bluuebunny/crossref_metadata_2025_split huggingface dataset:
GlycoEnzOnto: A GlycoEnzyme Pathway and Molecular Function Ontology
Authors: Groth Theodore , Gunawan Rudiyanto , Diehl Alexander D. , Neelamegham Sriram 
Published: June 2022

ABSTRACTThe ‘glycoEnzymes’ include a set of proteins having related enzymatic, metabolic, transport, structural and cofactor functions. Current there is no established ontology to describe glycoEnzyme properties and to relate them to glycan biosynthesis pathways. We present GlycoEnzOnto, an ontology describing 386 human glycoEnzymes curated along 135 glycosylation pathways, 134 molecular functions and 22 cellular compartments. The pathways described regulate nucleotide-sugar metabolism, glycosyl-substrate/donor transport, glycan biosynthesis, and degradation. The role of each enzyme in the glycosylation initiation, elongation/branching, and capping/termination phases is described. IUPAC linear strings present systematic human/machine readable descriptions of individual reaction steps and enable automated knowledge-based curation of biochemical networks. All GlycoEnzOnto knowledge is integrated with the Gene Ontology (GO) biological processes. GlycoEnzOnto enables improved transcript overrepresentation analyses and glycosylation pathway identification compared to other available schema, e.g. KEGG and Reactome. Overall, GlycoEnzOnto represents a holistic glycoinformatics resource for systems-level analyses.Availabilityhttps://github.com/neel-lab/GlycoEnzOnto
Gene amplification acts as a molecular foothold to facilitate cross-species adaptation and evasion of multiple antiviral pathways
Authors: Banerjee Shefali , Smith Cathy , Geballe Adam , Rothenburg Stefan , Kitzman Jacob O. , Brennan Greg 
Published: June 2022

AbstractCross-species spillover events are responsible for many of the pandemics in human history including COVID-19; however, the evolutionary mechanisms that enable these events are poorly understood. We have previously modeled this process using a chimeric vaccinia virus expressing the rhesus cytomegalovirus-derived PKR antagonist RhTRS1 in place of its native PKR antagonists; E3L and K3L (VACVΔEΔK+RhTRS1). Using this virus, we demonstrated that gene amplification of rhtrs1 occurred early during experimental evolution and was sufficient to fully rescue virus replication in partially resistant African green monkey (AGM) fibroblasts. Notably, this rapid gene amplification also allowed limited virus replication in otherwise completely non-permissive human fibroblasts, suggesting that gene amplification may act as a “molecular foothold” to facilitate viral adaptation to multiple species. In this study, we demonstrate that there are multiple barriers to VACVΔEΔK+RhTRS1 replication in human cells, mediated by both PKR and RNase L. We experimentally evolved three AGM-adapted virus populations in human fibroblasts. Each population adapted to human cells bimodally, via an initial 10-fold increase in replication after only two passages followed by a second 10-fold increase in replication by passage nine. Using our Illumina-based pipeline, we found that some SNPs which had evolved during the prior AGM adaptation were rapidly lost, while 13 singlebase substitutions and short indels increased over time, including two SNPs unique to HFF adapted populations. Many of these changes were associated with components of the viral RNA polymerase, although no variant was shared between all three populations. Taken together, our results demonstrate that rhtrs1 amplification was sufficient to increase viral tropism after passage in an “intermediate species” and subsequently enabled the virus to adopt different, species-specific adaptive mechanisms to overcome distinct barriers to viral replication in AGM and human cells.
Amygdalar and ERC Rostral Atrophy and Tau Pathology Reconstruction in Preclinical Alzheimer’s Disease
Authors: Stouffer Kaitlin M. , Chen Claire , Kulason Sue , Xu Eileen , Witter Menno P. , Ceritoglu Can , Albert Marilyn S. , Mori Susumu , Troncoso Juan , Tward Daniel J. , Miller Michael I. 
Published: June 2022

