bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extensive mitochondrial population structure and haplotype-specific phenotypic variation in theDrosophilaGenetic Reference Panel
Authors: Bevers Roel P.J. , Litovchenko Maria , Kapopoulou Adamandia , Braman Virginie S. , Robinson Matthew R. , Auwerx Johan , Hollis Brian , Deplancke Bart 
Published: November 2018

AbstractTheDrosophilaGenetic Reference Panel (DGRP) serves as a valuable resource to better understand the genetic landscapes underlying quantitative traits. However, such DGRP studies have so far only focused on nuclear genetic variants. To address this, we sequenced the mitochondrial genomes of >170 DGRP lines, identifying 229 variants including 21 indels and 7 frameshifts. We used our mitochondrial variation data to identify 12 genetically distinct mitochondrial haplotypes, thus revealing important population structure at the mitochondrial level. We further examined whether this population structure was reflected on the nuclear genome by screening for the presence of potential mito-nuclear genetic incompatibilities in the form of significant genotype ratio distortions (GRDs) between mitochondrial and nuclear variants. In total, we detected a remarkable 1,845 mito-nuclear GRDs, with the highest enrichment observed in a 40 kb region around the geneSex-lethal(Sxl). Intriguingly, downstream phenotypic analyses did not uncover major fitness effects associated with these GRDs, suggesting that a large number of mito-nuclear GRDs may reflect population structure at the mitochondrial level rather than actual genomic incompatibilities. This is further supported by the GRD landscape showing particular large genomic regions associated with a single mitochondrial haplotype. Next, we explored the functional relevance of the detected mitochondrial haplotypes through an association analysis on a set of 259 assembled, non-correlating DGRP phenotypes. We found multiple significant associations with stress- and metabolism-related phenotypes, including food intake in males. We validated the latter observation by reciprocal swapping of mitochondrial genomes from high food intake DGRP lines to low food intake ones. In conclusion, our study uncovered important mitochondrial population structure and haplotype-specific metabolic variation in the DGRP, thus demonstrating the significance of incorporating mitochondrial haplotypes in geno-phenotype relationship studies.
Translationally Controlled Tumor ProteinTCTPas Peptide Vaccine againstSchistosoma japonicum: an Immunoinformatics Approach
Authors: Abdalrahman Rayan A , Ahmed Shima S , Elnaeem Mahmoud A , Mohammed Marwa S , Jammie Nawraz M , Yousif Israa A , Mohamed Wala H , Nasr Sabreen Y , Awad-Elkareem Mawadda A , Hassan Mohamed A 
Published: November 2018

AbstractSchistosoma japonicum is the most pathogenic causative form of schistosomiasis that causes a major health problem in its endemic countries. Until now, praziquantel is the only drug used to treat Schistosomiasis, but it does not prevent re-infection. So, repetition of the treatment is needed. Moreover, there is no effective vaccine against S. japonicum. Therefore, an urgent need for the development of vaccines is mandatory. This study aimed to analyze an immunogenic protein, Transitionally Controlled Tumor Protein (TCTP) using an immunoinformatics approach to design a universal peptide vaccine against Schistosoma japonicum. A set of 22 of TCTP sequences were retrieved from NCBI database. Conservancy of these sequences was tested and then conserved B cell and T cell epitopes were predicted using different tools available in IEBD. Epitopes having high scores in both B and T cell predicting tools were proposed. An epitope129YEHYI133was predicted as a most promising epitope with good prediction scores in surface accessibility and antigenicity. Besides that, epitopes129YEHYIGESM137and92YLKAIKERL100were predicted as the most promising epitopes concerning their binding to MHC I and MHC II allele respectively. The study revealed that our predicted epitopes could be used to develop an efficacious vaccine against Schistosoma japonicum in the future especially epitope YEHYIGESM as it is shared between MHC I and II alleles and overlapped with the most promising B cell epitope. Both in vitro and in vivo studies is recommended to confirm the efficacy of YEHYIGESM as a peptide vaccine.
Spatial epidemiology of gestational age and birth weight in Switzerland: Census-based linkage study
Authors: Skrivankova Veronika , Zwahlen Marcel , Adams Mark , Low Nicola , Kuehni Claudia E , Egger Matthias 
Published: November 2018

