bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical autism subscales have common genetic liabilities that are heritable, pleiotropic, and generalizable to the general population
Authors: Thomas Taylor R. , Koomar Tanner , Casten Lucas G. , Tener Ashton J. , Bahl Ethan , Michaelson Jacob J. 
Published: September 2021

AbstractThe complexity of autism’s phenotypic spectra is well-known, yet most genetic research uses case-control status as the target trait. It is undetermined if autistic symptom domain severity underlying this heterogeneity is heritable and pleiotropic with other psychiatric and behavior traits in the same manner as autism case-control status. In N = 6,064 autistic children in the SPARK cohort, we investigated the common genetic properties of twelve subscales from three clinical autism instruments measuring autistic traits: the Social Communication Questionnaire (SCQ), the Repetitive Behavior Scale-Revised (RBS-R), and the Developmental Coordination Disorder Questionnaire (DCDQ). Educational attainment polygenic scores (PGS) were significantly negatively correlated with eleven subscales, while ADHD and major depression PGS were positively correlated with ten and eight of the autism subscales, respectively. Loneliness and neuroticism PGS were also positively correlated with many subscales. Significant PGS by sex interactions were found –– surprisingly, the autism case-control PGS was negatively correlated in females and had no strong correlation in males. SNP-heritability of the DCDQ subscales ranged from 0.04 to 0.08, RBS-R subscales ranged from 0.09 - 0.24, and SCQ subscales ranged from 0 to 0.12. GWAS in SPARK followed by estimation of polygenic scores (PGS) in the typically-developing ABCD cohort (N = 5,285), revealed significant associations of RBS-R subscale PGS with autism-related behavioral traits, with several subscale PGS more strongly correlated than the autism case-control PGS. Overall, our analyses suggest that the clinical autism subscale traits show variability in SNP-heritability, PGS associations, and significant PGS by sex interactions, underscoring the heterogeneity in autistic traits at a genetic level. Furthermore, of the three instruments investigated, the RBS-R shows the greatest evidence of genetic signal in both (1) autistic samples (greater heritability) and (2) general population samples (strongest PGS associations).
Correlations between metabolites in the synovial fluid and serum: a mouse injury study
Authors: Wallace Cameron W. , Hislop Brady , Hahn Alyssa K. , Erdogan Ayten E. , Brahmachary Priyanka P. , June Ronald K. 
Published: September 2021

AbstractOsteoarthritis, the most common degenerative joint disease, occurs more frequently in joints that have sustained injury. Currently, osteoarthritis is diagnosed with imaging that finds radiographic changes after the disease has already progressed to multiple tissues. The primary objective of this study was to compare potential metabolomic biomarkers of joint injury between the synovial fluid and serum in a mouse model of post-traumatic osteoarthritis. The secondary objective was to gain insight into the pathophysiology of osteoarthritis by examining metabolomic profiles after joint injury. 12-week-old adult female C57BL/6 mice (n=12) were randomly assigned to control, day 1 post injury, or day 8 post injury groups. Randomly selected stifle (i.e., knee) joints were placed into a non-invasive injury apparatus and subjected to a single dynamic axial compression causing anterior translation of the tibia relative to the femur to tear the anterior cruciate ligament. At days 1 and 8 post injury, serum was extracted then mice were immediately euthanized prior to synovial fluid collection. Metabolites were extracted and analyzed by liquid chromatography coupled to mass spectrometry. We detected ~2500 metabolites across serum and synovial fluid. Of these metabolites 179 were positively correlated and 51 were negatively correlated between synovial fluid and serum, indicating potential for the development of metabolomic biomarkers. Synovial fluid appeared to capture differences in metabolomic profiles between injured mice at both day 1 and 8 after injury whereas serum did not. However, synovial fluid and serum were distinct at both days 1 and 8 after injury. In the synovial fluid, pathways of interest across different time points mapped to amino acid synthesis and degradation, bupropion degradation, and the tRNA charging pathway. In the serum, notable pathways across time points were amino acid synthesis and degradation, the phospholipase pathway, and nicotine degradation. These results provide a rich picture of the injury response at early time points following traumatic joint injury. Furthermore, the correlations between synovial fluid and serum metabolites suggest that there is potential to gain insight into intra-articular pathophysiology through analysis of serum metabolites.
The information signature of diverging lineages
Authors: Moore Douglas G. , Morales Matheo , Biddy Austin R. , Walker Sara I. , Dolby Greer A. 
Published: September 2021

