ALBERT

Description: The Journal of Physical Chemistry B DOI: 10.1021/acs.jpcb.8b05360

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b04763

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b06634

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01810

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01799

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01960

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01910

Description: Organic Letters DOI: 10.1021/acs.orglett.8b02033

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01892

Description: by Edvin Fuglebakk, Nathalie Reuter With remarkable spatial and temporal specificities, peripheral membrane proteins bind to biological membranes. They do this without compromising solubility of the protein, and their binding sites are not easily distinguished. Prototypical peripheral membrane binding sites display a combination of patches of basic and hydrophobic amino acids that are also frequently present on other protein surfaces. The purpose of this contribution is to identify simple but essential components for membrane binding, through structural criteria that distinguish exposed hydrophobes at membrane binding sites from those that are frequently found on any protein surface. We formulate the concepts of protruding hydrophobes and co-insertability and have analysed more than 300 families of proteins that are classified as peripheral membrane binders. We find that this structural motif strongly discriminates the surfaces of membrane-binding and non-binding proteins. Our model constitutes a novel formulation of a structural pattern for membrane recognition and emphasizes the importance of subtle structural properties of hydrophobic membrane binding sites.

Description: by Hugo Cruces-Solís, Zhizi Jing, Olga Babaev, Jonathan Rubin, Burak Gür, Dilja Krueger-Burg, Nicola Strenzke, Livia de Hoz Detecting regular patterns in the environment, a process known as statistical learning, is essential for survival. Neuronal adaptation is a key mechanism in the detection of patterns that are continuously repeated across short (seconds to minutes) temporal windows. Here, we found in mice that a subcortical structure in the auditory midbrain was sensitive to patterns that were repeated discontinuously, in a temporally sparse manner, across windows of minutes to hours. Using a combination of behavioral, electrophysiological, and molecular approaches, we found changes in neuronal response gain that varied in mechanism with the degree of sound predictability and resulted in changes in frequency coding. Analysis of population activity (structural tuning) revealed an increase in frequency classification accuracy in the context of increased overlap in responses across frequencies. The increase in accuracy and overlap was paralleled at the behavioral level in an increase in generalization in the absence of diminished discrimination. Gain modulation was accompanied by changes in gene and protein expression, indicative of long-term plasticity. Physiological changes were largely independent of corticofugal feedback, and no changes were seen in upstream cochlear nucleus responses, suggesting a key role of the auditory midbrain in sensory gating. Subsequent behavior demonstrated learning of predictable and random patterns and their importance in auditory conditioning. Using longer timescales than previously explored, the combined data show that the auditory midbrain codes statistical learning of temporally sparse patterns, a process that is critical for the detection of relevant stimuli in the constant soundscape that the animal navigates through.

Description: by Greg Holmes, Lening Zhang, Joshua Rivera, Ryan Murphy, Claudia Assouline, Lorraine Sullivan, Todd Oppeneer, Ethylin Wang Jabs Activating mutations of fibroblast growth factor receptors (FGFRs) are a major cause of skeletal dysplasias, and thus they are potential targets for pharmaceutical intervention. BMN 111, a C-type natriuretic peptide analog, inhibits FGFR signaling at the level of the RAF1 kinase through natriuretic peptide receptor 2 (NPR2) and has been shown to lengthen the long bones and improve skull morphology in the Fgfr3 Y367C/+ thanatophoric dysplasia mouse model. Here we report the effects of BMN 111 in treating craniosynostosis and aberrant skull morphology in the Fgfr2c C342Y/+ Crouzon syndrome mouse model. We first demonstrated that NPR2 is expressed in the murine coronal suture and spheno-occipital synchondrosis in the newborn period. We then gave Fgfr2c C342Y/+ and Fgfr2c +/+ (WT) mice once-daily injections of either vehicle or reported therapeutic levels of BMN 111 between post-natal days 3 and 31. Changes in skeletal morphology, including suture patency, skull dimensions, and long bone length, were assessed by micro-computed tomography. Although BMN 111 treatment significantly increased long bone growth in both WT and mutant mice, skull dimensions and suture patency generally were not significantly affected. A small but significant increase in the relative length of the anterior cranial base was observed. Our results indicate that the differential effects of BMN 111 in treating various skeletal dysplasias may depend on the process of bone formation targeted (endochondral or intramembranous), the specific FGFR mutated, and/or the specific signaling pathway changes due to a given mutation.

Description: by Irineu Loturco, Bret Contreras, Ronaldo Kobal, Victor Fernandes, Neilton Moura, Felipe Siqueira, Ciro Winckler, Timothy Suchomel, Lucas Adriano Pereira The capacity to rapidly generate and apply a great amount of force seems to play a key role in sprint running. However, it has recently been shown that, for sprinters, the technical ability to effectively orient the force onto the ground is more important than its total amount. The force-vector theory has been proposed to guide coaches in selecting the most adequate exercises to comprehensively develop the neuromechanical qualities related to the distinct phases of sprinting. This study aimed to compare the relationships between vertically-directed (loaded and unloaded vertical jumps, and half-squat) and horizontally-directed (hip-thrust) exercises and the sprint performance of top-level track and field athletes. Sixteen sprinters and jumpers (including three Olympic athletes) executed vertical jumps, loaded jump squats and hip-thrusts, and sprinting speed tests at 10-, 20-, 40-, 60-, 100-, and 150-m. Results indicated that the hip-thrust is more associated with the maximum acceleration phase (i.e., from zero to 10-m; r = 0.93), whereas the loaded and unloaded vertical jumps seem to be more related to top-speed phases (i.e., distances superior to 40-m; r varying from 0.88 to 0.96). These findings reinforce the mechanical concepts supporting the force-vector theory, and provide coaches and sport scientists with valuable information about the potential use and benefits of using vertically- or horizontally-based training exercises.

Description: by Pei-Chun Kao, Michaela A. Pierro, Konstantina Booras Cognitive-motor interference, a negative influence on the performance of one or both tasks, is manifested when simultaneously performing a cognitive and a motor task. Motor fatigue reduces the ability of generating a required force level. However, little is known about the effects of motor fatigue on the cognitive-motor dual-tasking performance, an important capability during our daily lives. This study investigated how motor fatigue affects dual-task walking performance. Eighteen healthy younger adults walked on a treadmill under three different conditions: walking only, walking while receiving the Paced Auditory Serial Addition Test (PASAT) or a modified Stroop test before and after a lower-extremity fatiguing exercise. We computed dynamic margins of stability (MOS), step and joint kinematic variability, and short-term local divergence exponent (LDE) of the trunk motion. We found that subjects had similar values of short-term LDE during all conditions, indicating that local stability was not affected by the motor fatigue or dual-task conditions. Compared to the baseline, subjects had significantly greater mean MOS after the fatiguing exercise by walking with greater step length and width while having significantly greater gait variability. In contrast, subjects walked with similar mean MOS but significantly less gait variability during the dual-task conditions, indicating that subjects used different adaptive strategies when walking with motor fatigue and during dual-task conditions. There were no significant differences in the number of errors for the two cognitive tests before and after the fatiguing exercise. The current findings demonstrate that motor fatigue does not affect cognitive but motor performance in younger adults.

Description: by Insu Lee, Daegyu Kim, Ga-Lahm Park, Tae-Joon Jeon, Sun Min Kim When living tissues are injured, they undergo a sequential process of homeostasis, inflammation, proliferation and maturation, which is called wound healing. The working mechanism of wound healing has not been wholly understood due to its complex environments with various mechanical and chemical factors. In this study, we propose a novel in vitro wound healing model using a microfluidic system that can manipulate the topography of the wound bed. The topography of the extracellular matrix (ECM) in the wound bed is one of the most important mechanical properties for rapid and effective wound healing. We focused our work on the topographical factor which is one of crucial mechanical cues in wound healing process by using various nano-patterns on the cell attachment surface. First, we analyzed the cell morphology and dynamic cellular behaviors of NIH-3T3 fibroblasts on the nano-patterned surface. Their morphology and dynamic behaviors were investigated for relevance with regard to the recovery function. Second, we developed a highly reproducible and inexpensive research platform for wound formation and the wound healing process by combining the nano-patterned surface and a microfluidic channel. The effect of topography on wound recovery performance was analyzed. This in vitro wound healing research platform will provide well-controlled topographic cue of wound bed and contribute to the study on the fundamental mechanism of wound healing.