ABSTRACTBackgroundGestational age and birth weight are strong predictors of infant morbidity and mortality. Understanding spatial variation can inform policies to reduce health inequalities. We examined small-area variation in gestational age and birth weight in Switzerland.MethodsAll singleton live births recorded in the Swiss Live Birth Register 2011 to 2014 were eligible. We deterministically linked the Live Birth Register with census and survey data to create datasets including neonatal and pregnancy-related variables, parental characteristics and geographical variables. We produced maps of 705 areas and fitted linear mixed-effect models to assess to what extent spatial variation was explained by these variables.ResultsWe analysed all 315,177 eligible live births. Area-level averages of gestational age varied between 272-279 days, and between 3138-3467g for birth weight. The fully adjusted models explained 31% and 87% of spatial variation of gestational age and birth weight, respectively. Language region explained most of the variation, with shorter gestational age and lower birth weight in French- and Italian- than in German-speaking areas. Other variables explaining variation were, for gestational age, the level of urbanisation, the parents’ nationality and missing father. For birth weight, they were gestational age, altitude, born out of wedlock, and parental nationality. In a subset of 69,463 live births with data on parental education, levels of education were only weakly associated with gestational age or birth weight.ConclusionsIn Switzerland, small area variation in birth weight is largely explained, and variation in gestational age partially explained by geocultural, socio-demographic and pregnancy factors.Strengths and limitations of this studyThis study was based on a large sample with national coverage, with data on neonatal and pregnancy-related predictors of gestational age and birth weight, and precise spatial data.No data were available on the mode of delivery, maternal smoking, mothers’ weight and height or gestational diabetes.The fully adjusted model explained about 80% of the regional variation in birth weight and about 40% of the variation in gestational age.Language region, a proxy for cultural, social and behavioural factors, was a strong explanatory factor, with lower birth weight and shorter gestation in the French and Italian compared to the German language region.Unknown father was associated with shorter gestation and lower birth weight, indicating that children not recognised by their fathers may be at higher risk of poor outcomes.
The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2
Authors: Kozlova Nina , Mennerich Daniela , Samoylenko Anatoly , Dimova Elitsa Y. , Koivunen Peppi , Biterova Ekaterina , Richter Kati , Hassinen Antti , Kellokumpu Sakari , Manninen Aki , Miinalainen Ilkka , Glumoff Virpi , Ruddock Lloyd , Drobot Lyudmyla , Kietzmann Thomas 
Published: November 2018

SummaryThe EGFR-adaptor protein CIN85 has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill-defined. Here, we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SH3 domains of CIN85 interact with the proline-arginine rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF-degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9 edited cells affected growth and migration properties as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2, and uncovered an essential survival function in tumor cells linking growth factor adaptors with hypoxia signaling.
Prolonged Antibiotic Treatment Generates a Fluoroquinolone Resistant Gut Microbiome and Collateral Multi-Drug Resistance
Authors: Dubinsky Vadim , Reshef Leah , Bar Nir , Rabinowitz Keren , Godny Lihi , Tulchinsky Hagit , Gophna Uri , Dotan Iris 
Published: November 2018

