groups presented positive association with CYP2C19 and 2C9 polymorphisms, however, both SNPs contributed to separation of cases and tolerants in a Classification and Regression Tree. Our findings indicate that drug metabolism genes can contribute in the tolerability of antiepileptics. CYP3A5*3 is the most prevalent CYP3A5 allele associated with reduced enzymatic function. The current study provides evidence that normal CYP3A5 activity might be a protective factor to aromatic antiepileptics-induced hypersensitivity reactions in Brazilian subjects.

Description: by Kecheng Zhang, Jianxin Cui, Hongqing Xi, Shibo Bian, Liangang Ma, Weisong Shen, Jiyang Li, Ning Wang, Bo Wei, Lin Chen Determining the expression level of human epidermal growth factor receptor 2 (HER2) in tumor tissue is of great importance for personalized therapy in gastric cancer. Although several studies have investigated whether serum HER2 can serve as a surrogate for tissue HER2 status, results have been inconsistent. We therefore performed a meta-analysis of published clinical studies in an attempt to address this problem. PubMed, Embase, Web of Science, the Cochrane Library and Science Direct were queried for eligible studies that could provide sufficient data to construct 2 × 2 contingency tables. The quality of the studies included in the meta-analysis was assessed in accordance with the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. The pooled sensitivity, specificity and diagnostic odds ratio (DOR) were calculated for the eligible studies. The summary receiver operating characteristic (SROC) curve was constructed and the area under the SROC (AUSROC) was used to evaluate overall diagnostic performance. Eight studies comprising a total of 1170 participants were included in our meta-analysis. The pooled sensitivity, specificity and DOR were 0.39 (95% CI: 0.21–0.61), 0.98 (95% CI: 0.87–1.00), and 27 (95% CI: 9–81), respectively. The AUSROC was 0.77 (95% CI: 0.73–0.80) and Deeks funnel plot suggested the absence of publication bias (p = 0.91). Meta-regression analysis indicated that threshold effect was the main source of heterogeneity. Assays for evaluating serum HER2 levels are highly specific and demonstrate moderate diagnostic performance for HER2 tissue status in gastric cancer.

Description: by Jiaorong Meng, Pingping Liu, Liling Zhu, Chengwu Zou, Jieqiu Li, Baoshan Chen Mulberry vein banding associated virus (MVBaV) that infects mulberry plants with typical vein banding symptoms had been identified as a tentative species of the genus Tospovirus based on the homology of N gene sequence to those of tospoviruses . In this study, the complete sequence of the tripartite RNA genome of MVBaV was determined and analyzed. The L RNA has 8905 nucleotides (nt) and encodes the putative RNA-dependent RNA polymerase (RdRp) of 2877 aa amino acids (aa) in the viral complementary (vc) strand. The RdRp of MVBaV shares the highest aa sequence identity (85.9%) with that of Watermelon silver mottle virus (WSMoV), and contains conserved motifs shared with those of the species of the genus Tospovirus . The M RNA contains 4731 nt and codes in ambisense arrangement for the NSm protein of 309 aa in the sense strand and the Gn/Gc glycoprotein precursor (GP) of 1,124 aa in the vc strand. The NSm and GP of MVBaV share the highest aa sequence identities with those of Capsicum chlorosis virus (CaCV) and Groundnut bud necrosis virus (GBNV) (83.2% and 84.3%, respectively). The S RNA is 3294 nt in length and contains two open reading frames (ORFs) in an ambisense coding strategy, encoding a 439-aa non-structural protein (NSs) and the 277-aa nucleocapsid protein (N), respectively. The NSs and N also share the highest aa sequence identity (71.1% and 74.4%, respectively) with those of CaCV. Phylogenetic analysis of the RdRp, NSm, GP, NSs, and N proteins showed that MVBaV is most closely related to CaCV and GBNV and that these proteins cluster with those of the WSMoV serogroup, and that MVBaV seems to be a species bridging the two subgroups within the WSMoV serogroup of tospoviruses in evolutionary aspect, suggesting that MVBaV represents a distinct tospovirus. Analysis of S RNA sequence uncovered the highly conserved 5’-/3’-ends and the coding regions, and the variable region of IGR with divergent patterns among MVBaV isolates.

Description: by Wenjie Zhu, Binghe Xu Background Anemia related to adjuvant chemotherapy might predict compromised survival in patients with breast cancer. The present population-based study was to investigate the correlation of pretreatment anemia with pathological response and long-term prognosis of breast cancer patients receiving neoadjuvant chemotherapy (NCT). Methods From 1999 to 2011, a total of 655 patients with operable or locally advanced breast cancer who underwent NCT before definitive surgery were reviewed. The patients were subdivided into anemic (baseline hemoglobin (Hb)

Description: by Hong Wang, Jian-en Gao, Xing-hua Li, Shao-long Zhang, Hong-jie Wang To evaluate the process of nitrate accumulation and leaching in surface and ground water, we conducted simulated rainfall experiments. The experiments were performed in areas of 5.3 m 2 with bare slopes of 3° that were treated with two nitrogen fertilizer inputs, high (22.5 g/m 2 NH 4 NO 3 ) and control (no fertilizer), and subjected to 2 hours of rainfall, with. From the 1st to the 7th experiments, the same content of fertilizer mixed with soil was uniformly applied to the soil surface at 10 minutes before rainfall, and no fertilizer was applied for the 8th through 12th experiments. Initially, the time-series nitrate concentration in the surface flow quickly increased, and then it rapidly decreased and gradually stabilized at a low level during the fertilizer experiments. The nitrogen loss in the surface flow primarily occurred during the first 18.6 minutes of rainfall. For the continuous fertilizer experiments, the mean nitrate concentrations in the groundwater flow remained at less than 10 mg/L before the 5th experiment, and after the 7th experiment, these nitrate concentrations were greater than 10 mg/L throughout the process. The time-series process of the changing concentration in the groundwater flow exhibited the same parabolic trend for each fertilizer experiment. However, the time at which the nitrate concentration began to change lagged behind the start time of groundwater flow by approximately 0.94 hours on average. The experiments were also performed with no fertilizer. In these experiments, the mean nitrate concentration of groundwater initially increased continuously, and then, the process exhibited the same parabolic trend as the results of the fertilization experiments. The nitrate concentration decreased in the subsequent experiments. Eight days after the 12 rainfall experiments, 50.53% of the total nitrate applied remained in the experimental soil. Nitrate residues mainly existed at the surface and in the bottom soil layers, which represents a potentially more dangerous pollution scenario for surface and ground water. The surface and subsurface flow would enter into and contaminate water bodies, thus threatening the water environment.

Description: by Alessandra Silvestri, Francesco Palumbo, Ignazio Rasi, Daniela Posca, Theodora Pavlidou, Serena Paoluzi, Luisa Castagnoli, Giovanni Cesareni Introduction Metformin is proposed as adjuvant therapy in cancer treatment because of its ability to limit cancer incidence by negatively modulating the PI3K/AKT/mTOR pathway. In vitro , in addition to inhibiting cancer cell proliferation, metformin can also induce apoptosis. The molecular mechanism underlying this second effect is still poorly characterized and published data are often contrasting. We investigated how nutrient availability can modulate metformin-induced apoptosis in three breast cancer cell lines. Material and Methods MCF7, SKBR3 and MDA-MB-231 cells were plated in MEM medium supplemented with increasing glucose concentrations or in DMEM medium and treated with 10 mM metformin. Cell viability was monitored by Trypan Blue assay and treatment effects on Akt/mTOR pathway and on apoptosis were analysed by Western Blot. Moreover, we determined the level of expression of pyruvate kinase M2 (PKM2), a well-known glycolytic enzyme expressed in cancer cells. Results Our results showed that metformin can induce apoptosis in breast cancer cells when cultured at physiological glucose concentrations and that the pro-apoptotic effect was completely abolished when cells were grown in high glucose/high amino acid medium. Induction of apoptosis was found to be dependent on AMPK activation but, at least partially, independent of TORC1 inactivation. Finally, we showed that, in nutrient-poor conditions, metformin was able to modulate the intracellular glycolytic equilibrium by downregulating PKM2 expression and that this mechanism was mediated by AMPK activation. Conclusion We demonstrated that metformin induces breast cancer cell apoptosis and PKM2 downregulation only in nutrient-poor conditions. Not only glucose levels but also amino acid concentration can influence the observed metformin inhibitory effect on the mTOR pathway as well as its pro-apoptotic effect. These data demonstrate that the reduction of nutrient supply in tumors can increase metformin efficacy and that modulation of PKM2 expression/activity could be a promising strategy to boost metformin anti-cancer effect.

Description: by Etienne Karita, Matt A Price, Shabir Lakhi, William Kilembe, Anatoli Kamali, Eugene Ruzagira, Eric Hunter, Paul Farmer, Susan Allen, Gwynn Stevens, Paramesh Chetty, Sabrina Welsh, Annie Yang, Jill Gilmour, Pat Fast, The IAVI Africa HIV Prevention Partnership Background 2013 WHO guidelines recommend starting ART at CD4+ T-cell counts ≤500 cells/μL. We present the T-cell counts from adult Africans with HIV shortly following transmission to their sexual partners. Methods HIV-discordant couples in Zambia, Uganda and Rwanda were followed prospectively and received couples counseling and condoms. HIV uninfected partners were tested for HIV at least quarterly and HIV-infected partners received HIV care and referral for ART per national guidelines. Upon diagnosis of incident HIV infection in the previously HIV-uninfected partner, a blood sample was collected from both partners to measure CD4+ T-cells and perform viral linkage. The estimated date of infection (EDI) of the incident case was calculated based on testing history. EDI was unknown for suspected transmitting partners. Results From 2006–2011, 4,705 HIV-discordant couples were enrolled in this cohort, and 443 cases of incident HIV infection were documented. Virus linkage analysis was performed in 374 transmission pairs, and 273 (73%) transmissions were linked genetically. CD4 counts in the transmitting partner were measured a median of 56 days after EDI (mean:90.5, min:10, max:396). The median CD4 count was 339 cells/μl (mean:386.4, min:15, max:1,434), and the proportion of partners with a CD4+ T-cell count above 500/μl was 25% (95% CI:21, 31). Conclusions In our cohort of discordant couples, 73% of HIV transmissions occurred within the relationship, and the transmitter CD4+ T cell count shortly after the transmission event was frequently higher than the WHO 2013 ART-initiation guidelines.