ABSTRACTDivergence and speciation are the generators of biodiversity on Earth. Yet, we still seek to understand why species are unevenly distributed across taxa and geographic settings. This is partly because we lack a way to directly compare aspects of population divergence across unrelated species and an integrative quantitative framework for how geographical setting relates to genetic divergence. Here we postulate that, based on communications theory, there is a communications channel between Earth’s surface and the structuring of genomic information among populations. Each species is a separate receiver of this message. Organism traits determine the clarity of that channel. Calculating the partial information decomposition (PID) of genetic metrics under different evolutionary scenarios can measure the signature of this communication. We showin silicohow the informational decomposition of 97,200 genetic lattices varies as lineages diverge. The decomposed nodes of Tajima’s D, θW, and π show strong context-dependent information signatures, while FSTwas least informative. Specific decompositions detected whether lineages divergence with or without gene flow better than current SFS-based tools. The study of information in an evolutionary genomic and landscape context suggests it may be a helpful framework and for understanding the diversity of life across Earth and their coevolution.
Heterologous synapsis in C. elegans is regulated by meiotic double-strand breaks and crossovers
Authors: Liu Hanwenheng , Gordon Spencer G. , Rog Ofer 
Published: September 2021

AbstractAlignment of the parental chromosomes during meiotic prophase is key to the formation of genetic exchanges, or crossovers, and consequently to the successful production of gametes. In almost all studied organisms, alignment involves synapsis: the assembly of a conserved inter-chromosomal interface called the synaptonemal complex (SC). While the SC usually synapses homologous sequences, it can assemble between heterologous sequences. However, little is known about the regulation of heterologous synapsis. Here we study the dynamics of heterologous synapsis in the nematode C. elegans. We characterize two experimental scenarios: SC assembly onto a folded-back chromosome that cannot pair with its homologous partner; and synapsis of pseudo-homologs, a fusion chromosome partnering with an unfused chromosome half its size. We observed elevated levels of heterologous synapsis when the number of meiotic double-strand breaks or crossovers were reduced, indicating that the promiscuity of synapsis is regulated by break formation or repair. By manipulating the levels of breaks and crossovers, we infer both chromosome-specific and nucleus-wide regulation on heterologous synapsis. Finally, we identify differences between the two conditions, suggesting that attachment to the nuclear envelope plays a role in regulating heterologous synapsis.
Analysis of changes occurring in Codon Positions due to mutations through the cellular automata transition rules
Authors: Sengupta Antara , Ghosh Sreeya , Choudhury Pabitra Pal 
Published: September 2021

AbstractVariation in the nucleotides of a codon may cause variations in the evolutionary patterns of a DNA or amino acid sequence. To address the capability of each position of a codon to have non-synonymous mutations, the concept of degree of mutation has been introduced. The degree of mutation of a particular position of codon defines the number of non-synonymous mutations occurring for the substitution of nucleotides at each position of a codon, when other two positions of that codon remain unaltered. A Cellular Automaton (CA), is used as a tool to model the mutations of any one of the four DNA bases A, C, T and G at a time where the DNA bases correspond to the states of the CA cells. Point mutation (substitution type) of a codon which characterizes changes in the amino acids, have been associated with local transition rules of a CA. Though there can be transitions of a 4-state CA with 3-neighbourhood cells, here it has been possible to represent all possible point mutations of a codon in terms of combinations of 16 local transition functions of the CA. Further these rules are divided into 4 classes of equivalence. Also, according to the nature of mutations, the 16 local CA rules of substitutions are classified into 3 sets namely, ‘No Mutation’, ‘Transition’ and ‘Transversion’. The experiment has been carried out with three sets of single nucleotide variations(SNVs) of three different viruses but the symptoms of the diseases caused by them are to some extent similar to each other. They are SARS-CoV-1, SARS-CoV-2 and H1N1 Type A viruses. The aim is to understand the impact of nucleotide substitutions at different positions of a codon with respect to a particular disease phenotype.
miR-573 rescues endothelial dysfunction during dengue infection under PPARγ regulation
Authors: Banerjee Shefali , Yuin Kong Hao , Xin Chin Wei , Hann Chu Justin Jang 
Published: September 2021

