bluuebunny/crossref_metadata_2025_split huggingface dataset:
An alternative mechanism for skeletal muscle dysfunction in long-term post-viral lung disease
Authors: Martin Ryan A. , Keeler Shamus P. , Wu Kangyun , Shearon William J. , Patel Devin , Hoang My , Hoffmann Christy M. , Hughes Michael E. , Holtzman Michael J. 
Published: October 2022

ABSTRACTChronic lung disease is often accompanied by disabling extrapulmonary symptoms, notably skeletal muscle dysfunction and atrophy. Moreover, the severity of respiratory symptoms correlates with decreased muscle mass and in turn lowered physical activity and survival rates. Previous models of muscle atrophy in chronic lung disease often modeled COPD and relied on cigarette smoke exposure and LPS-stimulation, but these conditions independently affect skeletal muscle even without accompanying lung disease. Moreover, there is an emerging and pressing need to understand the extrapulmonary manifestations of long-term post-viral lung disease (PVLD) as found in Covid-19. Here, we examine the development of skeletal muscle dysfunction in the setting of chronic pulmonary disease using a mouse model of PVLD caused by infection due to the natural pathogen Sendai virus. We identify a significant decrease in myofiber size when PVLD is maximal at 49 d after infection. We find no change in the relative types of myofibers, but the greatest decrease in fiber size is localized to fast-twitch type IIB myofibers based on myosin heavy chain immunostaining. Remarkably, all biomarkers of myocyte protein synthesis and degradation (total RNA, ribosomal abundance, and ubiquitin-proteasome expression) were stable throughout the acute infectious illness and chronic post-viral disease process. Together, the results demonstrate a distinct pattern of skeletal muscle dysfunction in a mouse model of long-term PVLD. The findings thereby provide new insight into prolonged limitations in exercise capacity in patients with chronic lung disease after viral infections and perhaps other types of lung injury.
Limited roles of Piezo mechanosensing channels in articular cartilage development and osteoarthritis progression
Authors: Young Cameron , Kobayashi Tatsuya 
Published: October 2022

AbstractOsteoarthritis (OA) is a prevalent disease characterized by degeneration of the joint and pain. Mechanical stress plays a central role in OA development. It is hypothesized that cells in the OA joints produce OA-promoting molecules upon mechanical stress, and therefore, the mechanosensing systems are a theoretical target for OA treatment. Piezo mechanosensing channels mediate high-level mechanical stress in chondrocytes and have been suggested to play an important role during OA progression. To test this hypothesis, we ablated Piezo1 and Piezo2 in joint tissues using Gdf5-Cre transgenic mice [Piezo1 and 2 doubly conditional knockout (cKO) mice, cKO mice]. cKO mice showed normal development of knee joints. Both control and cKO mice developed modest to severe OA 12 weeks after the induction of OA, although some cKO mice showed milder OA. We did not find significant differences in pain in mice or gene expression after fluid flow stress in primary cells between control and cKO. Our data demonstrate the limited role of Piezo channels in joint development and OA progression.SummaryObjectiveTo investigate the role of Piezo1 and Piezo 2 in surgically induced osteoarthritis (OA) in mice.DesignMale conditional knockout (cKO) mice missing Piezo1 and Piezo2 in the joint via Gdf5-Cre transgenic mice were induced post-traumatic osteoarthritis (OA) by destabilization of the medial meniscus (DMM) of the right knee joint at 12 weeks of age. The severity of OA was assessed at 24 weeks of age using a modified Osteoarthritis Research Society International (OARSI) scoring system. OA-associated pain was evaluated by static weight bearing analysis at 4, 8, and 12 weeks post-operation. Additionally, articular chondrocytes isolated from cKO mice were exposed to fluid flow shear stress (FFSS) to evaluate the expression of OA-associated genes.ResultsMice with conditional deletion of Piezo1 and Piezo 2 showed normal joint development with no overt histological changes in the knee joint at 12 weeks and 24 weeks. DMM surgery induced moderate to severe OA in both control and cKO mice, although a few cKO mice showed milder OA. Pain assessment by static weight-bearing analysis suggested Piezo ablation in the joint has no beneficial effects on pain. FFSS increased the expression of OA-related genes both in control and cKO mice to similar extents.ConclusionPiezo1 and Piezo2 are not essential for normal joint development. Genetic ablation of Piezo channels did not confer evident protective effects on OA progression in mice. In vitro data suggests that different mechanotransducers other than Piezo channels mediate FFSS in mechanical stress-induced gene expression.
Rap1 coordinates cell-cell adhesion and cytoskeletal reorganization to drive collective cell migration in vivo
Authors: Rothenberg Katheryn E. , Chen Yujun , McDonald Jocelyn , Fernandez-Gonzalez Rodrigo 
Published: October 2022

