bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipose tissue eQTL meta-analysis reveals the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits
Authors: Brotman Sarah M. , El-Sayed Moustafa Julia S. , Guan Li , Broadaway K. Alaine , Wang Dongmeng , Jackson Anne U. , Welch Ryan , Currin Kevin W. , Tomlinson Max , Vadlamudi Swarooparani , Stringham Heather M. , Roberts Amy L. , Lakka Timo A. , Oravilahti Anniina , Silva Lilian Fernandes , Narisu Narisu , Erdos Michael R. , Yan Tingfen , Bonnycastle Lori L. , Raulerson Chelsea K. , Raza Yasrab , Yan Xinyu , Parker Stephen C.J. , Kuusisto Johanna , Pajukanta Päivi , Tuomilehto Jaakko , Collins Francis S. , Boehnke Michael , Love Michael I. , Koistinen Heikki A. , Laakso Markku , Mohlke Karen L. , Small Kerrin S. , Scott Laura J. 
Published: October 2023

AbstractComplete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. Here, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34K conditionally distinct expression quantitative trait locus (eQTL) signals in 18K genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared to primary signals, non-primary signals had lower effect sizes, lower minor allele frequencies, and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTL with conditionally distinct genome-wide association study signals for 28 cardiometabolic traits identified 3,605 eQTL signals for 1,861 genes. Inclusion of non-primary eQTL signals increased colocalized signals by 46%. Among 30 genes with ≥2 pairs of colocalized signals, 21 showed a mediating gene dosage effect on the trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.
Dosage amplification dictates oncogenic regulation by theNKX2-1lineage factor in lung adenocarcinoma
Authors: Pulice John L. , Meyerson Matthew 
Published: October 2023

SUMMARYAmplified oncogene expression is a critical and widespread driver event in cancer, yet our understanding of how amplification-mediated elevated dosage mediates oncogenic regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage super-enhancer near theNKX2-1lineage transcription factor. TheNKX2-1super-enhancer is targeted by focal and co-amplification withNKX2-1, and activation or repression controlsNKX2-1expression. We find thatNKX2-1is a widespread dependency in LUAD cell lines, where NKX2-1 pioneers enhancer accessibility to drive a lineage addicted state in LUAD, and NKX2-1 confers persistence to EGFR inhibitors. Notably, we find that oncogenic NKX2-1 regulation requires expression above a minimum dosage threshold—NKX2-1 dosage below this threshold is insufficient for cell viability, enhancer remodeling, and TKI persistence. Our data suggest that copy-number amplification can be a gain-of-function alteration, wherein amplification elevates oncogene expression above a critical dosage required for oncogenic regulation and cancer cell survival.HighlightsThe most significant amplification event in LUAD targets a lineage super-enhancer that controls expression of theNKX2-1lineage oncogene.NKX2-1is a dosage dependency in most NKX2-1(+) LUAD cell linesNKX2-1 remodels lineage enhancer accessibility to drive a lineage addicted state and confer persistence to EGFR targeted therapyNKX2-1 oncogenic regulation requires a minimum oncogenic dosage, which dictates NKX2-1 regulation of enhancer remodeling, TKI persistence, and cancer cell viability
Unsupervised modeling of mutational landscapes of adeno-associated viruses viability
Authors: De Leonardis Matteo , Fernandez-de-Cossio-Diaz Jorge , Uguzzoni Guido , Pagnani Andrea 
Published: October 2023

