bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1
Authors: Tsui Joseph L.-H. , Lambert Ben , Bajaj Sumali , McCrone John T. , Inward Rhys P.D. , Bosetti Paolo , Hill Verity , Pena Rosario Evans , Zarebski Alexander E. , Peacock Thomas P. , Liu Luyang , Wu Neo , Davis Megan , Bogoch Isaac I. , Khan Kamran , Colquhoun Rachel , O’Toole Áine , Jackson Ben , Dasgupta Abhishek , Wilkinson Eduan , Tegally Houriiyah , de Oliveira Tulio ,   The COVID-19 Genomics UK (COG-UK) consortium, Connor Thomas R. , Loman Nicholas J. , Colizza Vittoria , Fraser Christophe , Volz Erik , Ji Xiang , Suchard Marc A. , Gutierrez Bernardo , Chand Meera , Dellicour Simon , Cauchemez Simon , Raghwani Jayna , Lemey Philippe , Rambaut Andrew , Pybus Oliver G. , Kraemer Moritz U.G. 
Published: January 2023

SummarySARS-CoV-2 variants of concern (VOCs) arise against the backdrop of increasingly heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron genomes, we identified >6,000 independent introductions of the antigenically distinct virus into England and reconstructed the dispersal history of resulting local transmission. Travel restrictions on southern Africa did not reduce BA.1 importation intensity as secondary hubs became major exporters. We explored potential drivers of BA.1 spread across England and discovered an early period during which viral lineage movements mainly occurred between larger cities, followed by a multi-focal spatial expansion shaped by shorter distance mobility patterns. We also found evidence that disease incidence impacted human commuting behaviours around major travel hubs. Our results offer a detailed characterisation of processes that drive the invasion of an emerging VOC across multiple spatial scales and provide unique insights on the interplay between disease spread and human mobility.HighlightsOver 6,000 introductions ignited the epidemic wave of Omicron BA.1 in EnglandImportations prior to international travel restrictions were responsible for majority of local BA.1 infections but importations continued from sources other than southern AfricaHuman mobility at regional and local spatial scales shaped dissemination and growth of BA.1Changes in human commuting patterns are associated with higher case incidence in travel hubs across England
ASTK: a machine learning-based integrative software for alternative splicing analysis
Authors: Huang Shenghui , He Jiangshuang , Yu Lei , Guo Jun , Jiang Shangying , Sun Zhaoxia , Cheng Linghui , Chen Xing , Ji Xiang , Zhang Yi 
Published: January 2023

AbstractAlternative splicing (AS) is a fundamental mechanism that regulates gene expression. Splicing dynamics is involved in both physiological and pathological processes. In this paper, we introduce ASTK, a software package covering upstream and downstream analysis of AS. Initially, ASTK offers a module to perform enrichment analysis at both the gene- and exon-level to incorporate various impacts by different spliced events on a single gene. We further cluster AS genes and alternative exons into three groups based on spliced exon sizes (micro-, mid-, and macro-), which are preferentially associated with distinct biological pathways. A major challenge in the field has been decoding the regulatory codes of splicing. ASTK adeptly extracts both sequence features and epigenetic marks associated with AS events. Through the application of machine learning algorithms, we identified pivotal features influencing the inclusion levels of most AS types. Notably, the splice site strength is a primary determinant for the inclusion levels in alternative 3’/5’ splice sites (A3/A5). For the alternative first exon (AF) and skipping exon (SE) classes, a combination of sequence and epigenetic features collaboratively dictate exon inclusion/exclusion. Our findings underscore ASTK’s capability to enhance the functional understanding of AS events and shed light on the intricacies of splicing regulation.
A dynamic partitioning mechanism polarizes membrane protein distribution
Authors: Banerjee Tatsat , Matsuoka Satomi , Biswas Debojyoti , Miao Yuchuan , Pal Dhiman Sankar , Kamimura Yoichiro , Ueda Masahiro , Devreotes Peter N. , Iglesias Pablo A. 
Published: January 2023