AbstractEarly prognosis of abnormal vasculopathy is essential for effective clinical management of severe dengue patients. An exaggerated interferon (IFN) response and release of vasoactive factors from endothelial cells cause vasculopathy. This study shows that dengue 2 (DENV2) infection of human umbilical vein endothelial cells (HUVEC) results in differentially regulated miRNAs important for endothelial function. miR-573 was significantly down-regulated in DENV2-infected HUVEC due to decreased Peroxisome Proliferator Activator Receptor Gamma (PPARγ) activity. Restoring miR-573 expression decreased endothelial permeability by suppressing the expression of vasoactive angiopoietin 2 (ANGPT2). We also found that miR-573 suppressed the proinflammatory IFN response through direct downregulation of toll like receptor 2 (TLR2) expression. Our study provides a novel insight into miR-573 mediated regulation of endothelial function during DENV2 infection which can be further translated into a potential therapeutic and prognostic agent for severe dengue patients.
In Silico analysis of PE_PGRS20 (Rv1068c) protein in Mycobacterium tuberculosis H37Rv
Authors: Ahmad Saleem , Kesavan AnupKumar 
Published: September 2021

AbstractThe genetic makeup of Mycobacterium tuberculosis reveals the presence of an unknown repeat sequence of PE_PGRS family proteins that are responsible for antigenic variations and many unknown functions that includes necrosis of macrophage and apoptosis. The structure and function of these glycine-rich proteins can be predictable by homology modeling, the Ab-initio method, or by using different tools of bioinformatics. In this study, we selected, PE_PGRS20 (Rv1068c) an unknown PE_PGRS protein. We suggest that the PE_PGRS20 gene is linked with the others genes of the espACD operon which are the virulence factors in the M. tuberculosis H37Rv strain. The genes associated with this protein secretion system can perform the synthesis of a special type of fatty acid known as phthioceroldimycocerates (PDIM).Docking with different anti TB drugs shows binding with PE_PGRS20 protein which suggests that the target protein may involve in the drug resistance.
Adaptation and Compensation in a Bacterial Gene Regulatory Network Evolving Under Antibiotic Selection
Authors: Patel Vishwa , Matange Nishad 
Published: September 2021

AbstractGene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves de-repression of PhoPQ signalling, a Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that de-repression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional up-regulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary ‘choice’ of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ de-repression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by strength of antibiotic selection, such that high pressures favour resistance, while low pressures favour cost-compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.
Stimulus degradation impairs performance in a rodent continuous performance test
Authors: DeBrosse Adrienne C. , Li Ye , Wiseman Robyn , Ross Racine , Garrison Sy’Keria , Hallock Henry L. , Barrow James C. , Martinowich Keri , Carr Gregory V. 
Published: September 2021

