bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Dialysis Duration With Outcomes After Kidney Transplantation in the Setting of Long Cold Ischemia Time
Authors: Bonner Keisha , Joshi Gaurang , Seibert Rachel , Kayler Liise K.
Published: December 2018

Background

There is no mechanism that matches hard-to-place kidneys with the most appropriate candidate. Thus, unwanted kidney offers are typically to recipients with long renal replacement time (vintage) which is a strong risk factor for mortality and graft failure, and in combination with prolonged cold ischemia time (CIT), may promote interactive effects on outcomes.

Methods

Consecutive adult isolated kidney transplants between October 2015 and December 2017 were stratified by vintage younger than 1 year and CIT longer than 30 hours.

Results

Long (n = 169) relative to short (n = 93) vintage recipients were significantly more likely to be younger (32.2 years vs 56.9 years, P = 0.02), black race (40.8% vs 18.3%, P = 0.02), have higher estimated posttransplant survival (52.6 vs 42.0, P = 0.04), and have a comorbid condition (45.6% vs 30.1%, P = 0.02); they were less likely to receive a donation after circulatory death kidney (27.8% vs 39.8%, P = 0.05). Long vintage was significantly associated with length of stay longer than 4 days (45.5% vs 30.1%, P = 0.02), and 30-day readmission (37.3% vs 22.6%, P = 0.02) but not additional operations (17.8% vs 15.1%, P = 0.58), short-term patient mortality (3.0% vs 2.2%, P = 0.70), or overall graft survival (P = 0.23). On multivariate logistic regression, long vintage remained an independent risk factor for 30-day readmission (adjusted odds ratio, 1.92; 95% confidence interval, 1.06-3.47); however, there was no interaction of vintage and CIT for this outcome (P = 0.84).

Conclusions

Readmission is significantly associated with pretransplant dialysis duration; however, CIT is not a modifying factor for this outcome.
Biomarkers of collagen synthesis predict progression in the PROFILE idiopathic pulmonary fibrosis cohort
Authors: Organ Louise A , Duggan Anne-Marie R , Oballa Eunice , Taggart Sarah C , Simpson Juliet K , Kang’ombe Arthur R , Braybrooke Rebecca , Molyneaux Philip L , Leeming Diana J , Karsdal Morten A , Nanthakumar Carmel B , Fahy William A , Marshall Richard P , Jenkins R Gisli , Maher Toby M
Published: December 2018

Idiopathic pulmonary fibrosis (IPF) is characterised by excessive extracellular matrix (ECM) deposition and remodelling. Measuring this activity provides an opportunity to develop tools capable of identifying individuals at-risk of progression. Longitudinal change in markers of ECM synthesis was assessed in 145 newly-diagnosed individuals with IPF.

Serum levels of collagen synthesis neoepitopes, PRO-C3 and PRO-C6 (collagen type 3 and 6), were elevated in IPF compared with controls at baseline, and progressive disease versus stable disease during follow up, (PRO-C3 p<0.001; PRO-C6 p=0.029). Assessment of rate of change in neoepitope levels from baseline to 3 months (defined as ‘slope to month 3’: HIGH slope, slope > 0 vs. LOW slope, slope <=0) demonstrated no relationship with mortality for these markers (PRO-C3 (HR 1.62, p=0.080); PINP (HR 0.76, p=0.309); PRO-C6 (HR 1.14, p=0.628)). As previously reported, rising concentrations of collagen degradation markers C1M, C3M, C6M and CRPM were associated with an increased risk of overall mortality (HR=1.84, CI 1.03 – 3.27, p=0.038, HR=2.44, CI 1.39–4.31, p=0.002; HR= 2.19, CI 1.25–3.82, p=0.006; HR= 2.13 CI 1.21–3.75, p=0.009 respectively).

Elevated levels of PRO-C3 and PRO-C6 associate with IPF disease progression. Collagen synthesis and degradation biomarkers have the potential to enhance clinical trials in IPF and may inform prognostic assessment and therapeutic decision making in the clinic.
Urinary biomarkers and cardiovascular outcomes in the UK Biobank: observational and Mendelian randomization analyses
Authors: Zanetti Daniela , Bergman Helene , Burgess Stephen , Assimes Themistocles L. , Bhalla Vivek , Ingelsson Erik
Published: December 2018

Background

Urinary biomarkers are associated with hypertension and cardiovascular disease (CVD), but the nature of these associations is incompletely understood.

Methods

We performed multivariable-adjusted regression models to assess associations of urinary sodium-potassium ratio (UNa/UK), and urinary albumin adjusted for creatinine (UAlb/UCr) with cardiovascular risk factors, CVD and type 2 diabetes (T2D) in 478,311 participants of the UK Biobank. Further, we studied above associations separately in men and women, and assessed the causal relationships of these kidney biomarkers with cardiovascular outcomes using the two-sample Mendelian randomization (MR) approach.

Results

In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke, lipid-lowering medication and T2D. In contrast, UAlb/UCr showed significant positive associations with AF, CAD, heart failure, hemorrhagic stroke, lipid-lowering medication and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. Generally, we detected consistent directionality in sex-stratified analyses, with some evidence for sex differences in the associations of urinary biomarkers with T2D and obesity. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with systolic BP (betaSBP≥2.63; betaDBP≥0.85 SD increase in systolic BP per SD change UNa/UK and UAlb/UCr; P≤0.038), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.023).