Description: by Tilen Koklic, Iztok Urbančič, Irena Zdovc, Majda Golob, Polona Umek, Zoran Arsov, Goran Dražić, Štefan Pintarič, Martin Dobeic, Janez Štrancar Bacterial infections acquired in healthcare facilities including hospitals, the so called healthcare acquired or nosocomial infections, are still of great concern worldwide and represent a significant economical burden. One of the major causes of morbidity is infection with Methicillin Resistant Staphylococcus aureus (MRSA), which has been reported to survive on surfaces for several months. Bactericidal activity of copper-TiO 2 thin films, which release copper ions and are deposited on glass surfaces and heated to high temperatures, is well known even when illuminated with very weak UVA light of about 10 μW/cm 2 . Lately, there is an increased intrerest for one-dimensional TiO 2 nanomaterials, due to their unique properties, low cost, and high thermal and photochemical stability. Here we show that copper doped TiO 2 nanotubes produce about five times more ·OH radicals as compared to undoped TiO 2 nanotubes and that effective surface disinfection, determined by a modified ISO 22196:2011 test, can be achieved even at low intensity UVA light of 30 μW/cm 2 . The nanotubes can be deposited on a preformed surface at room temperature, resulting in a stable deposition resistant to multiple washings. Up to 10 3 microorganisms per cm 2 can be inactivated in 24 hours, including resistant strains such as Methicillin-resistant Staphylococcus aureus (MRSA) and Extended-spectrum beta-lactamase Escherichia coli ( E . coli ESBL). This disinfection method could provide a valuable alternative to the current surface disinfection methods.

Description: by Tim J. Sloan, Jonna Jalanka, Giles A. D. Major, Shanthi Krishnasamy, Sue Pritchard, Salah Abdelrazig, Katri Korpela, Gulzar Singh, Claire Mulvenna, Caroline L. Hoad, Luca Marciani, David A. Barrett, Miranda C. E. Lomer, Willem M. de Vos, Penny A. Gowland, Robin C. Spiller Background & aims Ingestion of poorly digested, fermentable carbohydrates (fermentable oligo-, di-, mono-saccharides and polyols; FODMAPs) have been implicated in exacerbating intestinal symptoms and the reduction of intake with symptom alleviation. Restricting FODMAP intake is believed to relieve colonic distension by reducing colonic fermentation but this has not been previously directly assessed. We performed a randomised controlled trial comparing the effect of a low FODMAP diet combined with either maltodextrin or oligofructose on colonic contents, metabolites and microbiota. Methods A parallel randomised controlled trial in healthy adults (n = 37). All subjects followed a low FODMAP diet for a week and supplemented their diet with either maltodextrin (MD) or oligofructose (OF) 7g twice daily. Fasted assessments performed pre- and post-diet included MRI to assess colonic volume, breath testing for hydrogen and methane, and stool collection for microbiota analysis. Results The low FODMAP diet was associated with a reduction in Bifidobacterium and breath hydrogen, which was reversed by oligofructose supplementation. The difference in breath hydrogen between groups post-intervention was 27ppm (95% CI 7 to 50, P

Description: by Geethika Reddi, Kali Pruss, Kathryn L. Cottingham, Ronald K. Taylor, Salvador Almagro-Moreno Vibrio cholerae O1, the etiological agent of cholera, is a natural inhabitant of aquatic ecosystems. Motility is a critical element for the colonization of both the human host and its environmental reservoirs. In this study, we investigated the molecular mechanisms underlying the chemotactic response of V . cholerae in the presence of some of its environmental reservoirs. We found that, from the several oligosaccharides found in mucin, two specifically triggered motility of V . cholerae O1: N -acetylneuraminic acid (Neu5Ac) and N -acetylglucosamine (GlcNAc). We determined that the compounds need to be internally catabolized in order to trigger motility of V . cholerae . Interestingly, the catabolism of Neu5Ac and GlcNAc converges and the production of one molecule common to both pathways, glucosamine-6-phosphate (GlcN-6P), is essential to induce motility in the presence of both compounds. Mutants unable to produce GlcN-6P show greatly reduced motility towards mucin. Furthermore, we determined that the production of GlcN-6P is necessary to induce motility of V . cholerae in the presence of some of its environmental reservoirs such as crustaceans or cyanobacteria, revealing a molecular link between the two distinct modes of the complex life cycle of V . cholerae . Finally, cross-species comparisons revealed varied chemotactic responses towards mucin, GlcNAc, and Neu5Ac for environmental (non-pathogenic) strains of V . cholerae , clinical and environmental isolates of the human pathogens Vibrio vulnificus and Vibrio parahaemolyticus , and fish and squid isolates of the symbiotic bacterium Vibrio fischeri . The data presented here suggest nuance in convergent strategies across species of the same bacterial family for motility towards suitable substrates for colonization.

Description: by Anne C. Wheeler, Camila V. Ventura, Ty Ridenour, Danielle Toth, Lucélia Lima Nobrega, Lana Claudia Silva de Souza Dantas, Camilla Rocha, Donald B. Bailey Jr., Liana O. Ventura The recent Zika outbreak and its link to microcephaly and other birth defects in infants exposed in utero have garnered widespread international attention. Based on the severity of birth defects the extent of impairment in these infants is expected to be profound; however, virtually nothing is known regarding the developmental and behavioral sequela of congenital Zika syndrome. This pilot study collected parent-reported patterns of development and sleep in 47 infants with confirmed congenital Zika syndrome who are being followed for clinical services at the Altino Ventura Foundation (FAV) in Recife, Brazil. With assistance from clinicians at FAV, caregivers completed Brazilian Portuguese versions of the Ages and Stages Questionnaire, 3 rd edition (ASQ-3) and the Brief Infant Sleep Questionnaire (BISQ). All infants were between 13–22 months of age at the time of the assessment. At 16 months of age, none of the children displayed age appropriate developmental skills. Most (~ 75%) mastered some communication and gross motor skills at around a 6–8-month level. Communication and gross motor skills were relative strengths for the sample, while problem-solving and fine motor skills were relative weaknesses. Sleep was noted to be a problem for around 18% of the sample. In utero exposure to the Zika virus will have lifelong consequences for affected children and their families. Understanding the developmental and behavioral trajectories of affected infants will help identify appropriate family supports to improve quality of life.

Description: by Veronique Deschodt-Arsac, Romain Lalanne, Beatrice Spiluttini, Claire Bertin, Laurent M. Arsac Introduction Heart rate variability biofeedback (HRV-BFB) training, a method whereby one controls an unusually low breathing rate to reach cardiac coherence, has been shown to reduce anxiety and improve cardiac autonomic markers in diseased people, but much less is known about HRV-BFB benefits in healthy people. Here we investigated potential benefits in young competitors experiencing stress during university examinations as well as persistence of benefits after HRV-BFB training cessation. Methods A group of sports students (n = 12) practiced 5-min HRV-BFB training twice a day for 5-weeks using URGOfeel ® (URGOTECH) and was compared to a control group (n = 6). University examinations occurred immediately after HRV-BFB training (Exam1), then 12-weeks later (Exam2). Anxiety markers and cardiac autonomic markers were assessed at baseline, Exam1 and Exam2. Principal Component Analyses (PCA) that combined all these markers were computed at Exam1 and Exam2 to emphasize covariations. Results At Exam 1, immediately after HRV-BFB training cessation, the experimental group demonstrated greater autonomic markers but similar states of anxiety when compared to the Control group. Twelve weeks later at Exam2, autonomic markers were greater and anxiety scores were lesser among the experimental group. PCA highlighted covariations only within cardiac autonomic markers at Exam1. Rather, variations in cardiac markers were associated with anxiety markers at Exam2. Conclusion Short sessions of HRV-BFB training for a brief period of 5 weeks bring substantial benefits to autonomic markers and anxiety levels in young competitors. Here beneficial effects persisted for 12 weeks. Dissociated profiles of anxiety and cardiac autonomic adaptations shed new light on the role of the amygdala in heart-brain interactions after cardiac coherence training.

Description: by Karina T. Barretto, Calvin M. Swanson, Christopher L. Nguyen, Douglas S. Annis, Stephane J. Esnault, Deane F. Mosher, Mats W. Johansson Periostin, which is induced by interleukin (IL)-13, is an extracellular matrix (ECM) protein that supports α M β 2 integrin-mediated adhesion and migration of IL-5-stimulated eosinophils. Transforming growth factor (TGF)-β-induced protein (TGFBI) is a widely expressed periostin paralog known to support monocyte adhesion. Our objective was to compare eosinophil adhesion and migration on TGFBI and periostin in the presence of IL-5-family cytokines. Eosinophil adhesion after 1 h and random motility over 20 h in the presence of various concentrations of IL-5, IL-3, or granulocyte macrophage-colony stimulating factor (GM-CSF) were quantified in wells coated with various concentrations of TGFBI or periostin. Results were compared to video microscopy of eosinophils. Cytokine-stimulated eosinophils adhered equivalently well to TGFBI or periostin in a coating concentration-dependent manner. Adhesion was blocked by anti-α M β 2 and stimulated at the lowest concentration by GM-CSF. In the motility assay, periostin was more potent than TGFBI, the coating-concentration effect was bimodal, and IL-3 was the most potent cytokine. Video microscopy revealed that under the optimal coating condition of 5 μg/ml periostin, most eosinophils migrated persistently and were polarized and acorn-shaped with a ruffling forward edge and granules gathered together, in front of the nucleus. On 10 μg/ml periostin or TGFBI, more eosinophils adopted a flattened pancake morphology with dispersed granules and nuclear lobes, and slower migration. Conversion between acorn and pancake morphologies were observed. We conclude that TGFBI or periostin supports two modes of migration by IL-5 family cytokine-activated eosinophils. The rapid mode is favored by intermediate protein coatings and the slower by higher coating concentrations. We speculate that eosinophils move by haptotaxis up a gradient of adhesive ECM protein and then slow down to surveil the tissue.