AbstractSustained attention is a core cognitive domain that is often disrupted in neuropsychiatric disorders. Continuous performance tests (CPTs) are the most common clinical assay of sustained attention. In CPTs, participants produce a behavioral response to target stimuli and refrain from responding to non-target stimuli. Performance in CPTs is measured as the ability to discriminate between targets and non-targets. Rodent versions of CPTs (rCPT) have been developed and validated with both anatomical and pharmacological studies, providing a translational platform for understanding the neurobiology of sustained attention. In human studies, using degraded stimuli (decreased contrast) in CPTs impairs performance and patients with schizophrenia experience a larger decrease in performance compared to healthy controls. In this study, we tested multiple levels of stimulus degradation in a touchscreen version of the CPT in mice. We found that stimulus degradation significantly decreased performance in both males and females. The changes in performance consisted of a decrease in stimulus discrimination, measured as d’, and increases in hit reaction time and reaction time variability. These findings are in line with the effects of stimulus degradation in human studies. Overall, female mice demonstrated a more liberal response strategy than males, but response strategy was not affected by stimulus degradation. These data extend the utility of the mouse CPT by demonstrating that stimulus degradation produces equivalent behavioral responses in mice and humans. Therefore, the degraded stimuli rCPT has high translational value as a preclinical assay of sustained attention.
Population assessment and habitat associations of the Visayan HornbillPenelopides paniniin Northwest Panay, Philippines
Authors: Mynott Holly Isabelle , Lee David Charles , Santillan Rhea Aranas , Jürgen Schwarz Christian , Tacud Benjamin , Fernandez Arcel Dryden , Kerhoas Daphne 
Published: September 2021

AbstractBackgroundSeven out of 10 hornbill species in the Philippines are threatened with extinction. Among these is the Endangered Visayan hornbillPenelopides panini, found on Panay and Negros islands. Threatened by habitat loss and hunting, its population size is thought to have declined from 1,800 individuals 20 years ago to less than 1,000. However, a recent study on Negros estimated 3,564 individuals across three core forest blocks. This study aims to quantify the Visayan hornbill population size in and around the Northwest Panay Peninsula Natural Park (NWPPNP) on Panay, the largest contiguous low-elevation forest landscape remaining across its range, and its broad habitat associations across a gradient of environmental degradation.MethodsHornbills were surveyed using 10-minute Distance sampling point counts (n = 362) along transects (average length 1.1 km). Habitat variables were recorded, while habitat was classified into: primary forest, secondary forest, plantation or open habitat. Using Distance software, population densities were estimated for, and post-stratified by habitat, with the overall population estimate taken as a mean of habitat density estimates weighted by habitat area. Using logistic binary regression, hornbill occurrence was modelled against reduced habitat factors extracted from factor analysis of the habitat data.ResultsSurveys covered 204.4 km2of the 374.8 km2Northwest Panay Peninsula. Hornbills were not recorded in plantation or open habitats. The estimated density of hornbills was significantly higher in primary forest (17.7 individuals km−2± 29.7% CV) than in secondary forest (5.0 individuals km−2± 36.7 %CV;z= 9.538,P< 0.001). The overall population estimate is 2,231 individuals ± 24.4 %CV for the NWPPNP and environs, and 2,949 individuals ± 23.1 %CV for the entire Northwest Panay Peninsula. One habitat factor, described by increasing numbers of large trees, elevation and distance from the Park’s boundary, had a significant positive effect in explaining hornbill occurrence, with hornbills significantly more likely to occur in primary forest than the other habitat types.ConclusionsOur study demonstrates the habitat preference of the Visayan hornbill, highlights the importance of the NWPPNP for the species’ conservation, and provides strong evidence for re-assessing the global population size.
JAMMIT Analysis Defines 2 Semi-Independent Immune Processes Common to 29 Solid Tumors
Authors: Zitello Emory , Vo Michael , Chen Shaoqiu , Bowler Scott , Khadka Vedbar , Wenska Thomas , Hoffmann Peter , Okimoto Gordon , Deng Youping 
Published: September 2021