Conclusion

Our Mendelian randomization analyses mirror and extend findings from randomized interventional trials which have established sodium intake as a risk factor for hypertension. In addition, we detect a feed-back causal loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.
Software application profile: GLU: A tool for analysing continuously measured glucose in epidemiology
Authors: Millard Louise A C , Patel Nashita , Tilling Kate , Lewcock Melanie , Flach Peter A , Lawlor Debbie A
Published: December 2018

Motivation

Continuous glucose monitors (CGM) record interstitial glucose ‘continuously’, producing a sequence of measurements for each participant (e.g. the average glucose every 5 minutes over several days, both day and night). To analyze these data, researchers tend to derive summary variables such as the Area Under the Curve (AUC), to then use in subsequent analyses. To date, a lack of consistency and transparency of precise definitions used for these summary variables has hindered interpretation, replication and comparison of results across studies. We present GLU, an open-source software package for deriving a consistent set of summary variables from CGM data.

General features

GLU performs quality control of each CGM sample (e.g. addressing missing data), derives a diverse set of summary variables (e.g. AUC, and proportion of time spent in hypo-, normo- and hyper-glycaemic levels) covering six broad domains, and outputs these (with quality control information) to the user.

Implementation

GLU is implemented in R.

AVAILABILITY

GLU is available on GitHub at [https://github.com/MRCIEU/GLU]. Git tag v0.1 corresponds to the version presented here.
Genetic analyses of medication-use and implications for precision medicine
Authors: Wu Yeda , Byrne Enda M. , Zheng Zhili , Kemper Kathryn E. , Yengo Loic , Mallett Andrew J. , Yang Jian , Visscher Peter M. , Wray Naomi R.
Published: December 2018

It is common that one medication is prescribed for several indications, and conversely that several medications are prescribed for the same indication, suggesting a complex biological network for disease risk and its relationship with pharmacological function. Genome-wide association studies (GWASs) of medication-use may contribute to understanding of disease etiology, generation of new leads relevant for drug discovery and quantify prospects for precision medicine. We conducted GWAS to profile self-reported medication-use from 23 categories in approximately 320,000 individuals from the UK Biobank. A total of 505 independent genetic loci that met stringent criteria for statistical significance were identified. We investigated the implications of these GWAS findings in relation to biological mechanism, drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes were 16 known therapeutic-effect target genes for medications from 9 categories.
Nationwide population genetic screening improves outcomes of newborn screening for hearing loss in China
Authors: Wang Qiuju , Xiang Jiale , Sun Jun , Yang Yun , Guan Jing , Wang Dayong , Song Cui , Guo Ling , Wang Hongyang , Chen Yaqiu , Leng Junhong , Wang Xiaman , Zhang Junqing , Han Bing , Zou Jing , Yan Chenbin , Zhao Lidong , Luo Hongyu , Han Yuan , Yuan Wen , Zhang Hongyun , Wang Wei , Wang Jian , Yang Huanming , Xu Xun , Yin Ye , Morton Cynthia C. , Zhao Lijian , Zhu Shida , Shen Jun , Peng Zhiyu
Published: December 2018

Purpose: Concurrent newborn hearing and genetic screening has been reported, but its benefits have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of a large number of newborns with genetic screening results. Methods: Newborns in China were screened for 20 hearing-loss-related genetic variants from 2012-2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed-up via phone interviews. Results: We completed genetic screening on one million newborns and followed up 12,778. We found that a positive genetic result significantly indicated a higher positive predictive value of the initial hearing screening (60% vs. 5.0%, P<0.001) and a lower rate of loss-to-follow-up (5% vs. 22%, P<0.001) than an inconclusive one. Importantly, 42% of subjects in the positive group with reported or presymptomatic hearing loss were missed by conventional hearing screening. Furthermore, genetic screening identified 0.23% of subjects predisposed to preventable ototoxicity. Conclusion: Our results demonstrate that limited genetic screening identified additional cases, reduced loss-to-follow-up, and informed families of ototoxicity risks, providing convincing evidence to support integrating genetic screening into universal newborn hearing screening programs.
Cisandtrans-acting variants contribute to survivorship in a naïveDrosophila melanogasterpopulation exposed to ryanoid insecticides
Authors: Green Llewellyn , Battlay Paul , Fournier-Level Alexandre , Good Robert T. , Robin Charles
Published: December 2018

Insecticide resistance is a paradigm of microevolution and insecticides are responsible for the strongest cases of recent selection in the genome ofDrosophila melanogaster. Here we use a naïve population and a novel insecticide class to examine theab initiogenetic architecture of a potential selective response. Genome wide association studies of chlorantraniliprole susceptibility reveal variation in a gene of major effect,Stretchin Myosin light chain kinase(Strn-Mlck), which we validate with linkage mapping and transgenic manipulation of gene expression. We propose that allelic variation inStrn-Mlckalters sensitivity to the calcium depletion attributable to chlorantraniliprole’s mode of action. Genome-wide association studies also reveal a network of genes involved in neuromuscular biology. In contrast, phenotype to transcriptome associations identify differences in constitutive levels of multiple transcripts regulated by cnc, the homologue of mammalian Nrf2. This suggests that genetic variation acts intransto regulate multiple metabolic enzymes in this pathway. The most outstanding association is with the transcription level ofCyp12d1which is also affected incisby copy number variation. Transgenic overexpression ofCyp12d1reduces susceptibility to both chlorantraniliprole and the closely related insecticide cyantraniliprole. This systems genetics study reveals multiple allelic variants segregating at intermediate frequency in a population that is completely naïve to this new insecticide chemistry and it adumbrates a selective response among natural populations to these chemicals.

