bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic modifiers of Huntington’s disease differentially influence motor and cognitive domains
Authors: Lee Jong-Min , Huang Yuan , Orth Michael , Gillis Tammy , Siciliano Jacqueline , Hong Eunpyo , Mysore Jayalakshmi Srinidhi , Lucente Diane , Wheeler Vanessa C. , Seong Ihn Sik , McLean Zachariah L. , Mills James A. , McAllister Branduff , Lobanov Sergey V. , Massey Thomas H. , Ciosi Marc , Landwehrmeyer G. Bernhard , Paulsen Jane S. , Dorsey E. Ray , Shoulson Ira , Sampaio Cristina , Monckton Darren G. , Kwak Seung , Holmans Peter , Jones Lesley , MacDonald Marcy E. , Long Jeffrey D. , Gusella James F. 
Published: January 2022

AbstractGenome-wide association studies (GWAS) of Huntington’s disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat with subsequent triggering of neuronal damage. The largest studies have been limited to HD individuals with a rater-estimated age at motor onset. To capitalize on the wealth of phenotypic data in several large HD natural history studies, we have performed algorithmic prediction using common motor and cognitive measures to predict age at other disease landmarks as additional phenotypes for GWAS. Combined with imputation using the Trans-Omics for Precision Medicine reference panel, predictions using integrated measures provided objective landmark phenotypes with greater power to detect most modifier loci. Importantly, substantial differences in the relative modifier signal across loci, highlighted by comparing common modifiers at MSH3 and FAN1, revealed that individual modifier effects can act preferentially in the motor or cognitive domains. Individual components of the DNA maintenance modifier mechanisms may therefore act differentially on the neuronal circuits underlying the corresponding clinical measures. In addition, we identified new modifier effects at the PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7. These findings indicate that broadened discovery and characterization of HD genetic modifiers based on additional quantitative or qualitative phenotypes offers not only the promise of in-human validated therapeutic targets, but also a route to dissecting the mechanisms and cell types involved in both the somatic instability and toxicity components of HD pathogenesis.
Convolution Neural Networks for Point-of-Care Diagnostics of Bacterial Infections in Blood
Authors: Hegde Omkar , Chatterjee Ritika , Roy Durbar , Jaiswal Vivek , Chakravortty Dipshikha , Basu Saptarshi 
Published: January 2022

ABSTRACTA droplet of blood, when evaporated on a surface, leaves dried residue—the fractal patterns formed on the dried residues can act as markers for infection present in the blood. Exploiting the unique patterns found in the residues of a naturally dried droplet of blood, we propose a Point-of-Care (POC) diagnostic tool for detecting broad-spectrum of bacterial infections (such asEnterobacter aerogenes, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, Salmonella Typhi) in blood. The diagnosis process we propose is straightforward and can be performed with the following steps: A droplet of blood (healthy or infected) of volume range 0.5 to 2μlis allowed to dry on a clean glass surface and is imaged using a conventional optical microscope. A computer algorithm based on the framework of convolution neural network (CNN) is used to classify the captured images of dried blood droplets according to the bacterial infection. In total, our multiclass model reports an accuracy of 92% for detecting six bacterial species infections in the blood (with control being the uninfected or healthy blood). The high accuracy of detecting bacteria in the blood reported in this article is commensurate with the standard bacteriological tests. Thus, this article presents a proof-of-concept of a potential futuristic tool for a rapid and low-cost diagnosis of bacterial infection in the blood.
Performance evaluation of novel fluorescent-based lateral immune flow assay (LIFA) for rapid detection and quantitation of total anti-SARS-CoV-2 S-RBD binding antibodies in infected individuals
Authors: Shurrab Farah M. , Younes Nadin , Al-Sadeq Duaa W. , Qotba Hamda , Abu-Raddad Laith J. , Nasrallah Gheyath K. 
Published: January 2022