Description: by Lemmy Schakel, Dieuwke S. Veldhuijzen, Henriët van Middendorp, Pieter Van Dessel, Jan De Houwer, Rafael Bidarra, Andrea W. M. Evers There is initial support for the effectiveness of approach-avoidance trainings in altering food-related health behaviors. Furthermore, outcome expectancies induced by verbal suggestions might optimize the effectiveness of these interventions, as shown in placebo research. The present study investigated the effectiveness of a gamified approach-avoidance training on food-related outcomes and whether verbal suggestions could strengthen those effects. A total of 120 participants were randomly assigned to 1 of 4 conditions: serious gaming only, verbal suggestions only, serious gaming combined with verbal suggestions, or a gaming control condition. Virtual food preference and food choice were assessed with a food choice task, with pairs differing in healthiness or in healthiness and attractiveness. Implicit food preference was assessed with an Implicit Association Test and food intake with a bogus taste test. Participants in both serious gaming conditions made healthier food choices for pairs differing in healthiness and attractiveness and had healthier implicit food preferences compared to gaming control. No effects were found on food intake. These findings provide the first preliminary support for the effects of a gamified approach-avoidance training on virtual food choice and implicit food preference. Future studies should further elucidate these effects, also in other health domains such as physical activity.

Description: by Juan M. Castellote, Markus Kofler Objective To provide a neurophysiological tool for assessing sensorimotor pathways, which may differ for those involving distal muscles in simple tasks from those involving distal muscles in a kinetic chain task, or proximal muscles in both. Methods We compared latencies and magnitudes of motor responses in a reaction time paradigm in a proximal (biceps brachii, BB) and a distal (first dorsal interosseous, FDI) muscle following electrical stimuli used as imperative signal (IS) delivered to the index finger. These stimuli were applied during different motor tasks: simple tasks involving either one muscle, e.g. flexing the elbow for BB (FLEX), or pinching a pen for FDI (PINCH); combined tasks engaging both muscles by pinching and flexing simultaneously (PINCH-FLEX). Stimuli were of varying intensity and occasionally elicited a startle response, and a StartReact effect. Results In BB, response latencies decreased gradually and response amplitudes increased progressively with increasing IS intensities for non-startling trials, while for trials containing startle responses, latencies were uniformly shortened and response amplitudes similarly augmented across all IS intensities in both FLEX and PINCH-FLEX. In FDI, response latencies decreased gradually and response amplitudes increased progressively with increasing IS intensities in both PINCH and PINCH-FLEX for non-startling trials, but, unlike in BB for the simple task, in PINCH for trials containing startle responses as well. In PINCH-FLEX, FDI latencies were uniformly shortened and amplitudes similarly increased across all stimulus intensities whenever startle signs were present. Conclusions Our results suggest the presence of different sensorimotor pathways supporting a dissociation between simple tasks that involve distal upper limb muscles (FDI in PINCH) from simple tasks involving proximal muscles (BB in FLEX), and combined tasks that engage both muscles (FDI and BB in PINCH-FLEX), all in accordance with differential importance in the control of movements by cortical and subcortical structures. Significance Simple assessment tools may provide useful information regarding the differential involvement of sensorimotor pathways in the control of both simple and combined tasks that engage proximal and distal muscles.

Description: by Yuki Ideno, Kunihiko Hayashi, Junko Nakajima-Shimada, Yoko Onizuka, Mikiko Kishi, Tomomi Ueno, Shigeto Uchiyama Equol is one of the most active soy isoflavones. When the association between soy food intake in daily life and health outcomes is examined in epidemiological studies, it is important to define the equol-producing status of each individual. However, few studies have assessed equol-producing status without a soy challenge test. To determine a robust cutoff criterion for equol producer classification in observational studies, we conducted a urinary isoflavone concentration survey in daily life among women. Furthermore, we examined the association between eating habits regarding soy foods and equol-producing status. A total of 4,412 participants were included in the analyses. Urinary isoflavones were analyzed using a high-performance liquid chromatography method. We examined the distribution of the log 10 equol/daidzein ratios, finding a mixture of two normal distributions, corresponding to equol producer and non-producer subpopulations. Applying a finite mixture model, we estimated the means, standard deviations, and mixing proportions of these two distributions. The estimation was carried out using the SAS NLIN procedure. The optimal cutoff point for the log 10 equol/daidzein ratio in the study population was determined to be −1.42, according to the estimated parameters of the mixture distribution. Based on this criterion, 1,830 (41.5%) of the participants were identified as equol producers. Compared with non-consumers of soy foods, consumers of soy foods had significantly higher odds of being equol producers. Using log 10 -transformed equol/daidzein ratios ≥ −1.42 to define equol producers among Japanese women is reasonable and suitable for determining equol-producing status in epidemiological studies. We found that soy food eating habits were associated with equol-producing status. Further investigation is required to evaluate associations between equol-producing status in daily life and health outcomes. The results of this study suggest the best cutoff point to use in the definition of equol-producing status in daily life.

Description: by Ehsan Mirzakhalili, Bogdan I. Epureanu, Eleni Gourgou We propose a mathematical and computational model that captures the stimulus-generated Ca 2+ transients in the C . elegans ASH sensory neuron. The rationale is to develop a tool that will enable a cross-talk between modeling and experiments, using modeling results to guide targeted experimental efforts. The model is built based on biophysical events and molecular cascades known to unfold as part of neurons' Ca 2+ homeostasis mechanism, as well as on Ca 2+ signaling events. The state of ion channels is described by their probability of being activated or inactivated, and the remaining molecular states are based on biochemically defined kinetic equations or known biochemical motifs. We estimate the parameters of the model using experimental data of hyperosmotic stimulus-evoked Ca 2+ transients detected with a FRET sensor in young and aged worms, unstressed and exposed to oxidative stress. We use a hybrid optimization method composed of a multi-objective genetic algorithm and nonlinear least-squares to estimate the model parameters. We first obtain the model parameters for young unstressed worms. Next, we use these values of the parameters as a starting point to identify the model parameters for stressed and aged worms. We show that the model, in combination with experimental data, corroborates literature results. In addition, we demonstrate that our model can be used to predict ASH response to complex combinations of stimulation pulses. The proposed model includes for the first time the ASH Ca 2+ dynamics observed during both "on" and "off" responses. This mathematical and computational effort is the first to propose a dynamic model of the Ca 2+ transients' mechanism in C . elegans neurons, based on biochemical pathways of the cell's Ca 2+ homeostasis machinery. We believe that the proposed model can be used to further elucidate the Ca 2+ dynamics of a key C . elegans neuron, to guide future experiments on C . elegans neurobiology, and to pave the way for the development of more mathematical models for neuronal Ca 2+ dynamics.

Description: by Brittney M. Donovan, Nichole L. Nidey, Elizabeth A. Jasper, Jennifer G. Robinson, Wei Bao, Audrey F. Saftlas, Kelli K. Ryckman Biomarkers commonly assessed in prenatal screening have been associated with a number of adverse perinatal and birth outcomes. However, it is not clear whether first trimester measurements of prenatal screening biomarkers are associated with subsequent risk of gestational diabetes mellitus (GDM). We aimed to systematically review and statistically summarize studies assessing the relationship between first trimester prenatal screening biomarker levels and GDM development. We comprehensively searched PubMed/MEDLINE, EMBASE, CINAHL, and Scopus (from inception through January 2018) and manually searched the reference lists of all relevant articles. We included original, published, observational studies examining the association of first trimester pregnancy associated plasma protein-A (PAPP-A) and/or free β-human chorionic gonadotropin (free β-hCG) levels with GDM diagnosis. Mean differences were calculated comparing PAPP-A and free β-hCG multiples of median (MoM) levels between women who developed GDM and those who did not and were subsequently pooled using two-sided random-effects models. Our meta-analysis of 13 studies on PAPP-A and nine studies on free β-hCG indicated that first trimester MoM levels for both biomarkers were lower in women who later developed GDM compared to women who remained normoglycemic throughout pregnancy (MD -0.17; 95% CI -0.24, -0.10; MD -0.04; 95% CI -0.07–0.01). There was no evidence for between-study heterogeneity among studies on free β-hCG (I 2 = 0%). A high level of between-study heterogeneity was detected among the studies reporting on PAPP-A (I 2 = 90%), but was reduced after stratifying by geographic location, biomarker assay method, and timing of GDM diagnosis. Our meta-analysis indicates that women who are diagnosed with GDM have lower first trimester levels of both PAPP-A and free β-hCG than women who remain normoglycemic throughout pregnancy. Further assessment of the predictive capacity of these biomarkers within large, diverse populations is needed.

