bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using brain cell-type-specific protein interactomes to interpret genetic data in schizophrenia
Authors: Hsu Yu-Han H. , Nacu Eugeniu , Liu Ruize , Pintacuda Greta , Kim April , Tsafou Kalliopi , Petrossian Natalie , Crotty William , Suh Jung Min , Riseman Jackson , Martin Jacqueline M. , Biagini Julia C. , Ching Joshua K.T. , Malolepsza Edyta , Li Taibo , Singh Tarjinder , Ge Tian , Egri Shawn B. , Tanenbaum Benjamin , Stanclift Caroline R. , Apffel Annie M. ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium,   Stanley Global Asia Initiatives, Carr Steven A. , Schenone Monica , Jaffe Jake , Fornelos Nadine , Huang Hailiang , Eggan Kevin C. , Lage Kasper 
Published: October 2021

AbstractGenetics have nominated many schizophrenia risk genes that lack functional interpretation. To empower such interpretation, we executed interaction proteomics for six risk genes in human induced neurons and found the resulting protein network to be enriched for common variant risk of schizophrenia in Europeans and East Asians. The network is down-regulated in layer 5/6 cortical neurons of patients and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and also contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in patients with schizophrenia and bipolar disease. Our findings establish brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and psychiatric diseases.One Sentence SummaryNeuronal protein interactomes is an organizing framework for integrating genetic and transcriptomic data in schizophrenia.
Identification of a novel modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast
Authors: Sing Cierra N. , Garcia Enrique J. , Lipkin Thomas G. , Huckaba Thomas M. , Tsang Catherine A. , Coughlin Arielle C. , Yang Emily J. , Boldogh Istvan R. , Higuchi-Sanabria Ryo , Pon Liza A. 
Published: October 2021

AbstractIn yeast, actin cables are F-actin bundles that are essential for cell division through their function as tracks for cargo movement from mother to daughter cell. Actin cables also affect yeast lifespan by promoting transport and inheritance of higher-functioning mitochondria to daughter cells. Here, we report that actin cable stability declines with age. Our genome-wide screen for genes that affect actin cable stability identified the open reading frame YKL075C. Deletion of YKL075C results in increases in actin cable stability and abundance, mitochondrial fitness, and replicative lifespan. Transcriptome analysis revealed a role for YKL075C in regulating branched-chain amino acid (BCAA) metabolism. Consistent with this, modulation of BCAA metabolism or decreasing leucine levels promotes actin cable stability and function in mitochondrial quality control. Our studies support a role for actin stability in yeast lifespan, and demonstrate that this process is controlled by BCAA and a previously uncharacterized ORF YKL075C, which we refer to as actin, aging and nutrient modulator protein 1 (AAN1).
Large-scale discovery of candidate type VI secretion effectors with antibacterial activity
Authors: Geller Alexander Martin , Zlotkin David , Levy Asaf 
Published: October 2021

AbstractType VI secretion systems (T6SS) are common bacterial contractile injection systems that inject toxic “effector” proteins into neighboring cells. Effector discovery is generally done manually, and computational approaches used for effector discovery depend on genetic linkage to T6SS genes and/or sequence similarity to known effectors. We bioinformatically investigated T6SS in more than 11,832 genomes of Gram negative bacteria. We found that T6SS encoding bacteria are host-associated and pathogenic, enriched in specific human and plant tissues, while depleted in marine, soil, and engineered environments. Analysis of T6SS cores with C-terminal domains (“evolved” cores) showed “evolved” HCP are rare, overwhelmingly encoded in orphan operons, and are largely restricted toEscherichia. Using the wealth of data generated from our bioinformatic analysis, we developed two algorithms for large-scale discovery of T6SS effector proteins (T6Es). We experimentally validated ten putative antibacterial T6SS effector proteins and one cognate immunity gene from a diverse species. This study provides a systematic genomic perspective of the role of the T6SS in nature, a thorough analysis of T6E evolution and genomic properties, and discovery of a large number of candidate T6Es using new approaches.
A bacteria-based assay to study SARS-CoV-2 protein-protein interactions
Authors: Springstein Benjamin L. , Deighan Padraig , Grabe Grzegorz , Hochschild Ann 
Published: October 2021

