bluuebunny/crossref_metadata_2025_split huggingface dataset:
Privacy-preserving genotype imputation with fully homomorphic encryption
Authors: Gürsoy Gamze , Chielle Eduardo , Brannon Charlotte M. , Maniatakos Michail , Gerstein Mark 
Published: May 2020

AbstractGenotype imputation is the statistical inference of unknown genotypes using known population haplotype structures observed in large genomic datasets, such as HapMap and 1000 genomes project. Genotype imputation can help further our understanding of the relationships between genotypes and traits, and is extremely useful for analyses such as genome-wide association studies and expression quantitative loci inference. Increasing the number of genotyped genomes will increase the statistical power for inferring genotype-phenotype relationships, but the amount of data required and the compute-intense nature of the genotype imputation problem overwhelms servers. Hence, many institutions are moving towards outsourcing cloud services to scale up research in a cost effective manner. This raises privacy concerns, which we propose to address via homomorphic encryption. Homomorphic encryption is a type of encryption that allows data analysis on cipher texts, and would thereby avoid the decryption of private genotypes in the cloud. Here we develop an efficient, privacy-preserving genotype imputation algorithm, p-Impute, using homomorphic encryption. Our results showed that the performance of p-Impute is equivalent to the state-of-the-art plaintext solutions, achieving up to 99% micro area under curve score, and requiring a scalable amount of memory and computational time.
CryoEM reveals how the small molecule EGCG binds to Alzheimer’s brain-derived tau fibrils and initiates fibril disaggregation
Authors: Seidler PM , Boyer DR , Sawaya MR , Ge P , Shin WS , DeTure MA , Dickson DW , Jiang L , Eisenberg DS 
Published: May 2020

AbstractEGCG, the most abundant favanol in green tea, is one of the few natural compounds known to inhibit amyloid fibril formation of proteins associated with neurodegeneration, and to disaggregate amyloid fibrils. Little is known of the mechanism of molecular action of EGCG, or how it or other small molecules interact with amyloid fibrils. Here we present a 3.9 Å resolution cryoEM structure that reveals the site of EGCG binding to Alzheimer’s disease (AD) brain-derived tau fibrils. The structure suggests that EGCG disaggregates fibrils of AD-tau by wedging into a cleft that is at the interface of two protofilaments of the paired helical filament, and by causing charge repulsions between tau layers of the fibril. In support of this, we observe separation of the protofilaments that EGCG wedges between, and accompanying displacement of the adjacent β-helix domain. By resolving the site of EGCG binding, our structure defines a pharmacophore-like cleft in the AD-tau fibril that will be of use for the discovery of surrogate compounds with more desirable drug-like properties.
Wnt3 distribution in the zebrafish brain is determined by expression, diffusion and multiple molecular interactions
Authors: Veerapathiran Sapthaswaran , Teh Cathleen , Zhu Shiwen , Kartigayen Indira , Korzh Vladimir , Matsudaira Paul T. , Wohland Thorsten 
Published: May 2020

AbstractWnt3 proteins are lipidated and glycosylated, secreted signaling molecules that play an important role in zebrafish neural patterning and brain development. However, the transport mechanism of lipid-modified Wnts through the hydrophilic extracellular environment for long-range action remains unresolved. Here, we determine how Wnt3 accomplishes long-range distribution in the zebrafish brain. First, we characterize the Wnt3-producing source and Wnt3-receiving target regions. Subsequently, we analyze Wnt3 mobility at different length scales by fluorescence correlation spectroscopy and fluorescence recovery after photo-bleaching. We demonstrate that Wnt3 spreads extracellularly and interacts with heparan sulfate proteoglycans (HSPG). We then determine the binding affinity of Wnt3 to its receptor, Frizzled1 (Fzd1), using fluorescence cross-correlation spectroscopy, and show that the co-receptor, low-density lipoprotein receptor-related protein 5 (Lrp5), is required for Wnt3-Fzd1 interaction. Our results are consistent with the extracellular distribution of Wnt3 by a diffusive mechanism that is modified by tissue morphology, interactions with HSPG and Lrp5-mediated receptor binding, to regulate zebrafish brain development.
Whole exome sequencing identifies genes associated with non-obstructive azoospermia
Authors: Zhang Hongguo , Huang Hui , Zhang Xinyue , Li Wei , Jiang Yuting , Li Jia , Li Leilei , Zhao Jing , He Jing , Chen Mucheng , Wang Ruixue , Wu Jing , Peng Zhiyu , Liu Ruizhi 
Published: May 2020

