bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selection for protein stability enriches for epistatic interactions
Authors: Posfai Anna , Zhou Juannan , Plotkin Joshua B. , Kinney Justin B. , McCandlish David M. 
Published: June 2018

AbstractA now classical argument for the marginal thermodynamic stability of proteins explains the distribution of observed protein stabilities as a consequence of an entropic pull in protein sequence space. In particular, most sequences that are sufficiently stable to fold will have stabilities near the folding threshold. Here we extend this argument to consider its predictions for epistatic interactions for the effects of mutations on the free energy of folding. Although there is abundant evidence to indicate that the effects of mutations on the free energy of folding are nearly additive and conserved over evolutionary time, we show that these observations are compatible with the hypothesis that a non-additive contribution to the folding free energy is essential for observed proteins to maintain their native structure. In particular through both simulations and analytical results, we show that even very small departures from additivity are sufficient to drive this effect.
High-throughput mapping of meiotic crossover and chromosome mis-segregation events in interspecific hybrid mice
Authors: Yin Y. , Jiang Y. , Berletch J. B. , Disteche C. M. , Noble W. S. , Steemers F. J. , Adey A. C. , Shendure J. A. 
Published: June 2018

AbstractWe developed “sci-LIANTI”, a high-throughput, high-coverage single-cell DNA sequencing method that combines single-cell combinatorial indexing (“sci”) and linear amplification via transposon insertion (“LIANTI”). To characterize rare chromosome mis-segregation events in male meiosis and their relationship to the landscape of meiotic crossovers, we applied sci-LIANTI to profile the genomes of 6,928 sperm and sperm precursors from infertile, interspecific F1 male mice. From 1,663 haploid and 292 diploid cells, we mapped 24,672 crossover events and identified genomic and epigenomic contexts that influence crossover hotness. Surprisingly, we observed frequent mitotic chromosome segregation during meiosis. Moreover, segregation during meiosis in individual cells was highly biased towards either mitotic or meiotic events. We anticipate that sci-LIANTI can be applied to fully characterize various recombination landscapes, as well as to other fields requiring high-throughput, high-coverage single-cell genome sequencing.One Sentence SummarySingle-cell genome sequencing maps crossover and non-meiotic chromosome segregation during spermatogenesis in interspecific hybrid mice.
Resource supply drives even spacing of individuals along multiple trait axes in light-limited phytoplankton populations
Authors: Fontana Simone , Thomas Mridul K. , Reyes Marta , Pomati Francesco 
Published: June 2018

AbstractIndividual-level variation arising from responses to environmental gradients influences population and community dynamics. How such responses empirically relate to the mechanisms that govern species coexistence is however not well understood. Previous results from lake phytoplankton communities suggested that the evenness of organisms in multidimensional trait space increases with resource limitation, possibly due to resource partitioning at the individual level. Here we experimentally tested the emergence of this pattern by growing two phytoplankton species (Pseudokirchneriella subcapitata, Microcystis aeruginosa) under a gradient of light intensity, in monoculture and jointly. Under low light (resource) conditions, the populations diversified into a wide range of phenotypes, which were evenly distributed in multidimensional trait space (defined by four pigment-related trait dimensions), confirming the observed field pattern. Our results provide prime experimental evidence that resource limitation induces even spacing of conspecific and heterospecific microbial phenotypes along trait axes, and advances our understanding of trait-based coexistence.
An Integrative Boosting Approach for Predicting Survival Time With Multiple Genomics Platforms
Authors: Wong K. Y. , Fan C. , Tanioka M. , Parker J. S. , Nobel A. B. , Zeng D. , Lin D. Y. , Perou C. M. 
Published: June 2018

AbstractRecent technological advances have made it possible to collect multiple types of genomics data on the same set of patients. It is of great interest to integrate multiple genomics data types together for predicting disease outcomes. We propose a variable selection method, termed Integrative Boosting (I-Boost), that makes proper use of all available clinical and genomics data in predicting individual patient survival time. Through simulation studies and applications to data sets from The Cancer Genome Atlas, we demonstrate that I-Boost provides substantially higher prediction accuracy than existing variable selection methods. Using I-Boost, we show that (1) the integration of multiple genomics platforms with clinical variables significantly improves the prediction accuracy for survival time over the use of clinical variables alone; (2) gene expression values are typically more prognostic of survival time than other genomics data types; and (3) gene modules/signatures are at least as prognostic as the collection of individual gene expression data.
Differential GAP requirement for Cdc42-GTP polarization during proliferation and sexual reproduction
Authors: Castro Daniela Gallo , Martin Sophie G 
Published: June 2018

AbstractThe formation of a local zone of Cdc42 GTPase activity, which governs cell polarization in many cell types, requires not only local activation but also switch-off mechanisms. Here we identify Rga3, a paralog of Rga4, as a novel Cdc42 GTPase activating protein (GAP) in the fission yeastS. pombe. Contrary to Rga4, Rga3 localizes with Cdc42-GTP to sites of polarity. Rga3 is dispensable for cell polarization during mitotic growth, but limits the lifetime of unstable Cdc42-GTP patches that underlie cell pairing during sexual reproduction, masking a partly compensatory patch wandering motion. In consequence, cells lackingrga3hyperpolarize and loose out in mating competition. Rga3 synergizes with the Cdc42 GAPs Rga4 and Rga6 to restrict Cdc42-GTP zone sizes during mitotic growth. Surprisingly, triple mutant cells, which are almost fully round, retain pheromone-dependent dynamic polarization of Cdc42-GTP, extend a polarized projection and mate. Thus, the requirement for Cdc42-GTP hydrolysis by GTPase activating proteins is distinct during polarization by intrinsic or extrinsic cues.
Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions
Authors: Cascarina Sean M. , Ross Eric D. 
Published: June 2018

AbstractProteins with low-complexity domains continue to emerge as key players in both normal and pathological cellular processes. Although low-complexity domains are often grouped into a single class, individual low-complexity domains can differ substantially with respect to amino acid composition. These differences may strongly influence the physical properties, cellular regulation, and molecular functions of low-complexity domains. Therefore, we developed a bioinformatic approach to explore relationships between amino acid composition, protein metabolism, and protein function. We find that local compositional enrichment within protein sequences affects the translation efficiency, abundance, half-life, subcellular localization, and molecular functions of proteins on a proteome-wide scale. However, these effects depend upon the type of amino acid enriched in a given sequence, highlighting the importance of distinguishing between different types of low-complexity domains. Furthermore, many of these effects are discernible at amino acid compositions below those required for classification as low-complexity or statistically-biased by traditional methods and in the absence of homopolymeric amino acid repeats, indicating that thresholds employed by classical methods may not reflect biologically relevant criteria. Application of our analyses to composition-driven processes, such as the formation of membraneless organelles, reveals distinct composition profiles even for closely related organelles. Collectively, these results provide a unique perspective and detailed insights into relationships between amino acid composition, protein metabolism, and protein functions.Author SummaryLow-complexity domains in protein sequences are regions that are composed of only a few amino acids in the protein “alphabet”. These domains often have unique chemical properties and play important biological roles in both normal and disease-related processes.While a number of approaches have been developed to define low-complexity domains, these methods each possess conceptual limitations. Therefore, we developed a complementary approach that focuses on local amino acid composition (i.e. the amino acid composition within small regions of proteins). We find that high local composition of individual amino acids is associated with pervasive effects on protein metabolism, subcellular localization, and molecular function on a proteome-wide scale. Importantly, the nature of the effects depend on the type of amino acid enriched within the examined domains, and are observable in the absence of classically-defined low-complexity (and related) domains. Furthermore, we define the compositions of proteins involved in the formation of membraneless, protein-rich organelles such as stress granules and P-bodies. Our results provide a coherent view and unprecedented resolution of the effects of local amino acid enrichment on protein biology.
Bacillus thuringiensistargets the host intestinal epithelial junctions for successful infection ofCaenorhabditis elegans
Authors: Wan Liting , Lin Jian , Du Hongwen , Bravo Alejandra , Soberón Mario , Peng Donghai , Sun Ming 
Published: June 2018

ABSTRACTPathogenic bacteria use different strategies to infect their hosts including the simultaneous production of pore forming toxins and several virulence factors that help to synergize their pathogenic effects. However, how the pathogenic bacteria are able to complete their life cycle and break out the host intestinal barrier is poorly understood. The infectious cycle ofBacillus thuringiensis(Bt) bacterium inCaenorhabditis elegansis a powerful model system to study the early stages of the infection process. Bt produces Cry pore-forming toxins during the sporulation phase that are key virulence factors involved in Bt pathogenesis. Here we show that during the early stages of infection, the Cry toxins disrupt the midgut epithelial tissue allowing the germination of spores. The vegetative Bt cells then trigger a quorum sensing response that is activated by PlcR regulator resulting in production of different virulence factors, such as the metalloproteinases ColB and Bmp1, that besides Cry toxins are necessary to disrupt the nematode epithelial junctions causing efficient bacterial host infection and dead of the nematode. Overall our work describes a novel mechanism for Bt infection, targeting the epithelial junctions of its host midgut cells.Author summaryThe entomopathogenic bacteriaBacillus thuringiensis(Bt) are used worldwide as biopesticides due to their insecticidal properties. Crystal proteins (Cry) produced by Bt during the sporulation phase of growth are mainly responsible for their insecticidal properties. The infection process of Bt includes three successive steps, virulence, necrotrophic, and sporulation processes. During the virulence process, after ingestion by the susceptible hosts, the Cry toxins form pores in the apical membrane of intestinal cells, inducing favorable conditions for bacterial spore germination. Vegetative bacteria multiply in the host and coordinate their behavior by using the quorum sensor regulator PlcR, which leads to the production of virulence factors allowing the bacteria to kill the host. However, how the bacteria are able to disrupt the host intestinal barrier during the early stages of infection remains unknown. Here we show that Bt employs the nematicidal Cry toxins and additional virulence factors controlled by the PlcR regulon to disrupt the intestinal epithelial junctions ofC. elegansat the early stages of infection allowing that Bt bacteria complete its life cycle in the worms. Our work provides new insights into the pathogenesis of Bt, and highlights the importance of breaking down host epithelial junctions for a successful infection, a similar mechanism could be used by other pathogens-host interactions since epithelial junctions are conserved structures from insects to mammals.
ALV-J and REV synergistically activate a new oncogene of KIAA1199 via NF-κB and EGFR signaling regulated by miR-147
Authors: Zhou Defang , Xue Jingwen , Zhuang Pingping , Cui Xiyao , He Shuhai , Su Shuai , Wang Guihua , Zhang Li , Li Chengui , Huang Libo , Shang Yingli , Yao Yongxiu , Nair Venugopal , Zhang Huangge , cheng ziqiang 
Published: June 2018

AbstractThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection of avian leucosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV), as two oncogenic retroviruses, showed synergistic pathogenic effects characterized by enhanced tumor initiation and progression. The molecular mechanism underlying synergistic effects of ALV-J and REV on the neoplasia remains unclear. Here, we found co-infection of ALV-J and REV enhanced the ability of virus infection, increased viral life cycle, maintained cell survival and enhanced tumor formation. We combined the high-throughput proteomic readout with a large-scale miRNA screening to identify which molecules are involved in the synergism. Our results revealed co-infection of ALV-J and REV activated a latent oncogene of KIAA1199 and inhibited the expression of tumor suppressor miR-147. Further, enhanced KIAA1199, down-regulated miR-147, activated NF-κB and EGFR were demonstrated in co-infected tissues and tumor. Mechanistically, we showed ALV-J and REV synergistically enhanced KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. Our results contributed to the understanding of the molecular mechanisms of viral synergistic tumorgenesis, which provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes.Author summaryThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection with ALV-J and REV showed synergistic pathogenic effects characterized by enhanced tumor progression, however, the molecular mechanism on the neoplasia remains unclear. Our results revealed co-infection of ALV-J and REV promotes tumorigenesis by both induction of a latent oncogene of KIAA1199 and suppression of the expression of tumor suppressor miR-147. Mechanistic studies revealed that ALV-J and REV synergistically enhance KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. These results provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes, indicating the potential preventive target and predictive factor for ALV-J and REV induced tumorigenesis.
Efficient inference of single cell expression profiles with overlapping pooling and compressed sensing
Authors: Wen Xingzhao , Xu Weiqiang , Sun Xiao , Tu Jing , Lu Zuhong 
Published: June 2018

SUMMARYPlate-based single cell RNA-Seq (scRNA-seq) methods can detect a comprehensive profile for gene expression but suffers from high library cost of each single cell. Although cost can be reduced significantly by massively parallel scRNA-seq techniques, these approaches lose sensitivity for gene detection. Inspired by group testing and compressed sensing, here, we designed a computational framework to close the gap between sensitivity and library cost. In our framework, single cells were overlapped assigned into plenty of pools. Expression profile of each pool was then obtained by using plate-based sequence approach. The expression profile of all single cells was recovered based on the pool expression and the overlapped pooling design. The inferred expression profile showed highly consistency with the original data in both accuracy and cell types identification. A parallel computing scheme was designed to boost speed when processing the enormous single cells, and elastic net regression was combined with compressed sensing to auto-adapt for both sparsely and densely expressed genes.
Overexpressed microRNA-141-3p enhance proliferation via targeting PLAG1 in non-diabetic macrosomia
Authors: Guo Dan , Jiang Hua , Chen Yiqiu , Yang Jing , Fu Ziqiang , Li Jing , Han Xiumei , Wu Xian , Xia Yankai , Wang Xinru , Chen Liping , Tang Qiuqin , Wu Wei 
Published: June 2018

AbstractSeveral studies have shown microRNAs (miRNAs) could regulate the placental development, yet the role and mechanism of miRNAs in the development of non-diabetic macrosomia (NDFMS) remains unclear. The key miRNA that abnormal expressed in NDFMS placentas was screened out by miRNA microarray and verified using qRT-PCR in 91 subjects. The effects of the key miRNA were verified by proliferation assay and invasion assay in HTR-8/SVneo cell, and also in pregnant C57BL/6J mice. miR-141-3p was determined as the key miRNA with the most significant difference, which could promote the proliferation and invasion by regulating the expression of target gene PLAG1. Overexpression of PLAG1 could reverse the effect of cell proliferation and invasion ability caused by miR-141-3p overexpression. Significant difference in fetal birth weight was observed between the control group and treated group with miR-141-3p agomir in late pregnancy, but not in early pregnancy. This study revealed miR-141-3p could increase the proliferation of placenta to participate in the occurrence and development of NDFMS through regulating PLAG1 expression.
Heteromeric GABAAreceptor structures in positively-modulated active states
Authors: Miller Paul S. , Masiulis Simonas , Malinauskas Tomas , Kotecha Abhay , Rao Shanlin , Chavali Sreenivas , De Colibus Luigi , Pardon Els , Hannan Saad , Scott Suzanne , Sun Zhaoyang , Frenz Brandon , Klesse Gianni , Li Sai , Diprose Jonathan M. , Siebert C. Alistair , Esnouf Robert M. , DiMaio Frank , Tucker Stephen J. , Smart Trevor G. , Steyaert Jan , Babu M. Madan , Sansom Mark S. P. , Huiskonen Juha T. , Aricescu A. Radu 
Published: June 2018