AbstractCollective cell movements contribute to tissue development and repair, and spread metastatic disease. In epithelia, cohesive cell movements require reorganization of adherens junctions and the actomyosin cytoskeleton. However, the mechanisms that coordinate cell-cell adhesion and cytoskeletal remodelling during collective cell migration in vivo are unclear. We investigated the mechanisms of collective cell migration during wound healing in the Drosophila embryonic epidermis. Upon wounding, the cells adjacent to the wound internalize cell-cell adhesion molecules and polarize actin and the motor protein myosin II to form a supracellular cable around the wound that coordinates cell movements. The cable anchors at former tricellular junctions (TCJs) along the wound edge, and TCJs are reinforced during wound closure. We found that the small GTPase Rap1 was both necessary and sufficient for rapid wound repair. Rap1 promoted actomyosin polarization to the wound edge and E-cadherin accumulation at TCJs. Using embryos expressing a mutant form of the Rap1 effector Canoe/Afadin that cannot bind Rap1, we found that Rap1 signals through Canoe for adherens junction remodelling, but not for actomyosin cable assembly. Rap1 was necessary and sufficient for RhoA/Rho1 activation at the wound edge. Consistent with this, the RhoGEF Ephexin localized to the wound edge in a Rap1-dependent manner, and Ephexin was necessary for myosin polarization and rapid wound repair, but not for E-cadherin redistribution. Together, our data show that Rap1 coordinates the molecular rearrangements that drive embryonic wound healing and independently drives actomyosin cable assembly through Ephexin-Rho1, and E-cadherin redistribution through Canoe, thus enabling rapid collective cell migration in vivo.
A Canine Model of Chronic Ischemic Heart Failure
Authors: Khan Muhammad S. , Smego Douglas , Ishidoya Yuki , Hirahara Annie M. , Offei Emmanuel , Castillo Sofia R. , Gharbia Omar , Palatinus Joseph A. , Krueger Lauren , Hong TingTing , Hoareau Guillaume L. , Ranjan Ravi , Selzman Craig , Shaw Robin , Dosdall Derek J. 
Published: October 2022

BackgroundThere is a paucity of novel therapeutics for chronic heart failure (HF). Preclinical large animal models of chronic HF are crucial to translating fundamental discoveries. Canine models of ischemic cardiomyopathy are frequently utilized but are severely limited by competing needs to both induce sufficient muscle injury which results in an appropriately severe degree of left ventricular dysfunction yet to also minimize early mortality.MethodsTwenty-eight healthy adult dogs (30±4 kg, 15/28 male) underwent thoracotomy procedures followed by one of three types of left anterior descending (LAD) coronary artery ligations: Simple LAD (proximal and distal LAD ligation), LAD and Lateral (proximal and distal LAD, distal first diagonal, and proximal first obtuse marginal), and Total LAD Devascularization (TLD including the proximal and distal LAD, proximal aspects of the first, second, and third diagonals, and proximal aspects of first and second epicardial right ventricular branches of the LAD). Invasive and non-invasive hemodynamics were followed until attainment of chronic severe HF, which was achieved when left ventricular ejection fraction (LVEF) was <40% and N-terminal prohormone B-type Natriuretic peptide (NT-proBNP) >900 pmol/L, both for two consecutive measurements.ResultsOverall post-ligation early mortality (within 48 h of coronary ligation) was 18% (n=5/28), and the overall survival rate at 5 weeks post-ligation was 68% (n=19/28). At post-ligation week 1, LVEF was acutely reduced in all animals, from 54±4 to 38±1%, p<0.001. Beyond week 1, systolic function recovered over 3-4 weeks and then slowly declined as the left ventricle dilated and both systolic and diastolic function worsened. The magnitude of the initial decline in LVEF predicted ultimate HF development. Dogs with Simple LAD and LAD plus Lateral had excellent and limited survival at 48 hours (100% and 47%, respectively), yet the second group more likely developed chronic HF at 9 – 14 weeks (50% versus 57%, respectively). Dogs with TLD had both improved survival at 48 hours (90%) and excellent development of chronic HF (100%).ConclusionsBy focusing on the LAD only and limiting collateral flow to it by ligating all side branches, optimal survival and attainment of chronic ischemic HF can be achieved in the canine heart.
Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus
Authors: Heffel Matthew G. , Zhou Jingtian , Zhang Yi , Lee Dong-Sung , Hou Kangcheng , Alonso Oier Pastor , Abuhanna Kevin , Schmitt Anthony D. , Li Terence , Haeussler Maximilian , Wick Brittney , Zhang Martin Jinye , Xie Fangming , Ziffra Ryan S. , Mukamel Eran A. , Eskin Eleazar , Pasaniuc Bogdan , Ecker Joseph R. , Dixon Jesse , Nowakowski Tomasz J , Paredes Mercedes F. , Luo Chongyuan 
Published: October 2022