Description: by Hsin-Hua Chen, Wen-Cheng Chao, Tsai-Ling Liao, Ching-Heng Lin, Der-Yuan Chen Objective To estimate the relative risk of autoimmune rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren’s syndrome (SS), dermatomyositis (DM) and polymyositis (PM), among patients with palindromic rheumatism (PR) compared with non-PR individuals. Methods The study utilized 2003–2013 claims data from the Taiwanese National Health Insurance Research Database. We identified 4,421 cases of PR from 2007 to 2012 and randomly chose 44,210 non-PR individuals who matched (1:10) for age, sex and the year of index date without prior history of RA, SLE, SSc, SS, DM, or PM. After adjusting for age, sex, and the Charlson comorbidity index, we calculated the hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard model to quantify the risk of RA, SLE, SS, DM and PM in PR patients compared with that in matched non-PR individuals. Results Among the 4,421 patients with PR, 569 (12.87%) developed RA, 269 (6.08%) developed SS, 113 (2.56%) developed SLE, 5 (0.11%) developed SSc, 8 (0.18%) developed PM, and 1 (0.02%) developed DM. After adjusting for potential confounders, the patients with PR had an increased risk of RA (HR, 118.76; 95% CI, 89.81–157.04), SS (HR, 59.57; 95% CI, 43.87–80.88), SLE (HR, 51.56; 95% CI, 32.96–80.66) PM (HR, 57.38; 95% CI, 6.90–476.83), and SSc (HR, 13.42; 95% CI, 3.79–47.55) but not of DM (HR, 3.44; 95% CI, 0.34–34.59). Conclusion Patients with PR had an increased risk of developing RA, SS, SLE, PM, and SSc.

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b02321

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01746

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01009

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01630

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b00877

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b02155

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b02015

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b00885

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b00962

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01211

Description: Biochemistry DOI: 10.1021/acs.biochem.8b00542

Description: Crystal Growth & Design DOI: 10.1021/acs.cgd.8b00786

Description: Journal of Chemical Information and Modeling DOI: 10.1021/acs.jcim.8b00263

Description: Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00194

Description: Journal of Chemical Information and Modeling DOI: 10.1021/acs.jcim.8b00155

Description: Journal of Chemical & Engineering Data DOI: 10.1021/acs.jced.8b00251

Description: Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00737

Description: The Journal of Organic Chemistry DOI: 10.1021/acs.joc.8b01002

Description: The Journal of Organic Chemistry DOI: 10.1021/acs.joc.8b01301

Description: Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00540

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b04189

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b05934

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b06291

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b06476

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b01596

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b03931

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01956

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01758

Description: Journal of the American Chemical Society DOI: 10.1021/jacs.8b05490

Description: Organic Letters DOI: 10.1021/acs.orglett.8b01969

Description: by Keira Sztukowski, Kaila Nip, Paige N. Ostwald, Matheus F. Sathler, Julianna L. Sun, Jiayi Shou, Emily T. Jorgensen, Travis E. Brown, John H. Elder, Craig Miller, Franz Hofmann, Sue VandeWoude, Seonil Kim Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca 2+ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca 2+ activity using intracellular Ca 2+ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca 2+ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca 2+ by the activation of the endoplasmic reticulum (ER)-associated Ca 2+ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95’s stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca 2+ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca 2+ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca 2+ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.

Description: by Weilong Chen, Yuanyuan Qin, Dong Wang, Lei Zhou, Yin Liu, Sheng Chen, Liang Yin, Yaoxing Xiao, Xiao-Hong Yao, Xiaoli Yang, Wei Ma, Weifeng Chen, Xueyan He, Lixing Zhang, Qifeng Yang, Xiuwu Bian, Zhi-ming Shao, Suling Liu Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.

Description: by Luigi Acerbi, Kalpana Dokka, Dora E. Angelaki, Wei Ji Ma The precision of multisensory perception improves when cues arising from the same cause are integrated, such as visual and vestibular heading cues for an observer moving through a stationary environment. In order to determine how the cues should be processed, the brain must infer the causal relationship underlying the multisensory cues. In heading perception, however, it is unclear whether observers follow the Bayesian strategy, a simpler non-Bayesian heuristic, or even perform causal inference at all. We developed an efficient and robust computational framework to perform Bayesian model comparison of causal inference strategies, which incorporates a number of alternative assumptions about the observers. With this framework, we investigated whether human observers’ performance in an explicit cause attribution and an implicit heading discrimination task can be modeled as a causal inference process. In the explicit causal inference task, all subjects accounted for cue disparity when reporting judgments of common cause, although not necessarily all in a Bayesian fashion. By contrast, but in agreement with previous findings, data from the heading discrimination task only could not rule out that several of the same observers were adopting a forced-fusion strategy, whereby cues are integrated regardless of disparity. Only when we combined evidence from both tasks we were able to rule out forced-fusion in the heading discrimination task. Crucially, findings were robust across a number of variants of models and analyses. Our results demonstrate that our proposed computational framework allows researchers to ask complex questions within a rigorous Bayesian framework that accounts for parameter and model uncertainty.

Description: by Simon Heilbronner, Ian R. Monk, Jeremy R. Brozyna, David E. Heinrichs, Eric P. Skaar, Andreas Peschel, Timothy J. Foster

Description: by Ida Friis, Ilia A. Solov’yov The non-homologous end joining of a DNA double strand break is initiated by the MRE11-NBS1-RAD50 complex whose subunits are the first three proteins to arrive to the breakage site thereby making the recruitment time of MRE11, NBS1 and RAD50 essential for cell survival. In the present investigation, the nature of MRE11 and NBS1 transportation from the cytoplasm to the nucleus, hosting the damaged DNA strand, is hypothesized to be a passive diffusive process. The feasibility of such a mechanism is addressed through theoretical and computational approaches which permit establishing the characteristic recruitment time of MRE11 and NBS1 by the nucleus. A computational model of a cell is constructed from a set of biological parameters and the kinetic Monte Carlo algorithm is used to simulate the diffusing MRE11 and NBS1 particles as a random walk process. To accurately describe the experimented data, it is discovered that MRE11 and NBS1 should start diffusion from significantly different starting positions which suggests that diffusion might not be the only transport mechanism of repair protein recruitment to the DNA break.

Description: by Lin Yang, Xiaoyan Kong, Shuli Yang, Xinxing Dong, Jianfa Yang, Xiao Gou, Hao Zhang The Tibetan horse is a species endemic to the Tibetan plateau, with considerable economic value in the region. However, we currently have little genetic evidence to verify whether the breed originated in Tibet or if it entered the area via an ancient migratory route. In the present study, we analyzed the hypervariable segment I sequences of mitochondrial DNA (mtDNA) in 2,050 horses, including 290 individuals from five Tibetan populations and 1,760 from other areas across Asia. Network analysis revealed multiple maternal lineages in the Tibetan horse. Component analysis of sub-lineage F3 indicated that it decreased in frequency from east to west, a trend reflected both southward and northward from Inner Mongolia. Analysis of population genetics showed that the Deqen horse of eastern Tibet was more closely related to the Ningqiang horse of northern China than to other Tibetan horses or the Yunnan horse. These results indicated that the Tibetan horse migrated first from Central Asia to Mongolia, moved south to eastern Tibet (near Deqen), then finally westward to other regions of Tibet. We also identified a novel lineage K that mainly comprises Tibetan and Yunnan horses, suggesting autochthonous domesticated origin for some Tibetan horse breeds from local wild horses. In conclusion, our study demonstrated that modern Tibetan horse breeds originated from the introgression of local wild horses with exotic domesticated populations outside China.