AbstractMethods for detecting and dissecting the interactions of virally encoded proteins are essential for probing basic viral biology and providing a foundation for therapeutic advances. The dearth of targeted therapeutics for the treatment of COVID-19, an ongoing global health crisis, underscores the importance of gaining a deeper understanding of the interactions of SARS-CoV-2-encoded proteins. Here we describe the use of a convenient bacteria-based two-hybrid (B2H) system to analyze the SARS-CoV-2 proteome. We identify sixteen distinct intraviral protein-protein interactions (PPIs), involving sixteen proteins. We find that many of the identified proteins interact with more than one partner. We further show how our system facilitates the genetic dissection of these interactions, enabling the identification of selectively disruptive mutations. We also describe a modified B2H system that permits the detection of disulfide bond-dependent PPIs in the normally reducing Escherichia coli cytoplasm and we use this system to detect the interaction of the SARS-CoV-2 spike protein receptor-binding domain (RBD) with its cognate cell surface receptor ACE2. We then examine how the RBD-ACE2 interaction is perturbed by several RBD amino acid substitutions found in currently circulating SARS-CoV-2 variants. Our findings illustrate the utility of a genetically tractable bacterial system for probing the interactions of viral proteins and investigating the effects of emerging mutations. In principle, the system could also facilitate the identification of potential therapeutics that disrupt specific interactions of virally encoded proteins. More generally, our findings establish the feasibility of using a B2H system to detect and dissect disulfide bond-dependent interactions of eukaryotic proteins.ImportanceUnderstanding how virally encoded proteins interact with one another is essential in elucidating basic viral biology, providing a foundation for therapeutic discovery. Here we describe the use of a versatile bacteria-based system to investigate the interactions of the protein set encoded by SARS-CoV-2, the virus responsible for the current pandemic. We identify sixteen distinct intraviral protein-protein interactions, involving sixteen proteins, many of which interact with more than one partner. Our system facilitates the genetic dissection of these interactions, enabling the identification of selectively disruptive mutations. We also describe a modified version of our bacteria-based system that permits detection of the interaction between the SARS-CoV-2 spike protein (specifically its receptor binding domain) and its cognate human cell surface receptor ACE2 and we investigate the effects of spike mutations found in currently circulating SARS-CoV-2 variants. Our findings illustrate the general utility of our system for probing the interactions of virally encoded proteins.
Novel Investigation of SARS-CoV-2 in COVID-19 Survivors’ Semen in Surabaya, Indonesia
Authors: Supardi Supardi , Nidom Reviany V. , Sisca Eni M. , Tribowo Jefry A. , Kandar Patricia S. , Budiharto Joice M. , Siswidiyanto Eko , Wen Maitra Djiang , Kirana Tiara , Nidom Astria N. , Ansori Arif N. M. , Normalina Irine , Indrasari Setyarina , I’tishom Reny 
Published: October 2021

AbstractThe emergence and the widespread of Coronavirus disease 2019 (COVID-19) demands an accurate detection method to establish a diagnosis. Real-time polymerase chain reaction (real-time PCR) is accounted for the perfect point of reference in detecting this virus. The notion that this virus also invades the male reproductive tract requires further investigation to prove the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in the semen. This investigation was designed to detect SARS-CoV-2 in COVID-19 survivors’ semen. This study design was a cross-sectional examination and conducted between November 2020 and March 2021 in the Andrology Unit of Dr. Soetomo General Hospital and Professor Nidom Foundation, both located in the City of Surabaya, Indonesia. The sample was 34 male participants aged above 18 years old and had been confirmed COVID-19 by nasopharyngeal swab PCR test. Part of the semen was taken for real-time PCR testing with the QuantStudio 5 Applied Biosystem (AB) PCR machine and the kits utilized were the STANDARD M nCOV Real-Time Detection Kit and mBioCov-19 RT-PCR Kit. Furthermore, the mean of participants’ ages was 35.74 years old with 25% of them had had a history of primary infertility and 21.8% of secondary infertility. From the real-time PCR COVID-19 of the semen examination, this investigation found that 27 participants had been negatives (74.4%), six inconclusive (17.6%), and one positive (3%) of SARS CoV-2. In summary, SARS-CoV-2 could be found in the semen of COVID-19 survivors. This should be a concern for the potential impact of COVID-19 in male fertility and the possibility of transmission reproductively.
Distinctive modularity and resilience of structural covariance network in first-episode antipsychotic-naive psychoses
Authors: Lewis Madison , Santini Tales , Theis Nicholas , Muldoon Brendan , Dash Katherine , Keshavan Matcheri S. , Prasad Konasale M. 
Published: October 2021

AbstractObjectiveDivergent findings in structural brain alterations in psychoses suggest that often-observed regions may exist within a network of susceptible regions. We built structural covariance networks (SCN) of volumes, cortical thickness, and surface area using the Human Connectome Project atlas-based parcellation of 358 regions on structural MRI data from 79 first-episode antipsychotic-naive psychosis patients (FEAP) and 68 controls.MethodsUsing graph theoretic methods, we obtained representative graph metrics of integration, segregation, resilience, centrality, importance, community structure, and hub distribution for all 3-morphometric features. We compared networks for resilience by simulated removal (“attacks”) of nodes and hubs, and simulated replacement of correlations among nodes in FEAP with that of controls using DeltaCon metric.ResultsVolume and thickness SCNs of FEAP showed differences in many graph metrics in opposite directions compared to controls but not surface area SCN. Network resilience did not show differences in the replacement simulation and hub “attacks, but betweenness centrality-based node “attacks” showed FEAP network disintegrating with relatively fewer node removals with preserved global efficiency compared to controls. In FEAP, communities consisted of regions from different lobes and hubs were more distributed than in controls.ConclusionsOur findings suggest decreased heterogeneity and less differentiated community structure of FEAP network that may not be attributed to illness chronicity and medications. Contribution of cortical thickness but not surface area suggests that disease/developmental processes may preferentially affect cortical thickness. Near-similar resilience of FEAP and control networks may shield controls from developing illness but may prevent fuller long-term recovery in FEAP.
Time-resolved, integrated analysis of clonally evolving genomes
Authors: Legrand Carine , Andriantsoa Ranja , Lichter Peter , Lyko Frank 
Published: October 2021

AbstractClonal genome evolution is a key aspect for parthenogenetic species and cancer. While many studies describe precise landscapes of clonal evolution in cancer, few determine the underlying evolutionary parameters from molecular data, and even fewer integrate theory with data. We derived theoretical results linking mutation rate, time, expansion dynamics, and clinical parameters. We then inferred time-resolved estimates of evolutionary parameters from mutation accumulation, mutational signatures and selection. Using this framework, we traced the speciation of the clonally evolving marbled crayfish population to a time window between 1986 and 1990, which is consistent with biological records. We also used our framework to analyze a published dataset of glioblastoma samples, which identified tumor expansion patterns, cell survival at resection, and selective forces as important factors for tumor development. In conclusion, our framework allowed a time-resolved, integrated analysis of key parameters in clonally evolving genomes, and provided novel insights into the evolutionary age of marbled crayfish and the progression of glioblastoma.
Single Cell App: An App for Single Cell RNA-sequencing Data Visualization, Comparison and Discovery
Authors: Lewsey Mathew G. , Yi Changyu , Berkowitz Oliver , Ayora Felipe , Bernado Maurice , Whelan James 
Published: October 2021

SummaryThe Single Cell App is a cloud-based application that allows visualisation and comparison of scRNA-seq data and is scalable according to use. Users upload their own or publicly available scRNA-seq datasets after pre-processing to be visualised using a web browser. The data can be viewed in two colour modes, Cluster - representing cell identity, and Values – level of expression, and data queried using keyword or gene identification number(s). Using the app to compare four different studies we determined that some genes frequently used as cell-type markers are in fact study specific. Phosphate transporter and hormone response genes were exemplary investigated with the app. This showed that the apparent cell specific expression of PHO1;H3 differed between GFP-tagging and scRNA-seq studies. Some phosphate transporter genes were induced by protoplasting, they retained cell specificity, indicating that cell specific stress responses (i.e. protoplasting). Examination of the cell specificity of hormone response genes revealed that 132 hormone responsive genes display restricted expression and that the jasmonate response gene TIFY8 is expressed in endodermal cells which differs from previous reports. It also appears that JAZ repressors have cell-type specific functions. These differences, identified using the Single Cell App, highlight the need for resources to enable researchers to find common and different patterns of cell specific gene expression. Thus, the Single Cell App enables researchers to form new hypothesis, perform comparative studies, allows for easy re-use of data for this emerging technology to provide novel avenues to crop improvement.
Tear miRNAs identified in a murine model of Sjögren’s Syndrome as potential diagnostic biomarkers and indicators of disease mechanism
Authors: Kakan Shruti Singh , Edman Maria C. , Yao Alexander , Okamoto Curtis T. , Hjelm Brooke E. , Hamm-Alvarez Sarah F. 
Published: October 2021

ABSTRACTObjectiveThe tear miRNAome of the male NOD mouse, a model of ocular symptoms of Sjögren’s syndrome (SS), was analyzed to identify possible tear biomarkers of the disease.MethodsMale NOD mice, aged 12-14 weeks, were used to identify tear miRNAs associated with development of autoimmune dacryoadenitis. Age-matched female NOD mice that do not develop the autoimmune dacryoadenitis characteristic of SS were used as negative controls while age- and sex-matched male BALB/c mice served as healthy controls. Total RNA was isolated from stimulated tears pooled from 5 mice per sample and tear miRNAs were sequenced and analyzed. Putative miRNA hits were validated using RT-qPCR in a separate mouse cohort, and the pathways influenced by the validated hits were identified using Ingenuity Pathway Analysis.ResultsIn comparison to tears from both healthy (male BALB/c) and negative control (female NOD) mice, initial analysis identified 7 upregulated and 7 downregulated miRNAs in male NOD mouse tears. Of these, 8 were subsequently validated by RT-qPCR in tears from additional mouse cohorts. miRNAs previously implicated in SS pathology included mmu-miR-146a/b-5p, which were significantly downregulated in the male NOD mouse tears, as well as mmu-miR-150-5p and mmu-miR-181a-5p, which were upregulated in the male NOD mouse tears. All other validated hits including the upregulated miR-181b-5p and mmu-miR-203-3p, as well as the downregulated mmu-miR-322-5p and mmu-miR-503-5p, represent novel putative indicators of autoimmune dacryoadenitis in SS.ConclusionsA panel of differentially expressed miRNAs were identified in tears of SS model male NOD mice, including some never previously linked to SS. These may have potential utility as diagnostic biomarkers for ocular symptoms of SS; evaluation of the pathways influenced by these dysregulated miRNAs may also provide further insights into SS pathogenesis.
Inbreeding is associated with shorter early-life telomere length in a wild passerine
Authors: Le Pepke Michael , Niskanen Alina K. , Kvalnes Thomas , Boner Winnie , Sæther Bernt-Erik , Ringsby Thor Harald , Jensen Henrik 
Published: October 2021

ABSTRACTInbreeding can have negative effects on survival and reproduction, which may be of conservation concern in small and isolated populations. However, the physiological mechanisms underlying inbreeding depression are not well-known. The length of telomeres, the DNA sequences protecting chromosome ends, has been associated with health or fitness in several species. We investigated effects of inbreeding on early-life telomere length in two small island populations of wild house sparrows (Passer domesticus) known to be affected by inbreeding depression. Using genomic and pedigree-based measures of inbreeding we found that inbred nestling house sparrows have shorter telomeres. This negative effect of inbreeding on telomere length may have been complemented by a heterosis effect resulting in longer telomeres in individuals that were less inbred than the population average. Furthermore, we found some evidence of stronger effects of inbreeding on telomere length in males than females. Thus, telomere length may reveal subtle costs of inbreeding in the wild and demonstrate a route by which inbreeding negatively impacts the physiological state of an organism already at early life-history stages.
Waning grasslands: a quantitative temporal evaluation of the grassland habitats across human-dominated upper Gangetic Plains, north India
Authors: Paul Shrutarshi , Saha Sohini , Nigam Parag , Ali SK Zeeshan , Page Navendu , Khan Aamer Sohel , Kumar Mukesh , Habib Bilal , Mohan Dhananjai , Pandav Bivash , Mondol Samrat 
Published: October 2021