AbstractThe human frontal cortex and hippocampus play critical roles in learning and cognition. We investigated the epigenomic and 3D chromatin conformational reorganization during the development of the frontal cortex and hippocampus, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation (sn-m3C-seq). The remodeling of DNA methylation predominantly occurs during late-gestational to early-infant development and is temporally separated from chromatin conformation dynamics. Neurons have a unique Domain-Dominant chromatin conformation that is different from the Compartment-Dominant conformation of glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type differentiation and found putatively causal common variants for schizophrenia strongly overlap with chromatin loop-connected, cell-type-specific regulatory regions. Our data demonstrate that single-cell 3D-regulome is an effective approach for dissecting neuropsychiatric risk loci.
Horizontally transferred genes as RNA interference targets for aphid and whitefly control
Authors: Feng Honglin , Chen Wenbo , Hussain Sonia , Shakir Sara , Tzin Vered , Adegbayi Femi , Ugine Todd , Fei Zhangjun , Jander Georg 
Published: October 2022

AbstractRNA interference (RNAi)-based technologies are starting to be commercialized as a new approach for agricultural pest control. Horizontally transferred genes (HTGs), which have been transferred into insect genomes from viruses, bacteria, fungi, or plants, are attractive targets for RNAi-mediated pest control. HTGs are often unique to a specific insect family or even genus, making it unlikely that RNAi constructs targeting such genes will have negative effects on ladybugs, lacewings, and other beneficial predatory insect species. In this study, we sequenced the genome of a red, tobacco-adapted isolate ofMyzus persicae(green peach aphid) and bioinformaticaly identified 30 HTGs. We then used plant-mediated virus-induced gene silencing (VIGS) to show that several HTGs of bacterial and plant origin are important for aphid growth and/or survival. Silencing the expression of fungal HTGs did not affect aphid survivorship, but decreased aphid reproduction. Importantly, although there was uptake of plant-expressed RNA byCoccinella septempunctata(seven-spotted ladybugs) via the aphids that they consumed, we did not observe negative effects on ladybugs from aphid-targeted VIGS constructs. In other experiments, we targeted fiveBemisia tabaci(whitefly) HTGs using VIGS and demonstrated that knockdown of some of these genes affected whitefly survival. As functional HTGs have been identified in the genomes of numerous pest species, we propose that these HTGs should be explored further as efficient and safe targets for control of insect pests using plant-mediated RNA interference.
Altered GC- and AT-biased genotypes ofOphiocordyceps sinensisin the stromal fertile portions and ascospores of naturalCordyceps sinensis
Authors: Li Yu-Ling , Gao Ling , Yao Yi-Sang , Li Xiu-Zhang , Wu Zi-Mei , Tan Ning-Zhi , Luo Zhou-Qing , Xie Wei-Dong , Wu Jian-Yong , Zhu Jia-Shi 
Published: October 2022

