bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct neocortical mechanisms underlie human SI responses to median nerve and laser evoked peripheral activation
Authors: Thorpe Ryan V. , Black Christopher J. , Borton David A. , Hu Li , Saab Carl Y. , Jones Stephanie R. 
Published: October 2021

AbstractMagneto- and/or electro-encephalography (M/EEG) are non-invasive clinically-relevant tools that have long been used to measure electromagnetic fields in somatosensory cortex evoked by innocuous and noxious somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in primary somatosensory cortex (SI) linked to innocuous and noxious sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful and/or painful somatosensation. Through a literature review, we detailed features of MN and LE responses source-localized to SI that are robust and reproducible across studies. We showed that the first peak in the MN response at ∼20 ms post-stimulus (i.e., MN N1) corresponds to outward-directed deep-to-superficial electrical current flow through the cortical laminae, which is followed by inward-directed current at ∼30 ms (i.e., MN P1). In contrast, the initial LE response occurs later at ∼170 ms (i.e., LE N1) and is oriented inward and opposite the direction of the MN N1. We then examined the neocortical circuit mechanisms contributing to the robust features of each response using the Human Neocortical Neurosolver (HNN) neural modeling software tool (Neymotin et al., 2020). Using HNN as a hypothesis development and testing tool, model results predicted the MN response can be simulated with a sequence of layer specific thalamocortical and cortico-cortical synaptic drive similar to that previously reported for tactile evoked responses (Jones et al., 2007; Neymotin et al., 2020), with the novel discovery that an early excitatory input to supragranular layers at ∼30 ms is an essential mechanism contributing to the inward current flow of the MN P1. Model results further predicted that the initial ∼170 ms inward current flow of the LE N1 was generated by a burst of repetitive gamma-frequency (∼40 Hz) excitatory synaptic drive to supragranular layers, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as somatic sensitivity and acute neuropathic pain.
Anatomy of the Heart with the Highest Heart Rate
Authors: Chang Yun Hee , Sheftel Boris I. , Jensen Bjarke 
Published: October 2021

ABSTRACTShrews occupy the lower extreme of the seven orders of magnitude mammals range in size. Their hearts are large relative to body weight and heart rate can exceed a thousand beats a minute. To investigate whether cardiac traits that are typical mammalian scale to these extremes, we assessed the heart of three species of shrew (genusSorex) following the sequential segmental analysis developed for human hearts. Using micro-computed tomography we describe the overall structure and find, in agreement with previous studies, a large and elongate ventricle. The atrial and ventricular septums and the atrioventricular and arterial valves are typically mammalian. The ventricular walls comprise mostly compact myocardium and especially the right ventricle has few trabeculations on the luminal side. A developmental process of compaction is thought to reduce trabeculations in mammals, but in embryonic shrews the volume of trabeculations increase for every gestational stage, only slower than the compact volume. By expression of Hcn4, we identify a sinus node and an atrioventricular conduction axis which is continuous with the ventricular septal crest. Outstanding traits include pulmonary venous sleeve myocardium that reaches farther into the lungs than in any other mammals. Typical proportions of coronary arteries-to-aorta do not scale and the shrew coronary arteries are proportionally enormous, presumably to avoid the high resistance to blood flow of narrow vessels. In conclusion, most cardiac traits do scale to the miniscule shrews. The shrew heart, nevertheless, stands out by its relative size, elongation, proportionally large coronary vessels, and extent of pulmonary venous myocardium.
Distinct dendritic Ca2+ spike forms produce opposing input-output transformations in rat CA3 pyramidal cells
Authors: Magó Ádám , Kis Noémi , Lükő Balázs , Makara Judit K. 
Published: October 2021

AbstractProper integration of different inputs targeting the dendritic tree of CA3 pyramidal cells (CA3PCs) is critical for associative learning and recall. Dendritic Ca2+ spikes have been proposed to perform associative computations in other PC types, by detecting conjunctive activation of different afferent input pathways, initiating afterdepolarization (ADP) and triggering burst firing. Implementation of such operations fundamentally depends on the actual biophysical properties of dendritic Ca2+ spikes; yet little is known about these properties in dendrites of CA3PCs. Using dendritic patch-clamp recordings and two-photon Ca2+ imaging in acute slices from male rats we report that, unlike CA1PCs, distal apical trunk dendrites of CA3PCs exhibit distinct forms of dendritic Ca2+ spikes. Besides ADP-type global Ca2+ spikes, a majority of dendrites expresses a novel, fast Ca2+ spike type that is initiated locally without backpropagating action potentials, can recruit additional Na+ currents, and is compartmentalized to the activated dendritic subtree. Occurrence of the different Ca2+ spike types correlates with dendritic structure, indicating morpho-functional heterogeneity among CA3PCs. Importantly, ADPs and dendritically initiated spikes produce opposing somatic output: bursts versus strictly single action potentials, respectively. The uncovered variability of dendritic Ca2+ spikes may underlie heterogeneous input-output transformation and bursting properties of CA3PCs, and might specifically contribute to key associative and non-associative computations performed by the CA3 network.
Highly resolved spatial transcriptomics for detection of rare events in cells
Authors: Groiss Silvia , Pabst Daniela , Faber Cynthia , Meier Andreas , Bogdoll Annette , Unger Conny , Nilges Benedikt , Strauss Sascha , Föderl-Höbenreich Esther , Hardt Melina , Geipel Andreas , Reinecke Frank , Korfhage Christian , Zatloukal Kurt 
Published: October 2021