One Sentence SummaryThe majority of the gut microbiome develops antibiotic resistance via point-mutations in addition to collateral resistance whereas its density is only moderately decreased following long-term antibiotic treatment.ABSTRACTAntibiotic resistance in bacterial pathogens represents a growing threat to modern medicine. Limitation of lengthy and broad-spectrum antibacterial treatment regimens is generally recommended. Nevertheless, some conditions may require prolonged antibiotic treatment. The effects of such treatments on bacterial communities, specifically their resistome, is yet unknown. Here, we followed a unique cohort of patients with ulcerative colitis who underwent total large bowel resection and the formation of an ileal pouch from their normal small bowel. The majority of these patients tend to develop inflammation of this previously normal small bowel, known as “pouchitis”. Pouchitis is commonly treated with repeated or prolonged courses of broad-spectrum antibiotics. By using metagenomics of faecal samples obtained longitudinally from patients treated with antibiotics for prolonged periods, we hereby show that the majority of their gut commensal bacteria develop antibiotic resistance by point-mutations. In addition, some bacterial species had acquired multidrug resistance loci with genes that confer resistance to the drug used in the treatment (ciprofloxacin) but co-localized with genes encoding extended-spectrum β-lactamases and other resistance-conferring enzymes. We further show that bacterial density in faecal samples is only modestly reduced despite the long-term antibiotic treatment, thereby questioning the current rationale that antibiotic efficacy in treating pouch inflammation is due to the reduction of bacterial load. This study reveals the impact and dynamics of prolonged antibiotic treatment on human gut microbiomes and provides insights that may guide the development of future IBD therapies. It also provides novel insights into bacterial community recovery after cessation of such prolonged treatment, and highlights the increased risk of spreading mobile antibiotic resistance.
Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis
Authors: Zhu Jinsheng , Lau Kelvin , Harmel Robert K. , Puschmann Robert , Broger Larissa , Dutta Amit K. , Jessen Henning J. , Hothorn Ludwig A. , Fiedler Dorothea , Hothorn Michael 
Published: November 2018

AbstractMany eukaryotic proteins regulating phosphate (Pi) homeostasis contain SPX domains. We have previously shown that these domains act as cellular receptors for inositol pyrophosphate (PP-InsP) signaling molecules, suggesting that PP-InsPs may regulate Pi homeostasis. Here we report that simultaneous deletion of two diphosphoinositol pentakisphosphate kinases VIH1 and 2 in Arabidopsis impairs plant growth and leads to constitutive Pi starvation responses. We demonstrate that VIH1 and VIH2 are bifunctional cytosolic enzymes able to generate and break-down PP-InsPs. Point-mutants targeting the kinase and phosphatase active sites have opposing effects on plant Pi content and Pi starvation responses, while VIH1 and VIH2 protein levels remain constant in different Pi growth conditions. Enzymatic assays reveal that ATP-Mg2+ substrate levels can shift the relative kinase and phosphatase activities of full-length diphosphoinositol pentakisphosphate kinases. Deletion of phosphate starvation response transcription factors rescues vih1 vih2 mutant phenotypes, placing diphosphoinositol pentakisphosphate kinases and PP-InsPs in plant phosphate signal transduction cascades. We propose that VIH1 and VIH2 relay changes in cellular ATP concentration to changes in PPInsP levels, allowing plants to maintain cellular Pi concentrations constant and to trigger Pi starvation responses.
Developing Future Biologists: creating and assessing a portable short course to engage underrepresented undergraduate students in developmental biology
Authors: Pinskey Justine M. , Dulka Eden A. , Ramos Andrea I. , Echevarría-Andino Martha L. , Lorberbaum David S. , Carpenter Brandon S. , Martinez-Marquez Jorge Y. , Budaitis Breane G. , Holloway Emily M. , Raj Samhitha , Chin Alana M. , Suarez Edu , Buttitta Laura A. , Gumucio Deb L. , Wellik Deneen M. , Insolera Ryan , Marty-Santos Leilani , Allen Benjamin L. , Barolo Scott 
Published: November 2018