AbstractBackgroundGenetic etiology is the main cause of non-obstructive azoospermia, but little is known about the landscape of the disease causative genes.ObjectiveTo identify the association of non-obstructive azoospermia and the putative causative genetic factors.Design, setting, and participantsA single-center perspective case-control study of 133 patients, with clinicopathologic non-obstructive azoospermia and 495 fertile men control was performed. Eleven trio families were available and enrolled from the 133 patients’ families.Outcome measurements and statistical analysisWhole exome sequencing based rare variant association study between the cases and controls was performed by means of gene burden association testing. Linkage analysis on the trio family was also described to screen the causative genes.Results and limitationsTotally 80 genes (p < 0.05) were identified associated with non-obstructive azoospermia (2 of which were previously reported), meanwhile 5 novel genes out of which were also found potentially causative through the linkage analysis on the trio families. The pathway enrichment analysis was also provided to assess the potential interaction between genes identified in this study and previously reported together. The 5 novel identified overlap genes by both above mentioned test with the rare mutations account for an overall 20% (26 /133 patients) incidence, together with the 2 known genes together would account for an overall 20% incidence for non-obstructive azoospermia in this study. The study is limited by the lack of functional biological study.ConclusionsFive novel genes were identified associated with non-obstructive azoospermia by means of both rare variant association study and linkage analysis through trio families. They could account for about 20% clinical incidence among the patients in our study.Patient summary133 infertile patients (11 of them with parents enrolled) with idiopathic non-obstructive azoospermia and 300 fertile male controls were recruited from single clinic center.All patients underwent semen analyses at least on three different occasions.
Novel Vβ specific germline contacts shape an elite controller T cell response
Authors: Wang Yang , Tsitsiklis Alexandra , Gao Wei , Chu H. Hamlet , Zhang Yan , Li Wei , Wong Wing Ki , Deane Charlotte M. , Neau David , Slansky Jill E. , Thomas Paul G. , Robey Ellen A. , Dai Shaodong 
Published: June 2020

AbstractCertain CD8 T cell responses are particularly effective at controlling infection, as exemplified by elite control of HIV in individuals harboring HLA-B57. To understand the structural features that contribute to CD8 T cell elite control, we focused on a strongly protective CD8 T cell response directed against a parasite-derived peptide (HF10) presented by an atypical MHC-I molecule, H-2Ld. This response exhibits a focused TCR repertoire dominated by Vβ2, and a representative TCR (TG6) in complex with Ld-HF10 reveals an unusual structure in which both MHC and TCR contribute extensively to peptide specificity, along with a parallel footprint of TCR on its pMHC ligand. The parallel footprint is a common feature of Vβ2-containing TCRs and correlates with an unusual Vα-Vβ interface, CDR loop conformations, and Vβ2-specific germline contacts with peptide. Vβ2 and Ldmay represent “specialist” components for antigen recognition that allow for particularly strong and focused T cell responses.
Enzymatic RNA Biotinylation for Affinity Purification and Identification of RNA-protein Interactions
Authors: Busby Kayla N. , Fulzele Amitkumar , Zhang Dongyang , Bennett Eric J. , Devaraj Neal K. 
Published: June 2020