Significance

Around the world insecticides are being deregistered and banned, as their environmental costs are deemed too great or their efficacy against pest insects is reduced through the evolution of insecticide resistance. With the introduction of replacement insecticides comes the responsibility to assess the way new insecticides perturb various levels of biological systems; from insect physiology to ecosystems. We used a systems genetics approach to identify genetic variants affecting survivorship ofDrosophila melanogasterexposed to chlorantraniliprole. The study population was completely naïve to this insecticide chemistry and yet we find associations with variants in neuromuscular genes and co-regulated detoxification genes. We predict that these variants will increase in populations of this ‘sentinel species’ as these insecticides are applied in the environment.
Genome characterization, prevalence and transmission mode of a novel picornavirus associated with the Threespine Stickleback (Gasterosteus aculeatus)
Authors: Hahn Megan A , Dheilly Nolwenn M.
Published: December 2018

The complete genome sequence of an RNA virus was assembled from RNA sequencing of virus particles purified from threespine stickleback intestine samples. This new virus is most closely related to the Eel Picornavirus and can be assigned to the genus Potamipivirus in the family Picornoviridae. Its unique genetic properties are sufficient to establish a new species, dubbed the Threespine Stickleback Picornavirus (TSPV). Due to their broad geographic distribution throughout the northern hemisphere and parallel adaptation to freshwater, threespine sticklebacks have become a model in evolutionary ecology. Further analysis using diagnostic PCRs revealed that TSPV is highly prevalent in both anadromous and freshwater populations of threespine sticklebacks and is transmitted vertically to offspring obtained from in vitro fertilization in laboratory settings. It is thus necessary to test the impact of TSPV on the biology of threespine sticklebacks as this widespread virus could interfere with the behavioral, physiological, or immunological studies that employ threespine sticklebacks as model system.
Measuring rank robustness in scored protein interaction networks
Authors: Bozhilova Lyuba V. , Whitmore Alan V. , Wray Jonny , Reinert Gesine , Deane Charlotte M.
Published: December 2018

Background

Protein interaction databases often provide confidence scores for each recorded interaction based on the available experimental evidence. Protein interaction networks (PINs) are then built by thresholding on these scores, so that only interactions of sufficiently high quality are included. These networks are used to identify biologically relevant motifs or nodes using metrics such as degree or betweenness centrality. This type of analysis can be sensitive to the choice of threshold. If a node metric is to be useful for extracting biological signal, it should induce similar node rankings across PINs obtained at different reasonable confidence score thresholds.

Results

We propose three measures—rank continuity, identifiability, and instability—to evaluate how robust a node metric is to changes in the score threshold. We apply our measures to twenty-five metrics and identify four as the most robust: the number of edges in the step-1 ego network, as well as the leave-one-out differences in average redundancy, average number of edges in the step-1 ego network, and natural connectivity. Our measures show good agreement across PINs from different species and data sources. Analysis of synthetically generated scored networks shows that robustness results are context-specific, and depend both on network topology and on how scores are placed across network edges.

Conclusion

Due to the uncertainty associated with protein interaction detection, and therefore network structure, for PIN analysis to be reproducible, it should yield similar results across different confidence score thresholds. We demonstrate that while certain node metrics are robust with respect to threshold choice, this is not always the case. Promisingly, our results suggest that there are some metrics that are robust across networks constructed from different databases, and different scoring procedures.
Low-Density Lipoprotein Receptor-Mediated Lipidome-Transcriptome Reprogramming Impulses to Cisplatin Insensitivity
Authors: Chang Wei-Chun , Wang Hsiao-Ching , Cheng Wei-Chung , Yang Juan-Cheng , Chung Wei-Min , Chen Lumin , Ho Yen-Pin , Hung Yao-Ching , Ma Wen-Lung
Published: December 2018