ABSTRACTThe plasma membrane is widely regarded as the hub of the signal transduction network activities that drives numerous physiological responses, including cell polarity and migration. Yet, the symmetry breaking process in the membrane, that leads to dynamic compartmentalization of different proteins, remains poorly understood. Using multimodal live-cell imaging, here we first show that multiple endogenous and synthetic lipid-anchored proteins, despite maintaining stable tight association with the inner leaflet of the plasma membrane, were unexpectedly depleted from the membrane domains where the signaling network was spontaneously activated such as in the new protrusions as well as within the propagating ventral waves. Although their asymmetric patterns resembled those of standard peripheral “back” proteins such as PTEN, unlike the latter, these lipidated proteins did not dissociate from the membrane upon global receptor activation. Our experiments not only discounted the possibility of recurrent reversible translocation from membrane to cytosol as it occurs for weakly bound peripheral membrane proteins, but also ruled out the necessity of directed vesicular trafficking and cytoskeletal supramolecular structure-based restrictions in driving these dynamic symmetry breaking events. Selective photoconversion-based protein tracking assays suggested that these asymmetric patterns instead originate from the inherent ability of these membrane proteins to “dynamically partition” into distinct domains within the plane of the membrane. Consistently, single-molecule measurements showed that these lipid-anchored molecules have substantially dissimilar diffusion profiles in different regions of the membrane. When these profiles were incorporated into an excitable network-based stochastic reaction-diffusion model of the system, simulations revealed that our proposed “dynamic partitioning” mechanism is sufficient to give rise to familiar asymmetric propagating wave patterns. Moreover, we demonstrated that normally uniform integral and lipid-anchored membrane proteins inDictyosteliumand mammalian neutrophil cells can be induced to partition spatiotemporally to form polarized patterns, by optogenetically recruiting membrane domain-specific peptides to these proteins. Together, our results indicate “dynamic partitioning” as a new mechanism of plasma membrane organization, that can account for large-scale compartmentalization of a wide array of lipid-anchored and integral membrane proteins in different physiological processes.
HPC-Atlas: Computationally Constructing A Comprehensive Atlas of Human Protein Complexes
Authors: Pan Yuliang , Li Ruiyi , Li Wengen , Lv Liuzhenghao , Guan Jihong , Zhou Shuigeng 
Published: January 2023

AbstractA fundamental principle of biology is that proteins tend to form complexes to play significant roles in the core functions of cells. For a complete understanding of human cellular functions, it is crucial to have a comprehensive atlas of human protein complexes. Unfortunately, we still lack such a comprehensive atlas of experimentally validated protein complexes, which prevents us from gaining a complete understanding of the compositions and functions of human protein complexes and biological mechanisms. To fill this gap, we built HPC-Atlas, as far as we know, the most accurate and comprehensive atlas of human protein complexes available to date. We integrated two latest protein interaction networks, and developed a novel computational method to identify nearly 9000 protein complexes, including many previously uncharacterized complexes. Compared with the existing works, our method achieves outstanding performance on both test and independent sets. Furthermore, with HPC-Atlas we identified 751 SARS-CoV-2 affected human protein complexes, and 456 multifunctional proteins that contain many potential moonlighting proteins. These results suggest that HPC-Atlas can serve as not only a computing framework to effectively identify biologically meaningful protein complexes by integrating multiple protein data sources, but also a valuable resource for exploring new biological findings. The HPC-Atlas webserver is freely available athttp://www.yulpan.top/HPC-Atlas.
Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis
Authors: Gui Yuan , Tao Jianling , Wang Yuanyuan , Palanza Zachary , Qiao Yi , Hargis Geneva , Kreutzer Donald L. , Liu Silvia , Bastacky Sheldon I. , Wang Yanlin , Yu Yanbao , Fu Haiyan , Zhou Dong 
Published: January 2023

AbstractIn the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy; however, how cellular mechanics and metabolism are connected remains unclear. Our proteomics revealed that actin filament binding and cell metabolism are the two most dysregulated events in the fibrotic kidneys. As a prominent actin stabilizer, Calponin 2 (CNN2) is predominantly expressed in fibroblasts and pericytes. CNN2 knockdown preserves kidney function and alleviates fibrosis. Global proteomics profiled that CNN2 knockdown enhanced the activities of the key rate-limiting enzymes and regulators of fatty acid oxidation (FAO) in diseased kidneys. Inhibiting carnitine palmitoyltransferase 1α in the FAO pathway results in lipid accumulation and extracellular matrix deposition in the fibrotic kidneys, which were restored after CNN2 knockdown. In patients, increased serum CNN2 levels are correlated with lipid content. Bioinformatics and chromatin immunoprecipitation showed that CNN2 interactor, estrogen receptor 2 (ESR2) binds peroxisome proliferator-activated receptor-α (PPARα) to transcriptionally regulate FAO downstream target genes expression amid kidney fibrosis.In vitro, ESR2 knockdown repressed the mRNA levels of PPARα and the key genes in the FAO pathway. Conversely, activation of PPARα reduced CNN2-induced matrix inductions. Our results suggest that balancing cell mechanics and metabolism is crucial to develop therapeutic strategies to halt kidney fibrosis.
A critical role of retinoic acid concentration for the induction of a fully human-like atrial phenotype in hiPSC-CM
Authors: Schulz Carl , Sönmez Muhammed , Krause Julia , Schwedhelm Edzard , Bangfen Pan , Alihodzic Dzenefa , Hansen Arne , Eschenhagen Thomas , Christ Torsten 
Published: January 2023