AbstractSingle-cell spatial transcriptomics technologies leveraged the potential to transcriptionally landscape sophisticated reactions in cells. Current methods to delineate such complex interplay lack the flexibility in rapid target adaptation and are particularly restricted in detecting rare transcripts. We developed a multiplex single-cell RNA In-situ hybridization technique, called ‘Molecular Cartography’ (MC) that can be easily tailored to specific applications and, by providing unprecedented sensitivity, specificity and resolution, is particularly suitable in tracing rare events at a subcellular level. Using a SARS-CoV-2 infection model, MC allows the discernment of single events in host-pathogen interactions, dissects primary from secondary responses, and illustrates differences in antiviral signaling pathways affected by SARS-CoV-2, simultaneously in various cell types.
Hypertrophic cardiomyopathy mutations in the pliant and light chain-binding regions of the lever arm of human β-cardiac myosin have divergent effects on myosin function
Authors: Morck Makenna M. , Bhowmik Debanjan , Dawood Aminah , Spudich James A. , Ruppel Kathleen M. 
Published: October 2021

ABSTRACTMutations in the lever arm of β-cardiac myosin are a frequent cause of hypertrophic cardiomyopathy (HCM), a disease characterized by hypercontractility and eventual hypertrophy of the left ventricle. Here, we studied five such mutations: three in the pliant region of the lever arm (D778V, L781P, and S782N) and two in the light chain-binding region (A797T and F834L). We investigated their effects on both motor function and myosin S2 tail-based autoinhibition. The pliant region mutations had varying effects on the motor function of a myosin construct lacking the S2 tail: overall, D778V increased power output, L781P reduced power output, and S782N had little effect on power output, while all three reduced the external force sensitivity of the actin detachment rate. With a myosin containing the motor domain and the proximal S2 tail, the pliant region mutations also attenuated autoinhibition in the presence of filamentous actin but had no impact in the absence of actin. By contrast, the light chain-binding region mutations had little effect on motor activity but produced marked reductions in autoinhibition in both the presence and absence of actin. Thus, mutations in the lever arm of β-cardiac myosin have divergent allosteric effects on myosin function, depending on whether they are in the pliant or light chain-binding regions.
Specific N-glycans regulate an extracellular adhesion complex during somatosensory dendrite patterning
Authors: Rahman Maisha , Ramirez-Suarez Nelson J. , Diaz-Balzac Carlos A. , Bülow Hannes E. 
Published: October 2021

AbstractN-glycans are molecularly diverse sugars borne by over 70% of proteins transiting the secretory pathway and have been implicated in protein folding, stability, and localization. Mutations in genes important for N-glycosylation result in congenital disorders of glycosylation that are often associated with intellectual disability. Here, we show that structurally distinct N-glycans regulate the activity of an extracellular protein complex involved in patterning of somatosensory dendrites in Caenorhabditis elegans. Specifically, aman-2/Golgi alpha-mannosidase II, a conserved key enzyme in the biosynthesis of specific N-glycans regulates the activity of the Menorin adhesion complex without obviously affecting protein stability and localization of its components. AMAN-2 functions cell-autonomously to ensure decoration of the neuronal transmembrane receptor DMA-1/LRR-TM with high-mannose/hybrid N-glycans. Moreover, distinct types of N-glycans on specific N-glycosylation sites regulate the DMA-1/LRR-TM receptor, which together with three other extracellular proteins forms the Menorin adhesion complex. In summary, specific N-glycan structures regulate dendrite patterning by coordinating the activity of an extracellular adhesion complex suggesting that the molecular diversity of N-glycans can contribute to developmental specificity in the nervous system.
Interactions between natural selection and recombination shape the genomic landscape of introgression
Authors: Duranton Maud , Pool John 
Published: October 2021