Platinum-based therapy remains the cornerstone for cancer patient management; however, its efficacy varies. This study demonstrated the differential expressions of low-density lipoprotein receptor (LDLR) in subtypes of epithelial ovarian carcinoma (EOC) determines cisplatin sensitivity. It's sensitive in serous EOCs (low LDLR), where insensitive in endometrioid and clear cell EOCs (high LDLR). Meanwhile, knocked-down or overexpressed LDLR in EOC could reversed the chemosensitivity pattern both in vitro and in vivo. Mechanistic dissection with transcriptome vs. lipidome trans-omics analyses elucidated the LDLR-->LPC (Lyso-PhosphotidylCholine)-->FAM83B (phospholipase-related)-->FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis in cisplatin insensitivity. Implementing LPC-liposome encapsulated cisplatin could facilitate DNA-adduct formation via lipid droplets (LDs) delivery. Furthermore, Bioinformatics analyses found that the LDL/R-->LD homeostasis alteration is critical for therapeutic prognosis. Lastly, using LPC-liposome-cisplatin improved cisplatin sensitivities in gastric cancer, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma cells. In conclusion, this report discovered a LDL/R-reprogrammed transcriptome-lipidome network, by which impulses platinum insensitivity and disease outcome. The drug specific lipidome for liposome manufacture might be an efficienct pharmaceutics strategy for chemoagents.
Emergence of the East-Central-South-African genotype of Chikungunya virus in Brazil and the city of Rio de Janeiro may have occurred years before surveillance detection
Authors: Souza Thiago Moreno L. , Vieira Yasmine Rangel , Delatorre Edson , Barbosa-Lima Giselle , Luiz Raul Leal Faria , Vizzoni Alexandre , Jain Komal , Mesquita Milene , Bhuva Nishit , Gogarten Jan F. , Ng James , Thakkar Riddhi , Calheiros Andrea Surrage , Monteiro Ana Paula Teixeira , Bozza Patrícia T. , Bozza Fernando A. , Tschoeke Diogo A. , Leomil Luciana , de Mendonça Marcos Cesar Lima , dos Santos Rodrigues Cintia Damasceno , Torres Maria C. , de Filippis Ana Maria Bispo , Nogueira Rita Maria Ribeiro , Thompson Fabiano L. , Lemos Cristina , Durovni Betina , Cerbino-Neto José , Morel Carlos M. , Lipkin W. Ian , Mishra Nischay
Published: December 2018

Brazil, which is hyperendemic for dengue virus (DENV), has had recentZika(ZIKV) and (CHIKV)Chikungunyavirus outbreaks. Since March 2016, CHIKV is the arbovirus infection most frequently diagnosed in Rio de Janeiro. In the analysis of 1835 syndromic patients, screened by real time RT-PCR, 56.4% of the cases were attributed to CHIKV, 29.6% to ZIKV, and 14.1% to DENV-4. Sequence analyses of CHIKV from sixteen samples revealed that the East-Central-South-African(ECSA) genotype of CHIKV has been circulating in Brazil since 2013 [95% bayesian credible interval (BCI): 03/2012-10/2013], almost a year before it was detected by arbovirus surveillance program. Brazilian cases are related to Central African Republic sequences from 1980’s. To the best of our knowledge, given the available sequence published here and elsewhere, the ECSA genotype was likely introduced to Rio de Janeiro early on 2014 (02/2014; BCI: 07/2013-08/2014) through a single event, after primary circulation in the Bahia state at the Northestern Brazil in the previous year. The observation that the ECSA genotype of CHIKV was circulating undetected underscores the need for improvements in molecular methods for viral surveillance.
Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
Authors: Bandaru Manoj K , Emmanouilidou Anastasia , Ranefall Petter , von der Heyde Benedikt , Mazzaferro Eugenia , Klingström Tiffany , Masiero Mauro , Dethlefsen Olga , Ledin Johan , Larsson Anders , Brooke Hannah L , Wählby Carolina , Ingelsson Erik , den Hoed Marcel
Published: December 2018

Background

Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.

Methods

We developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384), and used it to characterize three candidate genes in a GWAS-identified pleiotropic locus on chr 19p13.11 (n>500).

Results

Our results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1). Finally, our pipeline helped identify putative causal genes for circulating lipids and early-stage atherosclerosis (LPAR2andGATAD2A).

Conclusions

In summary, our pipeline facilitates systematic,in vivocharacterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.
The elasticity of individual protocadherin 15 molecules implicates cadherins as the gating springs for hearing
Authors: Bartsch Tobias F. , Hengel Felicitas E. , Oswald Aaron , Dionne Gilman , Chipendo Iris V. , Mangat Simranjit S. , El Shatanofy Muhammad , Shapiro Lawrence , Mueller Ulrich , Hudspeth A. J.
Published: December 2018

Hair cells, the sensory receptors of the inner ear, respond to mechanical forces originating from sounds and accelerations. An essential feature of each hair cell is an array of filamentous tip links, consisting of the proteins protocadherin 15 (PCDH15) and cadherin 23 (CDH23), whose tension is thought to directly gate the cell's transduction channels. These links are considered far too stiff to represent the gating springs that convert hair-bundle displacement into forces capable of opening the channels, and no mechanism has been suggested through which tip-link stiffness could be varied to accommodate hair cells of distinct frequency sensitivity in different receptor organs and animals. As a consequence, the gating spring's identity and mechanism of operation remain central questions in sensory neuroscience. Using a high-precision optical trap, we show that an individual monomersof PCDH15 acts as an entropic spring that is much softer than its enthalpic stiffness alone would suggest. This low stiffness implies that the protein is a significant part of the gating spring that controls a hair cell's transduction channels. The tip link's entropic nature then allows for stiffness control through modulation of its tension. We find that a PCDH15 molecule is unstable under tension and exhibits a rich variety of reversible unfolding events that are augmented when the Ca2+ concentration is reduced to physiological levels. Tip-link tension and Ca2+ concentration are therefore likely parameters through which nature tunes a gating spring's mechanical properties.
Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress responses
Authors: Szewczyk Magdalena M , Ishikawa Yoshinori , Organ Shawna , Sakai Nozomu , Li Fengling , Ackloo Suzanne , Eram Mohammad , Dilworth David , Fukushi Hideto , Harding Rachel , Seña Carlo C dela , Sugo Tsukasa , Hayashi Kozo , Macleod David , Zepeda Carlos , Takagi Shinji , Al-Awar Rima , Richard Stephane , Takizawa Masayuki , Arrowsmith Cheryl H , Vedadi Masoud , Brown Peter J , Nara Hiroshi , Barsyte-Lovejoy Dalia
Published: December 2018

Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective and cell active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells, is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 resulted in drastically reduced levels of arginine monomethylation of HSP70 family members and other stress-associated proteins. Structural and biochemical analysis revealed that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibited methylation of both constitutive and inducible forms of HSP70, and led to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.
Community venomics reveals intra-species variations in venom composition of a local population ofVipera kaznakoviin Northeastern Turkey
Authors: Petras Daniel , Hempel Benjamin-Florian , Göçmen Bayram , Karis Mert , Whiteley Gareth , Wagstaff Simon C. , Heiss Paul , Casewell Nicholas R. , Nalbantsoy Ayse , Süssmuth Roderich D.
Published: December 2018

We report on the variable venom composition of a population of the Caucasus viper (Vipera kaznakovi) in Northeastern Turkey. We applied a combination of venom gland transcriptomics, as well as de-complexing bottom-up and top-down venomics, enabling the comparison of the venom proteomes from multiple individuals. In total, we identified peptides and proteins from 15 toxin families, including snake venom metalloproteinases (svMP; 37.8%), phospholipases A2(PLA2; 19.0%), snake venom serine proteinases (svSP; 11.5%), C-type lectins (CTL; 6.9%) and cysteine-rich secretory proteins (CRISP; 5.0%), in addition to several low abundant toxin families. Furthermore, we identified intra-species variations of theV. kaznakovivenom composition, and find these were mainly driven by the age of the animals, with lower svSP abundance in juveniles. On a proteoform level, several small molecular weight toxins between 5 and 8 kDa in size, as well as PLA2s, drove the difference between juvenile and adult individuals. This study provides first insights into venom variability ofV. kaznakoviand highlights the utility of intact mass profiling for a fast and detailed comparison of snake venoms of individuals from a community.

Biological Significance

Population level and ontogenetic venom variation (e.g. diet, habitat, sex or age) can cause a loss of antivenom efficacy against snake bites from wide ranging snake populations. The state of the art for the analysis of snake venoms are de-complexing bottom-up proteomics approaches. While useful, these have the significant drawback of being time-consuming and following costly protocols, and consequently are often applied to pooled venom samples. To overcome these shortcomings and to enable rapid and detailed profiling of large numbers of individual venom samples, we integrated an intact protein analysis workflow into a transcriptomics-guided bottom-up approach. The application of this workflow to snake individuals of a local population ofV. kaznakovirevealed intra-species variations in venom composition, which are primarily explained by the age of the animals, and highlighted svSP abundance to be one of the molecular drivers for the compositional differences.

Highlights

First community venomic analysis of a local population of the Caucasian viper (Vipera kaznakovi).

The venom gland transcriptome ofV. kaznakoviidentified 46 toxin genes relating to 15 venom toxin families.

Bottom-up venomics revealed the identification of 25 proteins covering 7 toxin families mainly dominated by snake venom metalloproteinases (svMP).

Community venomics by top-down mass profiling revealed ontogenetic shifts between juvenile and adult snakes.
Population genomics perspectives on convergent adaptation
Authors: Lee Kristin M , Coop Graham
Published: December 2018

Convergent adaptation is the independent evolution of similar traits conferring a fitness advantage in two or more lineages. Cases of convergent adaptation inform our ideas about the ecological and molecular basis of adaptation. In judging the degree to which putative cases of convergent adaptation provide independent replication of the process of adaptation, it is necessary to establish the degree to which the evolutionary change is unexpected under null models and to show that selection has repeatedly, independently driven these changes. Here, we discuss the issues that arise from these questions particularly for closely-related populations, where gene flow and standing variation add additional layers of complexity. We outline a conceptual framework to guide intuition as to the extent to which evolutionary change represents the independent gain of information due to selection and show that this is a measure of how surprised we should be by convergence. Additionally, we summarize the ways population and quantitative genetics and genomics may help us address questions related to convergent adaptation, as well as open new questions and avenues of research.
The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination within heterochromatin
Authors: Kollarovic G. , Topping C. E. , Shaw E. P. , Chambers A. L.
Published: December 2018

Efficient double-strand break repair in eukaryotes requires manipulation of chromatin structure. ATP-dependent chromatin remodelling enzymes can facilitate different DNA repair pathways, during different stages of the cell cycle and in a range of chromatin environments. The contribution of remodelling factors to break repair within heterochromatin during G2 is unclear.