ABSTRACTThroughout their cellular lifetime, RNA transcripts are bound to proteins, playing crucial roles in RNA metabolism, trafficking, and function. Despite the importance of these interactions, identifying the proteins that interact with an RNA of interest in mammalian cells represents a major challenge in RNA biology. Leveraging the ability to site-specifically and covalently label an RNA of interest usingE. ColitRNA guanine transglycosylase and an unnatural nucleobase substrate, we establish the identification of RNA-protein interactions and the selective enrichment of cellular RNA in mammalian systems. We demonstrate the utility of this approach through the identification of known binding partners of 7SK snRNA via mass spectrometry. Through a minimal 4-nucleotide mutation of the long noncoding RNA HOTAIR, enzymatic biotinylation enables identification putative HOTAIR binding partners in MCF7 breast cancer cells that suggest new potential pathways for oncogenic function. Furthermore, using RNA sequencing and qPCR, we establish that an engineered enzyme variant achieves high levels of labeling selectivity against the human transcriptome allowing for 145-fold enrichment of cellular RNA directly from mammalian cell lysates. The flexibility and breadth of this approach suggests that this system could be routinely applied to the functional characterization of RNA, greatly expanding the toolbox available for studying mammalian RNA biology.
Serratia marcescenssecretes proteases and chitinases with larvicidal activity againstAnopheles dirus
Authors: Jupatanakul Natapong , Pengon Jutharat , Selisana Shiela Marie Gines , Choksawangkarn Waeowalee , Jaito Nongluck , Saeung Atiporn , Bunyong Ratchanu , Posayapisit Navaporn , Thammatinna Khrongkhwan , Kalpongnukul Nuttiya , Aupalee Kittipat , Pisitkun Trairak , Kamchonwongpaisan Sumalee 
Published: June 2020

ABSTRACTVector control, the most efficient tool to reduce mosquito-borne disease transmission, has been compromised by the rise of insecticide resistance. Recent studies suggest the potential of mosquito-associated microbiota as a source for new biocontrol agents or new insecticidal chemotypes. In this study, we identified a strain ofSerratia marcescensthat has larvicidal activity againstAnopheles dirus, an important malaria vector in Southeast Asia. This bacterium secretes heat-labile larvicidal macromolecules when cultured under static condition at 25°C but not 37°C. Two major protein bands of approximately 55 kDa and 110 kDa were present in spent medium cultured at 25°C but not at 37°C. The Liquid Chromatography-Mass Spectrometry (LC-MS) analyses of these two protein bands identified several proteases and chitinases that were previously reported for insecticidal properties against agricultural insect pests. The treatment with protease and chitinase inhibitors led to a reduction in larvicidal activity, confirming that these two groups of enzymes are responsible for the macromolecule’s toxicity. Taken together, our results suggest a potential use of these enzymes in the development of larvicidal agents againstAnophelesmosquitoes.
Instantaneous movement-unrelated midbrain activity modifies ongoing eye movements
Authors: Buonocore Antimo , Tian Xiaoguang , Khademi Fatemeh , Hafed Ziad M. 
Published: June 2020

AbstractAt any moment in time, new information is sampled from the environment and interacts with ongoing brain state. Often, such interaction takes place within individual circuits that are capable of both mediating the internally ongoing plan as well as representing exogenous sensory events. Here we investigated how sensory-driven neural activity can be integrated, very often in the same neuron types, into ongoing oculomotor commands for saccades. Despite the ballistic nature of saccades, visually-induced action potentials in the superior colliculus (SC), a structure known to drive eye movements, not only occurred intra-saccadically, but they were also associated with highly predictable modifications of ongoing eye movements. Such predictable modifications reflected a simultaneity of movement-related discharge at one SC site and visually-induced activity at another. Our results suggest instantaneous readout of the SC map during movement generation, irrespective of activity source, and they explain a significant component of kinematic variability of motor outputs.
Peripheral blood microbial signatures in COPD
Authors: Morrow Jarrett D. , Castaldi Peter J. , Chase Robert P. , Yun Jeong H. , Lee Sool , Liu Yang-Yu , Hersh Craig P. ,   the COPDGene Investigators
Published: June 2020

AbstractBackgroundThe human microbiome has a role in the development of human diseases. Individual microbiome profiles are highly personalized, though many species are shared. Understanding the relationship between the human microbiome and disease may inform future individualized treatments. Specifically, the blood microbiome, once believed sterile, may be a surrogate for some lung and gut microbial characteristics. We sought associations between the blood microbiome and lung-relevant host factors.MethodsBased on reads not mapped to the human genome, we detected microbial nucleic acid signatures in peripheral blood RNA-sequencing for 2,590 current and former smokers with and without chronic obstructive pulmonary disease (COPD) from the COPDGene study. We used the GATK microbial pipeline PathSeq to infer microbial profiles. We tested associations between the inferred profiles and lung disease relevant phenotypes and examined links to host gene expression pathways.ResultsThe four phyla with highest abundance across all subjects were Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. We observed associations between exacerbation phenotypes and the relative abundance ofStaphylococcus, AcidovoraxandCupriavidus. The genusFlavobacteriumwas associated with emphysema and change in emphysema. Our host-microbiome interaction analysis revealed clustering of genera associated with emphysema, systemic inflammation, airway remodeling and exacerbations, through links to lung-relevant host pathways.ConclusionsThis study is the first to identify a bacterial microbiome signature in the peripheral blood of current and former smokers. Understanding the relationships between the systemic microbial populations and lung disease severity may inform novel interventions and aid in the understanding of exacerbation phenotypes.
Silver nanoantibiotics display strong antifungal activity against the emergent multidrug-resistant yeastCandida aurisunder both planktonic and biofilm growing conditions
Authors: Vazquez-Munoz Roberto , Lopez Fernando D. , Lopez-Ribot Jose 
Published: June 2020

AbstractCandida aurisis an emergent multidrug-resistant pathogenic yeast with an unprecedented ability for a fungal organism to easily spread between patients in clinical settings, leading to major outbreaks in healthcare facilities. The formation of biofilms byC. auriscontributes to infection and its environmental persistence. Most antifungals and sanitizing procedures are not effective againstC. auris,but antimicrobial nanomaterials could represent a viable alternative to combat the infections caused by this emerging pathogen. We have previously described an easy and inexpensive method to synthesize silver nanoparticles (AgNPs) in non-specialized laboratories. Here we have assessed the antimicrobial activity of the resulting AgNPs onC. aurisplanktonic and biofilm growth phases. AgNPs displayed a strong antimicrobial activity against all the stages of allC. aurisstrains tested, representative of four different clades. Under planktonic conditions, MIC values of AgNPs against the different strains were <0.5 μg mL-1; whereas calculated IC50 values for inhibition of biofilms formation were < 2 μg mL-1for all but one of theC. aurisstrains tested. AgNPs were also active against preformed biofilms formed by all differentC. aurisstrains, with IC50 values ranging from 1.2 to 6.2 μg mL-1. Overall, our results indicate potent activity of AgNPs against strains ofC. auris, both under planktonic and biofilm growing conditions, and indicate that AgNPs may contribute to the control of infections caused by this emerging nosocomial threat.
Heat Shock Protein 27 Immune Complex Altered Signaling and Transport (ICAST): Novel Mechanisms of Attenuating Inflammation
Authors: Shi Chunhua , Deng Jingti , Chiu Michael , Chen Yong-Xiang , O’Brien Edward R. 
Published: June 2020

AbstractBlood levels of heat shock protein (HSP27) and natural IgG auto-antibodies to HSP27 (AAbs) are higher in healthy controls compared to cardiovascular disease patients. Vaccination of mice with recombinant HSP25 (rHSP25, murine ortholog of human rHSP27) increased AAb levels, attenuated atherogenesis and reduced plaque inflammation and cholesterol content. We sought to determine if the HSP27 immune complex (IC) altered MΦ inflammation signaling (Toll Like Receptor 4; TLR4), and scavenger receptors involved in cholesterol uptake (SR-AI, CD-36). Combining a validated polyclonal IgG anti-HSP27 antibody (PAb) with rHSP27 enhanced binding to THP-1 MΦ cell membranes and activation of NF-κB signaling via TLR4, competing away LPS and effecting an anti-inflammatory cytokine profile. Similarly, adding the PAb with rHSP27 enhanced binding to SR-AI and CD-36, as well as lowered oxLDL binding in HEK293 cells separately transfected with SR-AI and CD-36, or THP-1 MΦ. Finally, the PAb enhanced the uptake and internalization of rHSP27 in THP-1 MΦ. Thus, the HSP27 IC potentiates HSP27 cell membrane signaling with receptors involved in modulating inflammation and cholesterol uptake, as well as HSP27 internalization. Going forward, we will explore HSP27 Immune Complex Altered Signaling and Transport (ICAST) as a new anti-inflammatory therapeutic strategyin vivo.
Human Parental Relatedness through Time - Detecting Runs of Homozygosity in Ancient DNA
Authors: Ringbauer Harald , Novembre John , Steinrücken Matthias 
Published: June 2020