ABSTRACTAdeno-associated viruses 2 (AAV2) are minute viruses renowned for their capacity to infect human cells and akin organisms. They have recently emerged as prominent candidates in the field of gene therapy, primarily attributed to their inherent non-pathogenic nature in humans and the safety associated with their manipulation. The efficacy of AAV2 as gene therapy vectors hinges on their ability to infiltrate host cells and subsequently replicate within them, a phenomenon reliant on their competence to construct a capsid capable of breaching the nucleus of the target cell. To enhance their infection potential, researchers have extensively scrutinized various combinatorial libraries by introducing mutations into the capsid, aiming to boost their effectiveness. The emergence of high-throughput experimental techniques, like Deep Mutational Scanning (DMS), has made it feasible to experimentally assess the fitness of these libraries for their intended purpose. Notably, machine learning is starting to demonstrate its potential in addressing predictions within the mutational landscape from sequence data. In this context, we introduce a biophysically-inspired model designed to predict the viability of genetic variants in DMS experiments. This model is tailored to a specific segment of the CAP region within AAV2’s capsid protein. To evaluate its effectiveness, we conduct model training with diverse datasets, each tailored to explore different aspects of the mutational landscape influenced by the selection process. Our assessment of the biophysical model centers on two primary objectives: (i) providing quantitative forecasts for the log-selectivity of variants and (ii) deploying it as a binary classifier to categorize sequences into viable and non-viable classes.
Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma
Authors: Nejo Takahide , Wang Lin , Leung Kevin K. , Wang Albert , Lakshmanachetty Senthilnath , Gallus Marco , Kwok Darwin W. , Hong Chibo , Chen Lee H. , Carrera Diego A. , Zhang Michael Y. , Stevers Nicholas O. , Maldonado Gabriella C. , Yamamichi Akane , Watchmaker Payal , Naik Akul , Shai Anny , Phillips Joanna J. , Chang Susan M. , Wiita Arun P. , Wells James A. , Costello Joseph F. , Diaz Aaron A. , Okada Hideho 
Published: October 2023

AbstractBackgroundDespite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter-and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of neoantigens.ResultsIn this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface neoantigens that could be targeted by antibodies and chimeric antigen receptor (CAR)-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas [TCGA]) and 9,166 normal tissue samples (from the Genotype-Tissue Expression project [GTEx]), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, includingPTPRZ1andBCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative neoantigens.ConclusionsOur investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.
Degradation of Fatty Acid Export Protein1 by Rhomboid-Like Protease11 Contributes to Cold Tolerance in Arabidopsis
Authors: John Annalisa , Krämer Moritz , Lehmann Martin , Kunz Hans-Henning , Aarabi Fayezeh , Alseekh Saleh , Fernie Alisdair , Sommer Frederik , Schroda Michael , Zimmer David , Mühlhaus Timo , Peisker Helga , Gutbrod Katharina , Dörmann Peter , Neunzig Jens , Philippar Katrin , Neuhaus H. Ekkehard 
Published: October 2023

AbstractPlants need to adapt to different stresses to optimize growth under unfavorable conditions. The abundance of the chloroplast envelope located Fatty Acid Export Protein1 (FAX1) decreases after the onset of low temperatures. However, it was unclear how FAX1 degradation occurs and whether altered FAX1 abundance contributes to cold tolerance in plants. The rapid cold-induced increase in rhomboid-like protease11 (RBL11) transcript, the physical interaction of RBL11 with FAX1, the specific FAX1 degradation after RBL11 expression, and the absence of cold-induced FAX1 degradation inrbl11loss-of-function mutants suggest that this enzyme is responsible for FAX1 degradation. Proteomic analyses showed thatrbl11mutants have higher levels of FAX1 and other proteins involved in membrane lipid homeostasis, suggesting that RBL11 is a key element in the remodeling of membrane properties during cold. Consequently, in the cold,rbl11mutants show a shift in lipid biosynthesis towards the eukaryotic pathway, which coincides with impaired cold tolerance. To demonstrate that cold sensitivity is due to increased FAX1 levels, FAX1 overexpressors were analyzed.rbl11and FAX1 overexpressor mutants show superimposable phenotypic defects upon exposure to cold temperatures. Our results show that the cold-induced degradation of FAX1 by RBL11 is critical for Arabidopsis to survive cold and freezing periods.One sentence summaryDegradation of the inner envelope protein Fatty Acid Export1 via Rhomboid Like Protease11 represents a critical process to achieve cold and frost tolerance in Arabidopsis
Transcription-driven DNA supercoiling activates bacterial chromatin at a distance
Authors: Figueroa-Bossi Nara , Fernández-Fernández Rocío , Kerboriou Patricia , Bouloc Philippe , Casadesús Josep , Sánchez-Romero María Antonia , Bossi Lionello 
Published: October 2023

AbstractIn all living cells, genomic DNA is compacted through interactions with dedicated proteins and/or the formation of plectonemic coils. In bacteria, DNA compaction is achieved dynamically, coordinated with dense and constantly changing transcriptional activity. H-NS, a major bacterial nucleoid structuring protein, is of special interest due to its interplay with RNA polymerase. H-NS:DNA nucleoprotein filaments inhibit transcription initiation by RNA polymerase. However, the discovery that genes silenced by H-NS can be activated by transcription originating from neighboring regions has suggested that elongating RNA polymerases can disassemble H-NS:DNA filaments. In this study, we present evidence that transcription-induced counter-silencing does not require transcription to reach the silenced gene; rather, it exerts its effect at a distance. Counter-silencing is suppressed by introducing a DNA gyrase binding site within the intervening segment, suggesting that the long-range effect results from transcription-driven positive DNA supercoils diffusing toward the silenced gene. We propose a model wherein H-NS:DNA complexes form in vivo on negaXvely supercoiled DNA, with H-NS bridging the two arms of the plectoneme. Rotational diffusion of positive supercoils generated by neighbouring transcription will cause the H-NS-bound negatively-supercoiled plectoneme to “unroll” disrupting the H-NS bridges and releasing H-NS.
Deep multi-omic profiling reveals extensive mitochondrial remodeling driven by glycemia in early diabetic kidney disease
Authors: Granata Cesare , Thallas-Bonke Vicki , Caruana Nikeisha J. , Huynh Kevin , Qin Cheng Xue , Laskowski Adrienne , Snelson Matthew , Anthonisz Jarryd , Jap Edwina , Ramm Georg , Cooper Mark E. , Meikle Peter J. , Stroud David A. , Ritchie Rebecca H. , Coughlan Melinda T. 
Published: October 2023

SummaryChanges in mitochondrial energy metabolism are thought to be central to the development of diabetic kidney disease (DKD); however, whether this response is explicitly driven by systemic glucose concentrations remains unknown. Here, we show that titrating blood glucose concentrationsin vivodirectly impacts mitochondrial morphology and bioenergetics and remodels the mitochondrial proteome in the kidney in early DKD. Mitoproteomic analysis revealed profound metabolic disturbances induced by severe hyperglycemia, including upregulation of enzymes involved in the TCA cycle and fatty acid metabolism, enhanced ketogenesis as well as dysregulation of the mitochondrial SLC25 carrier family. Untargeted metabolomics and lipidomics confirmed the enrichment of TCA cycle metabolites, an increase in triglyceride concentrations, and extensive and specific cardiolipin remodeling. Lowering blood glucose to moderate hyperglycemia stabilized all three omic landscapes, partially prevented changes in mitochondrial morphology and bioenergetics, and improved kidney injury. This study demonstrates altered substrate utilization and energy generation in the kidney early in diabetes, during moderate and severe hyperglycemia and provides new insights into kidney metabolism, which has implications for therapeutic strategies aiming at the reinvigoration of mitochondrial function and signaling in diabetes.
A whole-brain analysis of functional connectivity and immediate early gene expression revealed functional network shifts after operant learning
Authors: Kasahara Kazumi , Hikishima Keigo , Nakata Mariko , Tsurugizawa Tomokazu , Higo Noriyuki , Doya Kenji 
Published: October 2023

AbstractPrevious studies of operant learning have addressed neuronal activities and network changes in specific brain areas, such as the striatum, sensorimotor cortex, prefrontal/orbitofrontal cortices, and hippocampus. However, how changes in the whole-brain network are caused by cellular-level changes remains unclear. We combine resting-state functional magnetic resonance imaging (rsfMRI) and whole-brain immunohistochemical analysis of early growth response 1 (EGR1), a marker of neural plasticity, to elucidate the spatiotemporal functional network changes and underlying cellular processes during operant learning. We used an 11.7 Tesla scanner and whole-brain immunohistochemical analysis of EGR1 in mice during the early and late stages of operant learning. In the operant training, mice received a reward when they pressed the left and right buttons alternately and were punished with a bright light when they made a mistake. Control mice spent the same time and received the same amount of reward in the same operant box. A group of mice (n = 22) underwent the first rsfMRI before behavioral sessions, the second after 3 days of sessions (early stage), and the third after 21 days of sessions (late stage). Another group of mice (n = 40) was subjected to histological analysis 15 min after the early or late stages of behavioral sessions. After the early stage of training, functional connectivity was increased between the limbic areas and thalamus or auditory cortex, and the correlations of the number of EGR1-immunopositive cells between the limbic area and auditory cortex were also increased. After the late stage of training, the increases in functional connectivity and correlations of EGR1-immunopositive cells primarily occurred between the motor cortex, somatosensory cortex, and striatum. The subcortical networks centered around the limbic areas that emerged in the early stage have been implicated in rewards, pleasures, and fears. The connectivity between the motor cortex, somatosensory cortex, and striatum that consolidated in the late stage have been implicated in motor learning. Our multimodal longitudinal study successfully revealed the temporal shifts of brain regions involved in behavioral learning together with the underlying cellular-level plasticity between these regions for the first time. Our study represents a first step toward establishing a new experimental paradigm that combines rsfMRI and immunohistochemistry for linking macroscopic and microscopic mechanisms of learning.
Accelerated Molecular Dynamics and AlphaFold Uncover a Missing Conformational State of Transporter Protein OxlT
Authors: Ohnuki Jun , Jaunet-Lahary Titouan , Yamashita Atsuko , Okazaki Kei-ichi 
Published: October 2023

ABSTRACTTransporter proteins change their conformation to carry their substrate across the cell membrane. The conformational dynamics are vital to understanding the transport function. We have studied the oxalate transporter (OxlT), an oxalate:formate antiporter fromOxalobacter formigenes, significant in avoiding kidney stone formation. The atomic structure of OxlT has been recently solved in the outward-open and occluded states. However, the inward-open conformation is still missing, hindering a complete understanding of the transporter. Here, we performed an accelerated molecular dynamics simulation to sample the extensive conformational space of OxlT and successfully obtained the inward-open conformation where cytoplasmic substrate formate binding was preferred over oxalate binding. We also identified critical interactions for the inward- open conformation. The results were complemented by the highly accurate structure prediction by AlphaFold2. Although AlphaFold2 solely predicted OxlT in the outward-open conformation, mutation of the identified critical residues made it partly predict the inward-open conformation, identifying possible state-shifting mutations.TOC GRAPHICS
CXCL12drives natural variation in coronary artery anatomy across diverse populations
Authors: Rios Coronado Pamela E. , Zanetti Daniela , Zhou Jiayan , Naftaly Jeffrey A. , Prabala Pratima , Martínez Jaimes Azalia M. , Farah Elie N. , Fan Xiaochen , Kundu Soumya , Deshpande Salil S. , Evergreen Ivy , Kho Pik Fang , Hilliard Austin T. , Abramowitz Sarah , Pyarajan Saiju , Dochtermann Daniel , Program Million Veteran , Damrauer Scott M. , Chang Kyong-Mi , Levin Michael G. , Winn Virginia D. , Paşca Anca M. , Plomondon Mary E. , Waldo Stephen W. , Tsao Philip S. , Kundaje Anshul , Chi Neil C. , Clarke Shoa L. , Red-Horse Kristy , Assimes Themistocles L. 
Published: October 2023