AbstractHybridization between lineages that have not reached complete reproductive isolation appears more and more like a common phenomenon. Indeed, speciation genomics studies have now extensively shown that many species’ genomes have hybrid ancestry. However, genomic patterns of introgression are often heterogeneous across the genome. In many organisms, a positive correlation between introgression levels and recombination rate has been observed. It is usually explained by the purging of deleterious introgressed material due to incompatibilities. However, the opposite relationship was observed in a North American population of Drosophila melanogaster with admixed European and African ancestry. In order to explore how directional and epistatic selection can impact the relationship between introgression and recombination, we performed forward simulations of whole D. melanogaster genomes reflecting the North American population’s history. Our results revealed that the simplest models of positive selection often yield negative correlations between introgression and recombination such as the one observed in D. melanogaster. We also confirmed that incompatibilities tend to produce positive introgression-recombination correlations. And yet, we identify parameter space under each model where the predicted correlation is reversed. These findings deepen our understanding of the evolutionary forces that may shape patterns of ancestry across genomes, and they strengthen the foundation for future studies aimed at estimating genome-wide parameters of selection in admixed populations.
Ferroptosis Regulation by the NGLY1/NFE2L1 Pathway
Authors: Forcina Giovanni C. , Pope Lauren , Murray Magdalena , Dong Wentao , Abu-Remaileh Monther , Bertozzi Carolyn R. , Dixon Scott J. 
Published: October 2021

AbstractFerroptosis is an oxidative form of non-apoptotic cell death whose transcriptional regulation is poorly understood. Cap’n’collar (CNC) transcription factors including Nuclear Factor Erythroid-2 Related Factor 1 (NFE2L1/NRF1) and NFE2L2 (NRF2) are important regulators of oxidative stress responses. Here, we report that NFE2L1 expression inhibits ferroptosis, independent of NFE2L2. NFE2L1 inhibits ferroptosis by promoting expression of the key anti-ferroptotic lipid hydroperoxidase glutathione peroxidase 4 (GPX4). NFE2L1 abundance and function are regulated post-translationally by N-glycosylation. Functional maturation of NFE2L1 requires deglycosylation by cytosolic peptide:N-glycanase 1 (NGLY1). We find that loss of NGLY1 or NFE2L1 enhances ferroptosis sensitivity. Expression of wild-type NGLY1 but not a disease-associated NGLY1 mutant inhibits ferroptosis, and this effect is dependent on the presence of NFE2L1. Enhanced ferroptosis sensitivity in NFE2L1 and NFE2L2 knockout cells can be potently reverted by expression of an NFE2L1 mutant containing eight asparagine-to-aspartate protein sequence substitutions, which mimic NGLY1-catalyzed sequence editing. Enhanced ferroptosis sensitivity in NGLY1/NFE2L1 pathway mutants could also be reversed by overexpression of NFE2L2. These results suggest that ferroptosis sensitivity is regulated by NGLY1-catalyzed NFE2L1 deglycosylation, and highlight a broad role for CNC transcription factors in ferroptosis regulation.Significance StatementFerroptosis is an oxidative form of cell death whose biochemical regulation remains incompletely understood. NFE2L1/NRF1 is a cap’n’collar (CNC) transcription factor whose role in ferroptosis regulation is unclear. Unlike the CNC family member NFE2L2/NRF2, NFE2L1 is an N-glycoprotein whose abundance is regulated by post-translational deglycosylation catalyzed by the enzyme peptide:N-glycanase 1 (NGLY1). Our results indicate that NGLY1-mediated NFE2L1 deglycosylation, resulting in ‘editing’ of the NFE2L1 amino acid sequence, is necessary for NFE2L1 to inhibit ferroptosis. Mechanistically, NFE2L1 inhibits ferroptosis by via the anti-ferroptotic protein GPX4. This work demonstrates that CNC transcription factors beyond NFE2L2 can regulate ferroptosis. This work may suggest a role of misregulation of ferroptosis in NGLY1 deficiency, an ultrarare genetic disorder.
Histone H1 regulates non-coding RNA turnover on chromatin in a m6A-dependent manner
Authors: Fernández-Justel José Miguel , Santa-María Cristina , Ferrera-Lagoa Alberto , Salinas-Pena Mónica , Maslon Magdalena M. , Jordan Albert , Cáceres Javier F. , Gómez María 
Published: October 2021

