ALBERT

Description: by Eva R. M. Joosten, Shihab A. Shamma, Christian Lorenzi, Peter Neri Sound waveforms convey information largely via amplitude modulations (AM). A large body of experimental evidence has provided support for a modulation (bandpass) filterbank. Details of this model have varied over time partly reflecting different experimental conditions and diverse datasets from distinct task strategies, contributing uncertainty to the bandwidth measurements and leaving important issues unresolved. We adopt here a solely data-driven measurement approach in which we first demonstrate how different models can be subsumed within a common ‘cascade’ framework, and then proceed to characterize the cascade via system identification analysis using a single stimulus/task specification and hence stable task rules largely unconstrained by any model or parameters. Observers were required to detect a brief change in level superimposed onto random level changes that served as AM noise; the relationship between trial-by-trial noisy fluctuations and corresponding human responses enables targeted identification of distinct cascade elements. The resulting measurements exhibit a dynamic complex picture in which human perception of auditory modulations appears adaptive in nature, evolving from an initial lowpass to bandpass modes (with broad tuning, Q∼1) following repeated stimulus exposure.

Description: by Bihai Shi, Cui Zhang, Caihuan Tian, Jin Wang, Quan Wang, Tengfei Xu, Yan Xu, Carolyn Ohno, Robert Sablowski, Marcus G. Heisler, Klaus Theres, Ying Wang, Yuling Jiao Shoot branching requires the establishment of new meristems harboring stem cells; this phenomenon raises questions about the precise regulation of meristematic fate. In seed plants, these new meristems initiate in leaf axils to enable lateral shoot branching. Using live-cell imaging of leaf axil cells, we show that the initiation of axillary meristems requires a meristematic cell population continuously expressing the meristem marker SHOOT MERISTEMLESS ( STM ). The maintenance of STM expression depends on the leaf axil auxin minimum. Ectopic expression of STM is insufficient to activate axillary buds formation from plants that have lost leaf axil STM expressing cells. This suggests that some cells undergo irreversible commitment to a developmental fate. In more mature leaves, REVOLUTA ( REV ) directly up-regulates STM expression in leaf axil meristematic cells, but not in differentiated cells, to establish axillary meristems. Cell type-specific binding of REV to the STM region correlates with epigenetic modifications. Our data favor a threshold model for axillary meristem initiation, in which low levels of STM maintain meristematic competence and high levels of STM lead to meristem initiation.

Description: by Lauren A. Richardson Our first ever Open Highlights explores recent Open Access research into the complex relationship between host and pathogen during the course of an infection, and the factors that determine its eventual outcome.

Description: by Cuncong Zhong, Anna Edlund, Youngik Yang, Jeffrey S. McLean, Shibu Yooseph Analyses of metagenome data (MG) and metatranscriptome data (MT) are often challenged by a paucity of complete reference genome sequences and the uneven/low sequencing depth of the constituent organisms in the microbial community, which respectively limit the power of reference-based alignment and de novo sequence assembly. These limitations make accurate protein family classification and abundance estimation challenging, which in turn hamper downstream analyses such as abundance profiling of metabolic pathways, identification of differentially encoded/expressed genes, and de novo reconstruction of complete gene and protein sequences from the protein family of interest. The profile hidden Markov model (HMM) framework enables the construction of very useful probabilistic models for protein families that allow for accurate modeling of position specific matches, insertions, and deletions. We present a novel homology detection algorithm that integrates banded Viterbi algorithm for profile HMM parsing with an iterative simultaneous alignment and assembly computational framework. The algorithm searches a given profile HMM of a protein family against a database of fragmentary MG/MT sequencing data and simultaneously assembles complete or near-complete gene and protein sequences of the protein family. The resulting program, HMM-GRASPx, demonstrates superior performance in aligning and assembling homologs when benchmarked on both simulated marine MG and real human saliva MG datasets. On real supragingival plaque and stool MG datasets that were generated from healthy individuals, HMM-GRASPx accurately estimates the abundances of the antimicrobial resistance (AMR) gene families and enables accurate characterization of the resistome profiles of these microbial communities. For real human oral microbiome MT datasets, using the HMM-GRASPx estimated transcript abundances significantly improves detection of differentially expressed (DE) genes. Finally, HMM-GRASPx was used to reconstruct comprehensive sets of complete or near-complete protein and nucleotide sequences for the query protein families. HMM-GRASPx is freely available online from http://sourceforge.net/projects/hmm-graspx.

Description: by Dazhe Meng, Manu Dubin, Pei Zhang, Edward J. Osborne, Oliver Stegle, Richard M. Clark, Magnus Nordborg The extent to which epigenetic variation affects complex traits in natural populations is not known. We addressed this question using transcriptome and DNA methylation data from a sample of 135 sequenced A. thaliana accessions. Across individuals, expression was significantly associated with cis -methylation for hundreds of genes, and many of these associations remained significant after taking SNP effects into account. The pattern of correlations differed markedly between gene body methylation and transposable element methylation. The former was usually positively correlated with expression, and the latter usually negatively correlated, although exceptions were found in both cases. Finally, we developed graphical models of causality that adapt to a sample with heavy population structure, and used them to show that while methylation appears to affect gene expression more often than expression affects methylation, there is also strong support for both being independently controlled. In conclusion, although we find clear evidence for epigenetic regulation, both the number of loci affected and the magnitude of the effects appear to be small compared to the effect of SNPs.

Description: by Minghua Nie, Emily Arner, John Prudden, Lana Schaffer, Steven Head, Michael N. Boddy Posttranslational modifications (PTMs) provide dynamic regulation of the cellular proteome, which is critical for both normal cell growth and for orchestrating rapid responses to environmental stresses, e.g. genotoxins. Key PTMs include ubiquitin, the Small Ubiquitin-like MOdifier SUMO, and phosphorylation. Recently, SUMO-targeted ubiquitin ligases (STUbLs) were found to integrate signaling through the SUMO and ubiquitin pathways. In general, STUbLs are recruited to target proteins decorated with poly-SUMO chains to ubiquitinate them and drive either their extraction from protein complexes, and/or their degradation at the proteasome. In fission yeast, reducing or preventing the formation of SUMO chains can circumvent the essential and DNA damage response functions of STUbL. This result indicates that whilst some STUbL "targets" have been identified, the crucial function of STUbL is to antagonize SUMO chain formation. Herein, by screening for additional STUbL suppressors, we reveal crosstalk between the serine/threonine phosphatase PP2A-Pab1 B55 and the SUMO pathway. A hypomorphic Pab1 B55 mutant not only suppresses STUbL dysfunction, but also mitigates the phenotypes associated with deletion of the SUMO protease Ulp2, or mutation of the STUbL cofactor Rad60. Together, our results reveal a novel role for PP2A-Pab1 B55 in modulating SUMO pathway output, acting in parallel to known critical regulators of SUMOylation homeostasis. Given the broad evolutionary functional conservation of the PP2A and SUMO pathways, our results could be relevant to the ongoing attempts to therapeutically target these factors.

Description: by Edoardo Pasolli, Duy Tin Truong, Faizan Malik, Levi Waldron, Nicola Segata Shotgun metagenomic analysis of the human associated microbiome provides a rich set of microbial features for prediction and biomarker discovery in the context of human diseases and health conditions. However, the use of such high-resolution microbial features presents new challenges, and validated computational tools for learning tasks are lacking. Moreover, classification rules have scarcely been validated in independent studies, posing questions about the generality and generalization of disease-predictive models across cohorts. In this paper, we comprehensively assess approaches to metagenomics-based prediction tasks and for quantitative assessment of the strength of potential microbiome-phenotype associations. We develop a computational framework for prediction tasks using quantitative microbiome profiles, including species-level relative abundances and presence of strain-specific markers. A comprehensive meta-analysis, with particular emphasis on generalization across cohorts, was performed in a collection of 2424 publicly available metagenomic samples from eight large-scale studies. Cross-validation revealed good disease-prediction capabilities, which were in general improved by feature selection and use of strain-specific markers instead of species-level taxonomic abundance. In cross-study analysis, models transferred between studies were in some cases less accurate than models tested by within-study cross-validation. Interestingly, the addition of healthy (control) samples from other studies to training sets improved disease prediction capabilities. Some microbial species (most notably Streptococcus anginosus ) seem to characterize general dysbiotic states of the microbiome rather than connections with a specific disease. Our results in modelling features of the “healthy” microbiome can be considered a first step toward defining general microbial dysbiosis. The software framework, microbiome profiles, and metadata for thousands of samples are publicly available at http://segatalab.cibio.unitn.it/tools/metaml.

Description: by Anja S. Ziegler, Simon J. McIlroy, Poul Larsen, Mads Albertsen, Aviaja A. Hansen, Nicolas Heinen, Per Halkjær Nielsen Membrane fouling presents the greatest challenge to the application of membrane bioreactor (MBR) technology. Formation of biofilms on the membrane surface is the suggested cause, yet little is known of the composition or dynamics of the microbial community responsible. To gain an insight into this important question, we applied 16S rRNA gene amplicon sequencing with a curated taxonomy and fluorescent in situ hybridization to monitor the community of a pilot-scale MBR carrying out enhanced biological nitrogen and phosphorus removal with municipal wastewater. In order to track the dynamics of the fouling process, we concurrently investigated the communities of the biofilm, MBR bulk sludge, and the conventional activated sludge system used to seed the MBR system over several weeks from start-up. As the biofilm matured the initially abundant betaproteobacterial genera Limnohabitans , Hydrogenophaga and Malikia were succeeded by filamentous Chloroflexi and Gordonia as the abundant species. This study indicates that, although putative pioneer species appear, the biofilm became increasingly similar to the bulk community with time. This suggests that the microbial population in bulk water will largely determine the community structure of the mature biofilm.

Description: by Petra E. Verburg, Graeme Tucker, Wendy Scheil, Jan Jaap H. M. Erwich, Gus A. Dekker, Claire Trelford Roberts Objectives Sexual inequality starts in utero . The contribution of biological sex to the developmental origins of health and disease is increasingly recognized. The aim of this study was to assess and interpret sexual dimorphisms for three major adverse pregnancy outcomes which affect the health of the neonate, child and potentially adult. Methods Retrospective population-based study of 574,358 South Australian singleton live births during 1981–2011. The incidence of three major adverse pregnancy outcomes [preterm birth (PTB), pregnancy induced hypertensive disorders (PIHD) and gestational diabetes mellitus (GDM)] in relation to fetal sex was compared according to traditional and fetus-at-risk (FAR) approaches. Results The traditional approach showed male predominance for PTB [20–24 weeks: Relative Risk (RR) M/F 1.351, 95%-CI 1.274–1.445], spontaneous PTB [25–29 weeks: RR M/F 1.118, 95%-CI 1.044–1.197%], GDM [RR M/F 1.042, 95%-CI 1.011–1.074], overall PIHD [RR M/F 1.053, 95%-CI 1.034–1.072] and PIHD with term birth [RR M/F 1.074, 95%-CI 1.044–1.105]. The FAR approach showed that males were at increased risk for PTB [20–24 weeks: RR M/F 1.273, 95%-CI 1.087–1.490], for spontaneous PTB [25–29 weeks: RR M/F 1.269, 95%-CI 1.143–1.410] and PIHD with term birth [RR M/F 1.074, 95%-CI 1.044–1.105%]. The traditional approach demonstrated female predominance for iatrogenic PTB [25–29 weeks: RR M/F 0.857, 95%-CI 0.780–0.941] and PIHD associated with PTB [25–29 weeks: RR M/F 0.686, 95%-CI 0.581–0.811]. The FAR approach showed that females were at increased risk for PIHD with PTB [25–29 weeks: RR M/F 0.779, 95%-CI 0.648–0.937]. Conclusions This study confirms the presence of sexual dimorphisms and presents a coherent framework based on two analytical approaches to assess and interpret the sexual dimorphisms for major adverse pregnancy outcomes. The mechanisms by which these occur remain elusive, but sex differences in placental gene expression and function are likely to play a key role. Further research on sex differences in placental function and maternal adaptation to pregnancy is required to delineate the causal molecular mechanisms in sex-specific pregnancy outcome. Identifying these mechanisms may inform fetal sex specific tailored antenatal and neonatal care.

Description: by Harald Schrem, Valentin Schneider, Marlene Kurok, Alon Goldis, Maren Dreier, Alexander Kaltenborn, Wilfried Gwinner, Marc Barthold, Jan Liebeneiner, Markus Winny, Jürgen Klempnauer, Moritz Kleine Background The aim of this study is to identify independent pre-transplant cancer risk factors after kidney transplantation and to assess the utility of G-chart analysis for clinical process control. This may contribute to the improvement of cancer surveillance processes in individual transplant centers. Patients and Methods 1655 patients after kidney transplantation at our institution with a total of 9,425 person-years of follow-up were compared retrospectively to the general German population using site-specific standardized-incidence-ratios (SIRs) of observed malignancies. Risk-adjusted multivariable Cox regression was used to identify independent pre-transplant cancer risk factors. G-chart analysis was applied to determine relevant differences in the frequency of cancer occurrences. Results Cancer incidence rates were almost three times higher as compared to the matched general population (SIR = 2.75; 95%-CI: 2.33–3.21). Significantly increased SIRs were observed for renal cell carcinoma (SIR = 22.46), post-transplant lymphoproliferative disorder (SIR = 8.36), prostate cancer (SIR = 2.22), bladder cancer (SIR = 3.24), thyroid cancer (SIR = 10.13) and melanoma (SIR = 3.08). Independent pre-transplant risk factors for cancer-free survival were age 62.6 years (p = 0.001, HR: 1.29), polycystic kidney disease other than autosomal dominant polycystic kidney disease (ADPKD) (p = 0.001, HR: 0.68), high body mass index in kg/m 2 (p

Description: by Prasamit Saurav Baruah, Myriam Beauchemin, Josée Hébert, Richard Bertrand Bcl-xL proteins undergo dynamic phosphorylation/dephosphorylation on Ser49 and Ser62 residues during mitosis. The expression of Bcl-xL(S49A), (S62A) and dual (S49/62A) phosphorylation mutants in tumor cells lead to severe mitotic defects associated with multipolar spindle, chromosome lagging and bridging, and micro-, bi- and multi-nucleated cells. Because the above observations were made in tumor cells which already display genomic instability, we now address the question: will similar effects occur in normal human diploid cells? We studied normal human diploid BJ foreskin fibroblast cells expressing Bcl-xL (wild type), (S49A), (S49D), (S62A), (S62D) and the dual-site (S49/62A) and (S49/62D) mutants. Cells expressing S49 and/or S62 phosphorylation mutants showed reduced kinetics of cell population doubling. These effects on cell population doubling kinetics correlated with early outbreak of senescence with no impact on the cell death rate. Senescent cells displayed typical senescence-associated phenotypes including high-level of senescence-associated β-galactosidase activity, interleukin-6 (IL-6) secretion, tumor suppressor p53 and cyclin-dependent kinase inhibitor p21Waf1/Cip1 activation as well as γH2A.X-associated nuclear chromatin foci. Fluorescence in situ hybridization analysis and Giemsa-banded karyotypes revealed that the expression of Bcl-xL phosphorylation mutants in normal diploid BJ cells provoked chromosome instability and aneuploidy. These findings suggest that dynamic Bcl-xL(S49) and (S62) phosphorylation/dephosphorylation cycles are important in the maintenance of chromosome integrity during mitosis in normal cells. They could impact future strategies aiming to develop and identify compounds that could target not only the anti-apoptotic domain of Bcl-xL protein, but also its mitotic domain for cancer therapy.