Description: by Marya Plotkin, Dunstan Bishanga, Hussein Kidanto, Mary Carol Jennings, Jim Ricca, Amasha Mwanamsangu, Gaudiosa Tibaijuka, Ruth Lemwayi, Benny Ngereza, Mary Drake, Jeremie Zougrana, Neena Khadka, James A. Litch, Barbara Rawlins Background Globally, an estimated 2.7 million babies die in the neonatal period annually, and of these, about 0.7 million die from intrapartum-related events. In Tanzania 51,000 newborn deaths and 43,000 stillbirths occur every year. Approximately two-thirds of these deaths could be potentially prevented with improvements in intrapartum and neonatal care. Routine measurement of fetal intrapartum deaths and newborn deaths that occur in health facilities can help to evaluate efforts to improve the quality of intrapartum care to save lives. However, few examples exist of indicators on perinatal mortality in the facility setting that are readily available through health management information systems (HMIS). Methods From November 2016 to April 2017, health providers at 10 government health facilities in Kagera region, Tanzania, underwent refresher training on perinatal death classification and training on the use of handheld Doppler devices to assess fetal heart rate upon admission to maternity services. Doppler devices were provided to maternity services at the study facilities. We assessed the validity of an indicator to measure facility-based pre-discharge perinatal mortality by comparing perinatal outcomes extracted from the HMIS maternity registers to a gold standard perinatal death audit. Results Sensitivity and specificity of the HMIS neonatal outcomes to predict gold standard audit outcomes were both over 98% based on analysis of 128 HMIS–gold standard audit pairs. After this validation, we calculated facility perinatal mortality indicator from HMIS data using fresh stillbirths and pre-discharge newborn death as the numerator and women admitted in labor with positive fetal heart tones as the denominator. Further emphasizing the validity of the indicator, FPM values aligned with expected mortality by facility level, with lowest rates in health centers (range 0.3%– 0.5%), compared to district hospitals (1.5%– 2.9%) and the regional hospital (4.2%). Conclusion This facility perinatal mortality indicator provides an important health outcome measure that facilities can use to monitor levels of perinatal deaths occurring in the facility and evaluate impact of quality of care improvement activities.

Description: by Seung-Heon Shin, Mi-Kyung Ye, Dong-Won Lee, Mi-Hyun Che The essential oil of Chamaecyparis obtusa ( C . obtusa ), which is used in soap, toothpaste, and aromatic agents, has been known to have anti-inflammatory properties. In this study, we investigated the effects of microencapsulated C . obtusa essential oil on airborne fungus-induced dendritic cell (DC) activation and Th immune responses. We stimulated monocyte-derived DCs with Alternaria alternate and lipopolysaccharide (LPS). To determine the anti-inflammatory effects, we pre-treated DCs with various concentrations of microencapsulated C . obtusa essential oil and collected the supernatants to measure interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and we determined the expression of cell surface molecules. The effects of the essential oil on CD4 + T cells polarization was determine by culturing stimulated DCs and autologous CD4 + T cells. Alternaria enhanced the production of IL-6 and TNF-α from DCs, and pretreating DCs with 0.001, 0.01, and 0.05% of the essential oil significantly inhibited their production. Increased CD80 and CD86 expression by Alternaria was significantly inhibited with 0.05% of the essential oil. Alternaria -induced IL-5, IL-10, and interferon-gamma from CD4 + T cells were significantly inhibited with C . obtusa essential oil in a dose dependent manner. C . obtusa influenced both Alternaria - and LPS-induced Th1 and Th2 polarization of CD4 + T cells. These results suggest a novel pharmacological use for C . obtusa essential oil to treat inflammatory airway diseases.

Description: by P. Susthitha Menon, Fairus Atida Said, Gan Siew Mei, Dilla Duryha Berhanuddin, Akrajas Ali Umar, Sahbudin Shaari, Burhanuddin Yeop Majlis This work investigates the surface plasmon resonance (SPR) response of 50-nm thick nano-laminated gold film using Kretschmann-based biosensing for detection of urea and creatinine in solution of various concentrations (non-enzymatic samples). Comparison was made with the presence of urease and creatininase enzymes in the urea and creatinine solutions (enzymatic samples), respectively. Angular interrogation technique was applied using optical wavelengths of 670 nm and 785 nm. The biosensor detects the presence of urea and creatinine at concentrations ranging from 50–800 mM for urea samples and 10–200 mM for creatinine samples. The purpose of studying the enzymatic sample was mainly to enhance the sensitivity of the sensor towards urea and creatinine in the samples. Upon exposure to 670 nm optical wavelength, the sensitivity of 1.4°/M was detected in non-enzymatic urea samples and 4°/M in non-enzymatic creatinine samples. On the other hand, sensor sensitivity as high as 16.2°/M in urea-urease samples and 10°/M in creatinine-creatininase samples was detected. The enhanced sensitivity possibly attributed to the increase in refractive index of analyte sensing layer due to urea-urease and creatinine-creatininase coupling activity. This work has successfully proved the design and demonstrated a proof-of-concept experiment using a low-cost and easy fabrication of Kretschmann based nano-laminated gold film SPR biosensor for detection of urea and creatinine using urease and creatininase enzymes.

Description: by David A. Eavarone, Linah Al-Alem, Alexey Lugovskoy, Jillian M. Prendergast, Rawan I. Nazer, Jenna N. Stein, Daniel T. Dransfield, Jeff Behrens, Bo R. Rueda The expression of Sialyl-Tn (STn) in tumors is associated with metastatic disease, poor prognosis, and reduced overall survival. STn is expressed on ovarian cancer biomarkers including CA-125 (MUC16) and MUC1, and elevated serum levels of STn in ovarian cancer patients correlate with lower five-year survival rates. In the current study, we humanized novel anti-STn antibodies and demonstrated the retention of nanomolar (nM) target affinity while maintaining STn antigen selectivity. STn antibodies conjugated to Monomethyl Auristatin E (MMAE-ADCs) demonstrated in vitro cytotoxicity specific to STn-expressing ovarian cancer cell lines and tumor growth inhibition in vivo with both ovarian cancer cell line- and patient-derived xenograft models. We further validated the clinical potential of these STn-ADCs through tissue cross-reactivity and cynomolgus monkey toxicity studies. No membrane staining for STn was present in any organs of human or cynomolgus monkey origin, and the toxicity profile was favorable and only revealed MMAE-class associated events with none being attributed to the targeting of STn. The up-regulation of STn in ovarian carcinoma in combination with high affinity and STn-specific selectivity of the mAbs presented herein warrant further investigation for anti-STn antibody-drug conjugates in the clinical setting.

Description: by Laura K. Borkenhagen, Kerry A. Mallinson, Rick W. Tsao, Siaw-Jing Ha, Wei-Honn Lim, Teck-Hock Toh, Benjamin D. Anderson, Jane K. Fieldhouse, Sarah E. Philo, Kuek-Sen Chong, William G. Lindsley, Alejandro Ramirez, James F. Lowe, Kristen K. Coleman, Gregory C. Gray Background The large livestock operations and dense human population of Southeast Asia are considered a hot-spot for emerging viruses. Objectives To determine if the pathogens adenovirus (ADV), coronavirus (CoV), encephalomyocarditis virus (EMCV), enterovirus (EV), influenza A-D (IAV, IBV, ICV, and IDV), porcine circovirus 2 (PCV2), and porcine rotaviruses A and C (RVA and RVC), are aerosolized at the animal-interface, and if humans working in these environments are carrying these viruses in their nasal airways. Study This cross-sectional study took place in Sarawak, Malaysia among 11 pig farms, 2 abattoirs, and 3 animal markets in June and July of 2017. Pig feces, pig oral secretions, bioaerosols, and worker nasal wash samples were collected and analyzed via rPCR and rRT-PCR for respiratory and diarrheal viruses. Results In all, 55 pig fecal, 49 pig oral or water, 45 bioaerosol, and 78 worker nasal wash samples were collected across 16 sites. PCV2 was detected in 21 pig fecal, 43 pig oral or water, 3 bioaerosol, and 4 worker nasal wash samples. In addition, one or more bioaerosol or pig samples were positive for EV, IAV, and RVC, and one or more worker samples were positive for ADV, CoV, IBV, and IDV. Conclusions This study demonstrates that nucleic acids from a number of targeted viruses were present in pig oral secretions and pig fecal samples, and that several viruses were detected in bioaerosol samples or in the nasal passages of humans with occupational exposure to pigs. These results demonstrate the need for future research in strengthening viral surveillance at the human-animal interface, specifically through expanded bioaerosol sampling efforts and a seroepidemiological study of individuals with exposure to pigs in this region for PCV2 infection.

Description: by Vasileios Stavropoulos, Stefanos Mastrotheodoros, Tyrone L. Burleigh, Nicole Papadopoulos, Rapson Gomez Romantic development is a distinctive characteristic of puberty. However, a significant proportion of adolescents present with avoidant romantic attachment (ARA) tendencies, which have significant impact on their general adaptation. ARA variations have been suggested in relation to age, gender, engagement with a romantic partner and Excessive Internet Use (EIU) behaviours. In this longitudinal, two-wave study of a normative sample of 515 Greek adolescents at 16 and 18 years, ARA was assessed with the relevant subscale of the Experiences in Close Relationships-Revised and EIU with the Internet Addiction Test. A three-level hierarchical linear model found ARA tendencies to decrease between 16 and 18 while engagement in a romantic relationship and EIU were associated with lower and higher ARA tendencies respectively. Gender did not differentiate ARA severity either at the age of 16 or its changes over time. Results highlight the need of adopting a longitudinal-contextualized approach and provide implications for prevention and intervention initiatives in relation to the romantic development of adolescents.

Description: by Emma C. Johnson, Luke M. Evans, Matthew C. Keller Inbreeding increases the risk of certain Mendelian disorders in humans but may also reduce fitness through its effects on complex traits and diseases. Such inbreeding depression is thought to occur due to increased homozygosity at causal variants that are recessive with respect to fitness. Until recently it has been difficult to amass large enough sample sizes to investigate the effects of inbreeding depression on complex traits using genome-wide single nucleotide polymorphism (SNP) data in population-based samples. Further, it is difficult to infer causation in analyses that relate degree of inbreeding to complex traits because confounding variables (e.g., education) may influence both the likelihood for parents to outbreed and offspring trait values. The present study used runs of homozygosity in genome-wide SNP data in up to 400,000 individuals in the UK Biobank to estimate the proportion of the autosome that exists in autozygous tracts—stretches of the genome which are identical due to a shared common ancestor. After multiple testing corrections and controlling for possible sociodemographic confounders, we found significant relationships in the predicted direction between estimated autozygosity and three of the 26 traits we investigated: age at first sexual intercourse, fluid intelligence, and forced expiratory volume in 1 second. Our findings corroborate those of several published studies. These results may imply that these traits have been associated with Darwinian fitness over evolutionary time. However, some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that alternative explanations for these associations have not been eliminated. Care needs to be taken in the design and interpretation of ROH studies in order to glean reliable information about the genetic architecture and evolutionary history of complex traits.

Description: by David M. Brown, Sarah Jones, Zoe C. T. R. Daniel, Madelaine C. Brearley, Jo E. Lewis, Francis J. P. Ebling, Tim Parr, John M. Brameld Previously, we highlighted induction of an integrated stress response (ISR) gene program in skeletal muscle of pigs treated with a beta-adrenergic agonist. Hence we tested the hypothesis that the ER-stress inhibitor, sodium 4-phenylbutyrate (PBA), would inhibit Clenbuterol-mediated muscle growth and reduce expression of genes that are known indicators of an ISR in mice. Clenbuterol (1mg/kg/day) administered to C57BL6/J mice for 21 days increased body weight ( p

Description: by Charlotte Avet, Chantal Denoyelle, David L’Hôte, Florence Petit, Céline J. Guigon, Joëlle Cohen-Tannoudji, Violaine Simon Reproductive function is under the control of the neurohormone GnRH, which activates a G-protein-coupled receptor (GnRHR) expressed in pituitary gonadotrope cells. GnRHR activates a complex signaling network to regulate synthesis and secretion of the two gonadotropin hormones, luteinizing hormone and follicle-stimulating hormone, both regulating gametogenesis and steroidogenesis in gonads. Recently, in an attempt to identify the mechanisms underlying GnRHR signaling plasticity, we identified the first interacting partner of GnRHR, the proto-oncogene SET. We showed that SET binds to intracellular domains of GnRHR to enhance its coupling to cAMP pathway in αT3-1 gonadotrope cells. Here, we demonstrate that SET protein is rapidly regulated by GnRH, which increases SET phosphorylation state and decreases dose-dependently SET protein level. Our results highlight a post-translational regulation of SET protein involving the proteasome pathway. We determined that SET phosphorylation upon GnRH stimulation is mediated by PKC and that PKC mediates GnRH-induced SET down-regulation. Phosphorylation on serine 9 targets SET for degradation into the proteasome. Furthermore, a non-phosphorylatable SET mutant on serine 9 is resistant to GnRH-induced down-regulation. Altogether, these data suggest that GnRH-induced SET phosphorylation on serine 9 mediates SET protein down-regulation through the proteasome pathway. Noteworthy, SET down-regulation was also observed in response to pulsatile GnRH stimulation in LβT2 gonadotrope cells as well as in vivo in prepubertal female mice supporting its physiological relevance. In conclusion, this study highlights a regulation of SET protein by the neurohormone GnRH and identifies some of the mechanisms involved.

Description: by Wilson Mendoza, Dominick Mendola, Jang Kim, Charles Yarish, Alyssa Velloze, B. Greg Mitchell

Description: by Àngel Oliveras, Aina Baró, Laura Montesinos, Esther Badosa, Emilio Montesinos, Lidia Feliu, Marta Planas A collection of 36 lipopeptides were designed from the cecropin A-melittin hybrid peptide BP100 (H-Lys-Lys-Leu-Phe-Lys-Lys-Ile-Leu-Lys-Tyr-Leu-NH 2 ) previously described with activity against phytopathogenic bacteria. These lipopeptides were synthesized on solid-phase and screened for their antimicrobial activity, toxicity and proteolytic stability. They incorporated a butanoyl, a hexanoyl or a lauroyl group at the N-terminus or at the side chain of a lysine residue placed at each position of the sequence. Their antimicrobial activity and hemolysis depended on the fatty acid length and its position. In particular, lipopeptides containing a butanoyl or a hexanoyl chain exhibited the best biological activity profile. In addition, we observed that the incorporation of the acyl group did not induce the overexpression of defense-related genes in tomato. Best lipopeptides were BP370, BP378, BP381, BP387 and BP389, which were highly active against all the pathogens tested (minimum inhibitory concentration of 0.8 to 12.5 μM), low hemolytic, low phytotoxic and significantly stable to protease degradation. This family of lipopeptides might be promising functional peptides useful for plant protection.

Description: by The PLOS ONE staff

Description: by Fausto Petrelli, Chiara Lazzari, Raffaele Ardito, Karen Borgonovo, Alessandra Bulotta, Barbara Conti, Mary Cabiddu, Jody Filippo Capitanio, Matteo Brighenti, Mara Ghilardi, Luca Gianni, Sandro Barni, Vanesa Gregorc Background Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs. Material and methods A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR). Results A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1–65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3–55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naïve and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%. Conclusions Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy.

Description: by Steven Denyer, Abhiraj D. Bhimani, Steven Papastefan, Pouyan Kheirkhah, Tania Aguilar, Jack Zakrzewski, Clayton L. Rosinski, Akash S. Patel, Saavan Patel, Victoria Zakrzewski, Akop Seksenyan, Gail S. Prins, Ankit I. Mehta Vertebral compression fractures (VCFs) caused by metastatic malignancies or osteoporosis are devastating injuries with debilitating outcomes for patients. Minimally invasive kyphoplasty is a common procedure used for symptomatic amelioration. However, it fails in treating the underlying etiologies of VCFs. Use of systemic therapy is limited due to low perfusion to the spinal column and systemic toxicity. Localized delivery of drugs to the vertebral column can provide a promising alternative approach. A porcine kyphoplasty model was developed to study the magnetically guided drug delivery of systemically injected magnetic nanoparticles (MNPs). Jamshidi cannulated pedicle needles were placed into the thoracic vertebra and, following inflatable bone tamp expansion, magnetic bone cement was injected to the vertebral body. Histological analysis was performed after intravenous injection of MNPs. Qualitative analysis of harvested tissues revealed successful placement of magnetic cement into the vertebral body. Further quantitative analysis of histological sections of several vertebral bodies demonstrated enhanced accumulation of MNPs to regions that had magnetic cement injected during kyphoplasty compared to those that did not. By modifying the kyphoplasty bone cement to include magnets, thereby providing a guidance stimulus and a localizer, we were successfully able to guide intravenously injected magnetic nanoparticles to the thoracic vertebra. These results demonstrate an in-vivo proof of concept of a novel drug delivery strategy that has the potential to treat the underlying causes of VCFs, in addition to providing symptomatic support.

Description: by Maria Frølund, Arne Wikström, Peter Lidbrink, Waleed Abu Al-Soud, Niels Larsen, Christoffer Bugge Harder, Søren Johannes Sørensen, Jørgen Skov Jensen, Peter Ahrens Background Non-gonococcal urethritis (NGU) is a common syndrome in men. NGU may have several causes, but many cases are caused by sexually transmitted infections that may also cause complications in their female partners. Chlamydia trachomatis and Mycoplasma genitalium are the most common causes of NGU, but in up to 35% of the cases, none of the known viral or bacterial causes are found. Traditionally, pathogens have been detected using various culture techniques that may not identify all species present in the urethra. To address this, we used culture-independent methods for analysis of the male urethral microbiota. Methods This case-control study analysed first void urine samples, collected at STD clinics in Stockholm, Sweden from men with idiopathic urethritis (IU), i.e. negative for Neisseria gonorrhoeae , Chlamydia trachomatis , Mycoplasma genitalium , Ureaplasma urealyticum , Trichomonas vaginalis , adenovirus, and herpes simplex virus type 1 and -2 together with samples from men without urethritis. Forty-six controls and 39 idiopathic urethritis patients were analysed. Results The microbiota was highly diverse: None of the 302 operational taxonomic units (OTUs) found in negative controls and IU patients were found in all of the samples or even in all of the samples in one group. More than 50% of the OTUs were only found in one or two of the total of 85 samples. Still the most dominant 1/6 of the genera constituted 79% of the sequences.Hierarchical clustering in a heatmap showed no specific clustering of patients or controls.A number of IU patient samples were dominated by a single genus previously related to urethritis ( Gardnerella , Haemophilus , Ureaplasma ). Conclusion The male urethra contain a very diverse composition of bacteria, even in healthy controls. NGU may be caused by a number of different bacteria but more studies including a higher number of samples are needed for elucidation of the role of each species.

Description: by Yves Jackson, Adeline Paignon, Hans Wolff, Noelia Delicado Background Undocumented migrants endure adverse living conditions while facing barriers to access healthcare. Evidence is lacking regarding their healthcare needs, notably in regards to chronic diseases. Our goal was to investigate health conditions in undocumented migrants attended in primary care setting. Methods This study was conducted at the primary care outpatient clinic, Geneva University Hospitals, Switzerland. We retrospectively recorded and coded all medical conditions of a random sample of 731 undocumented migrants using the International Classification of Primary Care, 2nd version (ICPC-2). We dichotomized conditions as chronic or non-chronic and considered multimorbidity in the presence of three or more chronic conditions. Results Participants originated from 72 countries and were mainly female (65.5%) with a mean age of 42.4 (standard deviation [SD]: 11.4) years. They presented a mean of 2.9 (SD: 2.1; range: 1–17) health conditions. In multivariable analysis, the number of conditions was associated with female gender (p = 0.011) and older age (p

Description: by Kine Andenæs, Ida G. Lunde, Naiyereh Mohammadzadeh, Christen P. Dahl, Jan Magnus Aronsen, Mari E. Strand, Sheryl Palmero, Ivar Sjaastad, Geir Christensen, Kristin V. T. Engebretsen, Theis Tønnessen Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.

Description: by Bruno Rossitto De Marchi, Tonny Kinene, James Mbora Wainaina, Renate Krause-Sakate, Laura Boykin The whitefly, Bemisia tabaci , is a species complex of more than 40 cryptic species and a major agricultural pest. It causes extensive damage to plants mainly by transmitting plant viruses. There is still a lack of genomic data available for the different whitefly species found in Brazil and their bacterial endosymbionts. Understanding the genetic and transcriptomic composition of these insect pests, the viruses they transmit and the microbiota is crucial to sustainable solutions for farmers to control whiteflies. Illumina RNA-Seq was used to obtain the transcriptome of individual whiteflies from 10 different populations from Brazil including Middle East-Asia Minor 1 (MEAM1), Mediterranean (MED) and New World 2 (NW2). Raw reads were assembled using CLC Genomics Workbench and subsequently mapped to reference genomes. We obtained whitefly complete mitochondrial genomes and draft genomes from the facultative bacterial endosymbiont Hamiltonella for further phylogenetic analyses. In addition, nucleotide sequences of the GroEL chaperonin gene from Hamiltonella from different populations were obtained and analysed. There was concordance in the species clustering using the whitefly complete mitogenome and the mtCOI gene tree. On the other hand, the phylogenetic analysis using the 12 ORF’s of Hamiltonella clustered the native species NW2 apart from the exotics MEAM1 and MED. In addition, the amino acid analysis of GroEL chaperonin revealed a deletion only in Hamiltonella infecting NW2 among whiteflies populations analysed which was further confirmed by PCR and Sanger sequencing. The genomic data obtained in this study will aid understanding the functions that Hamiltonella may have in whitefly biology and serve as a reference for further studies regarding whiteflies in Brazil.

Description: by Wen-Kai Yang, An-Di Hsu, Chao-Kai Kang, Ivan Pochou Lai, Pei-Shao Liao, Tsung-Han Lee FXYD proteins are the regulators of sodium-potassium ATPase (Na + /K + -ATPase, NKA). In teleosts, NKA is a primary driving force for the operation of many ion transport systems in the osmoregulatory organs (e.g. intestines). Hence, the purpose of this study was to determine the expression of FXYD proteins and NKA α-subunit in the intestines of two closely related medakas ( Oryzias dancena and O . latipes ), which came from different salinity habitats and have diverse osmoregulatory capabilities, to illustrate the association between NKA and FXYD proteins of two medaka species in response to salinity changes. The results showed that the fxyd12 mRNA was the most predominant in the intestines of both medakas. The association of FXYD12 and NKA in the intestines of the two medaka species was demonstrated via double immunofluorescent staining and co-immunoprecipitation. Upon salinity challenge, the localization of FXYD12 and NKA was similar in the intestines of the two medaka species. However, the expression profiles of intestinal FXYD12 and NKA (mRNA and protein levels), as well as NKA activity differed between the medakas. These results showed that FXYD12 may play a role in modulating NKA activity in the intestines of the two medakas following salinity changes in the maintenance of internal homeostasis. These findings contributed to knowledge of the expression and potential role of vertebrate FXYD12, the regulators of NKA, upon salinity challenge.

Description: by Raissa Prior Migliorini, Felipe Bortolotto Peters, Marina Ochoa Favarini, Carlos Benhur Kasper Information about resource partitioning among small cat species that live in sympatry in South America is fairly incomplete. Knowledge about feeding habits is essential for understanding the role of these predators in the environment, the impact on prey populations, and potential competition among themselves and with other carnivores. This study aimed to describe and compare the diet of four sympatric small cats in the grasslands of southern Brazil. We analysed the stomach contents of 37 Geoffroy’s cats ( Leopardus geoffroyi ), 27 margays ( Leopardus wiedii ), 14 pampas cats ( Leopardus colocola ), and 20 jaguarundis ( Herpailurus yagouaroundi ) obtained as road kill in the Brazilian Pampa in southern Brazil. Small mammals were the most representative class consumed by all cats, followed by Aves, Reptilia, and Amphibia. Some items, such as rodents Cavia aperea , Akodon sp., Oligoryzomys sp. and Passeriformes were consumed by all cat species. Niche overlap varied widely, from 10% (margay x jaguarundi) to 92% (jaguarundi x pampas cat). Niche breadth indicated that jaguarundi were the most specialized of the cats ( B sta = 0.24) in this region, with a diet closely associated to C . aperea . Margay consumed more items associated with arboreal behaviour than other cat species, but consumed more terrestrial items than arboreal ones. The pampas cat consumed mostly terrestrial species associated with open fields. Geoffroy’s cat consumed mammals found in a diversity of habitats, indicating high ecological flexibility. Species with more similarity in diet such as jaguarundi and pampas cat probably present temporal segregation in activity. In conclusion, despite their habitat and diet similarities, these four species explore distinct microhabitats by foraging different prey groups, what favor them to live in sympatry.

Description: by Cagan Urkup, Burcin Bozkaya, F. Sibel Salman The rapid growth of mobile payment and geo-aware systems as well as the resulting emergence of Big Data present opportunities to explore individual consuming patterns across space and time. Here we analyze a one-year transaction dataset of a leading commercial bank to understand to what extent customer mobility behavior and financial indicators can predict the use of a target product, namely the Individual Consumer Loan product. After data preprocessing, we generate 13 datasets covering different time intervals and feature groups, and test combinations of 3 feature selection methods and 10 classification algorithms to determine, for each dataset, the best feature selection method and the most influential features, and the best classification algorithm. We observe the importance of spatio-temporal mobility features and financial features, in addition to demography, in predicting the use of this exemplary product with high accuracy (AUC = 0.942). Finally, we analyze the classification results and report on most interesting customer characteristics and product usage implications. Our findings can be used to potentially increase the success rates of product recommendation systems.