The human HELLS protein is a Snf2-like chromatin remodeller family member and is mutated or misregulated in several cancers and some cases of ICF syndrome. HELLS has been implicated in the DNA damage response, but its mechanistic function in repair is not well understood. We find that HELLS facilitates homologous recombination at two-ended breaks within heterochromatic regions during G2. HELLS enables end-resection and accumulation of CtIP at IR-induced foci. We identify an interaction between HELLS and CtIP and establish that the ATPase domain of HELLS is required to promote DSB repair. This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts.
VikNGS: A C++ Variant Integration Kit for Next Generation Sequencing association analysis
Authors: Baskurt Zeynep , Mastromatteo Scott , Gong Jiafen , Wintle Richard F. , Scherer Stephen W. , Strug Lisa J.
Published: December 2018

Motivation

Integration of next generation sequencing data (NGS) across different research studies can improve the power of genetic association testing by increasing sample size and can obviate the need for sequencing controls. Unfortunately, if differential genotype uncertainty across studies is not accounted for, combining data sets can also produce spurious association results. The robust variance score statistic (RVS) for genetic association of rare and common variants has been shown to effectively adjust for bias caused by the differences in read depth in case-control genetic association studies when the two groups were sequenced using different experimental designs. To enable consortium research, the aggregation of several data sets for genetic association analysis of quantitative and binary traits with covariate adjustment is required, and we developed the Variant Integration Kit for NGS (VikNGS) that expands the functionality of RVS (vRVS) for this purpose.

Results

VikNGS is a fast and computationally efficient cross-platform software package that provides an implementation for vRVS, as well as conventional rare and common variant genotype-based association analysis approaches. The package includes a graphical user interface that contains power simulation functionality and data visualization tools.

Availability and Implementation

The VikNGS package can be downloaded at http://www.tcag.ca/tools/index.html

Documentation can be found at https://VikNGSdocs.readthedocs.io/en/latest/

Contact

lisa.strug@sickkids.ca

Supplementary information

Supplementary data are available at Bioinformatics online.
A family-based phasing algorithm for sequence data
Authors: Battagin Mara , Gonen Serap , Ros-Freixedes Roger , Whalen Andrew , Gorjanc Gregor , Hickey John M
Published: December 2018

This paper describes a family-based phasing algorithm, for variable-coverage sequence data, that first minimises phasing errors and then maximises the proportion of alleles phased. This algorithm is one of the essential tools that underpin an overall strategy for generating highly accurate sequence data on whole populations at low cost. The algorithm is called AlphaFamSeq. It uses sequence data on the focal individual and at least two generations of ancestors to phase alleles. In the first step, AlphaFamSeq calculates allele probabilities using iterative peeling. In subsequent steps, the alleles are phased using heuristics deriving information from the sequence data of parents, grandparents and progenies and, if available, from other families in the pedigree. AlphaFamSeq was tested on a range of simulated data sets. AlphaFamSeq gives low phasing error rates and, if there is sufficient sequence information and haplotype sharing amongst individuals, it can give a high yield of correctly phased alleles. The allele threshold had a large effect and window size had a small effect on performance. When all individuals in a single family were sequenced at different coverages the highest correctly phased alleles reached 90% of the possible maximum (98.9%) at ~1/6 of the maximum aggregate coverage. Adding sequence information from other related individuals increased the percentage of correctly phased alleles. Imputation performance was high across all allele frequencies (average correlation by marker of 0.94), except for a slight decrease at very low frequencies (≤0.01 MAF). Within an overall strategy for generating highly accurate sequence data on whole populations at low cost the role of AlphaFamSeq is to provide very accurately phased haplotypes on focal individuals, who are individuals whose haplotypes are very common in the population.
The Genomic Geography and Evolution of Clusters of Tandemly Duplicated Genes in the Human and Mammal Genomes
Authors: Ortiz Juan F , Rokas Antonis
Published: December 2018

Clusters of duplicated genes (CTDGs) are nearly ubiquitous in life's genomes, and are associated with several well-known gene families, such as olfactory receptors, zinc fingers, and immunity-related genes, as well as with several highly variable traits, including olfaction, body plan architecture, and pathogen resistance. However, these observations are usually anecdotal, restricted to specific cases, and lacking evolutionary context. In this study, we use a robust statistical approach to characterize the CTDG repertoire and analyze the distribution of CTDGs across 18 mammal genomes, including human. We found that, on average, 18% of the genes in each species are parts of CTDGs. Although genes in CTDGs are enriched for several biological processes, these tend to be involved in the interactions between the organism and its environment. We further found that mammalian CTDGs are not uniformly distributed across chromosomes and that orthologs of the human chromosome 19 are among the most clustered chromosomes in nearly all mammalian genomes analyzed. We also found evidence that the human chromosome 19 was formed by a fusion event that occurred before the diversification of the rodent and primate lineages and maintained its high density of CTDGs during its subsequent evolution. Finally, using chromosome-level alignments across mammalian genomes, we show how the syntenic regions of the human chromosome 19 have been shrinking, increasing their gene density and possibly increasing the compactness of its CTDGs. These results suggest that CTDGs are a major feature of mammalian genomes and provide novel insights into the origin and evolution of regions with unusually high densities of CTDGs.
Phase Transitions in Mutualistic Communities under Invasion
Authors: Bray Samuel Roland , Fan Yuhang , Wang Bo
Published: December 2018

Predicting the outcome of species invasion in ecosystems is a challenge of both theoretical and practical significance. Progress so far has been limited by the intractability of the far-from-equilibrium nature of the transitions that occur during invasion events. Here, we address this limitation by solving for the transition dynamics of a cross-feeding community along an analytically tractable manifold defined by the system carrying capacity. We find that species invasion induces discontinuous transitions in the community composition, resembling phase transitions in physical systems. These sharp transitions are emergent properties of species-resource interactions and relate directly to the extent of niche overlap between invasive and native species. The high susceptibility of community structure to small variations in species phenotype and resource conditions near the phase boundaries can explain empirically observed stochasticity and the emergence of tipping points in ecosystems. Moreover, we demonstrate that these phase transitions can be modulated by environmental variations to construct nonlinear organization of species both in space and time.
The Caenorhabditis elegans HAM-1 protein modifies G protein signaling and membrane extension to reverse the polarity of asymmetric cell division
Authors: Teuliere Jerome , Garriga Gian
Published: December 2018

Asymmetric divisions often produce daughter cells that differ in both fate and size. The Caenorhabditis elegans HAM-1 protein regulates both daughter cell fate and daughter cell size asymmetry (DCSA) in a subset of asymmetric divisions. Here we focus on the divisions of the Q.a and Q.p neuroblasts, which use distinct mechanisms to divide with opposite polarity. Q.a divides by a ham-1-dependent, spindle-independent, myosin-dependent mechanism to produce a smaller anterior daughter that dies, whereas Q.p divides by a ham-1-independent, spindle-dependent, myosin-independent mechanism to produce a smaller posterior daughter that dies. Despite these differences, we found that membrane extension at the posterior of Q.a and at the anterior of Q.p promoted DCSA in these cells by a Wiscott-Aldrich protein (WASp)-dependent mechanism and that in ham-1 mutant Q.a divisions, the polarity of this extension was reversed. In addition, the spindle moved posteriorly during the Q.a division in a ham-1 mutant, a phenotype normally exhibited by Q.p. We found that this spindle movement in wild-type Q.p divisions required Gα proteins that promote spindle movement in other asymmetric divisions, and GPR-1, a protein involved in linking G proteins to microtubule asters, localized to the posterior cortex of Q.p. Genetic interactions suggest that ham-1 mutant Q.a divisions also require Gα proteins function to divide with a reversed polarity. The transformation of Q.a to Q.p-like polarity in the ham-1 mutant, however, appeared incomplete: ham-1 loss did not alter the asymmetric localization of the non-muscle myosin NMY-2 to the anterior cortex of Q.a. A GFP tagged ham-1 transgene revealed that Q.a but not Q.p expressed ham-1. Finally, we show that HAM-1 has both cortical and nuclear functions in Q,a DCSA. We propose a model where HAM-1 modifies a default Q.p-type polarity by localizing WASp function to the posterior Q.a membrane and by interfering with G-protein mediated spindle movement.
Timely double-strand break repair and pathway choice in pericentromeric heterochromatin depend on the histone demethylase dKDM4A
Authors: Janssen Aniek , Colmenares Serafin U. , Lee Timothy , Karpen Gary H.
Published: December 2018

Repair of DNA double-strand breaks (DSBs) must be orchestrated properly within diverse chromatin domains in order to maintain genetic stability. Euchromatin and heterochromatin domains display major differences in histone modifications, biophysical properties, and spatiotemporal dynamics of DSB repair. However, it is unclear whether differential histone-modifying activities are required for DSB repair in these distinct domains. We showed previously that the Drosophila melanogaster KDM4A (dKDM4A) histone demethylase is required for heterochromatic DSB mobility. Here we used locus-specific DSB induction in Drosophila animal tissues and cultured cells to more deeply interrogate the impact of dKDM4A on chromatin changes, temporal progression, and pathway utilization during DSB repair. We found that dKDM4A promotes the demethylation of heterochromatin-associated histone marks at DSBs in heterochromatin but not euchromatin. Most importantly, we demonstrate that dKDM4A is required to complete DSB repair in a timely manner and regulate the relative utilization of homologous recombination (HR) and nonhomologous end-joining (NHEJ) repair pathways but exclusively for heterochromatic DSBs. We conclude that the temporal kinetics and pathway utilization during heterochromatic DSB repair depend on dKDM4A-dependent demethylation of heterochromatic histone marks. Thus, distinct pre-existing chromatin states require specialized epigenetic alterations to ensure proper DSB repair.
Survey of the analysis of continuous conformational variability of biological macromolecules by electron microscopy
Authors: Sorzano C. O. S. , Jiménez A. , Mota J. , Vilas J. L. , Maluenda D. , Martínez M. , Ramírez-Aportela E. , Majtner T. , Segura J. , Sánchez-García R. , Rancel Y. , del Caño L. , Conesa P. , Melero R. , Jonic S. , Vargas J. , Cazals F. , Freyberg Z. , Krieger J. , Bahar I. , Marabini R. , Carazo J. M.
Published: December 2018