AbstractObjectiveTo examine multiple genotypes ofOphiocordyceps sinensisin a semi-quantitative manner in the stromal fertile portion (SFP) densely covered with numerous ascocarps and ascospores of naturalCordyceps sinensisand to outline the dynamic alterations of the coexistingO. sinensisgenotypes in different developmental phases.MethodsMatureCordyceps sinensisspecimens were harvested and continuously cultivated in our laboratory (altitude 2,254 m). The SFPs (with ascocarps) and fully and semi-ejected ascospores were collected for histological and molecular examinations. Biochip-based single nucleotide polymorphism (SNP) MALDI-TOF mass spectrometry (MS) was used to genotype multipleO. sinensismutants in the SFPs and ascospores.ResultsMicroscopic analysis revealed distinct morphologies of the SFPs (with ascocarps) before and after ascospore ejection and SFP of developmental failure, which, along with the fully and semi-ejected ascospores, were subjected to SNP MS genotyping analysis. Mass spectra showed the coexistence of GC- and AT-biased genotypes ofO. sinensisthat were genetically and phylogenetically distinct in the SFPs before and after ejection and of developmental failure and in fully and semi-ejected ascospores. The intensity ratios of MS peaks were dynamically altered in the SFPs and the fully and semi-ejected ascospores. Mass spectra also showed transversion mutation alleles of unknown upstream and downstream sequences with altered intensities in the SFPs and ascospores. Genotype #5 of AT-biased Cluster-A maintained a high intensity in all SFPs and ascospores. An MS peak with a high intensity containing AT-biased Genotypes #6 and #15 in pre-ejection SFPs was significantly attenuated after ascospore ejection. The abundance of Genotypes #5–6 and #16 of AT-biased Cluster-A was differentially altered in the fully and semi-ejected ascospores that were collected from the sameCordyceps sinensisspecimens.ConclusionMultipleO. sinensisgenotypes coexisted in different combinations with altered abundances in the SFPs prior to and after ejection, the SFP of developmental failure, and the two types of ascospores ofCordyceps sinensis, demonstrating their genomic independence. Metagenomic fungal members present in different combinations and with dynamic alterations play symbiotic roles in different compartments of naturalCordyceps sinensis.
Tight control of the APP-Mint1 interaction in regulating amyloid production
Authors: Henry Shawna M. , Bartling Christian R. O. , Strømgaard Kristian , Beffert Uwe , Ho Angela 
Published: October 2022

AbstractGeneration of amyloid-beta (Aβ) peptides through the proteolytic processing of the amyloid precursor protein (APP) is one pathogenic event in Alzheimer’s disease (AD). APP is a type I transmembrane protein and endocytosis of APP mediated by the endocytic YENPTY sequence is a key step in Aβ generation. We and others have found that Mints, a family of cytosolic adaptor proteins, directly binds to the YENPTY motif of APP via phosphotyrosine binding (PTB) domain of Mints, facilitates APP trafficking and processing. We also show mutation of Tyr633 of Mint1 (Mint1Y633A) enhances APP binding and processing. Now, we created a low-affinity Mint1 mutant that targets two conserved residues, Tyr549 and Phe610 (Mint1Y549A/F610A), that reduced APP binding. Here, we investigate how perturbing the APP-Mint1 interaction alters APP and Mint1 cellular dynamics as well as Mint1’s interaction with its other binding partners. We show that Mint1Y633A increased binding affinity specifically for APP and presenilin1, enhanced APP endocytosis, and Aβ secretion in primary neurons. Conversely, Mint1Y549A/F610A exhibited reduced APP affinity and Aβ secretion. In fact, the effect of Mint1Y549A/F610A on Aβ release was greater compared to knocking down all three Mint proteins, supporting targeting APP-Mint1 interaction as a potential AD therapeutic.
Noninvasive, automated and reliable detection of spreading depolarizations in severe traumatic brain injury using scalp EEG
Authors: Chamanzar Alireza , Elmer Jonathan , Shutter Lori , Hartings Jed , Grover Pulkit 
Published: October 2022