1.AbstractBackgroundThe vast majority of the commercially available LFIA is used to detect SARS-CoV-2 antibodies qualitatively. Recently, a novel fluorescence-based LIFA test was developed for quantitative measurement of the total binding antibody units (BAU/mL) against the receptor-binding domain of the SARS-CoV-2 spike protein (S-RBD).AimTo evaluate the performance of the fluorescence LIFA Finecare™ 2019-nCoV S-RBD test along with its reader (Model No.: FS-113).MethodsPlasma from 150 RT-PCR confirmed-positive individuals and 100 pre-pandemic samples were tested by FinCare™ to access sensitivity and specificity. For qualitative and quantitative validation of the FinCar™ measurements, the BAU/mL results of FinCare™ were compared with results of two reference assays: the surrogate virus-neutralizing test (sVNT, GenScript, USA), and the VIDAS®3 automated assay (BioMérieux, France).ResultsFinecare™ showed 92% sensitivity and 100% specificity compared to PCR. Cohen’s Kappa statistic denoted moderate and excellent agreement with sVNT and VIDAS®3, ranging from 0.557 (95% CI: 0.32-0.78) to 0.731 (95% CI: 0.51-0.95), respectively. A strong correlation was observed between Finecare™/sVNT (r=0.7, p<0.0001) and Finecare™/VIDAS®3 (r=0.8, p<0.0001).ConclusionFinecare™ is a reliable assay and can be used as a surrogate to assess binding and neutralizing antibody response post-infection or vaccination, particularly in none or small laboratory settings.
Genomic signatures of isolation, hybridization, and selection during speciation of island finches
Authors: Stervander Martin , Melo Martim , Jones Peter , Hansson Bengt 
Published: January 2022

ABSTRACTSister species occurring sympatrically on islands are rare and offer unique opportunities to understand how speciation can proceed in the face of gene flow. The São Tomé grosbeak is a massive-billed, ‘giant’ finch endemic to the island of São Tomé in the Gulf of Guinea, where it has diverged from its co-occurring sister species the Príncipe seedeater, an average-sized finch that also inhabits two neighbouring islands. Here, we show that the grosbeak carries a large number of unique alleles different from all three Príncipe seedeater populations, but also shares many alleles with the sympatric São Tomé population of the seedeater, a genomic signature signifying divergence in isolation as well as subsequent introgressive hybridization. Furthermore, genomic segments that remain unique to the grosbeak are situated close to genes, including genes that determine bill morphology, suggesting the preservation of adaptive variation through natural selection during divergence with gene flow. This study reveals a complex speciation process whereby genetic drift, introgression, and selection during periods of isolation and secondary contact all have shaped the diverging genomes of these sympatric island endemic finches.Abstract Figure
Resolution and b value dependent Structural Connectome in ex vivo Mouse Brain
Authors: Crater Stephanie , Maharjan Surendra , Qi Yi , Zhao Qi , Cofer Gary , Cook James J. , Johnson G. Allan , Wang Nian 
Published: January 2022

AbstractDiffusion magnetic resonance imaging has been widely used in both clinical and preclinical studies to characterize tissue microstructure and structural connectivity. The diffusion MRI protocol for the Human Connectome Project (HCP) has been developed and optimized to obtain high-quality, high-resolution diffusion MRI (dMRI) datasets. However, such efforts have not been fully explored in preclinical studies, especially for rodents. In this study, high quality dMRI datasets of mouse brains were acquired at 9.4T system from two vendors. In particular, we acquired a high-spatial resolution dMRI dataset (25 μm isotropic with 126 diffusion encoding directions), which we believe to be the highest spatial resolution yet obtained; and a high-angular resolution dMRI dataset (50 μm isotropic with 384 diffusion encoding directions), which we believe to be the highest angular resolution compared to the dMRI datasets at the microscopic resolution. We systematically investigated the effects of three important parameters that affect the final outcome of the connectome: b value (1000 s/mm2to 8000 s/mm2), angular resolution (10 to 126), and spatial resolution (25 µm to 200 µm). The stability of tractography and connectome increase with the angular resolution, where more than 50 angles are necessary to achieve consistent results. The connectome and quantitative parameters derived from graph theory exhibit a linear relationship to the b value (R2> 0.99); a single-shell acquisition with b value of 3000 s/mm2shows comparable results to the multi-shell high angular resolution dataset. The dice coefficient decreases and both false positive rate and false negative rate gradually increase with coarser spatial resolution. Our study provides guidelines and foundations for exploration of tradeoffs among acquisition parameters for the structural connectome in ex vivo mouse brain.
Chronic Cognitive and Cerebrovascular Function Following Mild Traumatic Brain Injury in Rats
Authors: Griffiths Daniel R. , Law L. Matthew , Young Conor , Fuentes Alberto , Truran Seth , Karamanova Nina , Bell Laura C. , Turner Gregory , Emerson Hannah , Mastroeni Diego , Gonzales Rayna , Reaven Peter D. , Quarles Chad C. , Migrino Raymond Q. , Lifshitz Jonathan 
Published: January 2022

ABSTRACTSevere traumatic brain injury results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (N=20) or sham (N=21). Cognitive function was assessed (3- and 6-month novel object recognition (NOR), novel object location (NOL) and temporal order object recognition (TOR)). 6-month cerebral blood flow (CBF) and blood volume (CBV) using contrast MRI and ex vivo pial artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed impaired NOR, with similar (non-significant) trends in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus and primary somatosensory barrel cortex while inversely correlating with arterial smooth muscle-dependent dilation. 6-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin II stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin II-stimulated smooth muscle-dependent vasoreactivity, a paradigm that could advance understanding of the long-term sequelae of human mild TBI.
Postnatal developmental trajectory of sex-biased gene expression in the mouse pituitary gland
Authors: Hou Huayun , Chan Cadia , Yuki Kyoko E. , Sokolowski Dustin , Roy Anna , Qu Rihao , Uusküla-Reimand Liis , Faykoo-Martinez Mariela , Hudson Matt , Corre Christina , Goldenberg Anna , Zhang Zhaolei , Palmert Mark R. , Wilson Michael D. 
Published: January 2022

ABSTRACTThe pituitary gland regulates essential physiological processes such as growth, pubertal onset, stress response, metabolism, reproduction, and lactation. While sex biases in these functions and hormone production have been described, the underlying identity, temporal deployment, and cell-type specificity of sex-biased pituitary gene regulatory networks are not fully understood. To capture sex differences in pituitary gene regulation dynamics during postnatal development, we performed 3’ untranslated region sequencing and small RNA sequencing to ascertain gene and microRNA expression respectively across five postnatal ages (postnatal days 12, 22, 27, 32, 37) that span the pubertal transition in female and male C57BL/6J mouse pituitaries (n=5-6 biological replicates for each sex at each age). We observed over 900 instances of sex-biased gene expression and 17 sex-biased microRNAs, with the majority of sex differences occurring with puberty. Using miRNA-gene target interaction databases, we identified 18 sex-biased genes that were putative targets of 5 sex-biased microRNAs. In addition, by combining our bulk RNA-seq with publicly available male and female mouse pituitary single-nuclei RNA-seq data, we obtained evidence that cell-type proportion sex differences exist prior to puberty and persist post-puberty for three major hormone-producing cell types: somatotropes, lactotropes, and gonadotropes. Finally, we predicted sex-biased genes in these three pituitary cell types after accounting for cell-type proportion differences between sexes. Our study reveals the identity and postnatal developmental trajectory of sex-biased gene expression in the mouse pituitary. This work also highlights the importance of considering sex biases in cell-type composition when understanding sex differences in the processes regulated by the pituitary gland.HighlightsMale and female mouse pituitary gland gene and miRNA expression was profiled across five postnatal ages spanning pubertal developmentAbundant sex differences in pituitary gene expression exist prior to puberty and become more prominent upon pubertyCombining expression data from genes and miRNAs revealed 18 putative sex-biased gene targets of 5 sex-biased miRNAsSex differences in the proportions of somatotropes, lactotropes, and gonadotropes are predicted to occur prior to puberty
Disruption of natural killer cell homing as a biomarker in persons aging with or without HIV
Authors: Kroll Kyle W. , Shah Spandan V. , Lucar Olivier A. , Premeaux Thomas A. , Shikuma Cecilia M. , Corley Michael J. , Mosher Matthew , Bowler Scott , Ndhlovu Lishomwa C. , Reeves R. Keith 
Published: January 2022

AbstractNatural killer (NK) cells are critical modulators of HIV transmission and disease. While recent evidence suggests a loss of NK cell cytotoxicity during aging, a compound analysis of NK cell biology and aging in persons with HIV (PWH) is lacking. We set out to perform one of the first large comprehensive analyses of people aging with and without HIV to determine NK phenotypic changes during aging and how these changes are modulated while aging with HIV. Utilizing high-dimensional polychromatic flow cytometry we analyzed 30 immune-related proteins spanning broad functions such as trafficking, activation/inhibition, NK specific receptors, and memory/checkpoint receptors on peripheral NK cells from health donors, PWH with viral suppression, and viremic PWH. NK cell phenotypes are dynamic across the age span but are significantly altered in HIV and ART and with co-factors such as CMV. Specifically, NK cells in healthy aging show increasing levels of ⍰4β7 and decreasing CCR7 expression during aging, a phenomenon nearly perfectly reversed in PWH. These HIV-associated trafficking changes could be in part due to NK cell recruitment to HIV reservoir formation in lymphoid tissue or failed mucosal signaling in the HIV-infected gut, but regardless appear to be tight biomarkers of age-related NK cell changes.
Treatment of wound infections in a mouse model using Zn2+-releasing phage bound to gold nanorods
Authors: Peng Huan , Rossetto Daniele , Mansy Sheref S. , Jordan Maria C. , Roos Kenneth P. , Chen Irene A. 
Published: January 2022

AbstractInfections caused by drug-resistant bacteria, particularly gram-negative organisms, are increasingly difficult to treat using antibiotics. A potential alternative is ‘phage therapy’, in which phages infect and lyse the bacterial host. However, phage therapy poses serious drawbacks and safety concerns, such as the risk of genetic transduction of antibiotic resistance genes, inconsistent pharmacokinetics, and unknown evolutionary potential. In contrast, metallic nanoparticles possess precise, tunable properties, including efficient conversion of electronic excitation into heat. In this work, we demonstrate that engineered phage-nanomaterial conjugates that target the gram-negative pathogen P. aeruginosa, are highly effective as a treatment of infected wounds in mice. Photothermal heating, performed as a single treatment (15 min) or as two treatments on consecutive days, rapidly reduced the bacterial load and released Zn2+ to promote wound healing. The phage-nanomaterial treatment was significantly more effective than systemic fluoroquinolone antibiotics in reducing both bacterial load and wound size, and was notably effective against a P. aeruginosa strain resistant to polymyxins, a last-line antibiotic therapy. Unlike these antibiotics, the phage-nanomaterial showed no detectable toxicity or systemic effects in mice, consistent with the short duration and localized nature of phage- nanomaterial treatment. Our results demonstrate that phage therapy controlled by inorganic nanomaterials can be a safe and effective antimicrobial strategy in vivo.
Redirecting RiPP biosynthetic enzymes to proteins and backbone-modified substrates
Authors: Walker Joshua A. , Hamlish Noah , Tytla Avery , Brauer Daniel D. , Francis Matthew B. , Schepartz Alanna 
Published: January 2022

AbstractRibosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products that include the FDA-approved analgesic ziconotide1,2 as well as compounds with potent antibiotic, antiviral, and anticancer properties.3 RiPP enzymes known as cyclodehydratases and dehydrogenases represent an exceptionally well-studied enzyme class.3 These enzymes work together to catalyze intramolecular, interresidue condensation3,4 and aromatization reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers, including aramids and beta-amino acids, within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse, non-alpha-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond. Both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. Moreover, as thiazoles and thiazoline heterocycles are replete in natural products,5–7 small molecule drugs,8,9 and peptide-mimetic therapeutics,10 their installation in protein-based biotherapeutics could improve or augment performance, activity, stability, and/or selectivity. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code.
Development of OPLS-AA/M Parameters for Simulations of G Protein-Coupled Receptors and Other Membrane Proteins
Authors: Robertson Michael J. , Skiniotis Georgios 
Published: January 2022

AbstractG protein-coupled receptors (GPCRs) and other membrane proteins are valuable drug targets, and their dynamic nature makes them attractive systems for study with molecular dynamics simulations and free energy approaches. Here, we report the development, implementation, and validation of OPLS-AA/M force field parameters to enable simulations of these systems. These efforts include the introduction of post-translational modifications including lipidations and phosphorylation. We also modify previously reported parameters for lipids to be more consistent with the OPLS-AA force field standard and extend their coverage. These new parameters are validated on a variety of test systems, with the results compared to high-level quantum mechanics calculations, experimental data, and simulations with CHARMM36m where relevant. The results demonstrate that the new parameters reliably reproduce the behavior of membrane protein systems.
Adolescents Hospitalized with SARS-CoV-2: Analysis of Clinical Profile and Risk Factors for Severe Disease over a two-year period
Authors: Ghosh Tamoghna , Suri Tejas M , Jat Kana Ram , Gupta Aditya Kumar , Bhatnagar Sushma , Tiwari Pawan , Mittal Saurabh , Mohan Anant 
Published: January 2022

AbstractIntroductionThere is a lack of studies in adolescents with COVID-19 from developing countries. We aimed to describe the clinical profile and risk factors for severe disease in adolescents hospitalized with COVID-19.MethodsA retrospective analysis of a prospectively admitted cohort of COVID-19 patients was performed at a tertiary hospital in north India. Adolescents aged 12 to 18 years who were hospitalized during the first wave (March 2020 to December 2020) and the second wave (March 2021 to June 2021) of the pandemic were included. Data on the demographic details, clinical presentation, laboratory parameters, disease severity at admission, treatments received, and in-hospital outcomes were retrieved and logistic regression was used to identify the risk factors for occurrence of moderate or severe disease.ResultsThe study included 197 adolescents with median (IQR) age 15 (13-17) years, of whom 117 (59.4%) were male. Among these, 170 (86.3%) were admitted during the 1st wave. Underlying comorbidities were present in 9 (4.6%) patients. At the time of hospital admission, 60 (30.9%) patients were asymptomatic. In the severity grading, 148 (84.6%) had mild, 16 (9.1%) had moderate, and 11 (6.3%) had severe disease. Fever (14.9%) and cough (14.9%) were the most commonly encountered symptoms. The median (IQR) duration of hospital stay was 10 (8-13) days and 6 (3.1%) patients died in hospital. The odds of moderate to severe disease were 3.8 for second wave, 1.9 for fever and 1.1 for raised C reactive protein (CRP).ConclusionIn our single-center study from northern India, adolescents admitted with COVID-19 had predominantly asymptomatic or mild disease. Admission during the second wave of COVID-19 pandemic, presence of fever and raised CRP were risk factors for moderate or severe disease.Lay SummaryFrom 3rd January 2022 onwards, adolescents between 15 to 18 years of age in India will be given Covaxin vaccine, as per the latest Indian government guidelines. In our study, we aimed to describe the clinical profile and risk factors for severe disease in adolescents hospitalized with COVID-19. Our study included 197 adolescents. 170 (86.3%) of them were admitted during the 1st wave and the rest 27 (13.7%) during the 2nd wave. At the time of hospital admission, 60 (30.9%) patients were asymptomatic. In the severity grading, 148 (84.6%) had mild, 16 (9.1%) had moderate, and 11 (6.3%) had severe disease. Fever (14.9%) and cough (14.9%) were the most commonly encountered symptoms. The median (IQR) duration of hospital stay was 10 (8-13) days and 6 (3.1%) patients died in hospital. 2nd wave, fever and high C reactive protein increased the odds of moderate to severe disease.