AbstractPrevious research has emphasized the unique impact of Alzheimer’s Disease (AD) pathology on the medial temporal lobe (MTL), a reflection that tau pathology is particularly striking in the entorhinal and transentorhinal cortex (ERC, TEC) early in the course of disease. However, other brain regions are affected by AD pathology during its early phases. Here, we use longitudinal diffeomorphometry to measure the atrophy rate from MRI of the amygdala compared with that in the ERC and TEC in controls, individuals who progressed from normal cognition to mild cognitive impairment (MCI), and individuals with MCI who progressed to AD dementia, using a dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Our results show significantly higher atrophy rates of the amygdala in both preclinical and MCI ‘converters’ compared to controls, with rates of volume loss comparable to rates of thickness loss in the ERC and TEC. Using our recently developed method, referred to as Projective LDDMM, we map measures of neurofibrillary tau tangles (NFTs) from digital pathology to MRI atlases and reconstruct, for the first time, dense 3D spatial distributions of NFT density within regions of the MTL. The distribution of NFTs is consistent with the MR atrophy rates, revealing high densities not only in ERC, but in the amygdala and rostral third of the MTL. The similarity of the location of NFTs and shape changes in a well-defined clinical population suggests that amygdalar atrophy rate, as measured through MRI may be a viable biomarker for AD.PACS0000, 11112000 MSC0000, 1111HighlightsAmygdala atrophy rate estimated from MRIs in preclinical Alzheimer’s disease (AD)3D distributions of neurofibrillary tau tangles (NFTs) reconstructed from 2D histologyNFTs highest in the rostral medial temporal lobe, including amygdala and ERCAmygdala atrophy rate is comparable to ERC atrophy rate in preclinical ADAmygdala and ERC atrophy rates as potential biomarkers rooted in NFT pathology
Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice
Authors: Lee Samuel M. , Muratalla Jose , Karimi Saman , Diaz-Ruiz Alberto , Frutos Maria Dolores , Guzman Grace , Ramos-Molina Bruno , Cordoba-Chacon Jose 
Published: June 2022

AbstractBackground & AimsNon-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) in humans. Although we previously showed that the expression of PPARγ in hepatocytes contributes to the development NASH in lean mice, the relevance of hepatocyte PPARγ in the development of NASH associated with obesity is still poorly understood.MethodsHepatocyte PPARγ was knocked out (PpargΔHep) after the development of high-fat diet-induced obesity in male and female mice and before NASH was induced with a high fat, cholesterol and fructose (HFCF) diet. We assessed the effect of the diets and PpargΔHep on body composition and glucose homeostasis, as well as on the liver pathology, gene expression, and metabolome. In addition, liver biopsies from a cohort of 102 bariatric surgery patients were assessed for liver histology and gene expression.ResultsPPARγ expression, specifically PPARγ2, is mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis. Interestingly, PpargΔHep reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and collagen- stained fibrotic area in the liver of HFCF-fed male mice. In addition, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. Specifically, PpargΔHep increased betaine-homocysteine methyltransferase expression and reduced homocysteine levels in HFCF- fed male mice. In a cohort of 102 bariatric surgery patients, 16 cases of NASH were associated with increased insulin resistance and hepatic PPARγ expression.ConclusionsHepatocyte PPARγ expression associated with obesity could regulate methionine metabolism and the progression of fibrosis in NASH.
Nirmatrelvir Resistant SARS-CoV-2 Variants with High Fitness in Vitro
Authors: Zhou Yuyong , Gammeltoft Karen Anbro , Ryberg Line Abildgaard , Pham Long V. , Fahnøe Ulrik , Binderup Alekxander , Hernandez Carlos Rene Duarte , Offersgaard Anna , Fernandez-Antunez Carlota , Peters Günther Herbert Johannes , Ramirez Santseharay , Bukh Jens , Gottwein Judith Margarete 
Published: June 2022