SUMMARYLinker histones are highly abundant chromatin-associated proteins with well-established structural roles in chromatin and as general transcriptional repressors. In addition, it has been long proposed that histone H1 exerts context-specific effects on gene expression. Here, we have identified a new function of histone H1 in chromatin structure and transcription using a range of genomic approaches. We show that histone H1-depleted cells accumulate nascent non-coding RNAs on chromatin, suggesting that histone H1 prevents non-coding RNA transcription and regulates non-coding transcript turnover on chromatin. Accumulated non-coding transcripts have reduced levels of m6A modification and cause replication-transcription conflicts. Accordingly, altering the m6A RNA methylation pathway rescues the replicative phenotype of H1 loss. This work unveils unexpected regulatory roles of histone H1 on non-coding RNA turnover and m6A deposition, highlighting the intimate relationship between chromatin conformation, RNA metabolism and DNA replication to maintain genome performance.
Transcriptome-wide Association Study and eQTL colocalization identify potentially causal genes responsible for bone mineral density GWAS associations
Authors: Al-Barghouthi Basel M. , Rosenow Will T. , Du Kang-Ping , Heo Jinho , Maynard Robert , Mesner Larry , Calabrese Gina , Nakasone Aaron , Senwar Bhavya , Gerstenfeld Louis , Ferguson Virginia , Ackert-Bicknell Cheryl , Morgan Elise , Brautigan David L. , Farber Charles R. 
Published: October 2021

AbstractGenome-wide association studies (GWASs) for bone mineral density (BMD) have identified over 1,100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant (Bonferroni <= 0.05) using both TWAS and eQTL colocalization. This set of genes was enriched for regulators of BMD and members of bone relevant biological processes. To investigate the significance of our findings, we selected PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.
Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing of MALT1
Authors: Jones Alisha N , Graß Carina , Meininger Isabel , Geerlof Arie , Klostermann Melina , Zarnack Kathi , Krappmann Daniel , Sattler Michael 
Published: October 2021

ABSTRACTAlternative splicing is controlled by differential binding of trans-acting RNA binding proteins (RBPs) to cis-regulatory elements in intronic and exonic pre-mRNA regions 1-3. How secondary structure in the pre-mRNA transcripts affects recognition by RBPs and determines alternative exon usage is poorly understood. The MALT1 paracaspase is a key component of signaling pathways that mediate innate and adaptive immune responses 4. Alternative splicing of MALT1 exon7 is critical for controlling optimal T cell activation 5,6. Here, we demonstrate that processing of the MALT1 pre-mRNA depends on RNA structural elements that shield the 5’ and 3’ splice sites of the alternatively spliced exon7. By combining biochemical analyses with chemical probing and NMR we show that the RBPs hnRNP U and hnRNP L bind competitively and with comparable affinities to identical stem-loop RNA structures flanking the 5’ and 3’ splice sites of MALT1 exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L unwinds these RNA elements to facilitate recruitment of the essential splicing factor U2AF2 to promote exon7 inclusion. Our data represent a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.
Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
Authors: Marcus Rebecca , Ferri-Borgogno Sammy , Hosein Abdel , Foo Wai Chin , Ghosh Bidyut , Zhao Jun , Rajapakshe Kimal , Brugarolas James , Maitra Anirban , Gupta Sonal 
Published: October 2021

AbstractIntrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss of function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) developed discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks, when compared to median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p <0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.
Shorter constant work rate cycling tests as proxies for longer tests in highly trained cyclists
Authors: Plessis Chantelle du , Andrews Mark , Mitchell Lachlan J G , Wilkie Jodie Cochrane , King Trish , Blazevich Anthony J 
Published: October 2021

AbstractSevere-intensity constant work rate (CWR) cycling tests are useful for monitoring training progression and adaptation as they impose significant physiological and psychological strain and thus simulate the high-intensity competition environment. However, fatiguing tests require substantial recovery and may disrupt athlete training or competition preparation. Therefore, the development of a brief, minimally fatiguing test providing comparable information is desirable.PurposeTo determine whether physiological variables measured during, and functional decline in maximal power output immediately after, a 2-min CWR test can act as a proxy for 4-min test outcomes.MethodsPhysiological stress was monitored and pre-to-post-CWR changes in 10-s sprint power computed (to estimate performance fatigability) during 2- and 4-min CWR tests in high-level cyclists.ResultsThe 2-min CWR test evoked a smaller decline in sprint mechanical power (32% vs. 47%, p<0.001), however both the physiological variables and sprint mechanical power were independently and strongly correlated between 2- and 4-min tests. Differences in V·O2peak and blood lactate concentration in both CWR tests were strongly associated with the decline in sprint mechanical power.ConclusionPhysiological variables measured during, and the loss in sprint mechanical power measured after, a severe-intensity 2-min CWR test were less than in the 4-min test. Yet strong correlations between 2- and 4-min test outcomes indicated that the 2-min test can be used as a proxy for the longer test. Because shorter tests are less strenuous, they should have less impact on training and competition preparation and may therefore be more practically applicable within the elite performance environment.