Description: by Shuyu Zhang, Changhe Shi, Chengyuan Mao, Bo Song, Haiman Hou, Jun Wu, Xinjing Liu, Haiyang Luo, Shilei Sun, Yuming Xu Background Multiple system atrophy (MSA) is a neurodegenerative disease, and its pathological hallmark is the accumulation of α-synuclein proteins. Homocysteine (Hcy) is an intermediate amino acid generated during the metabolism of methionine. Hcy may contribute to the pathogenesis of neurodegenerative disorders. Vitamin B12 and folate are cofactors necessary for the methylation of homocysteine. Methods This study compared the levels of serum Hcy, vitamin B12 and folate in patients with MSA with those in healthy people to reveal the possible association between MSA and plasma levels of Hcy, vitamin B12 and folate. We enrolled 161 patients with MSA and 161 healthy people in this study. The association between MSA and the levels of Hcy, vitamin B12 and folate were analyzed using binary logistic regression. Results The mean level of Hcy in patients with MSA was significantly higher than that in healthy controls (16.23 ± 8.09 umol/l vs 14.04 ± 4.25 umol/l, p 〈 0.05). After adjusting for age, sex and medical history, the odds ratio for Hcy was 1.07 (95% CI = 1.01–1.13, p 〈 0.05) for patients with MSA. Vitamin B12 and folate levels were not significantly different between patients with MSA and controls. Conclusion Our data suggest that higher levels of Hcy may be associated with an increased risk for MSA.

Description: by Jimmy Belotte, Nicole M. Fletcher, Mohammed G. Saed, Mohammed S. Abusamaan, Gregory Dyson, Michael P. Diamond, Ghassan M. Saed Ovarian cancer is the deadliest of all gynecologic cancers. Recent evidence demonstrates an association between enzymatic activity altering single nucleotide polymorphisms (SNP) with human cancer susceptibility. We sought to evaluate the association of SNPs in key oxidant and antioxidant enzymes with increased risk and survival in epithelial ovarian cancer. Individuals (n = 143) recruited were divided into controls, (n = 94): healthy volunteers, (n = 18), high-risk BRCA1/2 negative (n = 53), high-risk BRCA1/2 positive (n = 23) and ovarian cancer cases (n = 49). DNA was subjected to TaqMan SNP genotype analysis for selected oxidant and antioxidant enzymes. Of the seven selected SNP studied, no association with ovarian cancer risk (Pearson Chi-square) was found. However, a catalase SNP was identified as a predictor of ovarian cancer survival by the Cox regression model. The presence of this SNP was associated with a higher likelihood of death (hazard ratio (HR) of 3.68 (95% confidence interval (CI): 1.149–11.836)) for ovarian cancer patients. Kaplan-Meier survival analysis demonstrated a significant median overall survival difference (108 versus 60 months, p

Description: by Xiaoyu Wang, Meili Chen, Jingfa Xiao, Lirui Hao, David E. Crowley, Zhewen Zhang, Jun Yu, Ning Huang, Mingxin Huo, Jiayan Wu Cupriavidus sp. are generally heavy metal tolerant bacteria with the ability to degrade a variety of aromatic hydrocarbon compounds, although the degradation pathways and substrate versatilities remain largely unknown. Here we studied the bacterium Cupriavidus gilardii strain CR3, which was isolated from a natural asphalt deposit, and which was shown to utilize naphthenic acids as a sole carbon source. Genome sequencing of C . gilardii CR3 was carried out to elucidate possible mechanisms for the naphthenic acid biodegradation. The genome of C . gilardii CR3 was composed of two circular chromosomes chr1 and chr2 of respectively 3,539,530 bp and 2,039,213 bp in size. The genome for strain CR3 encoded 4,502 putative protein-coding genes, 59 tRNA genes, and many other non-coding genes. Many genes were associated with xenobiotic biodegradation and metal resistance functions. Pathway prediction for degradation of cyclohexanecarboxylic acid, a representative naphthenic acid, suggested that naphthenic acid undergoes initial ring-cleavage, after which the ring fission products can be degraded via several plausible degradation pathways including a mechanism similar to that used for fatty acid oxidation. The final metabolic products of these pathways are unstable or volatile compounds that were not toxic to CR3. Strain CR3 was also shown to have tolerance to at least 10 heavy metals, which was mainly achieved by self-detoxification through ion efflux, metal-complexation and metal-reduction, and a powerful DNA self-repair mechanism. Our genomic analysis suggests that CR3 is well adapted to survive the harsh environment in natural asphalts containing naphthenic acids and high concentrations of heavy metals.

Description: by Noriko Sasaki-Haraguchi, Takeshi Ikuyama, Shogo Yoshii, Tomoko Takeuchi-Andoh, David Frendewey, Tokio Tani Exons are ligated in an ordered manner without the skipping of exons in the constitutive splicing of pre-mRNAs with multiple introns. To identify factors ensuring ordered exon joining in constitutive pre-mRNA splicing, we previously screened for exon skipping mutants in Schizosaccharomyces pombe using a reporter plasmid, and characterized three exon skipping mutants named ods1 (ordered splicing 1), ods2 , and ods3 , the responsible genes of which encode Prp2/U2AF 59 , U2AF 23 , and SF1, respectively. They form an SF1-U2AF 59 -U2AF 23 complex involved in recognition of the branch and 3′ splice sites in pre-mRNA. In the present study, we identified a fourth ods mutant, ods4 , which was isolated in an exon-skipping screen. The ods4 + gene encodes Cwf16p, which interacts with the NineTeen Complex (NTC), a complex thought to be involved in the first catalytic step of the splicing reaction. We isolated two multi-copy suppressors for the ods4-1 mutation, Srp2p, an SR protein essential for pre-mRNA splicing, and Tif213p, a translation initiation factor, in S . pombe . The overexpression of Srp2p suppressed the exon-skipping phenotype of all ods mutants, whereas Tif213p suppressed only ods4-1 , which has a mutation in the translational start codon of the cwf16 gene. We also showed that the decrease in the transcriptional elongation rate induced by drug treatment suppressed exon skipping in ods4-1 . We propose that Cwf16p/NTC participates in the early recognition of the branch and 3′ splice sites and cooperates with the SF1-U2AF 59 -U2AF 23 complex to maintain ordered exon joining.

Description: by Shady Elmasry, Shihab Asfour, Juan Pablo de Rivero Vaccari, Francesco Travascio Tobacco smoking is associated with numerous pathological conditions. Compelling experimental evidence associates smoking to the degeneration of the intervertebral disc (IVD). In particular, it has been shown that nicotine down-regulates both the proliferation rate and glycosaminoglycan (GAG) biosynthesis of disc cells. Moreover, tobacco smoking causes the constriction of the vascular network surrounding the IVD, thus reducing the exchange of nutrients and anabolic agents from the blood vessels to the disc. It has been hypothesized that both nicotine presence in the IVD and the reduced solute exchange are responsible for the degeneration of the disc due to tobacco smoking, but their effects on tissue homeostasis have never been quantified. In this study, a previously presented computational model describing the homeostasis of the IVD was deployed to investigate the effects of impaired solute supply and nicotine-mediated down-regulation of cell proliferation and biosynthetic activity on the health of the disc. We found that the nicotine-mediated down-regulation of cell anabolism mostly affected the GAG concentration at the cartilage endplate, reducing it up to 65% of the value attained in normal physiological conditions. In contrast, the reduction of solutes exchange between blood vessels and disc tissue mostly affected the nucleus pulposus, whose cell density and GAG levels were reduced up to 50% of their normal physiological levels. The effectiveness of quitting smoking on the regeneration of a degenerated IVD was also investigated, and showed to have limited benefit on the health of the disc. A cell-based therapy in conjunction with smoke cessation provided significant improvements in disc health, suggesting that, besides quitting smoking, additional treatments should be implemented in the attempt to recover the health of an IVD degenerated by tobacco smoking.

Description: by Piers Dawes, Karen J. Cruickshanks, David R. Moore, Heather Fortnum, Mark Edmondson-Jones, Abby McCormack, Kevin J. Munro It is unclear what the contribution of prenatal versus childhood development is for adult cognitive and sensory function and age-related decline in function. We examined hearing, vision and cognitive function in adulthood according to self-reported birth weight (an index of prenatal development) and adult height (an index of early childhood development). Subsets (N = 37,505 to 433,390) of the UK Biobank resource were analysed according to visual and hearing acuity, reaction time and fluid IQ. Sensory and cognitive performance was reassessed after ~4 years (N = 2,438 to 17,659). In statistical modelling including age, sex, socioeconomic status, educational level, smoking, maternal smoking and comorbid disease, adult height was positively associated with sensory and cognitive function (partial correlations; pr 0.05 to 0.12, p 〈 0.001). Within the normal range of birth weight (10 th to 90 th percentile), there was a positive association between birth weight and sensory and cognitive function ( pr 0.06 to 0.14, p 〈 0.001). Neither adult height nor birth weight was associated with change in sensory or cognitive function. These results suggest that adverse prenatal and childhood experiences are a risk for poorer sensory and cognitive function and earlier development of sensory and cognitive impairment in adulthood. This finding could have significant implications for preventing sensory and cognitive impairment in older age.

Description: by Nicolas Guizard, Vladimir S. Fonov, Daniel García-Lorenzo, Kunio Nakamura, Bérengère Aubert-Broche, D. Louis Collins Neurodegenerative diseases such as Alzheimer's disease present subtle anatomical brain changes before the appearance of clinical symptoms. Manual structure segmentation is long and tedious and although automatic methods exist, they are often performed in a cross-sectional manner where each time-point is analyzed independently. With such analysis methods, bias, error and longitudinal noise may be introduced. Noise due to MR scanners and other physiological effects may also introduce variability in the measurement. We propose to use 4D non-linear registration with spatio-temporal regularization to correct for potential longitudinal inconsistencies in the context of structure segmentation. The major contribution of this article is the use of individual template creation with spatio-temporal regularization of the deformation fields for each subject. We validate our method with different sets of real MRI data, compare it to available longitudinal methods such as FreeSurfer, SPM12, QUARC, TBM, and KNBSI, and demonstrate that spatially local temporal regularization yields more consistent rates of change of global structures resulting in better statistical power to detect significant changes over time and between populations.

