bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bursts of genomic instability potentiate phenotypic and genomic diversification in Saccharomyces cerevisiae
Authors: Heasley Lydia R. , Argueso Juan Lucas 
Published: March 2022

AbstractHow microbial cells leverage their phenotypic potential to survive in a changing environment is a complex biological problem, with important implications for pathogenesis and species evolution. Stochastic phenotype switching, a particularly fascinating adaptive approach observed in numerous species across the tree of life, introduces phenotypic diversity into a population through mechanisms which have remained difficult to define. Here we describe our investigations into the mechanistic basis of colony morphology phenotype switching which occurs in populations of a pathogenic isolate of Saccharomyces cerevisiae, YJM311. We observed that clonal populations of YJM311 cells produce variant colonies that display altered morphologies and, using whole genome sequence analysis, discovered that these variant clones harbored an exceptional collection of karyotypes newly altered by de novo structural genomic variations (SVs). Overall, our analyses indicate that copy number alterations, more often than changes in allelic identity, provide the causative basis of this phenotypic variation. Individual variants carried between 1 and 16 de novo copy number variations, most of which were whole chromosomal aneuploidies. Notably, the inherent stability of the diploid YJM311 genome is comparable to that of domesticated laboratory strains, indicating that the collections of SVs harbored by variant clones did not arise by a chronic chromosomal instability (CIN) mechanism. Rather, variant clones acquired these complex karyotypic configurations simultaneously, during stochastic and transient episodes of punctuated systemic genomic instability (PSGI). Surprisingly, we found that the majority of these highly altered variant karyotypes were propagated with perfect fidelity in long-term passaging experiments, demonstrating that high aneuploidy burdens can often be conducive with prolonged genomic instability. Together, our results demonstrate that colony morphology switching in YJM311 is driven by a stochastic process in which genome stability and plasticity are integrally coupled to phenotypic heterogeneity. Consequently, this system simultaneously introduces both phenotypic and genomic variation into a population of cells, which can, in turn perpetuate population diversity for many generations thereafter.
Discordant calls across genotype discovery approaches elucidate variants with systematic errors
Authors: Atkinson Elizabeth G. , Artomov Mykyta , Karczewski Konrad J. , Loboda Alexander A. , Rehm Heidi L. , MacArthur Daniel G. , Neale Benjamin M. , Daly Mark J. 
Published: March 2022

AbstractLarge-scale next-generation sequencing datasets have been transformative for informing clinical variant interpretation and as reference panels for statistical and population genetic efforts. While such resources are often treated as ground truth, we find that in widely used reference datasets such as the Genome Aggregation Database (gnomAD), some variants pass gold standard filters yet are systematically different in their genotype calls across genotype discovery approaches. The inclusion of such discordant sites in study designs involving multiple genotype discovery strategies could bias results and lead to false-positive hits in association studies due to technological artifacts rather than a true relationship to the phenotype. Here, we describe this phenomenon of discordant genotype calls across genotype discovery approaches, characterize the error mode of wrong calls, provide a blacklist of discordant sites identified in gnomAD that should be treated with caution in analyses, and present a metric and machine learning classifier trained on gnomAD data to identify likely discordant variants in other datasets. We find that different genotype discovery approaches have different sets of variants at which this problem occurs but that there are characteristic variant features that can be used to predict discordant behavior. Discordant sites are largely shared across ancestry groups, though different populations are powered for discovery of different variants. We find that the most common error mode is that of a variant being heterozygous for one approach and homozygous for the other, with heterozygous in the genomes and homozygous reference in the exomes making up the majority of miscalls.
Physiological and molecular mechanisms regulated mesophyll conductance under severe drought in water-saving drought-resistant rice
Authors: He Haibing , Wang Lele , Zhang Xuelan , Zhan Li , Wang Quan , Yang Ru , You Cuicui , Ke Jian , Wu Liquan 
Published: March 2022

AbstractWater-saving and drought-resistant rice (WDR) is a new type of rice varieties. It plays an important role in responding to drought with high yield and has been widely planted in central China at present. High photosynthetic production potential caused by high mesophyll conductance (gm) is the main factor promoted high yield formation in drought for WDR. But little is known about physiological and molecular mechanisms regulated gm in drought for WDR. Therefore, WDR cultivar HY73 and drought-sensitive cultivar HLY898 were used for comparative studies with three irrigation regimes before applying severe drought treatment at heading to create different differential individuals of photosynthetic potential and gm. The results showed that cultivar HY73 had lower up-regulation different expression genes (DEGs) than cultivar HLY898 in drought at transcriptional level. Conversely, DEGs of down-regulation was higher in cultivar HY73 than cultivar HLY898. In addition, 3071 DEGs were clustered in 3 modules named Midnightblue (734 DEGs), Blue (921 DEGs), and Turquoise (1416 DEGs) in severe drought merged three irrigation regimes and both cultivars, which the modules had significant correlational relationship with gm based on weighted gene co-expression network analysis (P<0.05). Only DEGs in midnightblue module were enriched in photosynthesis process and positively regulated gm (P<0.05). The main biological process were photosynthesis (GO:0015979), light harvesting in photosystem I (GO:0009768), reductive pentose-phosphate cycle (GO:0019253), protein-chromophore linkage (GO:0018298), photosynthetic electron transport in photosystem I (GO:0009773), and photosystem II repair (GO:0010206). These results indicate that gm and energy distribution in PSI and PSII systems could synergistic effect photosynthetic production potential in severe drought for rice plants. In the modules, the 18 most highly connected hub genes were screened using co-expression networks method. RT-PCR analysis indicated that CSP41B, PGLP1A, LHCA5, and GSTU6 genes had a similar variation trend with gm among treatments for both cultivar. LHCA5 and CSP41B genes were significantly up-regulated in HY73 compared with HLY898 in drought (P<0.05). And the both genes locates in thylakoid membrane in photosystems. Therefore, LHCA5 and CSP41B genes could be key genes to synergistically manage gm and energy distribution in photosystems. Our results provide some new physiological and molecular mechanisms regulated gm in severe drought for WDR.
Machine Learning Enabled Non-invasive Diagnosis of Nonalcoholic Fatty Liver Disease and Assessment of Abdominal Fat from MRI Data
Authors: Pillai Arvind , Bliznashki Kamen , Hutchison Emmette , Kumar Chanchal , Challis Benjamin , Patel Mishal 
Published: March 2022

AbstractNonalcoholic fatty liver disease (NAFLD) is the most rapidly growing contributor to chronic liver disease worldwide with high disease burden and suffers from limitations in diagnosis. Inspired by recent advances in machine learning digital diagnostics, we explored the efficacy of training a neural network to classify high risk NAFLD vs. non-NAFLD patients in the UK Biobank dataset based on proton density fat fraction (PDFF). We compared the performance of several ResNet-derived architectures in the context of whole abdomen MRI, segmented liver and abdomen excluding liver (sans-liver). Non-local ResNet trained on whole abdomen MRI images yielded the highest precision (0.88 for NAFLD) and F1 (0.89 for NAFLD). Furthermore, our work on a second, larger cohort explored multi-task learning and the relationship among PDFF, visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT). Interestingly, multi-task learning experiments found a decline in performance for PDFF when combined with VAT and ASAT. We address this deterioration using Multi-gate Mixture-of-Experts (MMoE) approaches. Our work opens the possibility for using a non-invasive deep learning-based diagnostic for NAFLD, and directly enables clinical and genomic research using a larger cohort of potential NAFLD patients in the UK Biobank study.
PLO3S : Protein LOcal Surficial Similarity Screening
Authors: Sirugue Lea , Langenfeld Florent , Lagarde Nathalie , Montes Matthieu 
Published: March 2022

AbstractThe study of protein molecular surfaces enable to better understand and predict protein interactions. Different methods have been developed in computer vision to compare surfaces that can be applied to protein molecular surfaces. The present work proposes a method using the the Wave Kernel Signature : Protein LOcal Surficial Similarity Screening (PLO3S). The descriptor of the PLO3S method is a local surface shape descriptor projected on a unit sphere mapped onto a 2D plane and called Surface Wave Interpolated Maps (SWIM). PLO3S allows to rapidly compare protein surface shapes through local comparisons to filter large protein surfaces datasets in protein structures virtual screening protocols.
mTORC2 coordinates the leading and trailing edge cytoskeletal programs during neutrophil migration
Authors: Saha Suvrajit , Town Jason P. , Weiner Orion D. 
Published: March 2022

ABSTRACTBy acting both upstream and downstream of biochemical organizers of the cytoskeleton, physical forces function as central integrators of cell shape and movement. Here we use a combination of genetic, pharmacological, and optogenetic perturbations to probe the role of the conserved mechanoresponsive mTORC2 program in neutrophil polarity and motility. We find that the tension-based inhibition of leading edge signals (Rac, F-actin) that underlies protrusion competition is gated by the kinase-independent role of the complex, whereas the mTORC2 kinase arm is essential for regulation of Rho activity and Myosin II-based contraction at the trailing edge. Cells required mTORC2 for spatial and temporal coordination between the front and back polarity programs and persistent migration under confinement. mTORC2 is in a mechanosensory cascade, but membrane stretch did not suffice to stimulate mTORC2 unless the co-input PIP3 was also present. Our work suggests that different signalling arms of mTORC2 regulate spatially and molecularly divergent cytoskeletal programs allowing efficient coordination of neutrophil shape and movement.
Nr2f1 controls mitochondrial dynamics in mouse adult-born hippocampal neurons
Authors: Sara Bonzano , Filippo Michelon , Isabella Crisci , Ivan Molineris , Francesco Neri , Salvatore Oliviero , Ruth Beckervordersandforth , Chichung Lie Dieter , Paolo Peretto , Serena Bovetti , Michèle Studer , Silvia De Marchis 
Published: March 2022

AbstractThe nuclear receptor Nr2f1 plays a key role during cortical development by acting as a strong transcriptional regulator in embryonic and postnatal neural cells. In humans, its mutations cause the Bosch-Boonstra-Schaaf optic atrophy-intellectual syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including optic nerve atrophy, intellectual disability, and autistic traits. In this study by genome-wide and in silico analyses we found that key factors for mitochondrial function and dynamics represent potential genomic targets under direct Nr2f1 transcriptional control in neurons. Although mitochondrial dysfunction is increasingly implicated in neurodevelopmental disorders, whether and how Nr2f1 can regulate mitochondria function in neural cells is still completely unknown. To address these questions, we have combined mouse genetics, neuroanatomical and imaging approaches. To genetically manipulate Nr2f1 function in newborn neurons we focused on the adult mouse hippocampal dentate gyrus, a site of persistent neurogenesis where Nr2f1 is highly expressed. We showed that conditional Nr2f1 loss-of-function within the hippocampal neurogenic niche lead to a reduced mitochondrial mass associated to mitochondrial fragmentation in newborn neurons, likely reflecting alteration in mitochondrial dynamics. Accordingly, we showed that the fusion factor Mfn2, which is as a putative Nr2f1 target, is downregulated following both Nr2f1 adult depletion and embryonic haploinsufficiency in mice. Overall, our study provides the first evidence of a crucial role of Nr2f1 in shaping mitochondria in neurons and opens a promising avenue for the identification of new mechanisms implicated in BBSOAS pathogenesis involving mitochondrial dysfunction.
Two modes of mid-frontal theta suggest a role in conflict and error processing
Authors: Muralidharan Vignesh , Aron Adam R , Cohen Michael X , Schmidt Robert 
Published: March 2022

ABSTRACTMid-frontal theta increases during scenarios when conflicts are successfully resolved. Often considered as a generic signal of cognitive control, its temporal nature has hardly been investigated. Using advanced spatiotemporal techniques, we uncover that mid-frontal theta occurs as a transient oscillation or “event” at single trials with their timing reflecting computationally distinct modes. Single-trial analyses of electrophysiological data from participants performing the Flanker (N = 28) and Simon task (N = 18) were used to probe the relationship between theta and metrics of response conflict. We specifically investigated “partial errors”, in which a small burst of muscle activity in the incorrect response effector occurred, quickly followed by a correction. We found that transient theta events in single trials could be categorized into two distinct theta modes based on their relative timing to different task events. Theta events from the first mode occurred briefly after the task stimulus and might reflect conflict-related processing of the stimulus. In contrast, theta events from the second mode were more likely to occur around the time partial errors were committed, suggesting they were elicited by a potential upcoming error. Importantly, in trials in which a full error was committed, this “error-related theta” occurred too late with respect to the onset of the erroneous muscle response, supporting a role of theta also in error correction. We conclude that different modes of transient mid-frontal theta can be adopted in single trials not only to process stimulus conflict, but also to correct erroneous responses.
Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential
Authors: Carlessi Rodrigo , Denisenko Elena , Boslem Ebru , Koehn-Gaone Julia , Main Nathan , Abu Bakar N. Dianah B. , Shirolkar Gayatri D. , Jones Matthew , Poppe Daniel , Dwyer Benjamin J. , Jackaman Connie , Tjiam M. Christian , Lister Ryan , Karin Michael , Fallowfield Jonathan A. , Kendall Timothy J. , Forbes Stuart J. , Olynyk John K. , Yeoh George , Forrest Alistair R. R. , Ramm Grant A. , Febbraio Mark A. , Tirnitz-Parker Janina E. E. 
Published: March 2022

SUMMARYCurrent approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.
The role of optogenetic stimulations of parvalbumin-positive interneurons in the prefrontal cortex and the ventral hippocampus on an acute MK801 model of schizophrenia-like cognitive inflexibility
Authors: Patrono Enrico , Hrůzova Karolina , Svoboda Jan , Stuchlík Aleš 
Published: March 2022