AbstractImmunophenotype of solid tumors has relevance to cancer immunotherapy, as not all patients respond optimally to treatment utilizing monoclonal antibodies. Bioinformatic studies have failed to clearly identify tumor immunophenotype in a way that encompasses a wide variety of tumor types and highlights fundamental differences among them, complicating prediction of patient clinical response. The novel JAMMIT algorithm was used to analyze mRNA data for 33 cancer types in The Cancer Genome Atlas (TCGA). We found that B cells and T cells constitute the principal source of variation in most patient cohorts, and that virtually all solid malignancies formed three hierarchical clustering patterns with similar molecular features. The second main source of variability in transcriptomic studies we attribute to monocytes. We identified the three tumor types as TC1-mediated, TC17-mediated and non-immunogenic immunophenotypes and used a 3-gene signature to approximate infiltration by agranulocytes. Methods of in silico validation such as pathway analysis, Cibersort and published data from treated cohorts were used to substantiate these findings. Monocytic infiltrate is found to be related to patient survival according to immunophenotype, important differences in some solid tumors are identified and deficiencies of common bioinformatic approaches relevant to diagnosis are detailed by this work.
Cryo-ET of HIV reveals Env positioning on Gag lattice and structural variation among Env trimers
Authors: Prasad Vidya Mangala , Leaman Daniel P. , Lovendahl Klaus N. , Croft Jacob T. , Benhaim Mark A. , Hodge Edgar A. , Zwick Michael B. , Lee Kelly K. 
Published: September 2021

SummaryHIV-1 Env mediates viral entry into host cells and is the sole target for neutralizing antibodies. However, Env structure and organization in its native virion context has eluded detailed characterization. Here we used cryo-electron tomography to analyze Env in mature and immature HIV-1 particles. Immature particles showed distinct Env positioning relative to the underlying Gag lattice, providing insights into long-standing questions about Env incorporation. A 9.1Å sub-tomogram averaged reconstruction of virion-bound Env in conjunction with structural mass spectrometry revealed unexpected features, including a variable central core of the gp41 subunit, heterogeneous glycosylation between protomers plus a flexible stalk that allows Env tilting and variable exposure of neutralizing epitopes. Together, our results provide an integrative understanding of HIV assembly and structural variation in Env antigen presentation.
Neck motor unit activity displays neural signatures of temporal control during sequential saccade planning
Authors: Basu Debaleena , Sendhilnathan Naveen , Murthy Aditya 
Published: September 2021

SummaryGoal-directed behavior involves the transformation of neural movement plans into appropriate muscle activity patterns. Studies involving single saccades have shown that a rapid, direct pathway links saccade planning in frontal eye fields (FEF) to neck muscle activity. It is unknown if the rapid connection between FEF and neck muscle is maintained during sequential saccade planning. We show that sequence planning signals in the FEF are preserved in the neck EMG, although the activity is delayed specifically for the second saccade. Our results suggest that while the direct link between FEF and neck muscle facilitates downstream continuation of FEF response patterns, an indirect route exists through an inhibitory control center like the basal ganglia, limiting the information flow during processing of saccade sequences. Thus, the indirect and direct pathways from the FEF may function together to enable rapid synchronous, but controlled eye-head responses to sequential gaze shifts.
A Cytosolic Reductase Pathway is Required for Complete N-Glycosylation of an STT3B-Dependent Acceptor Site
Authors: van Lith Marcel , Pringle Marie Anne , Fleming Bethany , Gaeta Giorgia , Im Jisu , Gilmore Reid , Bulleid Neil J 
Published: September 2021

AbstractN-linked glycosylation of proteins entering the secretory pathway is an essential post-translational modification required for protein stability and function. Previously, it has been shown that there is a temporal relationship between protein folding and glycosylation, which influences the occupancy of specific glycosylation sites. Here we use an in vitro translation system that reproduces the initial stages of secretory protein translocation, folding and glycosylation under defined redox conditions. We found that the efficiency of glycosylation of hemopexin was dependent upon a robust NADPH-dependent cytosolic reductive pathway, which could also be mimicked by the addition of a membrane impermeable reducing agent. The identified hypoglycosylated acceptor site is adjacent to a cysteine involved in a short range disulfide bond, which has been shown to be dependent on the STT3B-containing oligosaccharyl transferase. We also show that efficient glycosylation at this site is dependent on the STT3A-containing oligosaccharide transferase. Our results provide further insight into the important role of the ER redox conditions in glycosylation site occupancy and demonstrate a link between redox conditions in the cytosol and glycosylation efficiency.