Description: by Samir Helmy, Yvonne Bader, Marianne Koch, Denise Tiringer, Christian Kollmann Objective Ultrasound is considered a safe imaging modality and is routinely applied during early pregnancy. However, reservations are expressed concerning the application of Doppler ultrasound in early pregnancy due to energy emission of the ultrasound probe and its conversion to heat. The objective of this study was to evaluate the thermal effects of emitted Doppler ultrasound of different ultrasound machines and probes by means of temperature increase of in-vitro test-media. Methods We investigated the energy-output of 5 vaginal and abdominal probes of 3 ultrasound machines (GE Healthcare, Siemens, Aloka). Two in-vitro test objects were developed at the Center for Medical Physics and Biomedical Engineering, Medical University Vienna (water bath and hydrogel bath). Temperature increase during Doppler ultrasound emission was measured via thermal sensors, which were placed inside the test objects or on the probes’ surface. Each probe was emitting for 5 minutes into the absorbing test object with 3 different TI/MI settings in Spectral Doppler mode. Results During water bath test, temperature increase varied between 0.1 and 1.0°C, depending on probe, setting and focus, and was found highest for spectral Doppler mode alone. Maximum temperature increase was found during the surface heating test, where values up to 2.4°C could be measured within 5 minutes of emission. Conclusions Activation of Doppler ultrasound in the waterbath model causes a significant increase of temperature within one minute. Thermally induced effects on the embryo cannot be excluded when using Doppler ultrasound in early pregnancy.

Description: by Anatoli Y. Kabakov, Paul A. Rosenberg Glutamate is the major excitatory neurotransmitter, but prolonged exposure even at micromolar concentrations causes neuronal death. Extracellular glutamate is maintained at nanomolar level by glutamate transporters, which, however, may reverse transport and release glutamate. If and when the reverse occurs depends on glutamate transport stoichiometry (GTS). Previously we found that in the presence of chloride, the coupled GLT-1 glutamate transporter current and its relationship to radiolabeled glutamate flux significantly decreased when extracellular glutamate concentration increased above 0.2 mM, which implies a change in GTS. Such high concentrations are feasible near GLT-1 expressed close to synaptic release site during excitatory neurotransmission. The aim of this study was to determine GLT-1 GTS at both low (19–75 μM) and high (300–1200 μM) glutamate concentration ranges. GTS experiments were conducted in the absence of chloride to avoid contributions by the GLT-1 uncoupled chloride conductance. Mathematical analysis of the transporter thermodynamic equilibrium allowed us to derive equations revealing the number of a particular type of ion transported per elementary charge based on the measurements of the transporter reversal potential. We found that GLT-1a expressed in COS-7 cells co-transports 1.5 Na + , 0.5 Glu - , 0.5 H + and counter-transports 0.6 K + per elementary charge in both glutamate concentration ranges, and at both 37°C and 26°C temperatures. The thermodynamic parameter Q 10 = 2.4 for GLT-1 turnover rate of 19 s -1 (37°C, -50 mV) remained constant in the 10 μM–10 mM glutamate concentration range. Importantly, the previously reported decrease in the current/flux ratio at high glutamate concentration was not seen in the absence of chloride in both COS-7 cells and cultured rat neurons. Therefore, only in the absence of chloride, GLT-1 GTS remains constant at all glutamate concentrations. Possible explanations for why apparent GTS might vary in the presence of chloride are discussed.

Description: by Ariel Afek, Hila Cohen, Shiran Barber-Zucker, Raluca Gordân, David B. Lukatsky Recent genome-wide experiments in different eukaryotic genomes provide an unprecedented view of transcription factor (TF) binding locations and of nucleosome occupancy. These experiments revealed that a large fraction of TF binding events occur in regions where only a small number of specific TF binding sites (TFBSs) have been detected. Furthermore, in vitro protein-DNA binding measurements performed for hundreds of TFs indicate that TFs are bound with wide range of affinities to different DNA sequences that lack known consensus motifs. These observations have thus challenged the classical picture of specific protein-DNA binding and strongly suggest the existence of additional recognition mechanisms that affect protein-DNA binding preferences. We have previously demonstrated that repetitive DNA sequence elements characterized by certain symmetries statistically affect protein-DNA binding preferences. We call this binding mechanism nonconsensus protein-DNA binding in order to emphasize the point that specific consensus TFBSs do not contribute to this effect. In this paper, using the simple statistical mechanics model developed previously, we calculate the nonconsensus protein-DNA binding free energy for the entire C . elegans and D . melanogaster genomes. Using the available chromatin immunoprecipitation followed by sequencing (ChIP-seq) results on TF-DNA binding preferences for ~100 TFs, we show that DNA sequences characterized by low predicted free energy of nonconsensus binding have statistically higher experimental TF occupancy and lower nucleosome occupancy than sequences characterized by high free energy of nonconsensus binding. This is in agreement with our previous analysis performed for the yeast genome. We suggest therefore that nonconsensus protein-DNA binding assists the formation of nucleosome-free regions, as TFs outcompete nucleosomes at genomic locations with enhanced nonconsensus binding. In addition, here we perform a new, large-scale analysis using in vitro TF-DNA preferences obtained from the universal protein binding microarrays (PBM) for ~90 eukaryotic TFs belonging to 22 different DNA-binding domain types. As a result of this new analysis, we conclude that nonconsensus protein-DNA binding is a widespread phenomenon that significantly affects protein-DNA binding preferences and need not require the presence of consensus (specific) TFBSs in order to achieve genome-wide TF-DNA binding specificity.

Description: by Abdoulaye J. Dabo, Neville Cummins, Edward Eden, Patrick Geraghty Increased lung levels of matrix metalloproteinase 9 (MMP9) are frequently observed during respiratory syncytial virus (RSV) infection and elevated MMP9 concentrations are associated with severe disease. However little is known of the functional role of MMP9 during lung infection with RSV. To determine whether MMP9 exerted direct antiviral potential, active MMP9 was incubated with RSV, which showed that MMP9 directly prevented RSV infectivity to airway epithelial cells. Using knockout mice the effect of the loss of Mmp9 expression was examined during RSV infection to demonstrate MMP9’s role in viral clearance and disease progression. Seven days following RSV infection, Mmp9 -/- mice displayed substantial weight loss, increased RSV-induced airway hyperresponsiveness (AHR) and reduced clearance of RSV from the lungs compared to wild type mice. Although total bronchoalveolar lavage fluid (BALF) cell counts were similar in both groups, neutrophil recruitment to the lungs during RSV infection was significantly reduced in Mmp9 -/- mice. Reduced neutrophil recruitment coincided with diminished RANTES, IL-1β, SCF, G-CSF expression and p38 phosphorylation. Induction of p38 signaling was required for RANTES and G-CSF expression during RSV infection in airway epithelial cells. Therefore, MMP9 in RSV lung infection significantly enhances neutrophil recruitment, cytokine production and viral clearance while reducing AHR.

Description: by Andrea Dueregger, Bernd Schöpf, Theresa Eder, Julia Höfer, Erich Gnaiger, Astrid Aufinger, Lukas Kenner, Bernhard Perktold, Reinhold Ramoner, Helmut Klocker, Iris E. Eder Tumor cells adapt via metabolic reprogramming to meet elevated energy demands due to continuous proliferation, for example by switching to alternative energy sources. Nutrients such as glucose, fatty acids, ketone bodies and amino acids may be utilized as preferred substrates to fulfill increased energy requirements. In this study we investigated the metabolic characteristics of benign and cancer cells of the prostate with respect to their utilization of medium chain (MCTs) and long chain triglycerides (LCTs) under standard and glucose-starved culture conditions by assessing cell viability, glycolytic activity, mitochondrial respiration, the expression of genes encoding key metabolic enzymes as well as mitochondrial mass and mtDNA content. We report that BE prostate cells (RWPE-1) have a higher competence to utilize fatty acids as energy source than PCa cells (LNCaP, ABL, PC3) as shown not only by increased cell viability upon fatty acid supplementation but also by an increased ß-oxidation of fatty acids, although the base-line respiration was 2-fold higher in prostate cancer cells. Moreover, BE RWPE-1 cells were found to compensate for glucose starvation in the presence of fatty acids. Of notice, these findings were confirmed in vivo by showing that PCa tissue has a lower capacity in oxidizing fatty acids than benign prostate. Collectively, these metabolic differences between benign and prostate cancer cells and especially their differential utilization of fatty acids could be exploited to establish novel diagnostic and therapeutic strategies.

Description: by Johannes Pfleging, Marius Stücheli, Radu Iovita, Jonas Buchli Reconstructing ancient technical gestures associated with simple tool actions is crucial for understanding the co-evolution of the human forelimb and its associated control-related cognitive functions on the one hand, and of the human technological arsenal on the other hand. Although the topic of gesture is an old one in Paleolithic archaeology and in anthropology in general, very few studies have taken advantage of the new technologies from the science of kinematics in order to improve replicative experimental protocols. Recent work in paleoanthropology has shown the potential of monitored replicative experiments to reconstruct tool-use-related motions through the study of fossil bones, but so far comparatively little has been done to examine the dynamics of the tool itself. In this paper, we demonstrate that we can statistically differentiate gestures used in a simple scraping task through dynamic monitoring. Dynamics combines kinematics (position, orientation, and speed) with contact mechanical parameters (force and torque). Taken together, these parameters are important because they play a role in the formation of a visible archaeological signature, use-wear. We present our new affordable, yet precise methodology for measuring the dynamics of a simple hide-scraping task, carried out using a pull-to (PT) and a push-away (PA) gesture. A strain gage force sensor combined with a visual tag tracking system records force, torque, as well as position and orientation of hafted flint stone tools. The set-up allows switching between two tool configurations, one with distal and the other one with perpendicular hafting of the scrapers, to allow for ethnographically plausible reconstructions. The data show statistically significant differences between the two gestures: scraping away from the body (PA) generates higher shearing forces, but requires greater hand torque. Moreover, most benchmarks associated with the PA gesture are more highly variable than in the PT gesture. These results demonstrate that different gestures used in ‘common’ prehistoric tasks can be distinguished quantitatively based on their dynamic parameters. Future research needs to assess our ability to reconstruct these parameters from observed use-wear patterns.