SummaryRetinoic acid (RA) induces an atrial phenotype in human induced pluripotent stem cells (hiPSC), but expression of atrium-selective currents such as the ultrarapid (IKur) and acetylcholine-stimulated K+current (IK,ACh) is variable and less than in adult human atrium. We suspected methodological issues and systematically investigated the concentration-dependency of RA. RA treatment increased IKurconcentration-dependently from 1.1±0.54 pA/pF (0 RA) to 3.8±1.1, 5.8±2.5 and 12.2±4.3 at 0.01, 0.1 and 1 µM, respectively. Only 1 µM RA induced enough IKurto fully reproduce human atrial AP shape and a robust shortening of action potentials (AP) upon carbachol. We found that sterile filtration caused substantial loss of RA. We conclude that 1 µM RA appears necessary and sufficient to induce a full atrial AP shape in hiPSC-CM in EHT format. RA concentrations are prone to methodological issues and may profoundly impact success of atrial differentiation.
Apolipoprotein E O-glycosylation is associated with amyloid plaques andAPOEgenotype
Authors: Lawler Paige E , Bollinger James G , Schindler Suzanne E , Hodge Cynthia R , Iglesias Nicolas J , Krishnan Vishal , Coulton John B , Li Yan , Holtzman David M , Bateman Randall J 
Published: January 2023

ABSTRACTAlthough theAPOEε4 allele is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues – one in the hinge region and one in the C-terminal region – and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels,APOEgenotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, andAPOEgenotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD.HighlightsSimultaneous quantification of unmodified and O-glycosylated apoE via LC-MS/MS.Total plasma apoE varies byAPOEgenotype in an isoform, dose-dependent fashion.CNS-derived apoE is more extensively O-glycosylated than peripherally derived apoE.Hinge region glycosylation occupancy of plasma apoE is associated with amyloidosis.
Metrics of Coral Microfragment Viability
Authors: Lager Claire , Perry Riley , Daly Jonathan , Page Christopher , Mizobe Mindy , Bouwmeester Jessica , Consiglio Anthony N. , Carter Jake , Powell-Palm Matthew J. , Hagedorn Mary 
Published: January 2023

AbstractCoral reefs are being degraded at unprecedented rates and decisive intervention actions are urgently needed to help them. One such intervention in aid of reefs is coral cryopreservation. Although the cryopreservation of coral sperm and larvae has been achieved, preservation of coral fragments including both its tissue and skeleton, has not. The goal of this paper was to understand and assess the physiological stressors that might underlie coral fragment cryopreservation and the long-term consequences of these physiological exposures to continued growth. Therefore, we assessed small fragments (∼0.5 x0.5 mm2) from the Hawaiian coral,Porites compressa, examining: 1) the sensitivity of the fragments and their algal symbionts to chilling temperatures; 2) the sensitivity of the coral to complex cryoprotectants; 3) methods to safely remove the algal symbionts from the coral fragment for cryopreservation, given the two symbiotic partners may require different cryopreservation protocols; 4) continued growth over time of coral fragments once returned to running seawater after treatment exposures; and, 5) assessment of health and viability of microfragments after treatments examining the distribution of green fluorescent protein and fluorescent symbionts. Technological advances in cryo-technology promise to support successful coral fragment cryopreservation soon, and its success could help secure much of the genetic and biodiversity of reefs in the next decade.
Drifting population dynamics with transient resets characterize sensorimotor transformation in the monkey superior colliculus
Authors: Heusser Michelle R. , Jagadisan Uday K. , Gandhi Neeraj J. 
Published: January 2023

ABSTRACTTo produce goal-directed eye movements known as saccades, we must channel sensory input from our environment through a process known as sensorimotor transformation. The behavioral output of this phenomenon (an accurate eye movement) is straightforward, but the coordinated activity of neurons underlying its dynamics is not well understood. We searched for a neural correlate of sensorimotor transformation in the activity patterns of simultaneously recorded neurons in the superior colliculus (SC) of three male rhesus monkeys performing a visually guided, delayed saccade task. Neurons in the intermediate layers produce a burst of spikes both following the appearance of a visual (sensory) stimulus and preceding an eye movement command, but many also exhibit a sustained activity level during the intervening time (“delay period”). This sustained activity could be representative of visual processing or motor preparation, along with countless cognitive processes. Using a novel measure we call the Visuomotor Proximity Index (VMPI), we pitted visual and motor signals against each other by measuring the degree to which each session’s population activity (as summarized in a low-dimensional framework) could be considered more visual-like or more motor-like. The analysis highlighted two salient features of sensorimotor transformation. One, population activity on average drifted systematically toward a motor-like representation and intermittently reverted to a visual-like representation following a microsaccade. Two, activity patterns that drift to a stronger motor-like representation by the end of the delay period may enable a more rapid initiation of a saccade, substantiating the idea that this movement initiation mechanism is conserved across motor systems.
gp120 envelope glycoproteins of HIV-1 Group M Subtype A and Subtype B differentially affect gene expression in human vascular endothelial cells
Authors: Suh Andrew J. , Suzuki Dante I. , Gychka Sergiy G. , Brelidze Tinatin I. , Suzuki Yuichiro J. 
Published: January 2023