AbstractType-A γ-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels (pLGICs), typically consisting of α/β/γ subunit combinations. They are the principal mediators of inhibitory neurotransmission throughout the central nervous system and targets of major clinical drugs, such as benzodiazepines (BZDs) used to treat epilepsy, insomnia, anxiety, panic disorder and muscle spasm. However, the structures of heteromeric receptors and the molecular basis of BZD operation remain unknown. Here we report the cryo-EM structure of a human α1β3γ2 GABAAR in complex with GABA and a nanobody that acts as a novel positive allosteric modulator (PAM). The receptor subunits assume a unified quaternary activated conformation around an open pore. We also present crystal structures of engineered α5 and α5γ2 GABAAR constructs, revealing the interfacial site for allosteric modulation by BZDs, including the binding modes and the conformational impact of the potent anxiolytic and partial PAM, bretazenil, and the BZD antagonist, flumazenil. These findings provide the foundation for understanding the mechanistic basis of GABAAR activation.
Proteomics reveals ablation of placental growth factor inhibits the insulin resistance pathways in diabetic mouse retina
Authors: Lennikov Madhu Sudhana , Lennikov Anton , Tang Shibo , Huang Hu 
Published: June 2018

AbstractThe underlying molecular mechanisms that placental growth factor (PlGF) mediates the early complications at non-proliferative diabetic retinopathy (DR) remain largely elusive. The objective of this study is to characterize expression profile due to PlGF ablation in the retina of diabetic mice. The quantitative label-free proteomics was carried out on retinal tissues collected from mouse strains (Akita; PlGF−/− and Akita.PlGF−/−). We have identified 3176 total proteins, and 107 were significantly different between the experimental groups, followed by gene ontology, functional pathways, and protein-protein network interaction analysis. Gnb1, Gnb2, Gnb4, Gnai2, Gnao1, Snap25, Stxbp1, Vamp2 and Gngt1 proteins are involved in insulin resistance pathways, which are down-regulated in PlGF ablation in Akita diabetics (Akita.PlGF−/− vs. Akita), up-regulation in Akita vs. C57, PlGF−/− vs. C57. Prdx6, Prdx5 (up-regulation) are known of antioxidant activity; Map2 is involved in neural protection pathways which are up-regulated in Akita.PlGF−/− vs. Akita. Our results suggest that inhibition of insulin resistance pathway and the enhancement of antioxidant defence and neural function may represent the potential mechanisms of anti-PlGF compounds in the treatment of DR.
Astrocytes promote a protective immune response to brainToxoplasma gondiiinfection via IL-33-ST2 signaling
Authors: Still Katherine M. , Batista Samantha J. , O’Brien Carleigh , Oyesola Oyebola O. , Früh Simon P. , Webb Lauren M. , Smirnov Igor , Kovacs Michael A. , Cowan Maureen N. , Hayes Nikolas W. , Thompson Jeremy A. , Tait-Wojno Elia D. , Harris Tajie H. 
Published: June 2018

SUMMARYUnderstanding how invading pathogens are sensed within the brain is necessary to uncover how effective immune response are mounted in immunoprivileged sites. The eukaryotic parasiteToxoplasma gondiicolonizes the brain of its hosts and initiates robust immune cell recruitment, but little is known about innate recognition ofT. gondiiwithin brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronicT. gondiiinfection, but the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes duringT. gondiiinfection, is released into the cerebrospinal fluid ofT. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment of peripheral anti-parasitic immune cells, including IFN-γ-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33R-deficient astrocytes fail to promote an adaptive immune response in the CNS and control parasite burden, demonstrating that astrocytes can directly respond to IL-33in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released and sensed locally, to engage the peripheral immune system in controlling a neurotropic pathogen.