AbstractTo efficiently distribute blood flow to cardiac muscle, the coronary artery tree must follow a specific branching pattern over the heart. How this pattern arises in humans is unknown due to the limitations of studying human heart development. Here, we leveraged a natural variation of coronary artery anatomy, known as coronary dominance, in genetic association studies to identify the first known driver of human coronary developmental patterning. Coronary dominance refers to whether the right, left, or both coronary arteries branch over the posterior left ventricle, but whether this variability is heritable and how it would be genetically regulated was completely unknown. By conducting the first large-scale, multi-ancestry genome-wide association study (GWAS) of coronary dominance in 61,043 participants of the VA Million Veteran Program, we observed moderate heritability (27.7%) with ten loci reaching genome wide significance. An exceptionally strong association mapped DNA variants to a non-coding region near the chemokineCXCL12in both European and African ancestries, which overlapped with variants associated with coronary artery disease. Genomic analyses predicted these variants to impactCXCL12levels, and imaging revealed dominance to develop during fetal life coincident withCXCL12expression. ReducingCxcl12in mice to model the human genetics altered septal artery dominance patterns and caused coronary branches to develop away fromCxcl12expression domains.Cxcl12heterozygosity did not compromise overall artery coverage as seen with full deletion, but instead changed artery patterning, reminiscent of the human scenario. Together, our data supportCXCL12as a critical determinant of human coronary artery growth and patterning and lay a foundation for the utilization of developmental pathways to guide future precision ‘medical revascularization’ therapeutics.
Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex
Authors: Naher Sharmin , Kikkawa Takako , Iemura Kenji , Miyashita Satoshi , Hoshino Mikio , Tanaka Kozo , Niwa Shinsuke , Tsai Jin-Wu , Osumi Noriko 
Published: October 2023

AbstractAccurate mitotic division of neural stem cell/progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and neurons in the developing cortex. Here, we investigated the pivotal role of Kif23, an N-kinesin motor protein, in embryonic mouse NSPCs. We found that Kif23 is highly expressed in the mitotic NSPCs within the embryonic cortex of both mouse and human. Knockdown (KD) ofKif23led to precocious neurogenesis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis.Kif23KD induced upregulation of the γ-H2AX-p53-p21 signaling pathway, ultimately culminating in cytokinetic failure. Additionally, Kif23 depletion perturbed the apical surface structure of NSPCs and disrupted the proper localization of apical junctional proteins. Importantly, we demonstrated the successful rescue ofKif23KD-induced phenotypes by introducing wild-type humanKIF23, but not by a variant ofKIF23with a microcephaly-associated mutation. Our findings underscore the critical role of Kif23 in cortical development and provide novel insights into the intricate molecular mechanisms underlying pathogenesis of microcephaly.Graphical abstract
Surviving beyond expiry: a systematic literature review of zombie firms
Authors: Upadhyay Arjun Pratap , Baag Pankaj Kumar 
Published: October 2023

PurposeThis paper reviews the literature on zombie firms to provide a holistic view by delineating their formation, impact, widespread nature, prevention and policy implications.Design/methodology/approachThis paper uses a systematic literature review methodology, in which 76 papers published in journals ranked on the Australian Business Deans Council (ABDC) 2022 list were reviewed. The study period was from 2000 to 2022.FindingsAmong the main findings, the widespread problems of zombie firms were evident. The authors found that consistent support, either in the form of government grants or a weak financial framework, was responsible for their formation. The suboptimal performance of factors of production, depressed job creation, low innovation and overall negative impact on economic activity are the consequences of zombification. This can be controlled by ensuring better bankruptcy codes, focused on government assistance, technology use and better due diligence by banks.Practical implicationsThis review serves as a reference point for future researchers as a cohesive and holistic study presenting a full picture of the problem, so that the proposed solutions are robust and tenable.Originality/valueThis review is among the initial attempts to comprehensively study published work on zombie firms in terms of analyzing their region-specific nature, with an emphasis on definition, causes, impact and prevention.