AbstractCardiovascular complications are seen among human immunodeficiency virus (HIV)-positive individuals who can now survive longer due to successful antiretroviral therapies. Among them, pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased blood pressure in the lung circulation due to vasoconstriction and vascular wall remodeling, resulting in the overworking of the heart. The prevalence of PAH in the HIVpositive population is dramatically higher than that in the general population. While HIV-1 Group M Subtype B is the most prevalent subtype in western countries, the majority of HIV-1 infections in eastern Africa and former Soviet Union countries are caused by Subtype A. Research on the mechanism of vascular complications in the HIV-positive population, especially in the context of subtype differences, however, has not been rigorous. Much of the research on HIV has focused on Subtype B and information on the molecular mechanisms of Subtype A is non-existent. The lack of such knowledge results in health disparities in the development of therapeutic strategies to prevent/treat HIV complications. The present study examined the effects of HIV-1 viral fusion protein gp120 of Subtypes A and B on cultured human pulmonary artery endothelial cells by performing protein arrays. We found that the gene expression changes caused by the gp120s of Subtypes A and B are different. Specifically, Subtype A is a more potent downregulator of perostasin, matrix metalloproteinase-2 (MMP-2), and ErbB/Her3 than Subtype B, while Subtype B is more effective in downregulating monocyte chemotactic protein-2 (MCP-2/CCL8), MCP-3 (CCL7), and thymus- and activation-regulated chemokine (TARC/CCL17) proteins. This is the first report of gp120 proteins affecting host cells in an HIV subtype-specific manner, opening up the possibility that vascular complications may occur differently in HIV patients throughout the world.
Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer
Authors: Duran Camille L. , Karagiannis George S. , Chen Xiaoming , Sharma Ved P. , Entenberg David , Condeelis John S. , Oktay Maja H. 
Published: January 2023

AbstractMetastasis is a multistep process that leads to the formation of clinically detectable tumor foci at distant organs and frequently patient demise. Only a subpopulation of breast cancer cells within the primary tumor can disseminate systemically and cause metastasis. To disseminate, cancer cells must express MenaINV, an isoform of the actin-regulatory protein Mena encoded by theENAHgene that endows tumor cells with transendothelial migration activity allowing them to enter and exit the blood circulation. We have previously demonstrated that MenaINV mRNA and protein expression is induced in cancer cells by macrophage contact. In this study, we discovered the precise mechanism by which macrophages induce MenaINV expression in tumor cells. We examined the promoter of the human and mouseENAHgene and discovered a conserved NF-κB transcription factor binding site. Using live imaging of an NF-κB activity reporter and staining of fixed tissues from mouse and human breast cancer we further determined that for maximal induction of MenaINV in cancer cell NF-κB needs to cooperate with the Notch1 signaling pathway. Mechanistically, Notch1 signaling does not directly increase MenaINV expression, but it enhances and sustains NF-κB signaling through retention of p65, an NF-κB transcription factor, in the nucleus of tumor cells, leading to increased MenaINV expression. In mice, these signals are augmented following chemotherapy treatment and abrogated upon macrophage depletion. Targeting Notch1 signalingin vivodecreased NF-κB signaling and MenaINV expression in the primary tumor and decreased metastasis. Altogether, these data uncover mechanistic targets for blocking MenaINV induction that should be explored clinically to decrease cancer cell dissemination and improve survival of patients with metastatic disease.
Mammary-specific ectopic expression of mutant human GATA3 did not potentiate medroxyprogesterone acetate-driven mouse mammary tumorigenesis
Authors: Lofgren Kristopher A. , Kenny Paraic A. 
Published: January 2023

ABSTRACTGATA3 is somatically mutated in approximately 15% of estrogen receptor positive human breast tumors, however the mechanism(s) by which these alterations contribute to tumorigenesis are unclear. The observed patterns of mutations suggest a strong selective pressure to mutate a single allele of GATA3 in a manner favoring retention of the first of two zinc finger domains. The non-mutated GATA3 allele is maintained and expressed. We and others have hypothesized that expression of the mutant GATA3 protein may actively contribute to breast tumorigenesis, however the aging of several independently generated mouse models with mammary-specific mutant GATA3 expression did not result in tumorigenesis. In this study, we evaluated whether a mammary tumor-promoting dose of medroxyprogesterone acetate could synergize with mammary specific mutant GATA3 (G335fs) expression and accelerate the kinetics of tumor formation. We report that the tumor incidence rate in these animals did not differ from that observed in wild-type littermate controls.