AbstractThe oral protease inhibitor nirmatrelvir is expected to play a pivotal role for prevention of severe cases of coronavirus disease 2019 (COVID-19). To facilitate monitoring of potentially emerging resistance, we studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escape from nirmatrelvir. Resistant variants selected in cell culture harbored different combinations of substitutions in the SARS-CoV-2 main protease (Mpro). Reverse genetic studies in a homologous infectious cell culture system revealed up to 80-fold resistance conferred by the combination of substitutions L50F and E166V. Resistant variants had high fitness increasing the likelihood of occurrence and spread of resistance. Molecular dynamics simulations revealed that E166V and L50F+E166V weakened nirmatrelvir-Mpro binding. The SARS-CoV-2 polymerase inhibitor remdesivir retained activity against nirmatrelvir resistant variants and combination of remdesivir and nirmatrelvir enhanced treatment efficacy compared to individual compounds. These findings have implications for monitoring and ensuring treatment programs with high efficacy against SARS-CoV-2 and potentially emerging coronaviruses.
A role for Flipons and miRNAs in Promoter Specification during Development
Authors: Herbert Alan , Pavlov Fedor , Konovalov Dmitrii , Poptsova Maria 
Published: June 2022

AbstractThe classical view of gene regulation is based on prokaryotic models and the operon concept with protein-based transcription factors controlling the expression of metabolic pathways essential for bacterial adaptations in response to environmental changes. A new view for establishing cell identity is emerging in eukaryotes where RNA-based pathways provide the framework for the readout of genomic information. Another perspective poses that alternative DNA structures encoded by flipons enable switching of cellular responses from one state to another. Here we provide evidence that these RNA and DNA mechanisms are deeply connected. We present data supporting a model where flipons open up binding sites for microRNAs (miRNAs), leading to the establishment of bivalent promoters early in development whose location structures lineage-specific events. These outcomes are potentially influenced by ovarian and spermatozoan miRNAs, transmissions with evident evolutionary ramifications. The data supports a new perspective on genetic regulation, one in which the genome provides a canvas framed by flipons, sketched with miRNAs and embellished by proteins.
Thymic Rejuvenation by Adult Grafts in the Lymph Node
Authors: Rao Aparna , Gupta Avni , Lagasse Eric 
Published: June 2022

AbstractImmunologic aging is defined as a process in which the immune system undergoes tremendous decline in T cell numbers and function, thus affecting one’s ability to effectively mount an immune response. The degeneration of the thymus, the primary immune organ responsible for T cell development, is central to immunologic aging. Various studies have assessed thymic regeneration as an effective way to offset immune function decline. In this study, we determined the effect of mouse adult thymus transplants in the lymph node of athymic nude mice to rejuvenate thymus function. We transplanted thymuses of increasing ages and assessed engrafted ectopic thymuses by histology as well as for blood T cell numbers and function. We observed that transplanting aged thymuses, up to 8 months old, in the lymph node regenerated thymus function and corresponding T cell activation with some thymic rejuvenation when compared to the expected native thymus in control animals. However, transplanting 11- and 14-month old thymus in the lymph node had decreased-to-limited thymic function with no thymic rejuvenation detected. These observations provide important insights into the plasticity and regenerative capabilities of the thymus during age-associated involution.
Efficient isolation of rare B cells using next-generation antigen barcoding
Authors: Hurtado Jonathan , Flynn Claudia , Lee Jeong Hyun , Salcedo Eugenia , Cottrell Christopher A. , Skog Patrick D. , Nemazee David , Schief William R. , Landais Elise , Sok Devin , Briney Bryan 
Published: June 2022

ABSTRACTThe ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and catalyze rational vaccine development. Traditional mAb discovery is a costly and labor-intensive process, although recent advances in single-cell genomics using emulsion microfluidics allow simultaneous processing of thousands of individual cells. Here we present a streamlined method for isolation and analysis of large numbers of antigen-specific B cells, including next generation antigen barcoding and an integrated computational framework for B cell multi-omics. We demonstrate the power of this approach by recovering thousands of antigen-specific mAbs, including the efficient isolation of extremely rare precursors of VRC01-class and IOMA-class broadly neutralizing HIV mAbs.
Selective degradation of an ER stress-induced protein by ER-associated degradation mechanism during stress recovery
Authors: Wang Yi , Ma Zhihui , Zhang Congcong , Chen Yongwu , Lin Liangguang , Mao Juan , Zhang Jianjun , Liu Linchuan , Wang Pengcheng , Li Jianming 
Published: June 2022