AbstractMany barriers discourage underrepresented students from pursuing science careers. To access graduate education, undergraduate students must first gain exposure to a particular subject and subsequently accumulate related coursework and research experience. Many underrepresented students lack exposure to developmental biology due to limited undergraduate course offerings and finite resources at smaller institutions. To address this disparity, a group of University of Michigan graduate students and postdoctoral fellows created a portable short course focusing on developmental biology, titled “Developing Future Biologists” (DFB). This weeklong educational initiative provides hands-on laboratory sessions, interactive lectures, and professional development workshops to teach students about developmental biology and increase awareness of scientific career options. To evaluate course effectiveness, we developed a pre-post assessment, incorporating main ideas from the BioCore Guide. Student understanding of basic concepts and perceived experience in developmental biology increased in DFB participants, despite the abbreviated nature of the course. Here, we provide all course materials and an in-depth analysis of the assessment we created. The DFB portable short course model is an easily adaptable tool that connects undergraduate students with opportunities for advanced study and lowers barriers for underrepresented students in science, technology, engineering, and mathematics.
Aged insulin resistant macrophages reveal dysregulated cholesterol biosynthesis, a pro-inflammatory profile and reduced foam cell formation capacity
Authors: Chabrier G , Hobson S , Yuldasheva N , Kearney M. T , Schurmans S , Pineda-Torra I , Gage M. C 
Published: November 2018

AbstractInsulin resistance is the central defining feature of type 2 diabetes and an independent risk factor for the development of atherosclerosis. In addition, aging is a major risk factor in the development of insulin resistance and cardiovascular disease. Macrophages play a pivotal roles the the developments of diabetes and atherosclerosis and express insulin receptors. Despite their relevance however, the effect of insulin and insulin resistance on macrophages regarding their inflammatory status, foam cell formation capacity and affect on atherosclerosis are unclear. By taking advantage of a mouse model that recapitulates the effects of chronic PI3K pathway hyperstimulation in macrophages through SHIP2 knock-down, we show that insulin resistance in aged macrophages promotes a proinflammatory phenotype while modulating the cholesterol biosynthesis pathway. These altered characteristics may contribute to the development of chronic inflammatory disease frequently observed with age. Moreover, aged insulin-resistant proinflammatory macrophages display an altered response to acute inflammatory stimulus and reduced foam cell formation capacity. Our work also highlights for the first time, the complex and contrasting immunomodulatory effects of insulin on macrophages in aged mice.SignificanceFirst study to explore the effects of macrophage insulin resistance in aged cells.Insulin resistance in aged macrophages results in the reprogramming of the transcriptome with more than 4000 genes being differentially regulated.Insulin resistance in aged macrophages results in upregulation of IFN signalling pathway, cholesterol biosynthesis pathway and inflammasome gene expression.Insulin directly regulates macrophage cholesterol biosynthesis, IFN and inflammasome gene expression in a time- and dose-dependent manner.Insulin resistant aged macrophages exhibit reduced capacity to become foam cells.
Novel Linguistic Evaluation of Prefrontal Synthesis (LEPS) test measures prefrontal synthesis acquisition in neurotypical children and predicts high-functioning versus low-functioning class assignment in individuals with autism
Authors: Vyshedskiy Andrey , Radi Katarina , DuBois Megan Catherine , Mugford Emma , Maslova Victoria , Braverman Julia , Piryatinsky Irene 
Published: November 2018

AbstractIn order to grasp the difference between “the cat on the mat” and “the mat on the cat,” understanding the words and the grammar is not enough. Rather it is essential to visually synthesize the cat and the mat together in front of the mind’s eye to appreciate their relations. This type of voluntary imagination, which involves juxtaposition of mental objects is conducted by the prefrontal cortex and is therefore called Prefrontal Synthesis (PFS). While PFS is essential for understanding of complex language, its acquisition has a strong experience-dependent critical period putting children with language delay in danger of never acquiring PFS and, consequently, not mastering complex language comprehension. In typical children, the timeline of PFS acquisition correlates with vocabulary expansion. Conversely, atypically developing children may learn hundreds of words but never acquire PFS. In these individuals, common tests of intelligence based on vocabulary assessment may miss the profound deficit in PFS. Accordingly, we developed a 5-minute test specific for PFS – Linguistic Evaluation of Prefrontal Synthesis or LEPS – and administered it to 50 neurotypical children, age 2 to 7 years (4.1±1.3) and to 23 individuals with impairments, age 8-21 years (16.4±3.0). All neurotypical children older than 4 years received the LEPS score 7/10 or greater indicating good PFS ability. Among individuals with impairments only 9 of 23 (39%) received the LEPS score 7/10 or greater. LEPS score was 90% correct in predicting high-functioning vs. low-functioning class assignment in individuals with autism, while full-scale IQ score was only 50% correct.
Evolutionary Models of Amino Acid Substitutions Based on the Tertiary Structure of their Neighborhoods
Authors: Primetis Elias , Chavlis Spyridon , Pavlidis Pavlos 
Published: November 2018