Description: by Matilda Aberese-Ako, Irene Akua Agyepong, Trudie Gerrits, Han Van Dijk Background and Objectives This paper analyses why and how conflicts occur and their influence on doctors and nurse-anaesthetists' motivation in the provision of maternal and neonatal health care in a specialist hospital. Methodology The study used ethnographic methods including participant observation, conversation and in-depth interviews over eleven months in a specialist referral hospital in Ghana. Qualitative analysis software Nvivo 8 was used for coding and analysis of data. Main themes identified in the analysis form the basis for interpreting and reporting study findings. Ethics Statement Ethical clearance was obtained from the Ghana Health Service Ethics Review board (approval number GHS-ERC:06/01/12) and from the University of Wageningen. Written consent was obtained from interview participants, while verbal consent was obtained for conversations. To protect the identity of the hospital and research participants pseudonyms are used in the article and the part of Ghana in which the study was conducted is not mentioned. Results Individual characteristics, interpersonal and organisational factors contributed to conflicts. Unequal power relations and distrust relations among doctors and nurse-anaesthetists affected how they responded to conflicts. Responses to conflicts including forcing, avoiding, accommodating and compromising contributed to persistent conflicts, which frustrated and demotivated doctors and nurse-anaesthetists. Demotivated workers exhibited poor attitudes in collaborating with co-workers in the provision of maternal and neonatal care, which sometimes led to poor health worker response to client care, consequently compromising the hospital's goal of providing quality health care to clients. Conclusion To improve health care delivery in health facilities in Ghana, health managers and supervisors need to identify conflicts as an important phenomenon that should be addressed whenever they occur. Effective mechanisms including training managers and health workers on conflict management should be put in place. Additionally promoting communication and interaction among health workers can foster team spirit. Also resolving conflicts using the collaborating response may help to create a conducive work environment that will promote healthy work relations, which can facilitate the delivery of quality maternal and neonatal health care. However, such an approach requires that unequal power relations, which is a root cause of the conflicts is addressed.

Description: by Masaaki Oi, Souichi Yoshikawa, Soichi Maruyama, Sadao Nogami Toxoplasma gondii is an important human health concern with respect to abortion, congenital hydrocephalus, and encephalitis in immunocompromised people. Cats and dogs both are potential sources of T . gondii because they have close contact with humans. However, no epidemiological surveys have been conducted in Tokyo over the past decade. Therefore, the present study investigated and compared the seroprevalence of T . gondii infection in shelter cats and dogs during 1999–2001 and 2009–2011 in Tokyo, Japan. Serum samples were collected from 337 shelter cats and 325 shelter dogs in urban and suburban areas of Tokyo, during 1999–2001 (233 cats and 219 dogs) and 2009–2011 (104 cats and 106 dogs). T . gondii antibodies were measured in the serum samples using a commercial latex agglutination test. Data were compared using the Fisher’s exact test, and significance was indicated at P 〈 0.05. The overall seroprevalence of T . gondii infection in cats was 5.6% (13 of 233) in 1999–2001 and 6.7% (7 of 104) in 2009–2011, and that in dogs was 1.8% (4 of 219) and 1.9% (2 of 106), respectively. Significantly higher seroprevalence was observed in cats from suburban areas compared with cats in urban areas during both periods ( P 〈 0.05). These results reveal that there has been little change in the feline and canine seroprevalence over the past decade, indicating that the risk of T . gondii exposure for cats and dogs in Tokyo is considerably low as the seroprevalence has reached a steady state.

Description: by Rosyana V. Albuquerque, Nívea S. Malcher, Lílian L. Amado, Michael D. Coleman, Danielle C. dos Santos, Rosivaldo Sa. Borges, Sebastião Aldo S. Valente, Vera C. Valente, Marta Chagas Monteiro Dapsone (DDS) hydroxylamine metabolites cause oxidative stress- linked adverse effects in patients, such as methemoglobin formation and DNA damage. This study evaluated the ameliorating effect of the antioxidant resveratrol (RSV) on DDS hydroxylamine (DDS-NHOH) mediated toxicity in vitro using human erythrocytes and lymphocytes. The antioxidant mechanism was also studied using in-silico methods. In addition, RSV provided intracellular protection by inhibiting DNA damage in human lymphocytes induced by DDS-NHOH. However, whilst pretreatment with RSV (10–1000 μM significantly attenuated DDS-NHOH-induced methemoglobinemia, but it was not only significantly less effective than methylene blue (MET), but also post-treatment with RSV did not reverse methemoglobin formation, contrarily to that observed with MET. DDS-NHOH inhibited catalase (CAT) activity and reactive oxygen species (ROS) generation, but did not alter superoxide dismutase (SOD) activity in erythrocytes. Pretreatment with RSV did not alter these antioxidant enzymes activities in erythrocytes treated with DDS-NHOH. Theoretical calculations using density functional theory methods showed that DDS-NHOH has a pro-oxidant effect, whereas RSV and MET have antioxidant effect on ROS. The effect on methemoglobinemia reversion for MET was significantly higher than that of RSV. These data suggest that the pretreatment with resveratrol may decrease heme-iron oxidation and DNA damage through reduction of ROS generated in cells during DDS therapy.

Description: by Lenka Roubalova, Miroslava Vosahlikova, Jana Brejchova, Jan Sykora, Vladimir Rudajev, Petr Svoboda Principal Findings HEK293 cells stably expressing PTX-insensitive δ-opioid receptor-Gi1α (C 351 I) fusion protein were homogenized, treated with low concentrations of non-ionic detergent Brij-58 at 0°C and fractionated by flotation in sucrose density gradient. In optimum range of detergent concentrations (0.025–0.05% w/v), Brij-58-treated, low-density membranes exhibited 2-3-fold higher efficacy of DADLE-stimulated, high-affinity [ 32 P]GTPase and [ 35 S]GTPγS binding than membranes of the same density prepared in the absence of detergent. The potency of agonist DADLE response was significantly decreased. At high detergent concentrations (〉0.1%), the functional coupling between δ-opioid receptors and G proteins was completely diminished. The same detergent effects were measured in plasma membranes isolated from PTX-treated cells. Therefore, the effect of Brij-58 on δ-opioid receptor-G protein coupling was not restricted to the covalently bound G i 1α within δ-opioid receptor-G i 1α fusion protein, but it was also valid for PTX-sensitive G proteins of G i /G o family endogenously expressed in HEK293 cells. Characterization of the direct effect of Brij-58 on the hydrophobic interior of isolated plasma membranes by steady-state anisotropy of diphenylhexatriene (DPH) fluorescence indicated a marked increase of membrane fluidity. The time-resolved analysis of decay of DPH fluorescence by the “wobble in cone” model of DPH motion in the membrane indicated that the exposure to the increasing concentrations of Brij-58 led to a decreased order and higher motional freedom of the dye. Summary Limited perturbation of plasma membrane integrity by low concentrations of non-ionic detergent Brij-58 results in alteration of δ-OR-G protein coupling. Maximum G protein-response to agonist stimulation (efficacy) is increased; affinity of response (potency) is decreased. The total degradation plasma membrane structure at high detergent concentrations results in diminution of functional coupling between δ-opioid receptors and G proteins.

Description: by Monica Konar, Peter T. Beernink, Dan M. Granoff Background Two meningococcal serogroup B vaccines contain Factor H binding protein (FHbp). Binding of Factor H (FH) to FHbp was thought to be specific for human or chimpanzee FH. However, in a previous study an amino acid polymorphism in rhesus macaque FH domain 6, tyrosine at position 352 (Y352) was associated with high binding to FHbp, whereas histidine at position 352 (H352) was associated with low binding. Methods and Results Here we report that a second FH polymorphism at position 360 also affects macaque FH binding. Of 43 macaques, 11 had high FH binding and 32 had low binding. As in our previous study, all 11 animals with high binding had Y352, and 24 with low binding had H352. However the remaining eight with low FH binding had Y352, which was predicted to yield high binding. All eight had S360 instead of P360. Thus, three allelic variants at positions 352 and 360 affect macaque FH binding to FHbp: HP (low), YS (low), and YP (high). We measured binding affinity of each FH sequence type to FHbp by surface plasmon resonance. Two animals with high binding types (YS/YP and HP/YP) had dissociation constants ( K D ) of 10.4 and 18.2 nM, respectively, which were similar to human FH (19.8 nM). Two macaques with low binding (HP/HP and HP/YS) had K D values approximately five-fold higher (100.3 and 99.5 nM, respectively). A third macaque with low binding (YS/YS) had a K D value too high to be measured. Conclusions Macaques have at least three allelic variants encoding FH with different affinities for FHbp (five genotypic combinations of these variants). Since in previous studies binding of FH to FHbp vaccines decreased protective antibody responses, our data will aid in selection of macaques with FH binding that is similar to humans for further investigation of FHbp vaccine immunogenicity.

Description: by Tulio Konstantyner, Ricardo Sesso, Maria Fernanda de Camargo, Luciana de Santis Feltran, Paulo Cesar Koch-Nogueira Introduction There are few reports in the literature estimating the epidemiologic characteristics of pediatric chronic dialysis. These patients have impaired physical growth, high number of comorbidities and great need for continuous attention of specialized services with high demand for complex and costly procedures. Objective The aim of this study was to estimate the incidence and prevalence rates and describe the characteristics of children and adolescents undergoing chronic dialysis treatment in a Brazilian demographic health survey. Materials and Methods A cross-sectional study was performed in a representative sample of dialysis centers (n c = 239) that was established from the 2011 Brazilian Nephrology Society Census (N c = 708). We collected data encompassing the five Brazilian macro-regions. We analyzed the data from all patients under 19 years of age. The sample population consisted of 643 children and adolescents who were on chronic dialysis program anytime in 2012. Data collection was carried out in the dialysis services by means of patients' records reviews and personal interviews with the centers’ leaders. Results We estimated that there were a total of 1,283 pediatric patients on chronic dialysis treatment in Brazil, resulting in a prevalence of 20.0 cases per million age-related population (pmarp) (95% CI: 14.8–25.3) and an incidence of 6.6 cases pmarp in 2012 (95% CI: 4.8–8.4). The South region had the highest prevalence and incidence rates of patients under dialysis therapy, 27.7 (95% CI: 7.3–48.1) and 11.0 (95% CI: 2.8–19.3) cases pmarp, respectively; the lowest prevalence and incidence rates were found in the North-Midwest region, 13.8 (95% CI: 6.2–21.4), and in the Northeast region, 3.8 (95% CI: 1.4–6.3) cases pmarp, respectively. Conclusion Brazil has an overall low prevalence of children on chronic dialysis treatment, figuring near the rates from others countries with same socioeconomic profile. There are substantial differences among regions related to pediatric chronic dialysis treatment. Joint strategies aiming to reduce inequities and improving access to treatment and adequacy of services across the Brazilian regions are necessary to provide an appropriate care setting for this population group.

Description: by Chaoxu Zeng, Jianshuang Wu, Xianzhou Zhang Biomass allocation is an essential concept for understanding above- vs. below-ground functions and for predicting the dynamics of community structure and ecosystem service under ongoing climate change. There is rare available knowledge of grazing effects on biomass allocation in multiple zonal alpine grassland types along climatic gradients across the Northern Tibetan Plateau. We collected the peak above- and below-ground biomass (AGB and BGB) values at 106 pairs of well-matched grazed vs. fenced sites during summers of 2010–2013, of which 33 pairs were subject to meadow, 52 to steppe and 21 to desert-steppe. The aboveground net primary productivity (ANPP) was represented by the peak AGB while the belowground net primary productivity (BNPP) was estimated from ANPP, the ratio of living vs. dead BGB, and the root turnover rate. Two-ways analyses of variance (ANOVA) and paired samples comparisons with t -test were applied to examine the effects of pasture managements (PMS, i.e., grazed vs. fenced) and zonal grassland types on both ANPP and BNPP. Allometric and isometric allocation hypotheses were also tested between logarithmically transformed ANPP and BNPP using standardized major axis (SMA) analyses across grazed, fenced and overall sites. In our study, a high community-dependency was observed to support the allometric biomass allocation hypothesis, in association with decreased ANPP and a decreasing-to-increasing BNPP proportions with increasing aridity across the Northern Tibetan Plateau. Grazing vs. fencing seemed to have a trivial effect on ANPP compared to the overwhelming influence of different zonal grassland types. Vegetation links above- and below-ground ecological functions through integrated meta-population adaptive strategies to the increasing severity of habitat conditions. Therefore, more detailed studies on functional diversity are essentially to achieve conservation and sustainability goals under ongoing climatic warming and intensifying human influences.

Description: by Daniela Almeida, Emanuel Maldonado, Vitor Vasconcelos, Agostinho Antunes Mitochondrial protein-coding genes (mt genes) encode subunits forming complexes of crucial cellular pathways, including those involved in the vital process of oxidative phosphorylation (OXPHOS). Despite the vital role of the mitochondrial genome (mt genome) in the survival of organisms, little is known with respect to its adaptive implications within marine invertebrates. The molluscan Class Cephalopoda is represented by a marine group of species known to occupy contrasting environments ranging from the intertidal to the deep sea, having distinct metabolic requirements, varied body shapes and highly advanced visual and nervous systems that make them highly competitive and successful worldwide predators. Thus, cephalopods are valuable models for testing natural selection acting on their mitochondrial subunits (mt subunits). Here, we used concatenated mt genes from 17 fully sequenced mt genomes of diverse cephalopod species to generate a robust mitochondrial phylogeny for the Class Cephalopoda. We followed an integrative approach considering several branches of interest–covering cephalopods with distinct morphologies, metabolic rates and habitats–to identify sites under positive selection and localize them in the respective protein alignment and/or tridimensional structure of the mt subunits. Our results revealed significant adaptive variation in several mt subunits involved in the energy production pathway of cephalopods: ND5 and ND6 from Complex I, CYTB from Complex III, COX2 and COX3 from Complex IV, and in ATP8 from Complex V. Furthermore, we identified relevant sites involved in protein-interactions, lining proton translocation channels, as well as disease/deficiencies related sites in the aforementioned complexes. A particular case, revealed by this study, is the involvement of some positively selected sites, found in Octopoda lineage in lining proton translocation channels (site 74 from ND5) and in interactions between subunits (site 507 from ND5) of Complex I.

Description: by Alexander Suh, Linnéa Smeds, Hans Ellegren The diversification of neoavian birds is one of the most rapid adaptive radiations of extant organisms. Recent whole-genome sequence analyses have much improved the resolution of the neoavian radiation and suggest concurrence with the Cretaceous-Paleogene (K-Pg) boundary, yet the causes of the remaining genome-level irresolvabilities appear unclear. Here we show that genome-level analyses of 2,118 retrotransposon presence/absence markers converge at a largely consistent Neoaves phylogeny and detect a highly differential temporal prevalence of incomplete lineage sorting (ILS), i.e., the persistence of ancestral genetic variation as polymorphisms during speciation events. We found that ILS-derived incongruences are spread over the genome and involve 35% and 34% of the analyzed loci on the autosomes and the Z chromosome, respectively. Surprisingly, Neoaves diversification comprises three adaptive radiations, an initial near-K-Pg super-radiation with highly discordant phylogenetic signals from near-simultaneous speciation events, followed by two post-K-Pg radiations of core landbirds and core waterbirds with much less pronounced ILS. We provide evidence that, given the extreme level of up to 100% ILS per branch in super-radiations, particularly rapid speciation events may neither resemble a fully bifurcating tree nor are they resolvable as such. As a consequence, their complex demographic history is more accurately represented as local networks within a species tree.

Description: by Xifu Shang, Zhengliang Luo, Xudong Wang, Todd Jaeblon, John V. Marymont, Yufeng Dong Recently we have demonstrated the importance of RBPjk-dependent Notch signaling in the regulation of mesenchymal stem cell (MSC) differentiation during skeletogenesis both in vivo and in vitro. Here we further performed RBPJK loss-of-function experiments to demonstrate for the first time that RBPJK deficient MSC shows enhanced differentiation and osteogenesis acts via up-regulation of the BMP signaling. In the present study, we first compared the spontaneous and osteogenic differentiation in normal and recombination signal binding protein for immunoglobulin kappa J region (RBPJK) deficient human bone marrow-derived mesenchymal stem cells (MSCs). It was found that RBPJK highly expressed in fresh isolated MSCs and its expression was progressing down-regulated during spontaneous differentiation and even greater in osteogenic media inducted differentiation. Deletion of RBPJK in MSCs not only enhances cell spontaneous differentiation, but also significantly accelerates condition media inducted osteogenic differentiation by showing enhanced alkaline phosphatase (ALP) activity, Alizarin red staining, gene expression of Runx2, Osteopontin (OPN), Type I collagen (COL1a1) in culture. Additionally, BMP signaling responsive reporter activity and phosphor-smad1/5/8 expression were also significantly increased upon removal of RBPJK in MSCs. These data proved that inhibition of Notch signaling in MSCs promotes cell osteogenic differentiation by up-regulation of BMP signaling, and RBPJK deficient MSC maybe a better cell population for cell-based bone tissue engineering.

Description: by Jack A. Kornblatt, Veronica Quiros, M. Judith Kornblatt The enolase produced by Streptococcus pyogenes is a homo-octamer whose overall shape resembles that of a donut. The octamer is best described as a tetramer of dimers. As such, it contains two types of interfaces. The first is common to almost all enolases as most enolases that have been studied are dimers. The second is unique to the octamers and includes residues near the carboxy-terminus. The primary sequence of the enolase contains 435 residues with an added 19 as an N-terminal hexahistine tag. We have systematically truncated the carboxy-terminus, individually removing the first 8 residues. This gave rise to a series of eight structures containing respectively, 435, 434, 433, 432, 431, 430, 429 and 427 residues. The truncations cause the protein to gradually dissociate from octamers to enzymatically inactive monomers with very small amounts of intermediate tetramers and dimers. We have evaluated the contributions of the missing residues to the monomer/octamer equilibrium using a combination of analytical ultracentrifugation and activity assays. For the dissociation reaction, octamer ⇐⇒ 8 monomer truncation of all eight C-terminal residues resulted in a diminution in the standard Gibbs energy of dissociation of about 59 kJ/mole of octamer relative to the full length protein. Considering that this change is spread over eight subunits, this translates to a change in standard Gibbs interaction energy of less than 8 kJ/mole of monomer distributed over the eight monomers. The resulting proteins, containing 434, 433, 432, 431, 430, 429 and 427 residues per monomer, showed intermediate free energies of dissociation. Finally, three other mutations were introduced into our reference protein to establish how they influenced the equilibrium. The main importance of this work is it shows that for homo-multimeric proteins a small change in the standard Gibbs interaction energy between subunits can have major physiological effects.

Description: by Zhongyu Liu, Jun Liu, Li Li, Dan Nie, Qilei Tao, Jian Wu, Jiajun Fan, Chen Lin, Shuwei Zhao, Dianwen Ju Nedaplatin, a cisplatin analog, was developed to reduce the toxicity of cisplatin, whereas it can be cross-resistant with cisplatin in some circumstances. This study aimed to investigate the role of autophagy in nedaplatin induced cell death in cisplatin-resistant nasopharyngeal carcinoma cells. Here, we showed that HNE1/DDP and CNE2/DDP cells were resistant to nedaplatin-induced cell death with reduced apoptotic activity. Nedaplatin treatment resulted in autophagosome accumulation and increased expression of LC3-II, indicating the induction of autophagy by nedaplatin in HNE1/DDP and CNE2/DDP cells. Inhibition of autophagy by Bafilomycin A1 (Baf A1) and 3-Methyladenine (3-MA) remarkably enhanced the antitumor efficacy of nedaplatin in HNE1/DDP and CNE2/DDP cells, suggesting that the resistance to nedaplatin-induced cell death was caused by enhanced autophagy in nedaplatin-resistant NPC cells. Additionally, Baf A1 enhanced reactive oxygen species (ROS) generation and apoptosis induced by nedaplatin in HNE1/DDP cells. Mechanistically, nedaplatin treatment caused activation of ERK1/2 and suppression of Akt/mTOR signaling pathways. While inhibition of ERK1/2 by MEK1/2 inhibitor, U0126, could reduce the expression of LC3-II in nedaplatin-resistant NPC cells. Furthermore, suppression of ROS could inhibit nedaplatin-induced ERK activation in HNE1/DDP cells, indicating that ROS and ERK were involved in nedaplatin-induced autophagy. Together, these findings suggested that autophagy played a cytoprotective role in nedaplatin-induced cytotoxicity of HNE1/DDP and CNE2/DDP cells. Furthermore, our results highlighted a potential approach to restore the sensitivity of cisplatin-resistant nasopharyngeal cancer cells to nedaplatin in combination with autophagy inhibitors.