Description: by Vera Kloten, Martin Schlensog, Julian Eschenbruch, Janina Gasthaus, Janina Tiedemann, Jolein Mijnes, Timon Heide, Till Braunschweig, Ruth Knüchel, Edgar Dahl NDRG2 , a member of the N-myc downstream-regulated gene family, is thought to be a putative tumor suppressor gene with promising clinical impact in breast cancer. Since breast cancer comprises heterogeneous intrinsic subtypes with distinct clinical outcomes we investigated the pivotal role of NDRG2 in basal-type breast cancers. Based on subtype classified tumor (n = 45) and adjacent normal tissues (n = 17) we examined NDRG2 mRNA expression and CpG-hypermethylation, whose significance was further validated by independent data sets from The Cancer Genome Atlas (TCGA). In addition, NDRG2 protein expression was evaluated immunohistochemically using a tissue micro array (TMA, n = 211). In vitro , we investigated phenotypic effects caused by NDRG2 silencing in the basal A-like HCC1806 as well as NDRG2 over-expression in basal A-like BT20 compared to luminal-type MCF7 breast cancer cells. Our tissue collections demonstrated an overall low NDRG2 mRNA expression in breast cancer subtypes compared to normal breast tissue in line with an increased CpG-hypermethylation in breast cancer tissue. Independent TCGA data sets verified a significant (P

Description: by Viorica Ionut, Orison O. Woolcott, Hasmik J. Mkrtchyan, Darko Stefanovski, Morvarid Kabir, Malini S. Iyer, Huiwen Liu, Ana V. B. Castro, Qiang Wu, Josiane L. Broussard, Cathryn M. Kolka, Isaac Asare-Bediako, Richard N. Bergman Background Exenatide’s effects on glucose metabolism have been studied extensively in diabetes but not in pre-diabetes. Objective We examined the chronic effects of exenatide alone on glucose metabolism in pre-diabetic canines. Design and Methods After 10 weeks of high-fat diet (HFD), adult dogs received one injection of streptozotocin (STZ, 18.5 mg/kg). After induction of pre-diabetes, while maintained on HFD, animals were randomized to receive either exenatide (n = 7) or placebo (n = 7) for 12 weeks. β-Cell function was calculated from the intravenous glucose tolerance test (IVGTT, expressed as the acute insulin response, AIR G ), the oral glucose tolerance test (OGTT, insulinogenic index) and the graded-hyperglycemic clamp (clamp insulinogenic index). Whole-body insulin sensitivity was assessed by the IVGTT. At the end of the study, pancreatic islets were isolated to assess β-cell function in vitro . Results OGTT: STZ caused an increase in glycemia at 120 min by 22.0% (interquartile range, IQR, 31.5%) (P = 0.011). IVGTT: This protocol also showed a reduction in glucose tolerance by 48.8% (IQR, 36.9%) (P = 0.002). AIR G decreased by 54.0% (IQR, 40.7%) (P = 0.010), leading to mild fasting hyperglycemia (P = 0.039). Exenatide, compared with placebo, decreased body weight (P

Description: by Ha Young Kim, Eun Jin Jang, ByeongJu Park, Tae-Young Kim, Soon-Ae Shin, Yong-Chan Ha, Sunmee Jang Background Asian-specific prediction models for estimating individual risk of osteoporotic fractures are rare. We developed a Korean fracture risk prediction model using clinical risk factors and assessed validity of the final model. Methods A total of 718,306 Korean men and women aged 50–90 years were followed for 7 years in a national system-based cohort study. In total, 50% of the subjects were assigned randomly to the development dataset and 50% were assigned to the validation dataset. Clinical risk factors for osteoporotic fracture were assessed at the biennial health check. Data on osteoporotic fractures during the follow-up period were identified by ICD-10 codes and the nationwide database of the National Health Insurance Service (NHIS). Results During the follow-up period, 19,840 osteoporotic fractures were reported (4,889 in men and 14,951 in women) in the development dataset. The assessment tool called the Korean Fracture Risk Score (KFRS) is comprised of a set of nine variables, including age, body mass index, recent fragility fracture, current smoking, high alcohol intake, lack of regular exercise, recent use of oral glucocorticoid, rheumatoid arthritis, and other causes of secondary osteoporosis. The KFRS predicted osteoporotic fractures over the 7 years. This score was validated using an independent dataset. A close relationship with overall fracture rate was observed when we compared the mean predicted scores after applying the KFRS with the observed risks after 7 years within each 10th of predicted risk. Conclusion We developed a Korean specific prediction model for osteoporotic fractures. The KFRS was able to predict risk of fracture in the primary population without bone mineral density testing and is therefore suitable for use in both clinical setting and self-assessment. The website is available at http://www.nhis.or.kr.

Description: by Cecilia Ma, Eva Monsma This paper examines the factor structure and measurement invariance of the Task and Ego Orientation in Sport Questionnaire (TEOSQ) across American and Chinese samples. Results based on the mean and covariance structure analyses supported configural invariance, metric invariance and scalar invariance across groups. Latent means analyses revealed that American sample had significantly higher mean scores on task and ego orientations than the Chinese sample. The findings suggest that the TEOSQ is a valid and reliable instrument in assessing achievement motivation across these two diverse populations.

Description: by Lin Yang, Liangping Xia, Yan Wang, Shaodong Hong, Haiyang Chen, Shaobo Liang, Peijian Peng, Yong Chen Background Poor nutritional status is associated with progression and advanced disease in patients with cancer. The prognostic nutritional index (PNI) may represent a simple method of assessing host immunonutritional status. This study was designed to investigate the prognostic value of the PNI for distant metastasis-free survival (DMFS) in patients with nasopharyngeal carcinoma (NPC). Methods A training cohort of 1,168 patients with non-metastatic NPC from two institutions was retrospectively analyzed. The optimal PNI cutoff value for DMFS was identified using the online tool “Cutoff Finder”. DMFS was analyzed using stratified and adjusted analysis. Propensity score-matched analysis was performed to balance baseline characteristics between the high and low PNI groups. Subsequently, the prognostic value of the PNI for DMFS was validated in an external validation cohort of 756 patients with NPC. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of different prognostic scores. Results The optimal PNI cutoff value was determined to be 51. Low PNI was significantly associated with poorer DMFS than high PNI in univariate analysis (P

Description: by Hung Yuan Chen, Yen Ling Chiu, Shih Ping Hsu, Mei Fen Pai, Ju Yeh Yang, Yu Sen Peng Background Fractures are a common morbidity that lead to worse outcomes in dialysis patients. Fetuin A inhibits vascular calcification (VC), potentially promotes bone mineralization and its level positively correlates with bone mineral density in the general population. On the other hand, the presence of VC is associated with low bone volume in dialysis patients. Whether the fetuin A level and VC can predict the occurrence of fractures in dialysis patients remains unknown. Methods We performed this prospective, observational cohort study including 685 dialysis patients (629 hemodialysis and 56 peritoneal dialysis) from a single center in Taiwan for a median follow-up period of 3.4 years. The baseline fetuin A level and status of presence of aortic arch calcification (VC) and incidence of major fractures (hip, pelvis, humerus, proximal forearm, lower leg or vertebrae) were assessed using adjusted Cox proportional hazards models, recursive partitioning analysis and competing risk models. Results Overall, 177 of the patients had major fractures. The incidence rate of major fractures was 3.29 per 100 person-years. In adjusted analyses, the patients with higher baseline fetuin A levels had a lower incidence of fractures (adjusted hazard ratio (HR), 0.3; 95% CI, 0.18‒0.5, fetuin A tertile 3 vs . tertile 1 and HR, 0.52; 95% CI, 0.34‒0.78, tertile 2 vs . tertile 1). The presence of aortic arch calcification (VC) independently predicted the occurrence of fractures (adjusted HR, 1.95; 95% CI, 1.34‒2.84) as well. When accounting for death as an event in competing risk models, the patients with higher baseline fetuin A levels remained to have a lower incidence of fractures (SHR, 0.31; 95% CI, 0.17‒0.56, fetuin A tertile 3 vs . tertile 1 and 0.51; 95% CI, 0.32‒0.81, tertile 2 vs . tertile 1). Interpretations Lower baseline fetuin A levels and the presence of VC were independently linked to higher risk of incident fractures in prevalent dialysis patients.

Description: by Zhenyu Yuan, Heiko Praxenthaler, Nassif Tabaja, Rubben Torella, Anette Preiss, Dieter Maier, Rhett A. Kovall Notch is a conserved signaling pathway that specifies cell fates in metazoans. Receptor-ligand interactions induce changes in gene expression, which is regulated by the transcription factor CBF1/Su(H)/Lag-1 (CSL). CSL interacts with coregulators to repress and activate transcription from Notch target genes. While the molecular details of the activator complex are relatively well understood, the structure-function of CSL-mediated repressor complexes is poorly defined. In Drosophila , the antagonist Hairless directly binds Su(H) (the fly CSL ortholog) to repress transcription from Notch targets. Here, we determine the X-ray structure of the Su(H)-Hairless complex bound to DNA. Hairless binding produces a large conformational change in Su(H) by interacting with residues in the hydrophobic core of Su(H), illustrating the structural plasticity of CSL molecules to interact with different binding partners. Based on the structure, we designed mutants in Hairless and Su(H) that affect binding, but do not affect formation of the activator complex. These mutants were validated in vitro by isothermal titration calorimetry and yeast two- and three-hybrid assays. Moreover, these mutants allowed us to solely characterize the repressor function of Su(H) in vivo.

Description: by Camille Attané, Marie-Line Peyot, Roxane Lussier, Dongwei Zhang, Erik Joly, S. R. Murthy Madiraju, Marc Prentki Many metabolic studies employ tissue-specific gene knockout mice, which requires breeding of floxed gene mice, available mostly on C57BL/6N (NN) genetic background, with cre or Flp recombinase-expressing mice, available on C57BL/6J (JJ) background, resulting in the generation of mixed C57BL/6NJ (NJ) genetic background mice. Recent awareness of many genetic differences between NN and JJ strains including the deletion of nicotinamide nucleotide transhydrogenase ( nnt ), necessitates examination of the consequence of mixed NJ background on glucose tolerance, beta cell function and other metabolic parameters. Male mice with NN and NJ genetic background were fed with normal or high fat diets (HFD) for 12 weeks and glucose and insulin homeostasis were studied. Genotype had no effect on body weight and food intake in mice fed normal or high fat diets. Insulinemia in the fed and fasted states and after a glucose challenge was lower in HFD-fed NJ mice, even though their glycemia and insulin sensitivity were similar to NN mice. NJ mice showed mild glucose intolerance. Moreover, glucose- but not KCl-stimulated insulin secretion in isolated islets was decreased in HFD-fed NJ vs NN mice without changes in insulin content and beta cell mass. Under normal diet, besides reduced fed insulinemia, NN and NJ mice presented similar metabolic parameters. However, HFD-fed NJ mice displayed lower fed and fasted insulinemia and glucose-induced insulin secretion in vivo and ex vivo , as compared to NN mice. These results strongly caution against using unmatched mixed genetic background C57BL/6 mice for comparisons, particularly under HFD conditions.

Description: by Jill A. Rahnert, Bin Zheng, Matthew B. Hudson, Myra E. Woodworth-Hobbs, S. Russ Price Muscle wasting associated with chronic diseases has been linked to decreased expression of PGC-1α and overexpression of PGC-1α counters muscle loss. CREB, in conjunction with the CREB-regulated transcription coactivator (CRTC2), is a positive modulator of PGC-1α transcription. We previously reported that PGC-1α expression is decreased in skeletal muscle of diabetic rats despite a high level of CREB phosphorylation (i.e., activation), suggesting that CRTC2-CREB signaling may be dysregulated. In this study, the relationship between CREB/CRTC signaling and PGC-1α expression was examined in L6 myotubes treated with dexamethasone (Dex, 48h) to induce atrophy. Dex decreased PGC-1α mRNA and protein as well as the levels of CRTC1 and CRTC2 in the nucleus. Dex also altered the nuclear levels of two known regulators of CRTC2 localization; the amount of calcinuerin catalytic A subunit (CnA) was decreased whereas SIK was increased. To assess PGC-1α transcription, muscle cells were transfected with a PGC-1α luciferase reporter plasmid (PGC-1α-Luc). Dex suppressed PGC-1α luciferase activity while both isobutylmethylxanthine (IBMX) and over-expression of CRTC1 or CRTC2 increased PGC-1α-Luc activity. Mutation of the CRE binding site from PGC-1α-Luc reporter attenuated the responses to both IBMX and the CRTC proteins. Consistent with the reporter gene results, overexpression of CRTC2 produced an increase in CRTC2 in the nucleus and in PGC-1α mRNA and PGC-1α protein. Overexpression of CRTC2 was not sufficient to prevent the decrease in PGC-1α mRNA or protein by Dex. In summary, these data suggest that attenuated CREB/CRTC signaling contributes to the decrease in PGC-1α expression during atrophy.

Description: by Fatima Ochoa-Gonzalez, Alberto R. Cervantes-Villagrana, Julio C. Fernandez-Ruiz, Hilda S. Nava-Ramirez, Adriana C. Hernandez-Correa, Jose A. Enciso-Moreno, Julio E. Castañeda-Delgado

Description: by Abdessamad Ababou, Vassilis Koronakis Gram-negative bacteria such as E . coli use tripartite efflux pumps such as AcrAB-TolC to expel antibiotics and noxious compounds. A key feature of the inner membrane transporter component, AcrB, is a short stretch of residues known as the gate/switch loop that divides the proximal and distal substrate binding pockets. Amino acid substitutions of the gate loop are known to decrease antibiotic resistance conferred by AcrB. Here we present two new AcrB gate loop variants, the first stripped of its bulky side chains, and a second in which the gate loop is removed entirely. By determining the crystal structures of the variant AcrB proteins in the presence and absence of erythromycin and assessing their ability to confer erythromycin tolerance, we demonstrate that the gate loop is important for AcrB export activity but is not required for erythromycin binding.