Description: by Amparo Lázaro, Asier R. Larrinaga Seed size is a fundamental life-history trait for plants. A seed number/size trade-off is assumed because the resources invested in reproduction are limited; however, such a trade-off is not always observed. This could be a consequence of the method used for testing it, where the null hypothesis is dictated by common statistical practice, rather than being based on any underlying theory. Alternatively, there might be some population- and species-dependent variables that affect resource availability and, in turn, influence the presence and intensity of this trade-off. Using data on 42 herbs from two communities (lowland and alpine) from Southern Norway, we tested the validity of the classical linear model vs. two previously proposed models, based on resource competition, when assessing the existence of this trade-off at different levels. We also evaluated whether some species- (fruit aggregation, ovules/flower) and population-dependent (pollen limitation) variables could affect this trade-off. Classical linear modelling outperformed the other proposed functional models. Significant seed number/size relationships were negative in single-fruited species, whereas they were positive in species with infructescences of one-seeded fruits. Concordantly, fruit organization was the most influencing variable for the intra-specific trade-off in the lowland community. In the alpine community, species suffering higher pollen limitation showed more strongly negative slopes between seed size and seed number at the fruit/infructescence level. Across species, seed size and number were negatively related, although the relationship was significant in only one of the communities. No evidence of trade-off was found at the plant level. Linear models provide a flexible framework that allows coping with the variability in the seed number/size relationship. The emergence of the intra-specific relationship between seed number and size depends on species- and population-dependent variables, related to resource allocation and the pollination environment.

Description: by Sunitha Kodidela, Sabina Ranjit, Namita Sinha, Carole McArthur, Anil Kumar, Santosh Kumar Cytokines and chemokines circulate in plasma and may be transferred to distant sites, via exosomes. HIV infection is associated with dysregulation of cytokines and chemokines, which subsequently contribute to the pathogenesis of HIV. Alcohol and tobacco exposure, which are prevalent in HIV-infected individuals, may induce changes in the expression of cytokines and chemokines. Therefore, our aim in this study was to quantify plasma exosomal cytokines and chemokines that we expect to exacerbate toxicity or disease progression in HIV-positive drug abusers. We measured the levels of cytokines and chemokines in the plasma and plasma exosomes of 39 patients comprising six groups: HIV-negative and HIV-positive non drug abusers, HIV-negative and HIV-positive alcohol users, and HIV-negative and HIV positive tobacco smokers. We measured six cytokines (TNF-α, IL-1β, IL-8, IL-6, IL-1ra, IL-10) and two chemokines (MCP-1 and RANTES). All were present in exosomes of healthy subjects, but their levels varied between different study groups. HIV-positive alcohol drinkers had higher levels of plasma IL-8 compared to those of HIV-positive non-drinkers. The IL-1ra level was significantly higher in exosomes of non-HIV-infected alcohol drinkers compared to those of HIV-positive alcohol drinkers. Interestingly, the IL-10 level was higher in exosomes compared with their respective plasma levels in all study groups except HIV-positive non-alcohol drinkers. IL-10 was completely packaged in exosomes of HIV-positive smokers. HIV-positive smokers had significantly higher levels of plasma IL-8 compared with HIV-positive non-smokers and significantly higher exosomal IL-6 levels compared with HIV-negative subjects. HIV-positive smokers had significantly increased plasma levels of IL-1ra compared to HIV-positive non-smokers. The MCP-1 levels in the plasma of HIV-positive smokers was significantly higher than in either HIV-positive non-drug abusers or HIV-negative smokers. Overall, the findings suggest that plasma cytokines and chemokines are packaged in exosomes at varying degrees in different study groups. Exosomal cytokines and chemokines are likely to have a significant biological role at distant sites including cells in the brain.

Description: by Mian Zhou, Monowar Aziz, Manhendar Ochani, Weng-Lang Yang, Archna Sharma, Ping Wang Decrease of CD4 T cell numbers causes immunosuppression in sepsis. We previously showed the beneficial role of ghrelin in sepsis. We hypothesize that the protective outcome of ghrelin in sepsis is mediated partially through the restoration of CD4 T cells’ proliferation. Sepsis was induced in mice by cecal ligation and puncture (CLP). The percentage of CD4 T cells in spleen was assessed by flow cytometry and their proliferation was determined by carboxyfluorescein succinimidyl ester (CSFE). Compared to sham mice, the percentages of splenic CD4 T cells were reduced by 20%, 21%, and 29% at day 1, 2 and 3 after CLP, respectively. Human ghrelin was given to 3 day septic mice by s . c . injection at 5 and 24 h after CLP. Treatment with ghrelin restored the loss of CD4 T cells by increasing their proliferation in septic mice. The expression of cyclin D1 and B1 was significantly increased, while the expression of p57 was decreased in ghrelin-treated mice compared to vehicle-treated mice in sepsis. Treatment with human ghrelin significantly increased the p-AKT levels in the spleen compared to vehicle-treated septic mice. Human ghrelin plays an important role in reestablishing the proliferation of CD4 T cells and serves as a promising therapeutic agent in sepsis.

Description: by Ann Machablishvili, Giorgi Chakhunashvili, Khatuna Zakhashvili, Irakli Karseladze, Olgha Tarkhan-Mouravi, Mari Gavashelidze, Tamar Jashiashvili, Lela Sabadze, Paata Imnadze, Rodney S. Daniels, Burcu Ermetal, John W. McCauley Background Influenza epidemiological and virologic data from Georgia are limited. We aimed to present Influenza Like Illness (ILI) and Severe Acute Respiratory Infection (SARI) surveillance data and characterize influenza viruses circulating in the country over three influenza seasons. Methods We analyzed sentinel site ILI and SARI data for the 2014–2017 seasons in Georgia. Patients’ samples were screened by real-time RT-PCR and influenza viruses isolated were characterized antigenically by haemagglutination inhibition assay and genetically by sequencing of HA and NA genes. Results 32% (397/1248) of ILI and 29% (581/1997) of SARI patients tested were positive for influenza viruses. In 2014–2015 the median week of influenza detection was week 7/2015 with B/Yamagata lineage viruses dominating (79%); in 2015–2016—week 5/2016 was the median with A/H1N1pdm09 viruses prevailing (83%); and in 2016–2017 a bimodal distribution of influenza activity was observed—the first wave was caused by A/H3N2 (55%) with median week 51/2016 and the second by B/Victoria lineage viruses (45%) with median week 9/2017. For ILI, influenza virus detection was highest in children aged 5–14 years while for SARI patients most were aged 〉15 years and 27 (4.6%) of 581 SARI cases died during the three seasons. Persons aged 30–64 years had the highest risk of fatal outcome, notably those infected with A/H1N1pdm09 (OR 11.41, CI 3.94–33.04, p

Description: by Juan Pablo Gutierrez, Sebastian Garcia-Saiso, Belkis M. Aracena Objective This study aimed to estimate the magnitude of the association between overall household health expenditures & the presence of members with a chronic disease in the household. Research design & methods This was a cross-sectional analysis of a probabilistic household survey, which gathered data on previously diagnosed type 2 diabetes mellitus and hypertension as well as health expenditure in Mexico. From an analytic sample of 44,000 households, we identified those having at least one member with diabetes or hypertension and determined their health expenditure. Using matching procedures, we compared these data with those of households lacking such individuals. Results We found that 24% of the households had at least one member who had been diagnosed with diabetes, hypertension, or both. Households with such members reported health expenditures that were 25%–34% ( P

Description: by Hong Li, Manuel Zeitelhofer, Ingrid Nilsson, Xicong Liu, Laura Allan, Benjamin Gloria, Angelo Perani, Carmel Murone, Bruno Catimel, A. Munro Neville, Fiona E. Scott, Andrew M. Scott, Ulf Eriksson PDGF-CC is a member of the platelet-derived growth factor (PDGF) family that stimulates PDGFRα phosphorylation and thereby activates intracellular signalling events essential for development but also in cancer, fibrosis and neuropathologies involving blood-brain barrier (BBB) disruption. In order to elucidate the biological and pathological role(s) of PDGF-CC signalling, we have generated high affinity neutralizing monoclonal antibodies (mAbs) recognizing human PDGF-CC. We determined the complementarity determining regions (CDRs) of the selected clones, and mapped the binding epitope for clone 6B3. Using the monoclonal 6B3, we determined the expression pattern for PDGF-CC in different human primary tumours and control tissues, and explored its ability to neutralize PDGF-CC-induced phosphorylation of PDGFRα. In addition, we showed that PDGF-CC induced disruption of the blood-retinal barrier (BRB) was significantly reduced upon intraperitoneal administration of a chimeric anti-PDGF-CC antibody. In summary, we report on high affinity monoclonal antibodies against PDGF-CC that have therapeutic efficacy in vivo .

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01978

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b00674

Description: Biochemistry DOI: 10.1021/acs.biochem.8b00473

Description: The Journal of Organic Chemistry DOI: 10.1021/acs.joc.8b01492

Description: The Journal of Physical Chemistry B DOI: 10.1021/acs.jpcb.8b06493

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01697

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01983

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b01996

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b02107

Description: ACS Sustainable Chemistry & Engineering DOI: 10.1021/acssuschemeng.8b02153