Description: by Chia-Ying Wu, Yi-Wen Lin, Chia-Ho Kuo, Wan-Hsin Liu, Hsiu-Fen Tai, Chien-Hung Pan, Yung-Tsung Chen, Pei-Wen Hsiao, Chi-Hsien Chan, Ching-Chuan Chang, Chung-Cheng Liu, Yen-Hung Chow, Juine-Ruey Chen Epidemics and outbreaks caused by infections of several subgenotypes of EV71 and other serotypes of coxsackie A viruses have raised serious public health concerns in the Asia-Pacific region. These concerns highlight the urgent need to develop a scalable manufacturing platform for producing an effective and sufficient quantity of vaccines against deadly enteroviruses. In this report, we present a platform for the large-scale production of a vaccine based on the inactivated EV71(E59-B4) virus. The viruses were produced in Vero cells in a 200 L bioreactor with serum-free medium, and the viral titer reached 10 7 TCID 50 /mL 10 days after infection when using an MOI of 10 −4 . The EV71 virus particles were harvested and purified by sucrose density gradient centrifugation. Fractions containing viral particles were pooled based on ELISA and SDS-PAGE. TEM was used to characterize the morphologies of the viral particles. To evaluate the cross-protective efficacy of the EV71 vaccine, the pooled antigens were combined with squalene-based adjuvant (AddaVAX) or aluminum phosphate (AlPO 4 ) and tested in human SCARB2 transgenic (Tg) mice. The Tg mice immunized with either the AddaVAX- or AlPO 4 -adjuvanted EV71 vaccine were fully protected from challenges by the subgenotype C2 and C4 viruses, and surviving animals did not show any degree of neurological paralysis symptoms or muscle damage. Vaccine treatments significantly reduced virus antigen presented in the central nervous system of Tg mice and alleviated the virus-associated inflammatory response. These results strongly suggest that this preparation results in an efficacious vaccine and that the microcarrier/bioreactor platform offers a superior alternative to the previously described roller-bottle system.

Description: by Fangfang Chen, Dingyong Sun, Yuming Guo, Wei Guo, Zhengwei Ding, Peilong Li, Jie Li, Lin Ge, Ning Li, Dongmin Li, Lu Wang, Zhe Wang

Description: by Fabian Schnitzler, Matthias Friedrich, Johannes Stallhofer, Ulf Schönermarck, Michael Fischereder, Antje Habicht, Nazanin Karbalai, Christiane Wolf, Marianne Angelberger, Torsten Olszak, Florian Beigel, Cornelia Tillack, Burkhard Göke, Reinhart Zachoval, Gerald Denk, Markus Guba, Christian Rust, Norbert Grüner, Stephan Brand Background Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort. Methods Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment. Results 4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn’s disease (CD) underwent SOT (p = 2.69 x 10 −6 , UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26–84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%). Conclusions SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.

Description: by Yu Hasegawa, Deanne Taylor, Dmitry A. Ovchinnikov, Ernst J. Wolvetang, Laurence de Torrenté, Jessica C. Mar An analysis of gene expression variability can provide an insightful window into how regulatory control is distributed across the transcriptome. In a single cell analysis, the inter-cellular variability of gene expression measures the consistency of transcript copy numbers observed between cells in the same population. Application of these ideas to the study of early human embryonic development may reveal important insights into the transcriptional programs controlling this process, based on which components are most tightly regulated. Using a published single cell RNA-seq data set of human embryos collected at four-cell, eight-cell, morula and blastocyst stages, we identified genes with the most stable, invariant expression across all four developmental stages. Stably-expressed genes were found to be enriched for those sharing indispensable features, including essentiality, haploinsufficiency, and ubiquitous expression. The stable genes were less likely to be associated with loss-of-function variant genes or human recessive disease genes affected by a DNA copy number variant deletion, suggesting that stable genes have a functional impact on the regulation of some of the basic cellular processes. Genes with low expression variability at early stages of development are involved in regulation of DNA methylation, responses to hypoxia and telomerase activity, whereas by the blastocyst stage, low-variability genes are enriched for metabolic processes as well as telomerase signaling. Based on changes in expression variability, we identified a putative set of gene expression markers of morulae and blastocyst stages. Experimental validation of a blastocyst-expressed variability marker demonstrated that HDDC2 plays a role in the maintenance of pluripotency in human ES and iPS cells. Collectively our analyses identified new regulators involved in human embryonic development that would have otherwise been missed using methods that focus on assessment of the average expression levels; in doing so, we highlight the value of studying expression variability for single cell RNA-seq data.

Description: by The PLOS Computational Biology Staff

Description: by Jean-David Moreau, Didier Néraudeau, Paul Tafforeau, Éric Dépré We report exceptionally well-preserved plant remains ascribed to the extinct conifer Glenrosa J. Watson et H.L. Fisher emend. V. Srinivasan inside silica-rich nodules from the Cenomanian of the Font-de-Benon quarry, Charente-Maritime, western France. Remains are preserved in three dimensions and mainly consist of fragmented leafy axes. Pollen cones of this conifer are for the first time reported and in some cases remain connected to leafy stems. Histology of Glenrosa has not previously been observed; here, most of internal tissues and cells are well-preserved and allow us to describe a new species, Glenrosa carentonensis sp. nov., using propagation phase-contrast X-ray synchrotron microtomography, a non-destructive technique. Leafy axes consist of characteristic helically arranged leaves bearing stomatal crypts. Glenrosa carentonensis sp. nov. differs from the other described species in developing a phyllotaxy 8/21, claw-shaped leaves, a thicker cuticle, a higher number of papillae and stomata per crypt. Pollen cones consist of peltate, helically arranged microsporophylls, each of them bearing 6–7 pollen sacs. The new high resolution tomographic approach tested here allows virtual palaeohistology on plants included inside a dense rock to be made. Most tissues of Glenrosa carentonensis sp. nov. are described. Lithological and palaeontological data combined with xerophytic features of Glenrosa carentonensis sp. nov. suggest that this conifer has been adapted to survive in harsh and instable environments such as coastal area exposed to hot, dry conditions.

Description: by Shanshan Zhang, Xiaoxi Sun, Wenjiao Chang, Yuanyuan Dai, Xiaoling Ma Background Vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with vancomycin treatment failure, and are becoming an increasing public health problem. Therefore, we undertook this study of 91 published studies and made subgroup comparisons of hVISA/VISA incidence in different study years, locations, and types of clinical samples. We also analyzed the genetic backgrounds of these strains. Methods A systematic literature review of relevant articles published in PubMed and EMBASE from January 1997 to August 2014 was conducted. We selected and assessed journal articles reporting the prevalence rates of hVISA/VISA. Results The pooled prevalence of hVISA was 6.05% in 99,042 methicillin-resistant S . aureus (MRSA) strains and that of VISA was 3.01% in 68,792 MRSA strains. The prevalence of hVISA was 4.68% before 2006, 5.38% in 2006–2009, and 7.01% in 2010–2014. VISA prevalence was 2.05%, 2.63%, and 7.93%, respectively. In a subgroup analysis of different isolation locations, the prevalence of hVISA strains was 6.81% in Asia and 5.60% in Europe/America, and that of VISA was 3.42% and 2.75%, respectively. The frequencies of hVISA isolated from blood culture samples and from all clinical samples were 9.81% and 4.68%, respectively, and those of VISA were 2.00% and 3.07%, respectively. The most prevalent genotype was staphylococcal cassette chromosome mec (SCC mec ) II, which accounted for 48.16% and 37.74% of hVISA and VISA, respectively. Sequence Type (ST) 239 was most prevalent. Conclusion The prevalence of hVISA/VISA has been increasing in recent years, but has been grossly underestimated. Its incidence is higher in Asia than in Europe/America. hVISA is isolated from blood culture samples more often than from other samples. These strains are highly prevalent in epidemic MRSA strains. This study clarifies the epidemiology of hVISA/VISA and indicates that the detection of these strains and the control of nosocomial infections must be strengthened.

Description: by Zhanwei Wang, Dionyssios Katsaros, Yi Shen, Yuanyuan Fu, Emilie Marion Canuto, Chiara Benedetto, Lingeng Lu, Wen-Ming Chu, Harvey A. Risch, Herbert Yu To investigate the biologic relevance and clinical implication of genes involved in multiple gene expression signatures for breast cancer prognosis, we identified 16 published gene expression signatures, and selected two genes, MAD2L1 and BUB1 . These genes appeared in 5 signatures and were involved in cell-cycle regulation. We analyzed the expression of these genes in relation to tumor features and disease outcomes. In vitro experiments were also performed in two breast cancer cell lines, MDA-MB-231 and MDA-MB-468, to assess cell proliferation, migration and invasion after knocking down the expression of these genes. High expression of these genes was found to be associated with aggressive tumors and poor disease-free survival of 203 breast cancer patients in our study, and the association with survival was confirmed in an online database consisting of 914 patients. In vitro experiments demonstrated that lowering the expression of these genes by siRNAs reduced tumor cell growth and inhibited cell migration and invasion. Our investigation suggests that MAD2L1 and BUB1 may play important roles in breast cancer progression, and measuring the expression of these genes may assist the prediction of breast cancer prognosis.

Description: by Harpreet Singh Raina, Ambika Singh, Sonam Popli, Neeti Pandey, Raman Rajagopal Bacterial endosymbionts have been associated with arthropods and large number of the insect species show interaction with such bacteria. Different approaches have been used to understand such symbiont- host interactions. The whitefly, Bemisia tabaci , a highly invasive agricultural pest, harbors as many as seven different bacterial endosymbionts. These bacterial endosymbionts are known to provide various nutritional, physiological, environmental and evolutionary benefits to its insect host. In this study, we have tried to compare two techniques, Polymerase chain reaction (PCR) and Flourescence in situ Hybridisation (FISH) commonly used for identification and localization of bacterial endosymbionts in B . tabaci as it harbors one of the highest numbers of endosymbionts which have helped it in becoming a successful global invasive agricultural pest. The amplified PCR products were observed as bands on agarose gel by electrophoresis while the FISH samples were mounted on slides and observed under confocal microscope. Analysis of results obtained by these two techniques revealed the advantages of FISH over PCR. On a short note, performing FISH, using LNA probes proved to be more sensitive and informative for identification as well as localization of bacterial endosymbionts in B . tabaci than relying on PCR. This study would help in designing more efficient experiments based on much reliable detection procedure and studying the role of endosymbionts in insects.