AbstractIntra-protein residual vicinities depend on the involved amino acids. Energetically favorable vicinities (or interactions) have been preserved during evolution, while unfavorable vicinities have been eliminated. We describe, statistically, the interactions between amino acids using resolved protein structures. Based on the frequency of amino acid interactions, we have devised an amino acid substitution model that implements the following idea: amino acids that have similar neighbors in the protein tertiary structure can replace each other, while substitution is more difficult between amino acids that prefer different spatial neighbors. Using known tertiary structures for α-helical membrane (HM) proteins, we build evolutionary substitution matrices. We constructed maximum likelihood phylogenies using our amino acid substitution matrices and compared them to widely-used methods. Our results suggest that amino acid substitutions are associated with the spatial neighborhoods of amino acid residuals, providing, therefore, insights into the amino acid substitution process.
A Novel Root-Knot Nematode Resistance QTL on Chromosome Vu01 in Cowpea
Authors: Ndeve Arsenio D. , Santos Jansen R. P. , Matthews William. C. , Huynh Bao L. , Guo Yi-Ning , Lo Sassoum , Muñoz-Amatriaín Maria , Roberts Philip A. 
Published: November 2018

ABSTRACTThe root-knot nematode (RKN) speciesMeloidogyne incognitaandM. javanicacause substantial root system damage and suppress yield of susceptible cowpea cultivars. The narrow-based genetic resistance conferred by theRkgene, present in some commercial cultivars, is not effective againstRk-virulent populations found in several cowpea production areas. The dynamics of virulence within RKN populations require a broadening of the genetic base of resistance in elite cowpea cultivars. As part of this goal, F1and F2populations from the cross CB46-Null (susceptible) x FN-2-9-04 (resistant) were phenotyped forM. javanicainduced root-galling (RG) and egg-mass production (EM) in controlled growth chamber and greenhouse infection assays. In addition, F2:3families of the same cross were phenotyped for RG on field sites infested withRk-avirulentM. incognitaandM. javanica. The response of F1to RG and EM indicated that resistance to RKN in FN-2-9-04 is partially dominant, as supported by the degree of dominance in the F2and F2:3populations. Two QTLs associated with both RG and EM resistance were detected on chromosomes Vu01 and Vu04. The QTL on Vu01 was most effective against aggressiveM. javanica, whereas both QTLs were effective against avirulentM. incognita. Allelism tests with CB46 x FN-2-9-04 progeny indicated that these parents share the same RKN resistance locus on Vu04, but the strong, broad-based resistance in FN-2-9-04 is conferred by the additive effect of the novel resistance QTL on Vu01. This novel resistance in FN-2-9-04 is an important resource for broadening RKN resistance in elite cowpea cultivars.
Biobank-wide association scan identifies risk factors for late-onset Alzheimer’s disease and endophenotypes
Authors: Yan Donghui , Hu Bowen , Darst Burcu F. , Mukherjee Shubhabrata , Kunkle Brian W. , Deming Yuetiva , Dumitrescu Logan , Wang Yunling , Naj Adam , Kuzma Amanda , Zhao Yi , Kang Hyunseung , Johnson Sterling C. , Cruchaga Carlos , Hohman Timothy J. , Crane Paul K. , Engelman Corinne D. ,   Alzheimer’s Disease Genetics Consortium (ADGC), Lu Qiongshi 
Published: November 2018

AbstractRich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer’s disease (AD; N=61,212). Among 1,738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Further, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD.