bluuebunny/crossref_metadata_2025_split huggingface dataset:
A selectivity filter in the EMC limits protein mislocalization to the ER
Authors: Pleiner Tino , Hazu Masami , Tomaleri Giovani Pinton , Nguyen Vy , Januszyk Kurt , Voorhees Rebecca M. 
Published: December 2022

SUMMARYTail anchored proteins (TAs) play essential roles at both the ER and mitochondria, and their accurate localization is critical to proteostasis. Biophysical similarities lead to mistargeting of mitochondrial TAs to the ER, where they are delivered to the ER membrane protein complex (EMC). We showed that the EMC directly contributes to sorting fidelity of mitochondrial TAs and multipass substrates that contain positively charged soluble domains. Leveraging an improved structural model of the human EMC, we used mutagenesis and site-specific crosslinking to map the path of a TA from its cytosolic capture by methionine-rich loops to its membrane insertion through a hydrophilic vestibule. Positively charged residues at the entrance to the vestibule function as a selectivity filter that uses charge-repulsion to reject mitochondrial TAs. Substrate discrimination by the EMC provides a biochemical explanation for one role of charge in TA sorting and protects compartment identity by limiting protein misinsertion.
Acute adenoviral infection elicits an arrhythmogenic substrate prior to myocarditis
Authors: Padget Rachel L. , Zeitz Michael J. , Blair Grace A. , Wu Xiaobo , North Michael D. , Tanenbaum Mira T. , Stanley Kari E. , Phillips Chelsea M. , King D. Ryan , Lamouille Samy , Gourdie Robert G. , Hoeker Gregory S. , Swanger Sharon A. , Poelzing Steven , Smyth James W. 
Published: December 2022

AbstractBackgroundViral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases, and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate prior to significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species-specificity, models of infection are lacking and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse Adenovirus Type-3 (MAdV-3) was previously reported as cardiotropic, yet has not been utilized to understand mechanisms of cardiac infection and pathology.MethodsWe have developed MAdV-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart prior to an appreciable immune response or gross cardiomyopathy.ResultsOptical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43Ser368 are protected against MAdV-3 induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of MAdV-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreasedIK1andIKscurrent density. Turning to human systems, we find human adenovirus type-5 (HAdV-5) increases phosphorylation of Cx43Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data.ConclusionsTogether, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.
No association between thePlasmodium vivax crt-oMS334 or In9pvcrtpolymorphisms and chloroquine failure in a clinical cohort from Malaysia
Authors: Rumaseb Angela , Moraes Barros Roberto R. , Sá Juliana M. , Juliano Jonathan J. , William Timothy , Braima Kamil A. , Barber Bridget E. , Anstey Nicholas M , Price Ric N. , Grigg Matthew J. , Auburn Sarah , Marfurt Jutta 
Published: December 2022

AbstractIncreasing reports of resistance to a frontline malaria blood-stage treatment, chloroquine (CQ), raise concerns for the elimination ofPlasmodium vivax. The absence of an effective molecular marker of CQ resistance inP. vivaxgreatly constrains surveillance of this emerging threat. A recent genetic cross between CQ sensitive (CQS) and CQ resistant (CQR) NIH-1993 strains ofP. vivaxlinked a moderate CQR phenotype with two candidate markers inP. vivaxCQ resistance transporter gene (pvcrt-o): MS334 and In9pvcrt. Longer TGAAGH motifs at MS334 were associated with CQ resistance, as were shorter motifs at the In9pvcrtlocus. In this study, high-grade CQR clinical isolates ofP. vivaxfrom Malaysia were used to investigate the association between the MS334 and In9pvcrtvariants and treatment efficacy. Amongst a total of 49 independent monoclonalP. vivaxisolates assessed, high-quality MS334 and In9pvcrtsequences could be derived from 30 (61%) and 23 (47%), respectively. Five MS334 and six In9pvcrtalleles were observed, with allele frequencies ranging from 2 to 76% and 3 to 71%, respectively. None of the clinical isolates had the same variant as the NIH-1993 CQR strain, and none were associated with CQ treatment failure (allp>0.05). Our findings suggest that thepvcrt-oMS334 and In9pvcrtmarkers cannot be used universally as markers of CQ treatment efficacy in an area of high-grade CQ resistance. Further studies applying hypothesis-free genome-wide approaches are warranted to identify more effective CQR markers forP. vivax.
Genome-wide meta-analysis identifies novel maternal risk variants and enables polygenic prediction of preeclampsia and gestational hypertension
Authors: Honigberg Michael C. , Truong Buu , Khan Raiyan R. , Xiao Brenda , Bhatta Laxmi , Vy Thi Ha , Guerrero Rafael F. , Schuermans Art , Selvaraj Margaret Sunitha , Patel Aniruddh P. , Koyama Satoshi , Cho So Mi Jemma , Vellarikkal Shamsudheen Karuthedath , Trinder Mark , Urbut Sarah M. , Gray Kathryn J. , Brumpton Ben M. , Patil Snehal , Zöllner Sebastian , Antopia Mariah C. ,   Genes & Health Research Team,   Estonian Biobank Research Team,   nuMoM2b Research Team, Saxena Richa , Nadkarni Girish N. , Do Ron , Yan Qi , Pe’er Itsik , Verma Shefali Setia , Gupta Rajat M. , Haas David M. , Martin Hilary C. , van Heel David A. , Laisk Triin , Natarajan Pradeep 
Published: December 2022

AbstractPreeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and offspring outcomes. Current tools for prediction, prevention, and treatment are limited. We tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 controls and with gestational hypertension in 11,027 cases and 412,788 controls across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are novel (e.g.,MTHFR-CLCN6,WNT3A,NPR3,PGR, andRGL3), including two loci (PLCE1,FURIN) identified in multi-trait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development, and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external datasets, independent of first trimester risk markers. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and advance pregnancy risk stratification.
Altered lipid homeostasis underlies selective neurodegeneration in SNX14 deficiency
Authors: Zhou Yijing , Sanchez Vanessa B. , Xu Peining , Flores-Mendez Marco , Ciesielski Brianna , Yoo Donna , Teshome Hiab , Henne Mike , O’Brien Tim , Mesaros Clementina , Akizu Naiara 
Published: December 2022

AbstractDysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that the cerebellar neurodegeneration caused by SNX14 deficiency is associated with lipid metabolism defects. Recentin vitroandin silicostudies indicate that SNX14 is an inter-organelle lipid transfer protein that regulates lipid droplet biogenesis and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates the human SNX14 deficiency at genetic and phenotypic level. Through histological and transcriptomic analyses, we demonstrate that cerebellar Purkinje cells are selectively vulnerable to SNX14 deficiency, while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14 deficient mice. Furthermore, we identify a unique lipid metabolite profile that links the accumulation of acylcarnitines with the selective cerebellar neurodegeneration in SNX14 deficiency. These findings highlight the importance of lipid homeostasis for neuronal function and survival and suggest a mechanism for selective cerebellar vulnerability to altered lipid homeostasis.
New gene evolution with subcellular expression patterns detected in PacBio-sequenced genomes ofDrosophilagenus
Authors: Dong Chuan , Zhang Li , Xia Shengqian , Sosa Dylan , Arsala Deanna , Long Manyuan 
Published: December 2022

AbstractPrevious studies described gene age distributions in the focal species ofDrosophila melanogaster. Using third-generation PacBio technology to sequenceDrosophilaspecies we investigated gene age distribution in the two subgenera ofDrosophila. Our work resulted in several discoveries. First, our data detected abundant new genes in entireDrosophilagenus. Second, in analysis of subcellular expression, we found that new genes tend to secret into extracellular matrix and are involved in regulation, environmental adaption, and reproductive functions. We also found that extracellular localization for new genes provides a possible environment to promote their fast evolution. Third, old genes tend to be enriched in mitochondrion and the plasma membrane compared with young genes which may support the endosymbiotic theory that mitochondria originate from bacteria that once lived in primitive eukaryotic cells. Fourth, as gene age becomes older the subcellular compartments in which their products reside broadens suggesting that the evolution of new genes in subcellular location drives functional evolution and diversity inDrosophilaspecies. Additionally, based on the analysis of RNA-Seq of twoD. melanogasterpopulations, we determined a universal paradigm of “from specific to constitutive” expression pattern during the evolutionary process of new genes.
Intercellular Mitochondrial Transfer as a Rescue Mechanism in Response to Protein Import Failure
Authors: Needs Hope I , Pereira Gonçalo C. , Glover Emily , Witt Alina , Hübner Wolfgang , Dodding Mark P. , Henley Jeremy M , Collinson Ian 
Published: December 2022

AbstractMitochondria are the powerhouses of eukaryotic cells, composed mostly of nuclear-encoded proteins imported from the cytosol. Thus, problems with the import machinery will disrupt their regenerative capacity and the cell’s energy (ATP) supplies–particularly troublesome for energy demanding cells like neurons and myocytes. Unsurprisingly then, dysfunctional import is implicated in disease. This study explores the consequences of import failure in mammalian cells; wherein, blocking the import machinery has profound effects on mitochondrial ultra-structure and dynamics, but, surprisingly, does not impact import. The explanation is an astonishing response involving intercellular mitochondrial transferviatunnelling nanotubes: for the import of healthy mitochondria and jettisoning of those with jammed import sites. These observations support the existence of a widespread mechanism for the rescue of mitochondrial protein import failure.One-Sentence SummaryA mitochondrial import rescue mechanism involving intercellular mitochondrial transport through tunneling nanotubes (TNTs).
Goal-directed modulation of stretch reflex gains is reduced in the non-dominant upper limb
Authors: Torell Frida , Franklin Sae , Franklin David W. , Dimitriou Michael 
Published: December 2022

AbstractMost individuals experience their dominant arm as being more dexterous than the non-dominant arm, but the neural mechanisms underlying this asymmetry in motor behaviour are unclear. Using a delayed reach task, we have recently demonstrated strong goal-directed tuning of stretch reflex gains in the dominant upper limb of human participants. Here, we used an equivalent experimental paradigm to address the neural mechanisms that underlie the preparation for reaching movements with the non-dominant upper limb. We found only minor goal-directed differences in the short latency stretch reflex of the non-dominant limb. There were consistent effects of load, preparatory delay duration and target direction on the long latency stretch reflex. However, by comparing stretch reflex responses in the non-dominant arm with those previously documented in the dominant arm, we demonstrate that goal-directed tuning of short and long latency stretch reflexes is markedly weaker in the non-dominant limb. The results indicate that the motor performance asymmetries across the two upper limbs is partly due to the more sophisticated control of reflexive stiffness in the dominant limb, likely facilitated by the superior goal-directed control of muscle spindle receptors. Our findings therefore suggest that independent fusimotor control plays a role in determining performance of complex motor behaviours and support existing proposals that the dominant arm is better supplied for executing more complex tasks, such as trajectory control.Key pointsMost of us routinely rely on the dominant arm to perform more complex and demanding motor tasks, but the mechanisms enabling the superior motor performance of the dominant limb are unclear.A better understanding of the motor asymmetry across the two arms might provide key insight into core sensorimotor principles.This study shows that goal-directed tuning of short and long latency stretch reflexes in the non-dominant arm is markedly weaker than in the dominant arm.Our results suggest that the more sophisticated control of reflexive stiffness in the dominant limb, likely facilitated by superior fusimotor control, partly underpins the laterality of motor performance.
Biologically plausible unsupervised learning in neural networks with sparse and asymmetric connectivity
Authors: Brodersen Paul J N , Akerman Colin J 
Published: December 2022

AbstractIn the search for biologically plausible but mathematically precise theories of learning in the brain, recent studies have begun to investigate how key assumptions underlying algorithms for supervised learning in artificial neural networks can be relaxed in biologically plausible ways. Turning to unsupervised learning, we develop biologically more plausible variants of the restricted Boltzmann machine (RBM), and benchmark their performance on MNIST. We show that RBMs with asymmetric connectivity can still be successfully trained with contrastive divergence, even if no two units are reciprocally connected. Furthermore, RBMs are able to learn if the forward, visible-to-hidden layer weights are kept constant and only the backward, hidden-to-visible layer weights are updated. These findings indicate that neural networks with biologically plausible connectivity support contrastive learning.
Mammalian glial protrusion transcriptomes predict localization ofDrosophilaglial transcripts required for synaptic plasticity
Authors: Gala Dalia S. , Lee Jeffrey Y. , Kiourlappou Maria , Titlow Joshua S. , Teodoro Rita O. , Davis Ilan 
Published: December 2022

SUMMARYThe polarization of cells often involves the transport of specific mRNAs and their localized translation in distal projections. Neurons and glia both contain long cytoplasmic processes with important functions. mRNA localization has been studied extensively in neurons, but very little in glia, especially in intact nervous systems. Here, we predicted 1,700 localizedDrosophilaglial transcripts by extrapolating from our meta-analysis of 8 existing studies characterizing the localized transcriptomes and translatomes of synaptically-associated mammalian glia. We tested these predictions in glia of the neuromuscular junction ofDrosophilalarvae and found that localization to mammalian glia is a strong predictor of mRNA localization of the high confidenceDrosophilahomologues. We further showed that some of these localized transcripts are required in glia for plasticity of the neuromuscular junction synapses. We conclude that peripheral glial mRNA localization is a common and conserved phenomenon and propose that it is likely to be functionally important.
The lncRNA landscape of cardiac resident macrophages and identification ofSchlafenlncas a regulator of macrophage migratory function
Authors: Dueck Anne , Althaus Lara , Heise Kathrin , Esfandyari Dena , Baygün Seren , Brandes Ralf P. , Gagneur Julien , Jaé Nicolas , Knolle Percy , Leisegang Matthias S. , Maegdefessel Lars , Meitinger Thomas , Petzold Niklas , Ramanujam Deepak , Sager Hendrik , Schulz Christian , Theodorakis Evangelos , Uzonyi Anna , Weinberger Tobias , Bader Michael , Schmidt-Supprian Marc , Engelhardt Stefan 
Published: December 2022

ABSTRACTCardiac resident macrophages (crMPs) were recently shown to exert pivotal functions in cardiac homeostasis and disease, but the underlying molecular mechanisms are largely unclear. Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulatory molecules in a number of cell types, but neither the identity nor the molecular mechanisms of lncRNAs in crMPs are known. Here, we have employed deep RNA-seq and single cell RNA sequencing to resolve the crMP lncRNA landscape from healthy and diseased murine myocardium. CrMPs express previously unknown and highly cell type-specific lncRNAs, among which one lncRNA, termedSchlafenlnc, was particularly abundant and enriched in crMPs. We foundSchlafenlncto be necessary for migration-associated gene expression in macrophagesin vitroandin vivoand essential for their adhesion and migration. Collectively, our data provide a basis to the systematic characterization of lncRNAs in crMPs and establishSchlafenlncas a critical regulator of macrophage migratory functions.
Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington’s disease
Authors: Tano Vincent , Utami Kagistia Hana , Yusof Nur Amirah Binte Mohammad , Pouladi Mahmoud A , Langley Sarah R 
Published: December 2022

ABSTRACTIn Huntington’s disease (HD), a CAG repeat expansion mutation in theHTTgene drives a gain-of-function toxicity that disrupts mRNA processing. Although widespread dysregulation of gene splicing in the striatum has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes due to neuronal loss and astrogliosis in late stage HD. This limits the ability to identify dysregulation related to early pathogenesis. To study alternative splicing changes in early HD, we performed RNA-sequencing analysis in an established isogenic HD neuronal cell model. We report cell type-associated and CAG length-dependent splicing changes, and find an enrichment of RNA processing genes coupled with neuronal function-related genes showing mutantHTT-associated splicing changes. Comparison with post-mortem data also identified splicing events associated with early pathogenesis that persist to later stages of disease. In summary, our results highlight splicing dysregulation in RNA processing genes in early and late-stage HD, which may lead to disrupted neuronal function and neuropathology.
Assessing the risk of endogeneity bias in health and mortality inequalities research using composite measures of multiple deprivation which include health-related indicators: A case study using the Scottish Index of Multiple Deprivation and population health and mortality data
Authors: Bradford D R R , Allik M , McMahon A D , Brown D 
Published: December 2022

ABSTRACTThe inclusion of health-related indicators in composite measures of multiple deprivation introduces a risk of endogeneity bias when using the latter in health inequalities research. This bias may ultimately result in the inappropriate allocation of healthcare resources and maintenance of preventable health inequalities. Mitigation strategies to avoid this bias include removing the health-related indicators or using single constituent domains (such as income or employment class) in isolation. These strategies have not been widely validated. This study used populationlevel health and mortality data with a contemporary composite measure of multiple deprivation (Scottish Index of Multiple Deprivation; SIMD) to assess these mitigation strategies. The differences between deprivation methods (original, health excluded, and income domain) were negligible. The results of quantitative research on health inequalities are unlikely to be affected by endogeneity bias.
A role for MCH neuron firing in hippocampal plasticity and learning
Authors: Harris Julia J. , Concetti Cristina , Peleg-Raibstein Daria , Burdakov Denis 
Published: December 2022

ABSTRACTIt has been revealed that melanin-concentrating hormone (MCH) neurons in the hypothalamus can influence learning (Liu et al., 2022) and memory formation (Kosse & Burdakov, 2019), but the cellular mechanisms by which they perform this function are not understood. Here, we examine the role of MCH neural input to the hippocampus, and showin vitrothat optogenetically increasing MCH axon activity facilitates hippocampal plasticity by lowering the threshold for synaptic potentiation.In vivo, we find that MCH neurons are naturally active in response to reinforcing cues during a spatial learning task, and that this activity is correlated with the speed of learning. Together, our results align with increasing evidence that MCH neurons play an ‘on-line’ regulatory role in learning, and reveal that this could be achieved through modulation of synaptic plasticity in the hippocampus.
Deep learning models of perceptual expertise support a domain-specific account
Authors: Yovel Galit , Grosbard Idan , Abudarham Naphtali 
Published: December 2022

AbstractPerceptual expertise is an acquired skill that enables fine discrimination of members of a homogenous category. The question of whether perceptual expertise is mediated by general-expert or domain-specific processing mechanisms has been hotly debated for decades in human behavioral and neuroimaging studies. To decide between these two hypotheses, most studies examined whether expertise for different domains is mediated by the same mechanisms used for faces, for which most humans are expert. Here we used deep convolutional neural networks (DCNNs) to test whether perceptual expertise is best achieved by computations that are optimized for face or object classification. We re-trained a face-trained and an object-trained DCNNs to classify birds at the sub-ordinate or individual-level of categorization. The face-trained DCNN required deeper retraining to achieve the same level of performance for bird classification as an object-trained DCNN. These findings indicate that classification at the subordinate- or individual-level of categorization does not transfer well between domains. Thus, fine-grained classification is best achieved by using domain-specific rather than domain-general computations.