Single-particle analysis by electron microscopy is a well established technique for analyzing the three-dimensional structures of biological macromolecules. Besides its ability to produce high-resolution structures, it also provides insights into the dynamic behavior of the structures by elucidating their conformational variability. Here, the different image-processing methods currently available to study continuous conformational changes are reviewed.
The structure and activity of the glutathione reductase fromStreptococcus pneumoniae
Authors: Sikanyika Mwilye , Aragão David , McDevitt Christopher A. , Maher Megan J.
Published: December 2018

The glutathione reductase (GR) fromStreptococcus pneumoniaeis a flavoenzyme that catalyzes the reduction of oxidized glutathione (GSSG) to its reduced form (GSH) in the cytoplasm of this bacterium. The maintenance of an intracellular pool of GSH is critical for the detoxification of reactive oxygen and nitrogen species and for intracellular metal tolerance to ions such as zinc. Here,S. pneumoniaeGR (SpGR) was overexpressed and purified and its crystal structure determined at 2.56 Å resolution.SpGR shows overall structural similarity to other characterized GRs, with a dimeric structure that includes an antiparallel β-sheet at the dimer interface. This observation, in conjunction with comparisons with the interface structures of other GR enzymes, allows the classification of these enzymes into three classes. Analyses of the kinetic properties ofSpGR revealed a significantly higher value forKm(GSSG)(231.2 ± 24.7 µM) in comparison to other characterized GR enzymes.
The redefined DNA-binding domain of human xeroderma pigmentosum complementation group A: production, crystallization and structure solution
Authors: Lian Fu-Ming , Yang Xiangwei , Yang Wancai , Jiang Yong-Liang , Qian Chengmin
Published: December 2018

Human xeroderma pigmentosum complementation group A (XPA) is a scaffold protein that plays significant roles in DNA-damage verification and in recruiting downstream endonucleases to facilitate the repair of DNA lesions in nucleotide-excision repair. XPA98–219 (residues 98–219) has been identified as a DNA-binding domain and has been extensively studied in the last two decades. However, the most recent studies have redefined the DNA-binding domain as XPA98–239 (residues 98–239); it exerts a remarkably higher DNA-binding affinity than XPA98–219 and has a binding affinity that is quite similar to that of the full-length protein. Here, the production, crystallization and structure solution of human XPA98–239 are described. Crystals were obtained using a precipitant composed of 1.8 M ammonium citrate tribasic pH 7.0. Native X-ray diffraction data and zinc single-wavelength anomalous diffraction (SAD) data were collected to 1.93 and 2.06 Å resolution, respectively. The crystals belonged to space group P3, with unit-cell parameters a = 67.1, b = 67.1, c = 35.6 Å, γ = 120.0°. Crystal-content analysis showed the presence of one molecule in the asymmetric unit, corresponding to a Matthews coefficient of 2.65 Å3 Da−1 and a solvent content of 53.6%. The initial phases were solved and the structure model was automatically built by zinc SAD using the AutoSol program. The initial structure model covered 119 of 142 residues in the asymmetric unit, with an R
work of 22.15% and an R
free of 25.82%. Compared with a previously obtained truncated solution NMR structure of XPA (residues 98–210), a 19-residue C-terminal extension (residues 211–229, corresponding to 10 of the 20 extra C-terminal residues in the redefined domain for enhanced DNA binding) was contained in this initial model. Refinement of the atomic coordinates of XPA is ongoing.
Crystal structure of 4-[(adamantan-1-yl)amino]naphthalene-1,2-dione
Authors: Lamoureux Guy , Alvarado-Rojas Mónica , Pineda Leslie W.
Published: December 2018

The title compound, C20H21NO2, an example of a stable 1,2-naphthoquinone, was determined by single-crystal X-ray diffraction analysis at 100 K. This structure illustrates steric buttressing of the adamantanyl group, forcing the N—H group into the coplanar aromatic C—H. The presence of strong delocalization between the planar N atom at the 4-position and the carbonyl group at the 2-position is indicated. In the crystal, C—H...O and C—H...π interactions link the molecules into a three-dimensional network.
Crystal structure of the ethyl 2,4-dihydroxy-6-methylbenzoate from Illicium difengpi K.I.B et K.I.M.
Authors: Xiong Huiping , Mao Shilong , Lv Qianzhou , Zhang Ning
Published: December 2018

The title compound, C10H12O4, was isolated from Illicium difengpi K.I.B et K.I.M. An intramolecular O—H...O hydrogen bond stabilizes the molecular conformation. In the crystal, the compound forms offset slanted stacks of alternating inversion-related molecules along the a axis direction. Intermolecular O—H...O hydrogen bonds link the molecules into double strands parallel to the [101] direction.
1-Methyl-1H-imidazol-3-ium methanesulfonate
Authors: Hmissa Taha , Mathivathanan Logesh , Thompson Alexander P. , Mirjafari Arsalan
Published: December 2018

The structure of the title salt, C4H7N2
+·CH3O3S−, has monoclinic (P21/n) symmetry. The 1-methylimidazolium cation and the methylsulfonate anion in the asymmetric unit are held together by a strong N—H...O hydrogen bond.