AbstractAt present day, human parental relatedness varies substantially across the globe, but little is known about the past. Here we use ancient DNA to provide new insights, leveraging that parental relatedness leaves traces in the offspring’s genome in the form of runs of homozygosity. We present a method to identify such runs in low-coverage ancient DNA data using linkage information from a reference panel of modern haplotypes. As a result, the method facilitates analysis of a much larger fraction of the global ancient DNA record than previously possible. Simulation and experiments show that this new method has power to detect runs of homozygosity longer than 4 centimorgan for ancient individuals with at least 0.3× coverage. We used this new method to analyze sequence data from 1,785 humans from the last 45,000 years. Generally, we detect very low rates of first cousin or closer unions across most ancient populations. Moreover, our results evidence a substantial impact of the adoption of agricultural lifestyles: We find a marked decay in background parental relatedness, co-occurring with or shortly after the advent of sedentary agriculture. We observe this signal, likely linked to increasing local population sizes, across several geographic regions worldwide.
Simultaneous decoding of cardiovascular and respiratory functional changes from pig intraneural vagus nerve signals
Authors: Vallone Fabio , Ottaviani Matteo Maria , Dedola Francesca , Cutrone Annarita , Romeni Simone , Panarese Adele Macrí , Bernini Fabio , Cracchiolo Marina , Gabisonia Khatia , Gorgodze Nikoloz , Mazzoni Alberto , Recchia Fabio A. , Micera Silvestro 
Published: June 2020

AbstractBioelectronic medicine is opening new perspectives for the treatment of some major chronic diseases through the physical modulation of autonomic nervous system activity. Being the main peripheral route for electrical signals between central nervous system and visceral organs, the vagus nerve (VN) is one of the most promising targets. Closed-loop neuromodulation would be crucial to increase effectiveness and reduce side effects, but it depends on the possibility of extracting useful physiological information from VN electrical activity, which is currently very limited.Here, we present a new decoding algorithm properly detecting different functional changes from VN signals. They were recorded using intraneural electrodes in anaesthetized pigs during cardiovascular and respiratory challenges mimicking increases in arterial blood pressure, tidal volume and respiratory rate. A novel decoding algorithm was developed combining discrete wavelet transformation, principal component analysis, and ensemble learning made of classification trees. It robustly achieved high accuracy levels in identifying different functional changes and discriminating among them. We also introduced a new index for the characterization of recording and decoding performance of neural interfaces. Finally, by combining an anatomically validated hybrid neural model and discrimination analysis, we provided new evidence suggesting a functional topographical organization of VN fascicles. This study represents an important step towards the comprehension of VN signaling, paving the way to the development of effective closed-loop bioelectronic systems.
Ancient Admixture into Africa from the ancestors of non-Africans
Authors: Cole Christopher B. , Zhu Sha Joe , Mathieson Iain , Prüfer Kay , Lunter Gerton 
Published: June 2020

AbstractGenetic diversity across human populations has been shaped by demographic history, making it possible to infer past demographic events from extant genomes. However, demographic inference in the ancient past is difficult, particularly around the out-of-Africa event in the Late Middle Paleolithic, a period of profound importance to our species’ history. Here we presentSMCSMC, a Bayesian method for inference of time-varying population sizes and directional migration rates under the coalescent-with-recombination model, to study ancient demographic events. We find evidence for substantial migration from the ancestors of present-day Eurasians into African groups between 40 and 70 thousand years ago, predating the divergence of Eastern and Western Eurasian lineages. This event accounts for previously unexplained genetic diversity in African populations, and supports the existence of novel population substructure in the Late Middle Paleolithic. Our results indicate that our species’ demographic history around the out-of-Africa event is more complex than previously appreciated.