AbstractGrassland habitats currently face severe anthropogenic exploitations leading to cascading effects on the survival of grassland-dependent biodiversity globally, particularly in non-protected areas. Significant amount of such biodiversity-rich grasslands in India are found outside protected areas but lack quantitative information on their status. We evaluated the current and historical (30 years) status of the grasslands using a combination of intensive field surveys and GIS tools across one of the most fertile, human-dominated region: the upper Gangetic Plains of north India. On-ground mapping and visual classifications revealed 57% decline in grassland habitats between 1985 (418 km2) and 2015 (178km2), mostly driven by conversion to croplands (74% contribution). Radio-telemetry data from the largest endemic cervid swamp deer (n=2) showed grassland-dominated average home range (50% BBMM) size of 1.02 km2. The animals highly preferred these patches (average Ivlev’s index- 0.85) and showed highest temporal continuity (88%) compared to other LULC classes. Camera trapping within the core habitats suggests critical use of these patches as fawning/breeding grounds. Habitat suitability analysis indicates only ∼18% of the entire area along Ganges is suitable for swamp deer. Accurate mapping (86% accuracy) and characterization of four major grass species revealed a total 144.04 km² vegetation area, dominted bySaccharumsp. (35%). We recommend protection and recovery of these critical grassland patches to maintain ‘dynamic corridors’ and other appropriate management strategies involving multiple stakeholders to ensure survival of this critical ecosystem. Such evaluations, if spatially expanded, would be critical to restore this rapidly vanishing ecosystem worldwide.
Walking strides direct rapid and flexible recruitment of visual circuits for course control inDrosophila
Authors: Fujiwara Terufumi , Brotas Margarida , Chiappe M Eugenia 
Published: October 2021

AbstractFlexible mapping between activity in sensory systems and movement parameters is a hallmark of successful motor control. This flexibility depends on continuous comparison of short-term postural dynamics and the longer-term goals of an animal, thereby necessitating neural mechanisms that can operate across multiple timescales. To understand how such body-brain interactions emerge to control movement across timescales, we performed whole-cell patch recordings from visual neurons involved in course control inDrosophila. We demonstrate that the activity of leg mechanosensory cells, propagating via specific ascending neurons, is critical to provide a clock signal to the visual circuit for stride-by-stride steering adjustments and, at longer timescales, information on speed-associated motor context to flexibly recruit visual circuits for course control. Thus, our data reveal a stride-based mechanism for the control of high-performance walking operating at multiple timescales. We propose that this mechanism functions as a general basis for adaptive control of locomotion.
Early mitochondrial stress and metabolic imbalance lead to photoreceptor cell death in retinal degeneration
Authors: Jiang Ke , Mondal Anupam Kumar , Adlakha Yogita K. , Gumerson Jessica , Aponte Angel , Gieser Linn , Kim Jung-Woong , Boleda Alexis , Brooks Matthew J. , Nellissery Jacob , Fox Donald A. , Balaban Robert , Covian Raul , Swaroop Anand 
Published: October 2021

ABSTRACTNeurodegenerative diseases exhibit extensive genetic heterogeneity and complex etiology with varying onset and severity. To deduce the mechanism leading to retinal degeneration, we adopted a temporal multi-omics approach and examined molecular and cellular events before the onset of photoreceptor cell death in the widely-used Pde6brd1/rd1 (rd1) mouse model. Transcriptome profiling of neonatal and developing rods revealed early downregulation of genes associated with anabolic pathways and energy metabolism. Quantitative proteomics of rd1 retina showed early changes in calcium signaling and oxidative phosphorylation, with specific partial bypass of complex I electron transfer, which precede the onset of cell death. Concurrently, we detected alterations in central carbon metabolism, including dysregulation of components associated with glycolysis, pentose phosphate and purine biosynthesis. Ex vivo assays of oxygen consumption and transmission electron microscopy validated early and progressive mitochondrial stress and abnormalities in mitochondrial structure and function of rd1 rods. These data uncover mitochondrial over-activation and related metabolic alterations as early determinants of pathology and implicate dysregulation of calcium signaling as the initiator of higher mitochondrial stress, which then transitions to mitochondrial damage and photoreceptor cell death in retinal degeneration. Our studies support the “one hit model” arguing against the cumulative damage hypothesis but suggest that cell death in neurodegenerative disease is initiated by specific rather than a random event.