Description: by Hai Liang, King-wa Fu Replication is an essential requirement for scientific discovery. The current study aims to generalize and replicate 10 propositions made in previous Twitter studies using a representative dataset. Our findings suggest 6 out of 10 propositions could not be replicated due to the variations of data collection, analytic strategies employed, and inconsistent measurements. The study’s contributions are twofold: First, it systematically summarized and assessed some important claims in the field, which can inform future studies. Second, it proposed a feasible approach to generating a random sample of Twitter users and its associated ego networks, which might serve as a solution for answering social-scientific questions at the individual level without accessing the complete data archive.

Description: by Lampros Perogamvros, Kristoffer Aberg, Marianne Gex-Fabry, Stephen Perrig, C. Robert Cloninger, Sophie Schwartz Background We previously suggested that abnormal sleep behaviors, i.e., as found in parasomnias, may often be the expression of increased activity of the reward system during sleep. Because nightmares and sleepwalking predominate during REM and NREM sleep respectively, we tested here whether exploratory excitability, a waking personality trait reflecting high activity within the mesolimbic dopaminergic (ML-DA) system, may be associated with specific changes in REM and NREM sleep patterns in these two sleep disorders. Methods Twenty-four unmedicated patients with parasomnia (12 with chronic sleepwalking and 12 with idiopathic nightmares) and no psychiatric comorbidities were studied. Each patient spent one night of sleep monitored by polysomnography. The Temperament and Character Inventory (TCI) was administered to all patients and healthy controls from the Geneva population (n = 293). Results Sleepwalkers were more anxious than patients with idiopathic nightmares (Spielberger Trait anxiety/STAI-T), but the patient groups did not differ on any personality dimension as estimated by the TCI. Compared to controls, parasomnia patients (sleepwalkers together with patients with idiopathic nightmares) scored higher on the Novelty Seeking (NS) TCI scale and in particular on the exploratory excitability/curiosity (NS1) subscale, and lower on the Self-directedness (SD) TCI scale, suggesting a general increase in reward sensitivity and impulsivity. Furthermore, parasomnia patients tended to worry about social separation persistently, as indicated by greater anticipatory worry (HA1) and dependence on social attachment (RD3). Moreover, exploratory excitability (NS1) correlated positively with the severity of parasomnia (i.e., the frequency of self-reported occurrences of nightmares and sleepwalking), and with time spent in REM sleep in patients with nightmares. Conclusions These results suggest that patients with parasomnia might share common waking personality traits associated to reward-related brain functions. They also provide further support to the notion that reward-seeking networks are active during human sleep.

Description: by Vartika Singh, Sundeep K. Pandita, Rajni Tewari, Peter J van Hengstum, Suresh S. K. Pillai, Deepa Agnihotri, Kamlesh Kumar, G. D. Bhat Exceptionally well-preserved organic remains of thecamoebians (testate amoebae) were preserved in marine sediments that straddle the greatest extinction event in the Phanerozoic: the Permian-Triassic Boundary. Outcrops from the Late Permian Zewan Formation and the Early Triassic Khunamuh Formation are represented by a complete sedimentary sequence at the Guryul Ravine Section in Kashmir, India, which is an archetypal Permian-Triassic boundary sequence [1]. Previous biostratigraphic analysis provides chronological control for the section, and a perspective of faunal turnover in the brachiopods, ammonoids, bivalves, conodonts, gastropods and foraminifera. Thecamoebians were concentrated from bulk sediments using palynological procedures, which isolated the organic constituents of preserved thecamoebian tests. The recovered individuals demonstrate exceptional similarity to the modern thecamoebian families Centropyxidae, Arcellidae, Hyalospheniidae and Trigonopyxidae, however, the vast majority belong to the Centropyxidae. This study further confirms the morphologic stability of the thecamoebian lineages through the Phanerozoic, and most importantly, their apparent little response to an infamous biological crisis in Earth’s history.

Description: by Arne C. Reimers Background Sampling methods have proven to be a very efficient and intuitive method to understand properties of complicated spaces that cannot easily be computed using deterministic methods. Therefore, sampling methods became a popular tool in the applied sciences. Results Here, we show that sampling methods are not an appropriate tool to analyze qualitative properties of complicated spaces unless RP = NP. We illustrate these results on the example of the thermodynamically feasible flux space of genome-scale metabolic networks and show that with artificial centering hit and run (ACHR) not all reactions that can have variable flux rates are sampled with variables flux rates. In particular a uniform sample of the flux space would not sample the flux variabilities completely. Conclusion We conclude that unless theoretical convergence results exist, qualitative results obtained from sampling methods should be considered with caution and if possible double checked using a deterministic method.

Description: by James Tamerius, Cécile Viboud, Jeffrey Shaman, Gerardo Chowell While a relationship between environmental forcing and influenza transmission has been established in inter-pandemic seasons, the drivers of pandemic influenza remain debated. In particular, school effects may predominate in pandemic seasons marked by an atypical concentration of cases among children. For the 2009 A/H1N1 pandemic, Mexico is a particularly interesting case study due to its broad geographic extent encompassing temperate and tropical regions, well-documented regional variation in the occurrence of pandemic outbreaks, and coincidence of several school breaks during the pandemic period. Here we fit a series of transmission models to daily laboratory-confirmed influenza data in 32 Mexican states using MCMC approaches, considering a meta-population framework or the absence of spatial coupling between states. We use these models to explore the effect of environmental, school–related and travel factors on the generation of spatially-heterogeneous pandemic waves. We find that the spatial structure of the pandemic is best understood by the interplay between regional differences in specific humidity (explaining the occurrence of pandemic activity towards the end of the school term in late May-June 2009 in more humid southeastern states), school vacations (preventing influenza transmission during July-August in all states), and regional differences in residual susceptibility (resulting in large outbreaks in early fall 2009 in central and northern Mexico that had yet to experience fully-developed outbreaks). Our results are in line with the concept that very high levels of specific humidity, as present during summer in southeastern Mexico, favor influenza transmission, and that school cycles are a strong determinant of pandemic wave timing.

Description: by Alireza Alemi, Carlo Baldassi, Nicolas Brunel, Riccardo Zecchina Understanding the theoretical foundations of how memories are encoded and retrieved in neural populations is a central challenge in neuroscience. A popular theoretical scenario for modeling memory function is the attractor neural network scenario, whose prototype is the Hopfield model. The model simplicity and the locality of the synaptic update rules come at the cost of a poor storage capacity, compared with the capacity achieved with perceptron learning algorithms. Here, by transforming the perceptron learning rule, we present an online learning rule for a recurrent neural network that achieves near-maximal storage capacity without an explicit supervisory error signal, relying only upon locally accessible information. The fully-connected network consists of excitatory binary neurons with plastic recurrent connections and non-plastic inhibitory feedback stabilizing the network dynamics; the memory patterns to be memorized are presented online as strong afferent currents, producing a bimodal distribution for the neuron synaptic inputs. Synapses corresponding to active inputs are modified as a function of the value of the local fields with respect to three thresholds. Above the highest threshold, and below the lowest threshold, no plasticity occurs. In between these two thresholds, potentiation/depression occurs when the local field is above/below an intermediate threshold. We simulated and analyzed a network of binary neurons implementing this rule and measured its storage capacity for different sizes of the basins of attraction. The storage capacity obtained through numerical simulations is shown to be close to the value predicted by analytical calculations. We also measured the dependence of capacity on the strength of external inputs. Finally, we quantified the statistics of the resulting synaptic connectivity matrix, and found that both the fraction of zero weight synapses and the degree of symmetry of the weight matrix increase with the number of stored patterns.

Description: by Heather A. Flores, Jaclyn E. Bubnell, Charles F. Aquadro, Daniel A. Barbash Many reproductive proteins from diverse taxa evolve rapidly and adaptively. These proteins are typically involved in late stages of reproduction such as sperm development and fertilization, and are more often functional in males than females. Surprisingly, many germline stem cell (GSC) regulatory genes, which are essential for the earliest stages of reproduction, also evolve adaptively in Drosophila. One example is the bag of marbles ( bam ) gene, which is required for GSC differentiation and germline cyst development in females and for regulating mitotic divisions and entry to spermatocyte differentiation in males. Here we show that the extensive divergence of bam between Drosophila melanogaster and D . simulans affects bam function in females but has no apparent effect in males. We further find that infection with Wolbachia pipientis , an endosymbiotic bacterium that can affect host reproduction through various mechanisms, partially suppresses female sterility caused by bam mutations in D . melanogaster and interacts differentially with bam orthologs from D . melanogaster and D . simulans . We propose that the adaptive evolution of bam has been driven at least in part by the long-term interactions between Drosophila species and Wolbachia . More generally, we suggest that microbial infections of the germline may explain the unexpected pattern of evolution of several GSC regulatory genes.

Description: by Patrik Htun, Jens Nee, Ursula Ploeckinger, Klaus Eder, Tobias Geisler, Meinrad Gawaz, Wolfgang Bocksch, Suzanne Fateh-Moghadam Background and Purpose Since patients with phenylketonuria (PKU) have to follow a lifelong restriction of natural protein to lower phenylalanine-intake, they never eat fish. This diet may lead to a chronic deficit of omega-3 and omega-6 fatty acids with the risk of early atherosclerotic changes. The aim of the study was to analyse the fatty acid profile of PKU patients and to correlate the results with surrogate markers of early atherosclerotic changes [enhanced carotid intima media thickness (CIMT) and ß-stiffness index] and platelet activation. Methods In 43 PKU patients and in 58 healthy controls we prospectively examined the fatty acid profile, CIMT, ß-stiffness index and platelet activation (flow cytometric determination of markers of platelet activation). CIMT was measured bilaterally by ultrasound. CIMT mean was defined as the mean value of the sum of CIMT left and CIMT right . Results Despite of lower HDL-cholesterol and higher triglyceride concentrations in the PKU group, there was no significant difference in the omega-6 or omega-3 fatty acid profile, CIMT, ß-stiffness index between both groups. Platelet activation was not enhanced in the PKU group. Conclusions Fish-free diet does not induce early atherosclerotic changes or enhanced platelet activation in PKU patients.