AbstractUnfolded protein response (UPR) is a conserved signaling pathway that is activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER) and stimulates production of ER chaperones to restore ER proteostasis. However, little is known how UPR-induced proteins return to their pre-stress levels upon removal of ER stress. TUNICAMYCIN-INDUCED1 (TIN1) is an Arabidopsis protein that is normally expressed in pollen but is rapidly induced by ER stresses in vegetative tissues. Here we show that the ER stress-induced TIN1 is rapidly degraded in the UPR recovery phase. We found that TIN1 degradation depends on its asparagine-linked glycans and requires both EMS-mutagenized bri1 suppressor 5 (EBS5) and EBS6 for its recruitment to the ER-associated degradation (ERAD) complex. Loss-of-function mutations in Arabidopsis ERAD components greatly stabilize TIN1. Interestingly, two other UPR-induced proteins that are coexpressed with TIN1 remained stable upon removal of ER stress, suggesting that rapid degradation during the stress-recovery phase likely applies to a subset of UPR-induced proteins. Further investigation should uncover the mechanisms by which the ERAD machinery differentially recognizes UPR-induced ER proteins.
ECPAS/Ecm29-Mediated 26S Proteasome Disassembly is an Adaptive Response to Glucose Starvation
Authors: Choi Won Hoon , Yun Yejin , Byun Insuk , Lee Seho , Sim Jiho , Levi Shahar , Kim Sumin , Park Seo Hyeong , Jun Jeongmoo , Kim Kwang Pyo , Kwon Yong Tae , Han Dohyun , Chiba Tomoki , Seok Chaok , Glickman Michael H. , Lee Min Jae 
Published: June 2022

AbstractThe 26S proteasome consists of loosely associated 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in eukaryotic cells exist as free 20S complexes; however, our mechanistic and physiological understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation in mammalian cells results in the uncoupling of 26S holoenzymes into intact 20S and 19S subcomplexes. Subcomplex affinity-purification and quantitative mass spectrometry revealed that Ecm29 proteasome adaptor and scaffold (ECPAS) is a crucial mediator of this structural remodeling. The loss of ECPAS abrogated 26S dissociation, leading to decreased degradation of 20S proteasome substrates such as puromycylated polypeptides and lysine-less cyclin B. In silico modeling analysis suggested that the conformational changes of ECPAS may commence the disassembly process. ECPAS was also essential for proper endoplasmic reticulum stress response and cell survival during glucose starvation. In addition, we evaluated the role of ECPAS in vivo using the mouse xenograft model and observed that glucose-deprived tumor tissues had significantly elevated 20S proteasome levels. Collectively, our results indicate that the 20S-19S disassembly mediated by ECPAS is a novel mechanism adapting global proteolysis to physiological needs and an effective cellular strategy against proteotoxic stress.
COVID-MVP: an interactive visualization for tracking SARS-CoV-2 mutations, variants, and prevalence, enabled by curated functional annotations and portable genomics workflow
Authors: Anwar Muhammad Zohaib , Gill Ivan S , Iseminger Madeline , Sehar Anoosha , Igwacho Kenyi D , Vora Khushi , Van Domselaar Gary , Gordon Paul M. K. , Hsiao William WL 
Published: June 2022

AbstractThe SARS-CoV-2 pandemic has reemphasized the importance of genomic epidemiology to track the evolution of the virus, dynamics of epidemics, geographic origins, and the emerging variants. It is vital in understanding the epidemiological spread of the virus on global, national, and local scales. Several analytical (bioinformatics) resources have been developed for molecular surveillance. However, a resource that combines genetic mutations and functional annotations on the impact of these mutations has been lacking in SARS-CoV-2 genomics surveillance. COVID-MVP provides an interactive visualization application that summarizes the mutations and their prevalence in SARS-CoV-2 viral lineages and provides functional annotations from the literature curated in an ongoing effort, Pokay. COVID-MVP is a tool that can be used for routine surveillance including spatio-temporal analyses. We have powered the visualization through a scalable and reproducible genomic analysis workflow nf-ncov-voc wrapped in Nextflow. COVID-MVP allows users to interactively explore data and download summarized surveillance reports. COVID-MVP, Pokay, and nf-ncov-voc are open-source tools available under the Massachusetts Institute of Technology (MIT) and GPL-3.0 licenses. COVID-MVP source code is available athttps://github.com/cidgoh/COVID-MVPand an instance is hosted athttps://covidmvp.cidgoh.ca.
The genomics of linkage drag in sunflower
Authors: Huang Kaichi , Jahani Mojtaba , Gouzy Jérôme , Legendre Alexandra , Carrere Sebastien , Lázaro-Guevara José Miguel , González Segovia Eric Gerardo , Todesco Marco , Mayjonade Baptiste , Rodde Nathalie , Cauet Stéphane , Dufau Isabelle , Staton S Evan , Pouilly Nicolas , Boniface Marie-Claude , Tapy Camille , Mangin Brigitte , Duhnen Alexandra , Gautier Véronique , Poncet Charles , Donnadieu Cécile , Mandel Tali , Hübner Sariel , Burke John M. , Vautrin Sonia , Bellec Arnaud , Owens Gregory L. , Langlade Nicolas , Muños Stéphane , Rieseberg Loren H. 
Published: June 2022

AbstractCrop wild relatives represent valuable sources of alleles for crop improvement, including adaptation to climate change and emerging diseases. However, introgressions from wild relatives might have deleterious effects on desirable traits, including yield, due to linkage drag. Here we comprehensively analyzed the genomic and phenotypic impacts of wild introgressions into cultivated sunflower to estimate the impacts of linkage drag. First, we generated new reference sequences for seven cultivated and one wild sunflower genotype, as well as improved assemblies for two additional cultivars. Next, relying on previously generated sequences from wild donor species, we identified introgressions in the cultivated reference sequences, as well as the sequence and structural variants they contain. We then used a ridge regression model to test the effects of the introgressions on phenotypic traits in the cultivated sunflower association mapping population. We found that introgression has introduced substantial sequence and structural variation into the cultivated sunflower gene pool, including > 3,000 new genes. While introgressions reduced genetic load at protein-coding sequences and positively affected traits associated with abiotic stress resistance, they mostly had negative impacts on yield and quality traits. Introgressions found at high frequency in the cultivated gene pool had larger effects than low frequency introgressions, suggesting that the former likely were targeted by artificial selection. Also, introgressions from more distantly related species were more likely to be maladaptive than those from the wild progenitor of cultivated sunflower. Thus, pre-breeding efforts should focus, as far as possible, on closely related and fully compatible wild relatives.
Development of an Escape-resistant SARS CoV-2 Neutralizing Synthetic Nanobody
Authors: Dormeshkin Dmitri , Shapira Michail , Dubovik Simon , Kavaleuski Anton , Katsin Mikalai , Migas Alexandr , Meleshko Alexander , Semyonov Sergei 
Published: June 2022

AbstractAn emerging COVID-19 pandemic resulted in a global crisis, but also accelerated vaccine development and antibody discovery. In this work, we identified a number of nanomolar-range affinity VHH binders to SARS-CoV-2 variants of concern (VoC) receptor binding domains (RBD), by screening synthetic humanized antibody library with more than 1011 diversity. In order to explore the most robust and fast method for affinity improvement, we performed affinity maturation by CDR1 and CDR2 shuffling and avidity engineering by multivalent trimeric VHH fusion protein construction. As a result, H7-Fc and G12×3-Fc binders were developed with the affinities in nM and pM range respectively. Importantly, their affinities are weakly influenced by SARS-CoV-2 VoC mutations. The plaque reduction neutralization test (PRNT) resulted in IC50 = 100 ng\ml and 9.6 ng\ml for H7-Fc and G12×3-Fc antibodies respectively for emerging Omicron variant. Therefore, these VHH could expand the present landscape of SARS-CoV-2 neutralization binders with the therapeutic potential for present and future SARS-CoV-2 variants.