Description: by Shou-Chieh Wang, Chin-Chin Huang, Cheng-Huang Shen, Lei-Chen Lin, Pei-Wen Zhao, Shih-Ying Chen, Yu-Chiao Deng, Yi-Wen Liu Bladder cancer is highly recurrent after therapy, which has an enormous impact on the health and financial condition of the patient. It is worth developing diagnostic tools for bladder cancer. In our previous study, we found that the bladder carcinogen BBN increased urothelial global DNA CpG methylation and decreased GSTM1 protein expression in mice. Here, the correlation of BBN-decreased GSTM1 and GSTM gene CpG methylation status was analyzed in mice bladders. BBN treatment decreased the protein and mRNA expression of GSTM1, and the CpG methylation ratio of GSTM1 gene promoter was slightly increased in mice bladders. Unlike mouse GSTM1, the human GSTM1 gene tends to be deleted in bladder cancers. Among 7 human bladder cancer cell lines, GSTM1 gene is really null in 6 cell lines except one, T24 cells. The CpG methylation level of GSTM1 was 9.9% and 5-aza-dC did not significantly increase GSTM1 protein and mRNA expression in T24 cells; however, the GSTM5 gene was CpG hypermethylated (65.4%) and 5-aza-dC also did not affect the methylation ratio and mRNA expression. However, in other cell lines without GSTM1, 5-aza-dC increased GSTM5 expression and decreased its CpG DNA methylation ratio from 84.6% to 61.5% in 5637, and from 97.4% to 75% in J82 cells. In summary, two biomarkers of bladder tumor were provided. One is the GSTM1 gene which is down-regulated in mice bladder carcinogenesis and is usually deleted in human urothelial carcinoma, while the other is the GSTM5 gene, which is inactivated by DNA CpG methylation.

Description: by Anna Moretti, Michele Ghidini, Carmine De Angelis, Matteo Lambertini, Chiara Cremolini, Martina Imbimbo, Rossana Berardi, Massimo Di Maio, Stefano Cascinu, Nicla La Verde Background and objectives Relevant heterogeneity exists among Postgraduate Schools in Medical Oncology, also within the same country. In order to provide a comprehensive overview of the landscape of Italian Postgraduate Schools in Medical Oncology, the Italian Association of Medical Oncology (AIOM) undertook an online survey, inviting all the residents to describe their daily activities and to express their overall satisfaction about their programs. Methods A team composed of five residents and three consultants in medical oncology prepared a 38 items questionnaire that was published online in a reserved section, accessible through a link sent by e-mail. Residents were invited to anonymously fill in the questionnaire that included the following sub-sections: quality of teaching, clinical and research activity, overall satisfaction. Results Three-hundred and eleven (57%) out of 547 invited residents filled in the questionnaire. Two-hundred and twenty-three (72%) participants declared that attending lessons was frequently difficult and 153 (49%) declared they did not gain substantial improvement in their knowledge from them. Fifty-five percent stated that they did not receive lessons on palliative care. Their overall judgment about didactic activity was low in 63% of the interviewed. The satisfaction for clinical activity was in 86% of cases good: 84% recognized that, during the training period, they acquired a progressive independence on patients' management. About research activity, the majority (79%) of participants in the survey was actively engaged in managing patients included in clinical trials but the satisfaction level for the involvement in research activities was quite low (54%). Overall, 246 residents (79%) gave a positive global judgment of their Medical Oncology Schools. Conclusions The landscape of Italian Postgraduate Schools in Medical Oncology is quite heterogeneous across the country. Some improvements in the organization of teaching and in the access to research opportunity are needed; the perception about clinical activity and the overall judgment of the programs are quite satisfactory.

Description: by Jian Song, Zhangxiong Liu, Huilong Hong, Yansong Ma, Long Tian, Xinxiu Li, Ying-Hui Li, Rongxia Guan, Yong Guo, Li-Juan Qiu Soybean seed coat exists in a range of colors from yellow, green, brown, black, to bicolor. Classical genetic analysis suggested that soybean seed color was a moderately complex trait controlled by multi-loci. However, only a couple of loci could be detected using a single biparental segregating population. In this study, a combination of association mapping and bulk segregation analysis was employed to identify genes/loci governing this trait in soybean. A total of 14 loci, including nine novel and five previously reported ones, were identified using 176,065 coding SNPs selected from entire SNP dataset among 56 soybean accessions. Four of these loci were confirmed and further mapped using a biparental population developed from the cross between ZP95-5383 (yellow seed color) and NY279 (brown seed color), in which different seed coat colors were further dissected into simple trait pairs (green/yellow, green/black, green/brown, yellow/black, yellow/brown, and black/brown) by continuously developing residual heterozygous lines. By genotyping entire F 2 population using flanking markers located in fine-mapping regions, the genetic basis of seed coat color was fully dissected and these four loci could explain all variations of seed colors in this population. These findings will be useful for map-based cloning of genes as well as marker-assisted breeding in soybean. This work also provides an alternative strategy for systematically isolating genes controlling relative complex trait by association analysis followed by biparental mapping.

Description: by Yuki Murai, Yuko Yotsumoto When individuals are asked to reproduce intervals of stimuli that are intermixedly presented at various times, longer intervals are often underestimated and shorter intervals overestimated. This phenomenon may be attributed to the central tendency of time perception, and suggests that our brain optimally encodes a stimulus interval based on current stimulus input and prior knowledge of the distribution of stimulus intervals. Two distinct systems are thought to be recruited in the perception of sub- and supra-second intervals. Sub-second timing is subject to local sensory processing, whereas supra-second timing depends on more centralized mechanisms. To clarify the factors that influence time perception, the present study investigated how both sensory modality and timescale affect the central tendency. In Experiment 1, participants were asked to reproduce sub- or supra-second intervals, defined by visual or auditory stimuli. In the sub-second range, the magnitude of the central tendency was significantly larger for visual intervals compared to auditory intervals, while visual and auditory intervals exhibited a correlated and comparable central tendency in the supra-second range. In Experiment 2, the ability to discriminate sub-second intervals in the reproduction task was controlled across modalities by using an interval discrimination task. Even when the ability to discriminate intervals was controlled, visual intervals exhibited a larger central tendency than auditory intervals in the sub-second range. In addition, the magnitude of the central tendency for visual and auditory sub-second intervals was significantly correlated. These results suggest that a common modality-independent mechanism is responsible for the supra-second central tendency, and that both the modality-dependent and modality-independent components of the timing system contribute to the central tendency in the sub-second range.

Description: by Martin W. von Websky, Koji Kitamura, Isis Ludwig-Portugall, Christian Kurts, Maximilian von Laffert, Joel LeMaoult, Edgardo D. Carosella, Kareem Abu-Elmagd, Joerg C. Kalff, Nico Schäfer The non-classical MHC I paralogue HLA-G is expressed by cytotrophoblast cells and implicated with fetomaternal tolerance by downregulating the maternal adaptive and innate immune response against the fetus. HLA-G expression correlates with favorable graft outcome in humans and recently promising immunosuppressive effects of therapeutic HLA-G in experimental transplantation (skin allograft acceptance) were shown. Consequently, we examined this novel therapeutic approach in solid organ transplantation. In this study, therapeutic recombinant HLA-G5 was evaluated for the first time in a solid organ model of acute rejection (ACR) after orthotopic intestinal transplantation (ITX). Allogenic ITX was performed in rats (Brown Norway to Lewis) with and without HLA-G treatment. It was found that HLA-G treatment significantly reduced histologically proven ACR at both an early and late postoperative timepoint (POD 4/7), concomitant to a functionally preserved graft contractility at POD 7. Interestingly, graft infiltration by myeloperoxidase+ cells was significantly reduced at POD7 by HLA-G treatment. Moreover, HLA-G treatment showed an effect on the allogenic T-cell immune response as assessed by flow cytometry: The influx of recipient-derived CD8 + T-cells into the graft mesenteric lymphnodes at POD7 was significantly reduced while CD4 + populations were not affected. As a potential mechanism of action, an induction of T-reg populations in the mesenteric lymphnodes was postulated, but flow cytometric analysis of classical CD4 + /CD25 + /FoxP3 + T reg -cells showed no significant alteration by HLA-G treatment. The novel therapeutic approach using recombinant HLA-G5 reported herein demonstrates a significant immunosuppressive effect in this model of allogenic experimental intestinal transplantation. This effect may be mediated via inhibition of recipient-derived CD8 + T-cell populations either directly or by induction of non-classical T reg populations.

Description: by Nayana Wijayathilaka, Madhava Meegaskumbura Vocalizing behavior of frogs and toads, once quantified, is useful for systematics, rapid species identification, behavioral experimentation and conservation monitoring. But yet, for many lineages vocalizations remain unknown or poorly quantified, especially in diversity rich tropical regions. Here we provide a quantitative acoustical analysis for all four Sri Lankan congeners of the genus Microhyla . Three of these species are endemic to the island, but Microhyla ornata is regionally widespread. Two of these endemics, M . karunaratnei (Critically Endangered) and M . zeylanica (Endangered), are highly threatened montane isolates; the other, M . mihintalei , is relatively common across the dry lowlands. We recorded and analyzed 100 advertisement calls from five calling males for each species, except for M . zeylanica , which only had 53 calls from three males suitable for analyses. All four species call in choruses and their vocal repertoires are simple compared to most frogs. Their calls contain multiple pulses and no frequency modulation. We quantified eight call characters. Call duration and number of pulses were higher for the two montane isolates (inhabiting cooler habitats at higher altitudes) compared to their lowland congeners. Microhyla zeylanica has the longest call duration (of 1.8 ± 0.12 s) and the highest number of pulses (of 61–92 pulses). The smallest of the species, Microhyla karunaratnei (16.2–18.3 mm), has the highest mean dominant frequency (3.3 ± 0.14 kHz) and pulse rate (77 ± 5.8 pulses per second). The calls separate well in the Principal Component space: PC1 axis is mostly explained by the number of pulses per call and call duration; PC2 is mostly explained by the pulse rate. A canonical means plot of a Discriminant Function analysis shows non-overlapping 95% confidence ellipses. This suggests that some call parameters can be used to distinguish these species effectively. We provide detailed descriptions for eight call properties and compare these with congeners for which data is available. This work provides a foundation for comparative bioacoustic analyses and species monitoring while facilitating the systematics of Microhyla across its range.

Description: by Rozalia Korbut, Foojan Mehrdana, Per Walter Kania, Marianne Halberg Larsen, Dorte Frees, Inger Dalsgaard, Louise von Gersdorff Jørgensen Immersion-vaccines (bacterins) are routinely used for aquacultured rainbow trout to protect against Yersinia ruckeri (Yr). During immersion vaccination, rainbow trout take up and process the antigens, which induce protection. The zebrafish was used as a model organism to study uptake mechanisms and subsequent antigen transport in fish. A genetically modified Yr was developed to constitutively express green fluorescent protein (GFP) and was used for bacterin production. Larval, juvenile and adult transparent zebrafish (tra:nac mutant) received a bath in the bacterin for up to 30 minutes. Samples were taken after 1 min, 15 min, 30 min, 2 h, 12 h and 24 h. At each sampling point fish were used for live imaging of the uptake using a fluorescence stereomicroscope and for immunohistochemistry (IHC). In adult fish, the bacterin could be traced within 30 min in scale pockets, skin, oesophagus, intestine and fins. Within two hours post bath (pb) Yr-antigens were visible in the spleen and at 24 h in liver and kidney. Bacteria were associated with the gills, but uptake at this location was limited. Antigens were rarely detected in the blood and never in the nares. In juvenile fish uptake of the bacterin was seen in the intestine 30 min pb and in the nares 2 hpb but never in scale pockets. Antigens were detected in the spleen 12 hpb. Zebrafish larvae exhibited major Yr uptake only in the mid-intestine enterocytes 24 hpb. The different life stages of zebrafish varied with regard to uptake locations, however the gut was consistently a major uptake site. Zebrafish and rainbow trout tend to have similar uptake mechanisms following immersion or bath vaccination, which points towards zebrafish as a suitable model organism for this aquacultured species.

Description: by Seema Thakur, Rajesh K. Grover, Sanjay Gupta, Ajay K. Yadav, Bhudev C. Das Of several subtypes of breast cancer, triple negative breast cancer (TNBC) is a highly aggressive tumor that lacks expression of hormone receptors for estrogen, progesterone and human epidermal growth factor receptor 2 and shows a worst prognosis. The small noncoding RNAs (miRNAs) considered as master regulator of gene expression play a key role in cancer initiation, progression and drug resistance and have emerged as attractive molecular biomarkers for diagnosis, prognosis and treatment targets in cancer. We have done expression profiling of selected miRNAs in paired serum and tissue samples of TNBC patients and corresponding cell lines and compared with that of other subtypes, in order to identify novel serum miRNA biomarkers for early detection and progression of TNBC. A total of 85 paired tumor tissues and sera with an equal number of adjacent normal tissue margins and normal sera from age matched healthy women including tissue and sera samples from 15 benign fibroadenomas were employed for the study. We report for the first time an extremely high prevalence (73.9%) of TNBC in premenopausal women below 35 years of age and a significant altered expression of a panel of three specific oncogenic miRNAs- miR-21, miR-221, miR-210, and three tumor suppressor miRNAs- miR-195, miR-145 and Let-7a in both tissues and corresponding sera of TNBC patients when compared with triple positive breast cancer (TPBC) patients. While miR-21, miR-221 and miR-210 showed significant over-expression, miR-195 and miR-145 were downregulated and well correlated with various clinicopathological and demographic risk factors, tumor grade, clinical stage and hormone receptor status. Interestingly, despite being a known tumor suppressor, Let-7a showed a significant overexpression in TNBCs. It is suggested that this panel of six miRNA signature may serve as a minimally invasive biomarker for an early detection of TNBC patients.

Description: by Martin G. Schwacha, Meenakshi Rani, Susannah E. Nicholson, Aaron M. Lewis, Travis L. Holloway, Salvador Sordo, Andrew P. Cap Background Gamma delta T-cells have been shown to be important to the early immunoinflammatory response to injury, independent of infection. This unique T-cell population acts to regulate cell trafficking and the release of cytokines and growth factors. We propose this sterile inflammatory response is in part associated with damage associated molecular patterns (DAMPs) generated by major injury, such as burn, and mediated via toll-like receptors (TLRs). It is unknown whether DAMPs can activate resident γδ T-cells that reside in skin. Methods Gamma delta T-cells were isolated from the skin of male C57BL/6 mice by enzymatic digestion. Mitochondrial DAMPs (MTDs) were generated from mitochondria isolated from mouse livers by sonication and centrifugation. Dermal γδ T-cells were incubated with MTDs (0–500 μg/ml) for 24 hr and cells and supernatants were collected for analysis. Results MTDs activated dermal γδ T-cells, as evidenced by increased TLR2 and TLR4 expression following in vitro exposure. MTDs also induced the production of inflammatory cytokines (IL-1β, IL-6), and growth factors (PDGF and VEGF) by γδ T-cells. Conclusions These findings herein support the concept that MTDs released after tissue/cellular injury are capable of activating dermal γδ T-cells. We propose that the activation of this unique T-cell population is central in the initiation of sterile inflammation and also contributes to the subsequent healing processes.