AbstractBackground and HypothesisSchizophrenia research arose in the last decades, focusing more on its neural basis. Executive functions such as decision making and cognitive flexibility are the main cognitive areas that are impaired and are considered schizophrenia endophenotypes. Recently, cognitive impairment has been connected with the ablation of glutamatergic NMDARs resulting in increased cortical activity. Selective NMDARs antagonists such as dizocilpine have been used to model cognitive inflexibility in schizophrenia. Moreover, a decreased GABAergic inhibitory activity has been shown elsewhere along with the enhanced cortical activity. This NMDARs/GABA unbalanced ratio may reduce the entrainment of prefrontal gamma and hippocampal theta rhythm, resulting in a prefrontal-hippocampal gamma/theta band desynchronization.Study DesignThe study addressed the role of acute administrations of dizocilpine to model schizophrenia-like cognitive inflexibility in rats. We used a new version of the attentional set-shifting task, where rats learned switching/reversing the relevant rule. Moreover, we used the new ASST after dizocilpine systemic injections to test cognitive flexibility. Finally, we used in vivo optogenetic stimulations at specific light pulses of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus.ResultsThe first experiments showed that acute dizocilpine in rats reproduced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that appropriate optogenetic light pulses frequencies could rescue the cognitive flexibility previously altered by acute dizocilpine.ConclusionsThese findings advance our knowledge on the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may serve as a standpoint for further research of this severe psychiatric disorder.
Telomerase-independent maintenance of telomere length in a vertebrate
Authors: Yu Qinghao , Gates Phillip B. , Rogers Samuel , Mikicic Ivan , Elewa Ahmed , Salomon Florian , Lachnit Martina , Caldarelli Antonio , Flores-Rodriguez Neftali , Cesare Anthony J , Simon Andras , Yun Maximina H. 
Published: March 2022

AbstractTelomere shortening places a key limitation on cell proliferation1. In all vertebrates explored to date, this limitation is overcome by telomerase-dependent telomere extension. Failure to maintain telomere length results in premature ageing and functional impairments in highly replicative cell populations as telomeres erode2. Alternative lengthening of telomeres (ALT), a telomerase-independent mechanism, compensates for telomere loss in a subset of human cancer cell lines 2. Here, we demonstrate that the highly regenerative newt Pleurodeles waltl lacks telomerase activity, contains telomeres distinct from all known vertebrates in both sequence and structure, and deploys ALT for physiological telomere maintenance. This constitutes the first report of telomerase-independent resolution of the end-replication problem at the whole-organism level within Chordata.One-Sentence SummaryP. waltl telomere biology is distinct amongst vertebrates and uses ALT at the whole-organism level.
Adversary of DNA integrity: a long non-coding RNA stimulates driver oncogenic chromosomal rearrangement in human thyroid cells
Authors: Demin Denis Eriksonovich , Murashko Matvey Mikhailovich , Uvarova Aksinya Nicolaevna , Stasevich Ekaterina Mikhailovna , Shyrokova Elena Yurievna , Gorlachev Gennady Efimovich , Korneev Kirill Viktorovich , Ustiugova Alina Sergeevna , Tkachenko Elena Andreevna , Kostenko Valentina Vitalevna , Tatosyan Karina Aleksandrovna , Sheetikov Saveliy Andreevich , Spirin Pavel Vladimirovich , Kuprash Dmitriy Vladimirovich , Schwartz Anton Markovich 
Published: March 2022

AbstractThe flurry of publications devoted to the functions of long non-coding RNAs (lncRNAs) published in the last decade leaves no doubt about the exceptional importance of lncRNAs in various areas including tumor biology. Contribution of lncRNAs to the early stages of oncogenesis remains poorly understood. In this study we explored a new role for lncRNAs: stimulation of driver oncogenic mutations that result from specific chromosomal rearrangements. We demonstrated that lncRNA CASTL1 (ENSG00000269945) stimulates the formation of the CCDC6-RET inversion (RET/PTC1) in human thyroid cells subjected to radiation or chemical DNA damage. Facilitation of chromosomal rearrangement requires lncRNA to contain regions complementary to the introns of both CCDC6 and RET genes as deletion of these regions deprives CASTL1 of the ability to stimulate the gene fusion. We found that CASTL1 expression is elevated in tumors with CCDC6-RET fusion which is the most frequent rearrangement in papillary thyroid carcinoma. Our results open a new venue for the studies of early oncogenesis in various tumor types, especially those associated with physical or chemical DNA damage.Graphical abstract