AbstractBackgroundNoninvasive detection of spreading depolarizations (SD), as a potentially treatable mechanism of worsening brain injuries after traumatic brain injuries (TBI), has remained elusive. Current methods to detect SDs are based on intracranial recording, an invasive method with limited spatial coverage. Less invasive methods to diagnose SD are needed to improve generalizability and application of this emerging science and to guide worsening brain injury treatments. Here, we demonstrate, for the first time, a signal processing paradigm that can enable automated detection of SDs using noninvasive electroencephalography (EEG).MethodsBuilding on our previously developed WAVEFRONT algorithm, we have designed a novel automated SD detection method. This algorithm, with learnable parameters and improved velocity estimation, extracts and tracks propagating power depressions, as well as near-DC shifts using low-density EEG. This modified WAVEFRONT is robust to the amplitude outliers and non-propagating depressions on the scalp. We show the feasibility of detecting SD events (700 total SDs) in continuous, low-density scalp EEG recording (95±42.2 hours with 19 electrodes) acquired from 12 severe TBI patients who underwent decompressive hemicraniectomy (DHC) and intracranial EEG that could be used as a ground truth for event detection. We quantify the performance of WAVEFRONT in terms of SD detection accuracy, including true positive rate (TPR) and false positive rate (FPR), as well as the accuracy of estimating the frequency of SDs.ResultsWAVEFRONT achieves the best average validation accuracy of 74% TPR (with 95% confidence interval of 70.8%-76.7%), with less than 1.5% FPR using Delta band EEG. Preliminary evidence suggests that WAVEFRONT can achieve a very good performance (regression with R2≃0.71) in the estimation of SD frequencies.ConclusionsWe demonstrate feasibility and quantify the performance of noninvasive SD detection after severe TBI using an automated algorithm. WAVEFRONT can potentially be used for diagnosis and monitoring of worsening brain injuries to guide treatments by providing a measure of SD frequency. Extension of these results to patients with intact skulls requires further study.
Efficiency of heterogenous functional connectomes explains variance in callous-unemotional traits after computational lesioning of cortical midline and salience regions
Authors: Winters Drew E. , Leopold Daniel R. , Sakai Joseph T. , Carter R. McKell 
Published: October 2022

AbstractCallous-unemotional (CU) traits are a youth antisocial phenotype hypothesized to be a result of differences in the integration of multiple brain systems. However, mechanistic insights into these brain systems are a continued challenge. Where prior work describes activation and connectivity of the connectome in relation to these systems, new mechanistic insights can be derived by removing nodes and characterizing changes in network properties (hereafter referred to as computational lesioning) to characterize the resilience and vulnerability of the brain’s functional connectome. Here, we study the resilience of connectome integration in CU traits by estimating changes in efficiency after computationally lesioning individual-level connectomes. From resting-state data of 86 participants (48% female, age 14.52±1.31) drawn from the Nathan Kline institute’s Rockland study, individual-level connectomes were estimated using graphical lasso. Computational lesioning was conducted both sequentially and by targeting global and local hubs. We calculated changes in network efficiency after each lesion. Then, elastic net regression was applied to determine how these changes explained variance in CU traits. Follow-up analyses characterized modeled node hubs, examined moderation, determined impact of targeting, and decoded the brain mask by comparing regions to meta-analytic maps. Elastic net regression revealed that computational lesioning of 23 nodes, network modularity, and Tanner stage explained variance in CU traits. Hub assignment of selected hubs differed at higher CU traits. No evidence for moderation between simulated lesioning and CU traits was found. Targeting global hubs increased efficiency and targeting local hubs had no effect at higher CU traits. Identified brain mask meta-analytically associated with more emotion and cognitive terms. Although reliable patterns were found across participants, adolescent brains were heterogeneous even for those with a similar CU traits score. Adolescent brain response to simulated lesioning revealed a pattern of connectome resiliency and vulnerability that explains variance in CU traits, which can aid prediction of youth at greater risk for higher CU traits.
Causality-Enriched Epigenetic Age Uncouples Damage and Adaptation
Authors: Ying Kejun , Liu Hanna , Tarkhov Andrei E. , Sadler Marie C. , Lu Ake T. , Moqri Mahdi , Horvath Steve , Kutalik Zoltán , Shen Xia , Gladyshev Vadim N. 
Published: October 2022

AbstractMachine learning models based on DNA methylation data can predict biological age but often lack causal insights. By harnessing large-scale genetic data through epigenome-wide Mendelian Randomization, we identified CpG sites potentially causal for aging-related traits. Neither the existing epigenetic clocks nor age-related differential DNA methylation are enriched in these sites. These CpGs include sites that contribute to aging and protect against it, yet their combined contribution negatively affects age-related traits. We established a novel framework to introduce causal information into epigenetic clocks, resulting in DamAge and AdaptAge—clocks that track detrimental and adaptive methylation changes, respectively. DamAge correlates with adverse outcomes, including mortality, while AdaptAge is associated with beneficial adaptations. These causality-enriched clocks exhibit sensitivity to short-term interventions. Our findings provide a detailed land-scape of CpG sites with putative causal links to lifespan and healthspan, facilitating the development of aging biomarkers, assessing interventions, and studying reversibility of age-associated changes.