Description: by Tamaki Hayase Like various stressors, the addictive use of nicotine (NC) is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB) system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC) inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM). Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test) and depression-like (forced swimming test) behaviors, which were observed in mice treated with repeated (4 days) NC (subcutaneous 0.8 mg/kg) and/or IM (10 min), were blocked by the HDAC inhibitors sodium butyrate (SB) and valproic acid (VA). The cannabinoid type 1 (CB1) agonist ACPA (arachidonylcyclopropylamide; AC) also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR), which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor-induced antidepressant-like effects may reflect the characteristic involvement of histone acetylation within the NC-related neurotransmitter systems other than the ECB system.

Description: by Mario Novkovic, Lucas Onder, Jovana Cupovic, Jun Abe, David Bomze, Viviana Cremasco, Elke Scandella, Jens V. Stein, Gennady Bocharov, Shannon J. Turley, Burkhard Ludewig Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8 + T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.

Description: by Jose L. Herrera, Ravi Srinivasan, John S. Brownstein, Alison P. Galvani, Lauren Ancel Meyers As infectious disease surveillance systems expand to include digital, crowd-sourced, and social network data, public health agencies are gaining unprecedented access to high-resolution data and have an opportunity to selectively monitor informative individuals. Contact networks, which are the webs of interaction through which diseases spread, determine whether and when individuals become infected, and thus who might serve as early and accurate surveillance sensors. Here, we evaluate three strategies for selecting sensors—sampling the most connected, random, and friends of random individuals—in three complex social networks—a simple scale-free network, an empirical Venezuelan college student network, and an empirical Montreal wireless hotspot usage network. Across five different surveillance goals—early and accurate detection of epidemic emergence and peak, and general situational awareness—we find that the optimal choice of sensors depends on the public health goal, the underlying network and the reproduction number of the disease ( R 0 ). For diseases with a low R 0 , the most connected individuals provide the earliest and most accurate information about both the onset and peak of an outbreak. However, identifying network hubs is often impractical, and they can be misleading if monitored for general situational awareness, if the underlying network has significant community structure, or if R 0 is high or unknown. Taking a theoretical approach, we also derive the optimal surveillance system for early outbreak detection but find that real-world identification of such sensors would be nearly impossible. By contrast, the friends-of-random strategy offers a more practical and robust alternative. It can be readily implemented without prior knowledge of the network, and by identifying sensors with higher than average, but not the highest, epidemiological risk, it provides reasonably early and accurate information.

Description: by Liying Guan, Xuehua Ma, Jingyan Zhang, Jia-Jia Liu, Yingchun Wang, Mei Ding Eukaryotic cells extend a variety of surface protrusions to direct cell motility. Formation of protrusions is mediated by coordinated actions between the plasma membrane and the underlying actin cytoskeleton. Here, we found that the single calponin homology (CH) domain-containing protein CHDP-1 induces the formation of cell protrusions in C . elegans . CHDP-1 is anchored to the cortex through its amphipathic helix. CHDP-1 associates through its CH domain with the small GTPase Rac1/CED-10, which is a key regulator of the actin cytoskeleton. CHDP-1 preferentially binds to the GTP-bound active form of the CED-10 protein and preserves the membrane localization of GTP-CED-10. Hence, by coupling membrane expansion to Rac1-mediated actin dynamics, CHDP-1 promotes the formation of cellular protrusions in vivo .

Description: by Masashi Naito, Masaki Mori, Masayo Inagawa, Kohei Miyata, Naohiro Hashimoto, Sakae Tanaka, Hiroshi Asahara Cell differentiation status is defined by the gene expression profile, which is coordinately controlled by epigenetic mechanisms. Cell type-specific DNA methylation patterns are established by chromatin modifiers including de novo DNA methyltransferases, such as Dnmt3a and Dnmt3b . Since the discovery of the myogenic master gene MyoD , myogenic differentiation has been utilized as a model system to study tissue differentiation. Although knowledge about myogenic gene networks is accumulating, there is only a limited understanding of how DNA methylation controls the myogenic gene program. With an aim to elucidate the role of DNA methylation in muscle development and regeneration, we investigate the consequences of mutating Dnmt3a in muscle precursor cells in mice. Pax3 promoter-driven Dnmt3a -conditional knockout (cKO) mice exhibit decreased organ mass in the skeletal muscles, and attenuated regeneration after cardiotoxin-induced muscle injury. In addition, Dnmt3a -null satellite cells (SCs) exhibit a striking loss of proliferation in culture. Transcriptome analysis reveals dysregulated expression of p57Kip2 , a member of the Cip/Kip family of cyclin-dependent kinase inhibitors (CDKIs), in the Dnmt3a -KO SCs. Moreover, RNAi-mediated depletion of p57Kip2 replenishes the proliferation activity of the SCs, thus establishing a role for the Dnmt3a - p57Kip2 axis in the regulation of SC proliferation. Consistent with these findings, Dnmt3a -cKO muscles exhibit fewer Pax7 + SCs, which show increased expression of p57Kip2 protein. Thus, Dnmt3a is found to maintain muscle homeostasis by epigenetically regulating the proliferation of SCs through p57Kip2 .

Description: by William Zerges

Description: by Wenjun Ji, Zhou Shi, Jingyi Huang, Shuo Li

Description: by Sheetal Prakash Silal, Francesca Little, Karen Irma Barnes, Lisa Jane White

Description: by Christian Vinueza-Burgos, María Cevallos, Lenin Ron-Garrido, Sophie Bertrand, Lieven De Zutter Salmonella is frequently found in poultry and represent an important source for human gastrointestinal infections worldwide. The aim of this study was to investigate the prevalence, genotypes and antimicrobial resistance of Salmonella serotypes in broilers from Ecuador. Caeca content from 388 at random selected broiler batches were collected in 6 slaughterhouses during 1 year and analyzed by the ISO 6579/Amd1 protocol for the isolation for Salmonella . Isolates were serotyped and genotypic variation was acceded by pulsed field gel electrophoresis. MIC values for sulfamethoxazole, gentamicin, ciprofloxacin, ampicillin, cefotaxime, ceftazidime, tetracycline, streptomycin, trimethropim, chloramphenicol, colistin, florfenicol, kanamycin and nalidixic acid were obtained. Presence of bla CTX-M , bla TEM, bla SHV and bla CMY ; and mcr-1 plasmid genes was investigated in resistant strains to cefotaxime and colistin respectively. Prevalence at batch level was 16.0%. The most common serotype was S . Infantis (83.9%) followed by S . Enteritidis (14.5%) and S . Corvallis (1.6%). The pulsed field gel electrophoresis analysis showed that S . Corvallis, S . Enteritidis and S . Infantis isolates belonged to 1, 2 and 12 genotypes respectively. S . Infantis isolates showed high resistance rates to 12 antibiotics ranging from 57.7% (kanamycin) up to 98.1% (nalidixic acid and sulfamethoxazole). All S . Enteritidis isolates showed resistance to colistin. High multiresistant patterns were found for all the serotypes. The bla CTX-M gene was present in 33 S . Infantis isolates while mcr-1 was negative in 10 colistin resistant isolates. This study provides the first set of scientific data on prevalence and multidrug-resistant Salmonella coming from commercial poultry in Ecuador.

Description: by Chun-Ta Huang, Yu-Chung Chuang, Yi-Ju Tsai, Wen-Je Ko, Chong-Jen Yu Background Severe sepsis is a potentially deadly illness and always requires intensive care. Do-not-resuscitate (DNR) orders remain a debated issue in critical care and limited data exist about its impact on care of septic patients, particularly in East Asia. We sought to assess outcome of severe sepsis patients with regard to DNR status in Taiwan. Methods A retrospective cohort study was conducted in intensive care units (ICUs) between 2008 and 2010. All severe sepsis patients were included for analysis. Primary outcome was association between DNR orders and ICU mortality. Volume of interventions was used as proxy indicator to indicate aggressiveness of care. Results Sixty-seven (9.4%) of 712 patients had DNR orders on ICU admission, and these patients were older and had higher disease severity compared with patients without DNR orders. Notably, DNR patients experienced high ICU mortality (90%). Multivariate analysis revealed that the presence of DNR orders was independently associated with ICU mortality (odds ratio: 6.13; 95% confidence interval: 2.66–14.10). In propensity score-matched cohort, ICU mortality rate (91%) in the DNR group was statistically higher than that (62%) in the non-DNR group (p

Description: by Abbas Mirvakili, Mohammad Hossein Dadgarnia, Mohammad Hossein Baradaranfar, Saeid Atighechi, Vahid Zand, Abdollah Ansari

Description: by Julie M. Butler, Karen E. Field, Karen P. Maruska Fishes use multimodal signals during both inter- and intra-sexual displays to convey information about their sex, reproductive state, and social status. These complex behavioral displays can include visual, auditory, olfactory, tactile, and hydrodynamic signals, and the relative role of each sensory channel in these complex multi-sensory interactions is a common focus of neuroethology. The mechanosensory lateral line system of fishes detects near-body water movements and is implicated in a variety of behaviors including schooling, rheotaxis, social communication, and prey detection. Cobalt chloride is commonly used to chemically ablate lateral line neuromasts, thereby eliminating water-movement cues to test for mechanosensory-mediated behavioral functions. However, cobalt acts as a nonspecific calcium channel antagonist and could potentially disrupt function of all superficially located sensory receptor cells, including those for chemosensing. Here, we examined whether CoCl 2 treatment used to ablate the lateral line system also impairs olfaction in three freshwater fishes, the African cichlid fish Astatotilapia burtoni , goldfish Carassius auratus , and the Mexican blind cavefish Astyanax mexicanus . To examine the impact of CoCl 2 on the activity of peripheral receptors, we quantified DASPEI fluorescence intensity of the olfactory epithelium from fish exposed to control and CoCl 2 solutions. In addition, we examined brain activation in olfactory processing regions of A . burtoni immersed in either control or cobalt solutions. All three species exposed to CoCl 2 had decreased DASPEI staining of the olfactory epithelium, and in A . burtoni , cobalt treatment caused reduced neural activation in olfactory processing regions of the brain. To our knowledge this is the first empirical evidence demonstrating that the same CoCl 2 treatment used to ablate the lateral line system also impairs olfactory function. These data have important implications for the use of CoCl 2 in future research and suggest that previous studies using CoCl 2 should be reinterpreted in the context of both impaired mechanoreception and olfaction.

Description: by Tsugiko Kurita, Kotaro Sakurai, Youji Takeda, Toru Horinouchi, Ichiro Kusumi Objective Surgical intervention can result in complete seizure remission rates of up to 80% in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). However, certain patients cannot be treated surgically for various reasons. We analyzed the very long-term clinical outcomes of patients with TLE-HS who could not be treated surgically. Methods Subjects were selected from among patients with TLE-HS who were actively followed up for 〉10 years and treated with medication without surgical treatment. Patient medical records were used to retrospectively study seizure frequency, various clinical factors, and social adjustment. Patients who were seizure-free or had only aura were classified into Group 1; the others were classified into Group 2. Clinical factors including both patient and disease-specific factors were compared between the two groups. Current social adjustment, including the education, work, and economic status of each patient, was also investigated. Results Forty-one (41) subjects met the criteria for analysis, of which 12 (29%) were classified into Group 1. The average age of patients in Group 1 was higher than that of Group 2 (p = 0.0468). Group 2 included a significantly higher rate of patients who had more than one seizure per week at the onset (p = 0.0328), as well as a greater mean number of anti-epileptic drugs taken (p = 0.0024). Regarding social adjustment, Group 2 contained significantly fewer current jobholders than Group 1 (p = 0.0288). Conclusions After very long-term follow-up periods, 29% of patients with TLE-HS had a good outcome through treatment with anticonvulsant medications. Older patients tended to have fewer seizures, and seizure frequency at the onset was the only factor that predicted outcome.

Description: by Ingebjørg Helena Nymo, Marit Seppola, Sascha Al Dahouk, Kathrine Ryvold Bakkemo, María Pilar Jiménez de Bagüés, Jacques Godfroid, Anett Kristin Larsen Pathology has not been observed in true seals infected with Brucella pinnipedialis . A lack of intracellular survival and multiplication of B . pinnipedialis in hooded seal ( Cystophora cristata ) macrophages in vitro indicates a lack of chronic infection in hooded seals. Both epidemiology and bacteriological patterns in the hooded seal point to a transient infection of environmental origin, possibly through the food chain. To analyse the potential role of fish in the transmission of B . pinnipedialis , Atlantic cod ( Gadus morhua ) were injected intraperitoneally with 7.5 x 10 7 bacteria of a hooded seal field isolate. Samples of blood, liver, spleen, muscle, heart, head kidney, female gonads and feces were collected on days 1, 7, 14 and 28 post infection to assess the bacterial load, and to determine the expression of immune genes and the specific antibody response. Challenged fish showed an extended period of bacteremia through day 14 and viable bacteria were observed in all organs sampled, except muscle, until day 28. Neither gross lesions nor mortality were recorded. Anti- Brucella antibodies were detected from day 14 onwards and the expression of hepcidin, cathelicidin, interleukin (IL)-1β, IL-10, and interferon (IFN)-γ genes were significantly increased in spleen at day 1 and 28. Primary mononuclear cells isolated from head kidneys of Atlantic cod were exposed to B . pinnipedialis reference (NCTC 12890) and hooded seal (17a-1) strain. Both bacterial strains invaded mononuclear cells and survived intracellularly without any major reduction in bacterial counts for at least 48 hours. Our study shows that the B . pinnipedialis strain isolated from hooded seal survives in Atlantic cod, and suggests that Atlantic cod could play a role in the transmission of B . pinnipedialis to hooded seals in the wild.

Description: by Muskan Jain, Rituraj Batth, Sumita Kumari, Ananda Mustafiz The glyoxalase pathway is ubiquitously found in all the organisms ranging from prokaryotes to eukaryotes. It acts as a major pathway for detoxification of methylglyoxal (MG), which deleteriously affects the biological system in stress conditions. The first important enzyme of this system is Glyoxalase I (GLYI). It is a metalloenzyme which requires divalent metal ions for its activity. This divalent metal ion can be either Zn 2+ as found in most of eukaryotes or Ni 2+ as seen in prokaryotes. In the present study, we have found three active GLYI enzymes (AtGLYI2, AtGLYI3 and AtGLYI6) belonging to different metal activation classes coexisting in Arabidopsis thaliana . These enzymes have been found to efficiently complement the GLYI yeast mutants. These three enzymes have been characterized in terms of their activity, metal dependency, kinetic parameters and their role in conferring tolerance to multiple abiotic stresses in E . coli and yeast. AtGLYI2 was found to be Zn 2+ dependent whereas AtGLYI3 and AtGLYI6 were Ni 2+ dependent. Enzyme activity of Zn 2+ dependent enzyme, AtGLYI2, was observed to be exceptionally high (~250–670 fold) as compared to Ni 2+ dependent enzymes, AtGLYI3 and AtGLYI6. The activity of these GLYI enzymes correlated well to their role in stress tolerance. Heterologous expression of these enzymes in E . coli led to better tolerance against various stress conditions. This is the first report of a higher eukaryotic species having multiple active GLYI enzymes belonging to different metal activation classes.

Description: by Tomohiko Kazama, Kinya Toriyama Nuclear genome substitutions between subspecies can lead to cytoplasmic male sterility (CMS) through incompatibility between nuclear and mitochondrial genomes. Boro-Taichung (BT)-type CMS rice was obtained by substituting the nuclear genome of Oryza sativa subsp. indica cultivar Chinsurah Boro II with that of Oryza sativa subsp. japonica cultivar Taichung 65. In BT-type CMS rice, the mitochondrial gene orf79 is associated with male sterility. A complete sequence of the Boro-type mitochondrial genome responsible for BT-type CMS has not been determined to date. Here, we used pyrosequencing to construct the Boro-type mitochondrial genome. The contiguous sequences were assembled into five circular DNA molecules, four of which could be connected into a single circle. The two resulting subgenomic circles were unable to form a reliable master circle, as recombination between them was scarcely detected. We also found an unequal abundance of DNA molecules for the two loci of atp6 . These results indicate the presence of multi-partite DNA molecules in the Boro-type mitochondrial genome. Expression patterns were investigated for Boro-type mitochondria-specific orf s, which were not found in the mitochondria from the standard japonica cultivar Nipponbare. Restorer of fertility 1 (RF1)-dependent RNA processing has been observed in orf79 -containing RNA but was not detected in other Boro-type mitochondria-specific orf s, supporting the conclusion that orf79 is a unique CMS-associated gene in Boro-type mitochondria.

Description: by Xierong Wei, Amanda J. Smith, David W. Forrest, Gabriel A. Cardenas, Dano W. Beck, Marlene LaLota, Lisa R. Metsch, Catlainn Sionean, S. Michele Owen, Jeffrey A. Johnson Objective To assess the utility of cost-effective dried blood spot (DBS) field sampling for incidence and drug resistance surveillance of persons at high risk for HIV infection. Methods We evaluated DBS collected in 2007–2010 in non-clinical settings by finger-stick from HIV-positive heterosexuals at increased risk of HIV infection (n = 124), men who have sex with men (MSM, n = 110), and persons who inject drugs (PWID, n = 58). Relative proportions of recent-infection findings among risk groups were assessed at avidity index (AI) cutoffs of ≤25%, ≤30%, and ≤35%, corresponding to an infection mean duration of recency (MDR) of 220.6, 250.4, and 278.3 days, respectively. Drug resistance mutation prevalence was compared among the risk groups and avidity indices. Results HIV antibody avidity testing of all self-reported ARV-naïve persons (n = 186) resulted in 9.7%, 11.3% and 14.0% with findings within the 221, 250, and 278-day MDRs, respectively. The proportion of ARV-naïve MSM, heterosexuals, and PWID reporting only one risk category who had findings below the suggested 30% AI was 23.1%, 6.9% and 3.6% (p

Description: by Li Zhang, Lihua Wu, Feng Tian, Zheng Wang A large amount of medical waste is produced during disaster relief, posing a potential hazard to the habitat and the environment. A comprehensive understanding of the composition and characteristics of medical waste that requires management is one of the most basic steps in the development of a plan for medical waste management. Unfortunately, limited reliable information is available in the open literature on the characteristics of the medical waste that is generated at disaster relief sites. This paper discusses the analysis of the composition and characteristics of medical waste at a disaster relief site using the retrospection-simulation-revision method. For this study, we obtained 35 medical relief records of the Wenchuan Earthquake, Sichuan, May 2008 from a field cabin hospital. We first present a retrospective analysis of the relief medical records, and then, we simulate the medical waste generated in the affected areas. We ultimately determine the composition and characteristics of medical waste in the affected areas using untreated medical waste to revise the composition of the simulated medical waste. The results from 35 cases showed that the medical waste generated from disaster relief consists of the following: plastic (43.2%), biomass (26.3%), synthetic fiber (15.3%), rubber (6.6%), liquid (6.6%), inorganic salts (0.3%) and metals (1.7%). The bulk density of medical relief waste is 249 kg/m 3 , and the moisture content is 44.75%. The data should be provided to assist the collection, segregation, storage, transportation, disposal and contamination control of medical waste in affected areas. In this paper, we wish to introduce this research method of restoring the medical waste generated in disaster relief to readers and researchers. In addition, we hope more disaster relief agencies will become aware of the significance of medical case recording and storing. This may be very important for the environmental evaluation of medical waste in disaster areas, as well as for medical waste management and disposal.

Description: by Jan Skoda, Marketa Hermanova, Tomas Loja, Pavel Nemec, Jakub Neradil, Petr Karasek, Renata Veselska Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of putative CSC markers—CD24, CD44, epithelial cell adhesion molecule (EpCAM), CD133, and nestin—by immunofluorescence, flow cytometry and quantitative PCR in 3 PDAC-derived cell lines and by immunohistochemistry in 3 corresponding tumor samples. We showed high expression of the examined CSC markers among all of the cell lines and tumor samples, with the exception of CD24 and CD44, which were enriched under in vitro conditions compared with tumor tissues. The proportions of cells positive for the remaining markers were comparable to those detected in the corresponding tumors. Co-expression analysis using flow cytometry revealed that CD24 + /CD44 + /EpCAM + /CD133 + cells represented a significant population of the cells (range, 43 to 72%) among the cell lines. The highest proportion of CD24 + /CD44 + /EpCAM + /CD133 + cells was detected in the cell line derived from the tumor of a patient with the shortest survival. Using gene expression profiling, we further identified the specific pro-tumorigenic expression profile of this cell line compared with the profiles of the other two cell lines. Together, CD24 + /CD44 + /EpCAM + /CD133 + cells are present in PDAC cell lines derived from primary tumors, and their increased proportion corresponds with a pro-tumorigenic gene expression profile.

Description: by Tarcísio Visintin da Silva Galdino, Sunil Kumar, Leonardo S. S. Oliveira, Acelino C. Alfenas, Lisa G. Neven, Abdullah M. Al-Sadi, Marcelo C. Picanço The Mango Sudden Decline (MSD), also referred to as Mango Wilt, is an important disease of mango in Brazil, Oman and Pakistan. This fungus is mainly disseminated by the mango bark beetle, Hypocryphalus mangiferae (Stebbing), by infected plant material, and the infested soils where it is able to survive for long periods. The best way to avoid losses due to MSD is to prevent its establishment in mango production areas. Our objectives in this study were to: (1) predict the global potential distribution of MSD, (2) identify the mango growing areas that are under potential risk of MSD establishment, and (3) identify climatic factors associated with MSD distribution. Occurrence records were collected from Brazil, Oman and Pakistan where the disease is currently known to occur in mango. We used the correlative maximum entropy based model (MaxEnt) algorithm to assess the global potential distribution of MSD. The MaxEnt model predicted suitable areas in countries where the disease does not already occur in mango, but where mango is grown. Among these areas are the largest mango producers in the world including India, China, Thailand, Indonesia, and Mexico. The mean annual temperature, precipitation of coldest quarter, precipitation seasonality, and precipitation of driest month variables contributed most to the potential distribution of MSD disease. The mango bark beetle vector is known to occur beyond the locations where MSD currently exists and where the model predicted suitable areas, thus showing a high likelihood for disease establishment in areas predicted by our model. Our study is the first to map the potential risk of MSD establishment on a global scale. This information can be used in designing strategies to prevent introduction and establishment of MSD disease, and in preparation of efficient pest risk assessments and monitoring programs.

Description: by Ge Song, Xiao-Xia Shao, Qing-Ping Wu, Zeng-Guang Xu, Ya-Li Liu, Zhan-Yun Guo We recently developed novel bioluminescent binding assays for several protein/peptide hormones to study their interactions with receptors using the so far brightest NanoLuc reporter. To validate the novel bioluminescent binding assay using a variety of protein/peptide hormones, in the present work we applied it to the fibroblast growth factor (FGF) family using the prototype member FGF2 as an example. A fully active recombinant FGF2 retaining a unique exposed cysteine (Cys) residue was chemically conjugated with an engineered NanoLuc carrying a unique exposed Cys residue at the C-terminus via formation of an intermolecular disulfide linkage. The NanoLuc-conjugated FGF2 (FGF2-Luc) retained high binding affinity to the overexpressed FGFR1 and the endogenous FGF receptor with the calculated dissociation constants of 161 ± 21 pM ( n = 3) and 25 ± 4 pM ( n = 3), respectively. In competition binding assays using FGF2-Luc as a tracer, receptor-binding potencies of wild-type or mutant FGF2s were accurately quantified. Thus, FGF2-Luc represents a novel non-radioactive tracer for the quantitative measurement of ligand–receptor interactions in the FGF family. These data suggest that the novel bioluminescent binding assay can be applied to a variety of protein/peptide hormones for ligand–receptor interaction studies.

Description: by Isabel C. Caballero, John M. Bates, Mary Hennen, Mary V. Ashley Peregrine falcons ( Falco peregrinus ) were extirpated from most of the continental United States by widespread use of the pesticide DDT in the 1960s. Populations have rebounded with banning of the pesticide and successful implementation of captive breeding and hacking programs. An essentially new population of Midwestern peregrines now exists that is comprised almost entirely of urban-nesting birds. The new population is considered to be of mixed ancestry, occurs at relatively high densities, and has nest sites in close proximity, factors that could influence breeding behaviors including mate fidelity, nest-site fidelity, extra-pair paternity, and natal dispersal. We investigated these behaviors using a combination of field observations and DNA microsatellite genotyping. Data for eleven microsatellite DNA markers, including eight newly developed for the species, were analyzed from a total of 350 birds from nine Midwestern cities, representing 149 broods collected at 20 nest sites. To document breeding behavior, parentage was inferred by likelihood techniques when both parents were sampled and by parental genotype reconstruction when only one parent was sampled. In cases where neither parent was sampled, a sibship reconstruction approach was used. We found high mate fidelity and nest-site fidelity in urban peregrines; in 122 nesting attempts made by long-term breeders, only 12 (9.8%) mate changes and six (4.9%) nest-site changes occurred. Only one brood (of 35 tested) revealed extra-pair paternity and involved a male tending two offspring of a recently acquired mate. Natal dispersal patterns indicated that female peregrines dispersed on average 226 km, almost twice the distance of males (average 124 km). Despite the novel environment of cities, our results suggest that monogamous breeding, nest fidelity, and female natal dispersal are high in urban peregrines, not unlike other raptors living in non-urban habitats.

Description: by Henrik H. Hansen, Katrine Fabricius, Pernille Barkholt, Pernille Kongsbak-Wismann, Chantal Schlumberger, Jacob Jelsing, Dick Terwel, Annelies Termont, Charles Pyke, Lotte Bjerre Knudsen, Niels Vrang One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i . e . the ‘London’ (hAPP Lon/ PS1 A246E ) and ‘Swedish’ mutation variant (hAPP Swe /PS1 ΔE9 ) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPP Lon/ PS1 A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPP Swe /PS1 ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPP Swe /PS1 ΔE9 mice exhibited considerably higher cerebral plaque load than hAPP Lon/ PS1 A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPP Lon /PS1 A246E and hAPP Swe /PS1 ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

Description: by Ye Fang, Yun Ding, Wei P. Feinstein, David M. Koppelman, Juana Moreno, Mark Jarrell, J. Ramanujam, Michal Brylinski Computational modeling of drug binding to proteins is an integral component of direct drug design. Particularly, structure-based virtual screening is often used to perform large-scale modeling of putative associations between small organic molecules and their pharmacologically relevant protein targets. Because of a large number of drug candidates to be evaluated, an accurate and fast docking engine is a critical element of virtual screening. Consequently, highly optimized docking codes are of paramount importance for the effectiveness of virtual screening methods. In this communication, we describe the implementation, tuning and performance characteristics of GeauxDock, a recently developed molecular docking program. GeauxDock is built upon the Monte Carlo algorithm and features a novel scoring function combining physics-based energy terms with statistical and knowledge-based potentials. Developed specifically for heterogeneous computing platforms, the current version of GeauxDock can be deployed on modern, multi-core Central Processing Units (CPUs) as well as massively parallel accelerators, Intel Xeon Phi and NVIDIA Graphics Processing Unit (GPU). First, we carried out a thorough performance tuning of the high-level framework and the docking kernel to produce a fast serial code, which was then ported to shared-memory multi-core CPUs yielding a near-ideal scaling. Further, using Xeon Phi gives 1.9× performance improvement over a dual 10-core Xeon CPU, whereas the best GPU accelerator, GeForce GTX 980, achieves a speedup as high as 3.5×. On that account, GeauxDock can take advantage of modern heterogeneous architectures to considerably accelerate structure-based virtual screening applications. GeauxDock is open-sourced and publicly available at www.brylinski.org/geauxdock and https://figshare.com/articles/geauxdock_tar_gz/3205249.

Description: by Rinske Loeffen, René van Oerle, Mathie P. G. Leers, Johannes A. Kragten, Harry Crijns, Henri M. H. Spronk, Hugo ten Cate Objective In acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS. Methods We measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis. Results Thrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310–885) vs. 380(235–540) μg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2–20.9] and 4.5 [1.1–18.9]). Conclusion ACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events.

Description: by Kristen R. Yeung, Christine L. Chiu, Suzanne Pears, Scott J. Heffernan, Angela Makris, Annemarie Hennessy, Joanne M. Lind Background Ageing is associated with changes at the molecular and cellular level that can alter cardiovascular function and ultimately lead to disease. The baboon is an ideal model for studying ageing due to the similarities in genetic, anatomical, physiological and biochemical characteristics with humans. The aim of this cross-sectional study was to investigate the changes in cardiovascular profile of baboons over the course of their lifespan. Methods Data were collected from 109 healthy baboons ( Papio hamadryas ) at the Australian National Baboon Colony. A linear regression model, adjusting for sex, was used to analyse the association between age and markers of ageing with P 〈 0.01 considered significant. Results Male (n = 49, 1.5–28.5 years) and female (n = 60, 1.8–24.6 years) baboons were included in the study. Age was significantly correlated with systolic (R 2 = 0.23, P 〈 0.001) and diastolic blood pressure (R 2 = 0.44, P 〈 0.001), with blood pressure increasing with age. Age was also highly correlated with core augmentation index (R 2 = 0.17, P 〈 0.001) and core pulse pressure (R 2 = 0.30, P 〈 0.001). Creatinine and urea were significantly higher in older animals compared to young animals (P 〈 0.001 for both). Older animals (〉12 years) had significantly shorter telomeres when compared to younger (

Description: by Emanuela Jirayu Tanprasertsuk, Binxing Li, Paul S. Bernstein, Rohini Vishwanathan, Mary Ann Johnson, Leonard Poon, Elizabeth J. Johnson

Description: by Gertrud L. G. Haverkamp, Bart Torensma, Anton C. M. Vergouwen, Adriaan Honig

Description: by The PLOS ONE Staff

Description: by Hunter R. Underhill, Jacob O. Kitzman, Sabine Hellwig, Noah C. Welker, Riza Daza, Daniel N. Baker, Keith M. Gligorich, Robert C. Rostomily, Mary P. Bronner, Jay Shendure Malignant tumors shed DNA into the circulation. The transient half-life of circulating tumor DNA (ctDNA) may afford the opportunity to diagnose, monitor recurrence, and evaluate response to therapy solely through a non-invasive blood draw. However, detecting ctDNA against the normally occurring background of cell-free DNA derived from healthy cells has proven challenging, particularly in non-metastatic solid tumors. In this study, distinct differences in fragment length size between ctDNAs and normal cell-free DNA are defined. Human ctDNA in rat plasma derived from human glioblastoma multiforme stem-like cells in the rat brain and human hepatocellular carcinoma in the rat flank were found to have a shorter principal fragment length than the background rat cell-free DNA (134–144 bp vs. 167 bp, respectively). Subsequently, a similar shift in the fragment length of ctDNA in humans with melanoma and lung cancer was identified compared to healthy controls. Comparison of fragment lengths from cell-free DNA between a melanoma patient and healthy controls found that the BRAF V600E mutant allele occurred more commonly at a shorter fragment length than the fragment length of the wild-type allele (132–145 bp vs. 165 bp, respectively). Moreover, size-selecting for shorter cell-free DNA fragment lengths substantially increased the EGFR T790M mutant allele frequency in human lung cancer. These findings provide compelling evidence that experimental or bioinformatic isolation of a specific subset of fragment lengths from cell-free DNA may improve detection of ctDNA.

Description: by Sajid Javed, Leanne Marsay, Alice Wareham, Kuiama S. Lewandowski, Ann Williams, Michael J. Dennis, Sally Sharpe, Richard Vipond, Nigel Silman, Graham Ball, Karen E. Kempsell

Description: by Haiyou Deng, Quan Liu, Wei Cao, Rong Gui, Chengzhang Ma, Ming Yi, Yuangen Yao Recently, a new type of small interfering RNAs (qiRNAs) of typically 20~21 nucleotides was found in Neurospora crassa and rice and has been shown to regulate gene silencing in the DNA damage response. Identification of qiRNAs is fundamental for dissecting regulatory functions and molecular mechanisms. In contrast to other expensive and time-consuming experimental methods, the computational prediction of qiRNAs is a conveniently rapid method for gaining valuable information for a subsequent experimental verification. However, no tool existed to date for the prediction of qiRNAs. To this purpose, we developed the novel qiRNA prediction software package qiRNApredictor. This software demonstrates a promising sensitivity of 93.55% and a specificity of 71.61% from the leave-one-out validation. These studies might be beneficial for further experimental investigation. Furthermore, the local package of qiRNApredictor was implemented and made freely available to the academic community at Supplementary material.

Description: by Abhirami A. Ananth, Lee-Hwa Tai, Casey Lansdell, Almohanad A. Alkayyal, Katherine E. Baxter, Leonard Angka, Jiqing Zhang, Christiano Tanese de Souza, Kyle B Stephenson, Kelley Parato, Jonathan L Bramson, John C Bell, Brian D Lichty, Rebecca C Auer

Description: by Amanda N. Bolton Hall, Binoy Joseph, Jennifer M. Brelsfoard, Kathryn E. Saatman Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at 48h intervals, or five sham injuries at 24h intervals were evaluated across a 10 week period after injury. Animals with repeated CHI exhibited motor coordination and memory deficits, but not gait abnormalities when compared to sham animals. At 10wks post-injury, no notable neuron loss or glial reactivity was observed in the cortex, hippocampus, or corpus callosum. Argyrophilic axons were found in the pyramidal tract of some injured animals, but neither silver stain accumulation nor inflammatory responses in the injury groups were statistically different from the sham group in this region. However, argyrophilic axons, microgliosis and astrogliosis were significantly increased within the optic tract of injured animals. Repeated mild CHI also resulted in microgliosis and a loss of neurofilament protein 200 in the optic nerve. Lengthening the inter-injury interval from 24h to 48h did not effectively reduce these behavioral or cellular responses. These results suggest that repeated mild CHI results in persistent behavioral dysfunction and chronic pathological changes within the visual system, neither of which was significantly attenuated by lengthening the inter-injury interval from 24h to 48h.

Description: by Hesung Now, Joo-Yeon Yoo A population often contains distinct sub-populations, thereby increasing the complexity of the overall heterogeneity. However, the cellular origin and biological relevance of sub-populations in cell population have not been clearly identified. Here we demonstrated the novel roles of ISGylation, which is an IFN-induced post-translational modification, controlling heterogeneity at the population level in cultured adherent cells. Without UBE1L, an E1 enzyme of ISGylation, mouse embryonic fibroblasts (MEF) exhibited low viral resistance despite high STAT1 and ISG expression compared with the wild-type MEF. We observe that Ube1l −/− MEF populations consist of two behaviorally distinguishable sub-populations with distinct basal STAT1 activity, while wild-type MEF populations are unimodal. This population heterogeneity in Ube1l knock-out cells was perturbed by tyrosine kinase inhibitors, AG490 and PF431396. In contrast, the neutralization of type I IFN did not affect population heterogeneity. Based on these results, we concluded that UBE1L functions to adjust basal immunological states with the regulation of population heterogeneity.

Description: by Silvia Wein, Birgit Beyer, Annika Gohlke, Ralf Blank, Cornelia C. Metges, Siegfried Wolffram Green tea catechins have various potential health benefits in humans including anti-inflammatory, anti-oxidative and hepato-protective effects. If present in the circulation, they might have similar effects in ruminants, which are exposed to oxidative stress and fatty liver disease such as dairy cows during the periparturient phase. However, the bioavailability of a substance is a prerequisite for any post absorptive effect in vivo . This study aimed to investigate the appearance of catechins from a green tea extract (GTE) in cattle plasma after intraruminal and intraduodenal administration because absorption is of major importance regarding the bioavailability of catechins. The studies were performed in 5 rumen-fistulated non-lactating heifers and 6 duodenally fistulated lactating dairy cows, respectively, equipped with indwelling catheters placed in a jugular vein. The GTE was applied intraruminally (10 and 50 mg/kg BW, heifers) or duodenally (10, 20 and 30 mg/kg BW, dairy cows) in a cross‐over design with a 2 d washout period between different dosages. Blood samples were drawn following the GTE administration at various pre-defined time intervals. The concentration of the major GTE catechins (gallocatechin, epigallocatechin, catechin, epicatechin, epigallocatechin-gallate, epicatechin-gallate) in plasma samples were analysed by HPLC with electrochemical detection. Irrespective of the dose, almost none of the catechins originally contained in the GTE were detected in plasma samples after intraruminal application. In contrast, intraduodenal administration of GTE resulted in increased plasma concentrations of epicatechin, epigallocatechin, epigallocatechin gallate in a dose‐dependent manner. Thus, we can conclude that intraruminally or orally administered catechins are intensively metabolized by ruminal microorganisms.

Description: by Haowen Tang, Bingmin Li, Aiqun Zhang, Wenping Lu, Canhong Xiang, Jiahong Dong Background and Objective Inflammation is deemed to play critical roles in tumor progression and metastasis, and an increased neutrophil-lymphocyte ratio (NLR) has been reported to correlate with poor survivals in various malignancies. However, association between NLR elevation and survival outcome in patients with colorectal liver metastasis (CRLM) remains controversial. The aim of this study was to investigate the prognostic significance of elevated NLR in CRLM. Methods The meta-analysis was conducted in adherence to the MOOSE guidelines. PubMed, Embase, Cochrane Library, Web of Science and the Chinese SinoMed were systematically searched to identify eligible studies from the initiation of the databases to May, 2016. Overall survival (OS) and recurrence free survival (RFS) were pooled by using hazard ratio (HR) with corresponding 95% confidence interval (CI). Correlation between NLR values and clinicopathological features was synthesized by using odds ratio (OR) with corresponding 95% CI. Results A total of 1685 patients from 8 studies (9 cohorts) were analyzed, consisting 347 (20.59%) in high pretreatment NLR value group and 1338 (79.41%) in low pretreatment NLR value one. The results demonstrated that elevated pretreatment NLR was significantly related to poor OS (HR 2.17, 95% CI 1.82–2.58) and RFS (HR 1.96, 95% CI 1.64–2.35) in patients with CRLM. Conclusion The result of this systematic review and meta-analysis indicated that an elevated pretreatment NLR was closely correlated with poor long-term survival (OS and RFS) in CRLM patients. NLR can be routinely monitored and serve as a useful and cost-effective marker with strong prognostic significance in patients with CRLM.

Description: by Peter C. Rowe, Kevin R. Fontaine, Megan Lauver, Samantha E. Jasion, Colleen L. Marden, Malini Moni, Carol B. Thompson, Richard L. Violand Chronic fatigue syndrome (CFS) is a complex, multisystem disorder that can be disabling. CFS symptoms can be provoked by increased physical or cognitive activity, and by orthostatic stress. In preliminary work, we noted that CFS symptoms also could be provoked by application of longitudinal neural and soft tissue strain to the limbs and spine of affected individuals. In this study we measured the responses to a straight leg raise neuromuscular strain maneuver in individuals with CFS and healthy controls. We randomly assigned 60 individuals with CFS and 20 healthy controls to either a 15 minute period of passive supine straight leg raise (true neuromuscular strain) or a sham straight leg raise. The primary outcome measure was the symptom intensity difference between the scores during and 24 hours after the study maneuver compared to baseline. Fatigue, body pain, lightheadedness, concentration difficulties, and headache scores were measured individually on a 0–10 scale, and summed to create a composite symptom score. Compared to individuals with CFS in the sham strain group, those with CFS in the true strain group reported significantly increased body pain (P = 0.04) and concentration difficulties (P = 0.02) as well as increased composite symptom scores (all P = 0.03) during the maneuver. After 24 hours, the symptom intensity differences were significantly greater for the CFS true strain group for the individual symptom of lightheadedness (P = 0.001) and for the composite symptom score (P = 0.005). During and 24 hours after the exposure to the true strain maneuver, those with CFS had significantly higher individual and composite symptom intensity changes compared to the healthy controls. We conclude that a longitudinal strain applied to the nerves and soft tissues of the lower limb is capable of increasing symptom intensity in individuals with CFS for up to 24 hours. These findings support our preliminary observations that increased mechanical sensitivity may be a contributor to the provocation of symptoms in this disorder.

Description: by Shweta Mendiratta, Shipra Bhatia, Shruti Jain, Taniya Kaur, Vani Brahmachari The presence of a highly conserved DNA binding domain in INO80 subfamily predicted that INO80 directly interacts with DNA and we demonstrated its DNA binding activity in vitro . Here we report the consensus motif recognized by the DBINO domain identified by SELEX method and demonstrate the specific interaction of INO80 with the consensus motif. We show that INO80 significantly down regulates the reporter gene expression through its binding motif, and the repression is dependent on the presence of INO80 but not YY1 in the cell. The interaction is lost if specific residues within the consensus motif are altered. We identify a large number of potential target sites of INO80 in the human genome through in silico analysis that can grouped into three classes; sites that contain the recognition sequence for INO80 and YY1, only YY1 and only INO80. We demonstrate the binding of INO80 to a representative set of sites in HEK cells and the correlated repressive histone modifications around the binding motif. In the light of the role of INO80 in homeotic gene regulation in Drosophila as an Enhancer of trithorax and polycomb protein (ETP) that can modify the effect of both repressive complexes like polycomb as well as the activating complex like trithorax, it remains to be seen if INO80 can act as a recruiter of chromatin modifying complexes.

Description: by Michal Cagalinec, Mailis Liiv, Zuzana Hodurova, Miriam Ann Hickey, Annika Vaarmann, Merle Mandel, Akbar Zeb, Vinay Choubey, Malle Kuum, Dzhamilja Safiulina, Eero Vasar, Vladimir Veksler, Allen Kaasik Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP 3 R) dysfunction and disturbed cytosolic Ca 2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca 2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.

Description: by Nandhitha Subramanian, Amanda J. Scopelliti, Jane E. Carland, Renae M. Ryan, Megan L. O’Mara, Robert J. Vandenberg

Description: by Byung-Whi Kong, Kentu Lassiter, Alissa Piekarski-Welsher, Sami Dridi, Antonio Reverter, Nicholas James Hudson, Walter Gay Bottje

Description: by Steve Jordan, J. Joseph Giersch, Clint C. Muhlfeld, Scott Hotaling, Liz Fanning, Tyler H. Tappenbeck, Gordon Luikart

Description: by Kaylyn L. Devlin, Tiffany Sanford, Lauren M. Harrison, Paul LeBourgeois, Laura M. Lashinger, Elizabeth Mambo, Stephen D. Hursting MicroRNAs have emerged as ubiquitous post-transcriptional regulators that coordinate many fundamental processes within cells, including those commonly linked to cancer when dysregulated. Profiling microRNAs across stages of cancer progression provides focus as to which microRNAs are key players in cancer development and are therefore important to manipulate with interventions to delay cancer onset and progression. Calorie restriction is one of the most effective preventive interventions across many types of cancer, although its effects on microRNAs have not been well characterized. We used the dimethylbenz[a]-anthracene-induced model of luminal mammary cancer in Sprague Dawley rats to elucidate which microRNAs are linked to progression in this type of cancer and, subsequently, to study how calorie restriction affects such microRNAs. We identified eight microRNAs (miR-10a, miR-10b, miR-21, miR-124, miR-125b, miR-126, miR-145 and miR-200a) to be associated with DMBA-induced mammary tumor progression. Calorie restriction, which greatly increased tumor-free survival and decreased the overall size of tumors that did develop, significantly decreased the expression of one microRNA, miR-200a, which was positively associated with tumor progression. We further showed that inhibition of miR-200a function, mimicking the effect of calorie restriction on this microRNA, inhibited proliferation in both rat (LA7) and human (MCF7) luminal mammary cancer cell lines. These findings present, for the first time, a stage-specific profile of microRNAs in a rodent model of luminal mammary cancer. Furthermore, we have identified the regulation of miR-200a, a microRNA that is positively associated with progression in this model, as a possible mechanism contributing to the anticancer effects of calorie restriction.

Description: by Fiorenzo Moscatelli, Giovanni Messina, Anna Valenzano, Vincenzo Monda, Andrea Viggiano, Antonietta Messina, Annamaria Petito, Antonio Ivano Triggiani, Michela Anna Pia Ciliberti, Marcellino Monda, Laura Capranica, Giuseppe Cibelli

Description: by Marcos Iglesias, Juan Jesús Augustin, Pilar Alvarez, Inés Santiuste, Jorge Postigo, Jesús Merino, Ramón Merino The inhibition of apoptotic cell death in T cells through the dysregulated expression of BCL2 family members has been associated with the protection against the development of different autoimmune diseases. However, multiple mechanisms were proposed to be responsible for such protective effect. The purpose of this study was to explore the effect of the T-cell overexpression of BCL2A1, an anti-apoptotic BCL2 family member without an effect on cell cycle progression, in the development of collagen-induced arthritis. Our results demonstrated an attenuated development of arthritis in these transgenic mice. The protective effect was unrelated to the suppressive activity of regulatory T cells but it was associated with a defective activation of p38 mitogen-activated protein kinase in CD4 + cells after in vitro TCR stimulation. In addition, the in vitro and in vivo T H 17 differentiation were impaired in BCL2A1 transgenic mice. Taken together, we demonstrated here a previously unknown role for BCL2A1 controlling the activation of CD4 + cells and their differentiation into pathogenic proinflammatory T H 17 cells and identified BCL2A1 as a potential target in the control of autoimmune/inflammatory diseases.

Description: by Tianle Chao, Guizhi Wang, Jianmin Wang, Zhaohua Liu, Zhibin Ji, Lei Hou, Chunlan Zhang High-throughput mRNA sequencing enables the discovery of new transcripts and additional parts of incompletely annotated transcripts. Compared with the human and cow genomes, the reference annotation level of the sheep genome is still low. An investigation of new transcripts in sheep skeletal muscle will improve our understanding of muscle development. Therefore, applying high-throughput sequencing, two cDNA libraries from the biceps brachii of small-tailed Han sheep and Dorper sheep were constructed, and whole-transcriptome analysis was performed to determine the unknown transcript catalogue of this tissue. In this study, 40,129 transcripts were finally mapped to the sheep genome. Among them, 3,467 transcripts were determined to be unannotated in the current reference sheep genome and were defined as new transcripts. Based on protein-coding capacity prediction and comparative analysis of sequence similarity, 246 transcripts were classified as portions of unannotated genes or incompletely annotated genes. Another 1,520 transcripts were predicted with high confidence to be long non-coding RNAs. Our analysis also revealed 334 new transcripts that displayed specific expression in ruminants and uncovered a number of new transcripts without intergenus homology but with specific expression in sheep skeletal muscle. The results confirmed a complex transcript pattern of coding and non-coding RNA in sheep skeletal muscle. This study provided important information concerning the sheep genome and transcriptome annotation, which could provide a basis for further study.

Description: by Simina M. Boca, Maki Nishida, Michael Harris, Shruti Rao, Amrita K. Cheema, Kirandeep Gill, Difei Wang, Lin An, Robinder Gauba, Haeri Seol, Lauren P. Morgenroth, Erik Henricson, Craig McDonald, Jean K. Mah, Paula R. Clemens, Eric P. Hoffman, Yetrib Hathout, Subha Madhavan

Description: by Xiaolin Qin, Heping Zheng, Yaohua Xue, Xuqi Ren, Bin Yang, Jinmei Huang, Shujie Huang, Xingzhong Wu, Weiying Zeng, Jiangli Ou, Yinyuan Lan, Sanmei Tang Background Chlamydia trachomatis is one of the most prevalent bacterial sexually transmitted infection in China. Although C . trachomatis genotypes can be discriminated by outer membrane protein gene ( omp A) sequencing, currently available methods have limited resolutions. This study used a high-resolution genotyping method, namely, multilocus variable number tandem-repeat analysis with omp A sequencing (MLVA)- omp A, to investigate the local epidemiology of C . trachomatis infections among men who have sex with men (MSM) and men who have sex with women (MSW) attending a sexually transmitted diseases (STD) clinic in Guangzhou, China. Methods Rectal specimens from MSM and urethral specimens from MSW were collected between January 2013 and July 2014 at the Guangdong Provincial Center STD clinic. The specimens were sent to the laboratory for analyses. All specimens that were tested positive for C . trachomatis by the commercial nucleic acid amplification tests were genotyped by MLVA- omp A. Results Fifty-one rectal specimens from MSM and 96 urethral specimens from MSW were identified with C . trachomatis . One hundred and forty-four of the 147 specimens were fully genotyped by MLVA- omp A. Rectal specimens from MSM were divided into four omp A genotypes and urethral specimens from MSW into nine genotypes. No mixed infections were found among all specimens. The most frequent genotypes were D, G, J, E and F. All specimens were further divided into 46 types after omp A genotyping was combined with MLVA. Genotypes D-8.7.1 and G-3.4a.3 were the most frequent among MSM, whereas genotypes D-3.4a.4, E-8.5.1, F-8.5.1, and J-3.4a.2 were the most frequent subtypes among MSW. The discriminatory index D was 0.90 for MLVA, 0.85 for omp A, and 0.95 for MLVA- omp A. Conclusions The most prevalent MLVA- omp A genotypes were significantly different between MSM and MSW from Guangzhou, China. Moreover, MLVA- omp A represented a more favorable degree of discrimination than omp A and could be a reliable complement for omp A for the routine subtypes of C . trachomatis .

Description: by Siiri Latvala, Jonas Hedberg, Sebastiano Di Bucchianico, Lennart Möller, Inger Odnevall Wallinder, Karine Elihn, Hanna L. Karlsson Occupational exposure to airborne nickel is associated with an elevated risk for respiratory tract diseases including lung cancer. Therefore, the increased production of Ni-containing nanoparticles necessitates a thorough assessment of their physical, chemical, as well as toxicological properties. The aim of this study was to investigate and compare the characteristics of nickel metal (Ni) and nickel oxide (NiO) particles with a focus on Ni release, reactive oxygen species (ROS) generation, cellular uptake, cytotoxicity and genotoxicity. Four Ni-containing particles of both nano-size (Ni-n and NiO-n) and micron-size (Ni-m1 and Ni-m2) were tested. The released amount of Ni in solution was notably higher in artificial lysosomal fluid (e.g. 80–100 wt% for metallic Ni) than in cell medium after 24h (ca. 1–3 wt% for all particles). Each of the particles was taken up by the cells within 4 h and they remained in the cells to a high extent after 24 h post-incubation. Thus, the high dissolution in ALF appeared not to reflect the particle dissolution in the cells. Ni-m1 showed the most pronounced effect on cell viability after 48 h (alamar blue assay) whereas all particles showed increased cytotoxicity in the highest doses (20–40 μg cm 2 ) when assessed by colony forming efficiency (CFE). Interestingly an increased CFE, suggesting higher proliferation, was observed for all particles in low doses (0.1 or 1 μg cm -2 ). Ni-m1 and NiO-n were the most potent in causing acellular ROS and DNA damage. However, no intracellular ROS was detected for any of the particles. Taken together, micron-sized Ni (Ni-m1) was more reactive and toxic compared to the nano-sized Ni. Furthermore, this study underlines that the low dose effect in terms of increased proliferation observed for all particles should be further investigated in future studies.

Description: by The PLOS ONE Staff

Description: by Sandra J. Connelly, James A. Stoeckel, Robert A. Gitzen, Craig E. Williamson, Maria J. González Recent studies have demonstrated substantial effects of environmental stress that vary among clones. Exposure to ultraviolet radiation (UV) is an important abiotic stressor that is highly variable in aquatic ecosystems due to diel and seasonal variations in incident sunlight as well as to differences in the UV transparency of water among water bodies, the depth distribution of organisms, and the ability of organisms to detect and respond to UV. In contrast to the convention that all UV is damaging, evidence is accumulating for the beneficial effects of exposure to low levels of UV radiation. Whereas UV has been frequently observed as the primary light-related stressor, herein we present evidence that dark conditions may be similarly “stressful” (reduction of overall fitness), and stress responses vary among clones of the freshwater crustacean Daphnia parvula . We have identified a significant relationship between survivorship and reduced fecundity of clones maintained in dark conditions, but no correlation between tolerance of the clones to dark and UV radiation. Low tolerance to dark conditions can have negative effects not only on accumulated stresses in organisms (e.g. the repair of UV-induced damage in organisms with photolyase), but potentially on the overall physiology and fitness of organisms. Our results support recent evidence of the beneficial effects of low-level UV exposure for some organisms.

Description: by Bonnie K. Harrington, Heather L. Gardner, Raquel Izumi, Ahmed Hamdy, Wayne Rothbaum, Kevin R. Coombes, Todd Covey, Allard Kaptein, Michael Gulrajani, Bart Van Lith, Cecile Krejsa, Christopher C. Coss, Duncan S. Russell, Xiaoli Zhang, Bridget K. Urie, Cheryl A. London, John C. Byrd, Amy J. Johnson, William C. Kisseberth Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL).

Description: by Mari Tohya, Takayasu Watanabe, Fumito Maruyama, Sakura Arai, Atsushi Ota, Taryn B. T. Athey, Nahuel Fittipaldi, Ichiro Nakagawa, Tsutomu Sekizaki Many bacterial species coexist in the same niche as heterogeneous clones with different phenotypes; however, understanding of infectious diseases by polyphenotypic bacteria is still limited. In the present study, encapsulation in isolates of the porcine pathogen Streptococcus suis from persistent endocarditis lesions was examined. Coexistence of both encapsulated and unencapsulated S . suis isolates was found in 26 out of 59 endocarditis samples. The isolates were serotype 2, and belonged to two different sequence types (STs), ST1 and ST28. The genomes of each of the 26 pairs of encapsulated and unencapsulated isolates from the 26 samples were sequenced. The data showed that each pair of isolates had one or more unique nonsynonymous mutations in the cps gene, and the encapsulated and unencapsulated isolates from the same samples were closest to each other. Pairwise comparisons of the sequences of cps genes in 7 pairs of encapsulated and unencapsulated isolates identified insertion/deletions (indels) ranging from one to 10 4 bp in different cps genes of unencapsulated isolates. Capsule expression was restored in a subset of unencapsulated isolates by complementation in trans with cps expression vectors. Examination of gene content common to isolates indicated that mutation frequency was higher in ST28 pairs than in ST1 pairs. Genes within mobile genetic elements were mutation hot spots among ST28 isolates. Taken all together, our results demonstrate the coexistence of dual phenotype (encapsulated and unencapsulated) bacterial clones and suggest that the dual phenotypes arose independently in each farm by means of spontaneous mutations in cps genes.

Description: by Yuki Nakano, Takeru Shimazaki, Nobuko Kobayashi, Yukiko Miyoshi, Aoi Ono, Mamoru Kobayashi, Chieko Shiragami, Kazuyuki Hirooka, Akitaka Tsujikawa Purpose To establish the normative database of retinal oximetry using Oxymap T1 in a healthy Japanese population, and study the reproducibility of the measurements in Japanese. Methods We measured oxygen saturation in the major retinal vessels with Oxymap T1 in 252 eyes of 252 healthy Japanese subjects. Fundus images acquired using Oxymap T1 were processed using built-in Oxymap Analyzer software. Reproducibility of retinal oximetry was investigated using 20 eyes of 20 healthy subjects. Results The mean retinal oxygen saturation of 4 quadrants in healthy Japanese was 97.0 ± 6.9% in arteries and 52.8 ± 8.3% in veins. The mean arteriovenous difference in oxygen saturation was 44.2 ± 9.2%. Both arterial and venous oxygen saturation were significantly lower in the temporal side of the retina, especially in the temporal-inferior vessels. However, the arteriovenous difference in oxygen saturation was limited in the 4 quadrants. Interphotograph, intervisit, and interevaluator intraclass correlation coefficients were 0.936–0.979, 0.809–0.837, and 0.732–0.947, respectively. In the major retinal arteries, oxygen saturation increased with age (r = 0.18, p

Description: by Guang Yang, Hongqin Xu, Huiping Zhang, Qiong Yu, Yanhua Wu, Jieping Shi, Wenwang Rao, Yueyue You, Changgui Kou, Yaqin Yu Objective The purpose of this study was to explore the association between single nucleotide polymorphisms (SNPs) in the phospholipase A2 (PLA2), group XIIA gene ( PLA2G12A ) and schizophrenia. Methods This study included 1,063 schizophrenia patients and 1,103 healthy controls from a Han Chinese Population in Northeast China. Four tagSNPs (rs11728699 in intron 1, synonymous rs2285714 in exon 3, rs3087494 in the 3’ UTR, and rs7694620 in the downstream region) in PLA2G12A were selected, and they were genotyped by the MALDI-TOF-MS technology. The Chi-square (χ 2 ) test and haplotype analysis were performed to analyze the association of PLA2G12A SNPs and schizophrenia using the software packages SPSS 16.0 and Haploview 4.2. Results Among the four tagSNPs, only SNP rs3087494 in the 3’ UTR of PLA2G12A showed significant differences in both allele frequencies (χ 2 = 20.136, P

Description: by Robert A. Colvin, Qiaoling Jin, Barry Lai, Lech Kiedrowski Increasing evidence suggests that metal dyshomeostasis plays an important role in human neurodegenerative diseases. Although distinctive metal distributions are described for mature hippocampus and cortex, much less is known about metal levels and intracellular distribution in individual hippocampal neuronal somata. To solve this problem, we conducted quantitative metal analyses utilizing synchrotron radiation X-Ray fluorescence on frozen hydrated primary cultured neurons derived from rat embryonic cortex (CTX) and two regions of the hippocampus: dentate gyrus (DG) and CA1. Comparing average metal contents showed that the most abundant metals were calcium, iron, and zinc, whereas metals such as copper and manganese were less than 10% of zinc. Average metal contents were generally similar when compared across neurons cultured from CTX, DG, and CA1, except for manganese that was larger in CA1. However, each metal showed a characteristic spatial distribution in individual neuronal somata. Zinc was uniformly distributed throughout the cytosol, with no evidence for the existence of previously identified zinc-enriched organelles, zincosomes. Calcium showed a peri-nuclear distribution consistent with accumulation in endoplasmic reticulum and/or mitochondria. Iron showed 2–3 distinct highly concentrated puncta only in peri-nuclear locations. Notwithstanding the small sample size, these analyses demonstrate that primary cultured neurons show characteristic metal signatures. The iron puncta probably represent iron-accumulating organelles, siderosomes. Thus, the metal distributions observed in mature brain structures are likely the result of both intrinsic neuronal factors that control cellular metal content and extrinsic factors related to the synaptic organization, function, and contacts formed and maintained in each region.