Description: by Shannon L. Pelini, Audrey M. Maran, Angus R. Chen, Justine Kaseman, Thomas W. Crowther Forest floor food webs play pivotal roles in carbon cycling, but they are rarely considered in models of carbon fluxes, including soil carbon dioxide emissions (respiration), under climatic warming. The indirect effects of invertebrates on heterotrophic (microbial and invertebrate) respiration through interactions with microbial communities are significant and will be altered by warming. However, the interactive effects of invertebrates and warming on heterotrophic respiration in the field are poorly understood. In this study we combined field and common garden laboratory approaches to examine relationships between warming, forest floor food web structure, and heterotrophic respiration. We found that soil animals can overwhelm the effects of warming (to 5 degrees Celsius above ambient) on heterotrophic respiration. In particular, the presence of higher trophic levels and burrowing detritivores strongly determined heterotrophic respiration rates in temperate forest soils. These effects were, however, context-dependent, with greater effects in a lower-latitude site. Without isolating and including the significant impact of invertebrates, climate models will be incomplete, hindering well-informed policy decisions.

Description: by Gijs den Besten, Albert Gerding, Theo H. van Dijk, Jolita Ciapaite, Aycha Bleeker, Karen van Eunen, Rick Havinga, Albert K. Groen, Dirk-Jan Reijngoud, Barbara M. Bakker The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

Description: by Gila Arad, Revital Levy, Iris Nasie, Dalia Hillman, Ziv Rotfogel, Uri Barash, Emmanuelle Supper, Tomer Shpilka, Adi Minis, Raymond Kaempfer

Description: by Diana M. Mitchell, Craig B. Stevens, Ruth A. Frey, Samuel S. Hunter, Ryuichi Ashino, Shoji Kawamura, Deborah L. Stenkamp The signaling molecule retinoic acid (RA) regulates rod and cone photoreceptor fate, differentiation, and survival. Here we elucidate the role of RA in differential regulation of the tandemly-duplicated long wavelength-sensitive ( LWS ) cone opsin genes. Zebrafish embryos were treated with RA from 48 hours post-fertilization (hpf) to 75 hpf, and RNA was isolated from eyes for microarray analysis. ~170 genes showed significantly altered expression, including several transcription factors and components of cellular signaling pathways. Of interest, the LWS1 opsin gene was strongly upregulated by RA. LWS1 is the upstream member of the tandemly duplicated LWS opsin array and is normally not expressed embryonically. Embryos treated with RA 48 hpf to 100 hpf or beyond showed significant reductions in LWS2 -expressing cones in favor of LWS1 -expressing cones. The LWS reporter line, LWS-PAC(H) provided evidence that individual LWS cones switched from LWS2 to LWS1 expression in response to RA. The RA signaling reporter line, RARE : YFP indicated that increased RA signaling in cones was associated with this opsin switch, and experimental reduction of RA signaling in larvae at the normal time of onset of LWS1 expression significantly inhibited LWS1 expression. A role for endogenous RA signaling in regulating differential expression of the LWS genes in postmitotic cones was further supported by the presence of an RA signaling domain in ventral retina of juvenile zebrafish that coincided with a ventral zone of LWS1 expression. This is the first evidence that an extracellular signal may regulate differential expression of opsin genes in a tandemly duplicated array.

Description: by Su Deng, Ingo Bothe, Mary K. Baylies The formation of multinucleated muscle cells through cell-cell fusion is a conserved process from fruit flies to humans. Numerous studies have shown the importance of Arp2/3, its regulators, and branched actin for the formation of an actin structure, the F-actin focus, at the fusion site. This F-actin focus forms the core of an invasive podosome-like structure that is required for myoblast fusion. In this study, we find that the formin Diaphanous (Dia), which nucleates and facilitates the elongation of actin filaments, is essential for Drosophila myoblast fusion. Following cell recognition and adhesion, Dia is enriched at the myoblast fusion site, concomitant with, and having the same dynamics as, the F-actin focus. Through analysis of Dia loss-of-function conditions using mutant alleles but particularly a dominant negative Dia transgene, we demonstrate that reduction in Dia activity in myoblasts leads to a fusion block. Significantly, no actin focus is detected, and neither branched actin regulators, SCAR or WASp, accumulate at the fusion site when Dia levels are reduced. Expression of constitutively active Dia also causes a fusion block that is associated with an increase in highly dynamic filopodia, altered actin turnover rates and F-actin distribution, and mislocalization of SCAR and WASp at the fusion site. Together our data indicate that Dia plays two roles during invasive podosome formation at the fusion site: it dictates the level of linear F-actin polymerization, and it is required for appropriate branched actin polymerization via localization of SCAR and WASp. These studies provide new insight to the mechanisms of cell-cell fusion, the relationship between different regulators of actin polymerization, and invasive podosome formation that occurs in normal development and in disease.

Description: by Tomas de Wouters, Christoph Jans, Tobias Niederberger, Peter Fischer, Patrick Alberto Rühs Bacterial adhesion to epithelial surfaces affects retention time in the human gastro-intestinal tract and therefore significantly contributes to interactions between bacteria and their hosts. Bacterial adhesion among other factors is strongly influenced by physico-chemical factors. The accurate quantification of these physico-chemical factors in adhesion is however limited by the available measuring techniques. We evaluated surface charge, interfacial rheology and tensiometry (interfacial tension) as novel approaches to quantify these interactions and evaluated their biological significance via an adhesion assay using intestinal epithelial surface molecules (IESM) for a set of model organisms present in the human gastrointestinal tract. Strain pairs of Lactobacillus plantarum WCFS1 with its sortase knockout mutant Lb . plantarum NZ7114 and Lb . rhamnosus GG with Lb . rhamnosus DSM 20021 T were used with Enterococcus faecalis JH2-2 as control organism. Intra-species comparison revealed significantly higher abilities for Lb . plantarum WCSF1 and Lb . rhamnosus GG vs. Lb . plantarum NZ7114 and Lb . rhamnosus DSM 20021 T to dynamically increase interfacial elasticity (10 −2 vs. 10 −3 Pa*m) and reduce interfacial tension (32 vs. 38 mN/m). This further correlated for Lb . plantarum WCSF1 and Lb . rhamnosus GG vs. Lb . plantarum NZ7114 and Lb . rhamnosus DSM 20021 T with the decrease of relative hydrophobicity (80–85% vs. 57–63%), Zeta potential (-2.9 to -4.5 mV vs. -8.0 to -13.8 mV) and higher relative adhesion capacity to IESM (3.0–5.0 vs 1.5–2.2). Highest adhesion to the IESM collagen I and fibronectin was found for Lb . plantarum WCFS1 (5.0) and E . faecalis JH2-2 (4.2) whereas Lb . rhamnosus GG showed highest adhesion to type II mucus (3.8). Significantly reduced adhesion (2 fold) to the tested IESM was observed for Lb . plantarum NZ7114 and Lb . rhamnosus DSM 20021 T corresponding with lower relative hydrophobicity, Zeta potential and abilities to modify interfacial elasticity and tension. Conclusively, the use of Zeta potential, interfacial elasticity and interfacial tension are proposed as suitable novel descriptive and predictive parameters to study the interactions of intestinal microbes with their hosts.

Description: by Jun Ho Ji, Young Lyun Oh, Mineui Hong, Jae Won Yun, Hyun-Woo Lee, DeokGeun Kim, Yongick Ji, Duk-Hwan Kim, Woong-Yang Park, Hyun-Tae Shin, Kyoung-Mee Kim, Myung-Ju Ahn, Keunchil Park, Jong-Mu Sun The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase ( ALK ) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5’ fusion partner of ALK , customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 ( GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 ( EML4 ) -ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1 - ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.

Description: by Hongliu Sun, Cai Qi, Yu Niu, Tengfei Kang, Yongxin Wei, Gang Jin, Xianzhi Dong, Chunhua Wang, Wei Zhu Background Cytomegalovirus (CMV) is the most common infectious cause of mental disability in newborns in developed countries. There is an urgent need to establish an early detection and high-throughput screening method for CMV infection using portable detection devices. Methods An antibody analysis method is reported for the detection and identification of CMV antibodies in serum using a biosensor based on high spatial resolution imaging ellipsometry (BIE). CMV antigen (CMV-3A) was immobilized on silicon wafers and used to capture CMV antibodies in serum. An antibody against human immunoglobulin G (anti-IgG) was used to confirm the IgG antibody against CMV captured by the CMV-3A. Results Our results show that this assay is rapid and specific for the identification of IgG antibody against CMV. Further, patient serum was quantitatively assessed using the standard curve method, and the quantitative results were in agreement with the enzyme-linked immunosorbent assay. The CMV antibody detection sensitivity of BIE reached 0.01 IU/mL. Conclusions This novel biosensor may be a valuable diagnostic tool for analysis of IgG antibody against CMV during CMV infection screening.

Description: by Vito Trianni, Manuel López-Ibáñez The application of multi-objective optimisation to evolutionary robotics is receiving increasing attention. A survey of the literature reveals the different possibilities it offers to improve the automatic design of efficient and adaptive robotic systems, and points to the successful demonstrations available for both task-specific and task-agnostic approaches (i.e., with or without reference to the specific design problem to be tackled). However, the advantages of multi-objective approaches over single-objective ones have not been clearly spelled out and experimentally demonstrated. This paper fills this gap for task-specific approaches: starting from well-known results in multi-objective optimisation, we discuss how to tackle commonly recognised problems in evolutionary robotics. In particular, we show that multi-objective optimisation (i) allows evolving a more varied set of behaviours by exploring multiple trade-offs of the objectives to optimise, (ii) supports the evolution of the desired behaviour through the introduction of objectives as proxies, (iii) avoids the premature convergence to local optima possibly introduced by multi-component fitness functions, and (iv) solves the bootstrap problem exploiting ancillary objectives to guide evolution in the early phases. We present an experimental demonstration of these benefits in three different case studies: maze navigation in a single robot domain, flocking in a swarm robotics context, and a strictly collaborative task in collective robotics.