Description: by Yasuhiro Takahashi, Yoshiyuki Kitaguchi, Shunsuke Nakakura, Hidenori Mito, Akiko Kimura, Hirohiko Kakizaki Purpose To examine the characteristics of excyclotropia correction through surgery on the inferior rectus muscle in patients with thyroid eye disease. Methods This was a retrospective, observational study at a single institution. We reviewed 36 patients who had undergone unilateral inferior rectus muscle recession, with or without nasal inferior rectus muscle transposition. The following factors were investigated as possibly influencing excyclotropia correction: inferior rectus muscle thickness, degree of adipose change in the inferior rectus muscle, smoking status, history of orbital radiotherapy, and the amount of inferior rectus muscle recession. Using T1-weighted coronal magnetic resonance imaging, we measured the cross-sectional area of the inferior rectus muscle at its largest point, as well as the bright-signal area of the inferior rectus muscle, which reflects intermuscular adipose change. We then calculated the percentage internal bright-signal area at the point of the largest inferior rectus muscle cross-sectional area. The history of orbital radiotherapy was graded using a binary system. We evaluated correlations among excyclotropia correction, the amount of nasal inferior rectus muscle transposition, and the possible influencing factors listed, using stepwise multiple regression analyses. Results The multiple regression model demonstrated a significant relationship among excyclotropia correction, amount of nasal inferior rectus muscle transposition, and the amount of inferior rectus muscle recession (Y CORRECTION = 8.546X TENDON WIDTH + 0.405X RECESSION − 0.908; r = 0.844; adjusted r 2 = 0.695; P 〈 0.001). Conclusions Excyclotropia correction was correlated with the amount of nasal inferior rectus muscle transposition and the amount of inferior rectus muscle recession, but not with the other factors. The regression model presented in this study will enable us to determine more precisely the amount of nasal inferior rectus muscle transposition in patients with excyclotropia of various angles.

Description: by Qi Zhao, Yun Zhu, Lyle G. Best, Jason G. Umans, Karan Uppal, ViLinh T. Tran, Dean P. Jones, Elisa T. Lee, Barbara V. Howard, Jinying Zhao Obesity is a typical metabolic disorder resulting from the imbalance between energy intake and expenditure. American Indians suffer disproportionately high rates of obesity and diabetes. The goal of this study is to identify metabolic profiles of obesity in 431 normoglycemic American Indians participating in the Strong Heart Family Study. Using an untargeted liquid chromatography–mass spectrometry, we detected 1,364 distinct m/z features matched to known compounds in the current metabolomics databases. We conducted multivariate analysis to identify metabolic profiles for obesity, adjusting for standard obesity indicators. After adjusting for covariates and multiple testing, five metabolites were associated with body mass index and seven were associated with waist circumference. Of them, three were associated with both. Majority of the obesity-related metabolites belongs to lipids, e.g., fatty amides, sphingolipids, prenol lipids, and steroid derivatives. Other identified metabolites are amino acids or peptides. Of the nine identified metabolites, five metabolites (oleoylethanolamide, mannosyl-diinositol-phosphorylceramide, pristanic acid, glutamate, and kynurenine) have been previously implicated in obesity or its related pathways. Future studies are warranted to replicate these findings in larger populations or other ethnic groups.

Description: by Zuzana Zákostelská, Jana Málková, Klára Klimešová, Pavel Rossmann, Michaela Hornová, Iva Novosádová, Zuzana Stehlíková, Martin Kostovčík, Tomáš Hudcovic, Renata Štepánková, Kateřina Jůzlová, Jana Hercogová, Helena Tlaskalová-Hogenová, Miloslav Kverka Psoriasis is a chronic inflammatory skin disease in which Th17 cells play a crucial role. Since indigenous gut microbiota influences the development and reactivity of immune cells, we analyzed the link among microbiota, T cells and the formation of psoriatic lesions in the imiquimod-induced murine model of psoriasis. To explore the role of microbiota, we induced skin inflammation in germ-free (GF), broad-spectrum antibiotic (ATB)-treated or conventional (CV) BALB/c and C57BL/6 mice. We found that both mice reared in GF conditions for several generations and CV mice treated with ATB were more resistant to imiquimod-induced skin inflammation than CV mice. The ATB treatment dramatically changed the diversity of gut bacteria, which remained stable after subsequent imiquimod application; ATB treatment resulted in a substantial increase in the order Lactobacillales and a significant decrease in Coriobacteriales and Clostridiales . Moreover, as compared to CV mice, imiquimod induced a lower degree of local and systemic Th17 activation in both GF and ATB-treated mice. These findings suggest that gut microbiota control imiquimod-induced skin inflammation by altering the T cell response.

Description: by Lu Zhang, Wen Wang, Yan Gao, Jie Lan, Lixin Xie Purpose To compare the efficacy and safety of current treatments in diabetic macular edema (DME). Methods PubMed, Embase and CENTRAL were systematically reviewed for randomized controlled trials of current treatments in DME through August 2015. Data on the mean change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) were extracted, and adverse events (AEs) were collected. Results A total of 21 trials were included in our network meta-analysis. Intravitreal ranibizumab improved BCVA most significantly (OR: +7.01 95%CI (2.56 to 11.39)) in 6 months and intravitreal aflibercept (+8.19 (5.07 to 11.96)) in 12 months. Intravitreal triamcinolone combined with LASER decreased CMT most significantly (-111.34 (-254.61 to 37.93)) in 6 months and intravitreal aflibercept (-110.83 (-190.25 to -35.27)) in 12 months. Compared with the relatively high rate of ocular AEs in the groups with administration of steroids, systematic AEs occurred more frequently in the groups with vascular endothelial growth factor inhibitors involved. Conclusions Our analysis confirms that intravitreal aflibercept is most favorable with both BCVA improvement and CMT decrease than other current therapies in the management of DME within 12 months. Vascular endothelial growth factor inhibitors for DME should be used with caution due to systematic AEs. Combined intravitreal triamcinolone with LASER has a stronger efficacy in decreasing CMT than the other interventions in the early stage after injection. More high-quality randomized controlled trials will be necessary.

Description: by Stefania Balzarotti, Barbara Colombo The dorsolateral prefrontal cortex (DLPFC) is generally thought to be involved in affect and emotional processing; however, the specific contribution of each hemisphere continues to be debated. In the present study, we employed unilateral tDCS to test the unique contribution of left DLPFC in the encoding and retrieval of emotional stimuli in healthy subjects. Forty-two right handed undergraduate students received either anodal, cathodal or sham stimulation of left DLPFC while viewing neutral, pleasant, and unpleasant pictures. After completing a filler task, participants were asked to remember as many pictures as possible. Results showed that participants were able to remember a larger amount of emotional (both pleasant and unpleasant) pictures than of neutral ones, regardless of the type of tDCS condition. Participants who received anodal stimulation recalled a significantly higher number of pleasant images than participants in the sham and cathodal conditions, while no differences emerged in the recall of neutral and unpleasant pictures. We conclude that our results provide some support to the role of left prefrontal cortex in the encoding and retrieval of pleasant stimuli.

Description: by Daiana Priscila Rodrigues-de-Souza, Domingo Palacios-Ceña, Lourdes Moro-Gutiérrez, Paula Rezende Camargo, Tania Fátima Salvini, Francisco Alburquerque-Sendín Background Low back pain (LBP) could be influenced by socio-cultural factors. Pain narratives are important to understand the influence of environment on patients with chronic LBP. There are few studies that have explored the experience of patients with chronic LBP in different socio-cultural environments. The aim of this study was to describe the experience of patients with chronic LBP in Spain and Brazil. Methods A qualitative phenomenology approach was implemented. Chronic LBP patients from the University Hospital of Salamanca (Spain), and/or Federal University of São Carlos (Brazil) were included, using purposeful sampling. Data were collected from 22 Spanish and 26 Brazilian patients during in-depth interviews and using researchers’ field notes and patients' personal diaries and letters. A thematic analysis was performed and the guidelines for reporting qualitative research were applied. Results Forty-eight patients with a mean age of 50.7 years (SD: ± 13.1 years) were included in the study. The themes identified included: a) ways of perceiving and expressing pain—the participants focused constantly on their pain and anything outside it was considered secondary; b) the socio-familial environment as a modulator of pain—most participants stated that no one was able to understand the pain they were experiencing; c) religion as a modulator of pain—all Brazilian patients stated that religious belief affected the experience of pain; and d) socio-economic and educational status as a modulator of pain—the study reported that economic factors influenced the experience of pain. Conclusions The influences of LBP can be determined based on the how a patient defines pain. Religion can be considered as a possible mechanism for patients to manage pain and as a form of solace.

Description: by Elske Sieswerda, Anna Font-Gonzalez, Johannes B. Reitsma, Marcel G. W. Dijkgraaf, Richard C. Heinen, Monique W. Jaspers, Helena J. van der Pal, Flora E. van Leeuwen, Huib N. Caron, Ronald B. Geskus, Leontien C. Kremer Hospitalization rates over time of childhood cancer survivors (CCS) provide insight into the burden of unfavorable health conditions on CCS and health care resources. The objective of our study was to examine trends in hospitalizations of CCS and risk factors in comparison with the general population. We performed a medical record linkage study of a cohort of 1564 ≥five-year CCS with national registers. We obtained a random sample of the general population matched on year of birth, gender and calendar year per CCS retrieved. We quantified and compared hospitalization rates of CCS and reference persons from 1995 until 2005, and we analyzed risk factors for hospitalization within the CCS cohort with multivariable Poisson models. We retrieved hospitalization information from 1382 CCS and 25583 reference persons. The overall relative hospitalization rate (RHR) was 2.2 (95%CI:1.9–2.5) for CCS compared to reference persons. CCS with central nervous system and solid tumors had highest RHRs. Hospitalization rates in CCS were increased compared to reference persons up to at least 30 years after primary diagnosis, with highest rates 5–10 and 20–30 years after primary cancer. RHRs were highest for hospitalizations due to neoplasms (10.7; 95%CI:7.1–16.3) and endocrine/nutritional/metabolic disorders (7.3; 95%CI:4.6–11.7). Female gender (P

Description: by Takahiro Ezaki, Yutaka Horita, Masanori Takezawa, Naoki Masuda Direct reciprocity, or repeated interaction, is a main mechanism to sustain cooperation under social dilemmas involving two individuals. For larger groups and networks, which are probably more relevant to understanding and engineering our society, experiments employing repeated multiplayer social dilemma games have suggested that humans often show conditional cooperation behavior and its moody variant. Mechanisms underlying these behaviors largely remain unclear. Here we provide a proximate account for this behavior by showing that individuals adopting a type of reinforcement learning, called aspiration learning, phenomenologically behave as conditional cooperator. By definition, individuals are satisfied if and only if the obtained payoff is larger than a fixed aspiration level. They reinforce actions that have resulted in satisfactory outcomes and anti-reinforce those yielding unsatisfactory outcomes. The results obtained in the present study are general in that they explain extant experimental results obtained for both so-called moody and non-moody conditional cooperation, prisoner’s dilemma and public goods games, and well-mixed groups and networks. Different from the previous theory, individuals are assumed to have no access to information about what other individuals are doing such that they cannot explicitly use conditional cooperation rules. In this sense, myopic aspiration learning in which the unconditional propensity of cooperation is modulated in every discrete time step explains conditional behavior of humans. Aspiration learners showing (moody) conditional cooperation obeyed a noisy GRIM-like strategy. This is different from the Pavlov, a reinforcement learning strategy promoting mutual cooperation in two-player situations.

Description: by Megan H. Brewer, Rabia Chaudhry, Jessica Qi, Aditi Kidambi, Alexander P. Drew, Manoj P. Menezes, Monique M. Ryan, Michelle A. Farrar, David Mowat, Gopinath M. Subramanian, Helen K. Young, Stephan Zuchner, Stephen W. Reddel, Garth A. Nicholson, Marina L. Kennerson With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when studying unsolved inherited peripheral neuropathy cases with no pathogenic coding mutations.

Description: by Julio C. Morales, Patricia Richard, Praveen L. Patidar, Edward A. Motea, Tuyen T. Dang, James L. Manley, David A. Boothman XRN2 is a 5’-3’ exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability.

Description: by Loke Ming Chou, Tai Chong Toh, Kok Ben Toh, Chin Soon Lionel Ng, Patrick Cabaitan, Karenne Tun, Eugene Goh, Lutfi Afiq-Rosli, Daisuke Taira, Rosa Celia Poquita Du, Hai Xin Loke, Aizat Khalis, Jinghan Li, Tiancheng Song Coral bleaching events have been predicted to occur more frequently in the coming decades with global warming. The susceptibility of corals to bleaching during thermal stress episodes is dependent on many factors and an understanding of these underlying drivers is crucial for conservation management. In 2013, a mild bleaching episode ensued in response to elevated sea temperature on the sediment-burdened reefs in Singapore. Surveys of seven sites highlighted variable bleaching susceptibility among coral genera– Pachyseris and Podabacia were the most impacted (31% of colonies of both genera bleached). The most susceptible genera such as Acropora and Pocillopora , which were expected to bleach, did not. Susceptibility varied between less than 6% and more than 11% of the corals bleached, at four and three sites respectively. Analysis of four of the most bleached genera revealed that a statistical model that included a combination of the factors (genus, colony size and site) provided a better explanation of the observed bleaching patterns than any single factor alone. This underscored the complexity in predicting the coral susceptibility to future thermal stress events and the importance of monitoring coral bleaching episodes to facilitate more effective management of coral reefs under climate change.

Description: by Xin Chen, Yange Yang, Zhaopeng Shi, Ming-Qing Gao, Yong Zhang This study was performed to investigate the effects of genetically modified (GM) milk containing human beta-defensin-3 (HBD3) on mice by a 90-day feeding study. The examined parameters included the digestibility of GM milk, general physical examination, gastric emptying function, intestinal permeability, intestinal microflora composition of mice, and the possibility of horizontal gene transfer (HGT). The emphasis was placed on the effects on gastrointestinal (GI) tract due to the fact that GI tract was the first site contacting with food and played crucial roles in metabolic reactions, nutrition absorption and immunity regulation in the host. However, the traditional methods for analyzing the potential toxicological risk of GM product pay little attention on GI health. In this study, the results showed GM milk was easy to be digested in simulated gastric fluid, and it did not have adverse effects on general and GI health compared to conventional milk. And there is little possibility of HGT. This study may enrich the safety assessment of GM product on GI health.