bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell-type specific auditory responses in the striatum are shaped by feed forward inhibition
Authors: Druart Mélanie , Kori Megha , Chaimowitz Corryn , Fan Catherine , Sippy Tanya 
Published: May 2024

Summary/AbstractThe posterior “tail” region of the striatum receives dense innervation from sensory brain regions and has been demonstrated to play a role in behaviors that require sensorimotor integration including discrimination1,2, avoidance3and defense4responses. The output neurons of the striatum, the D1 and D2 striatal projection neurons (SPNs) that make up the direct and indirect pathways, respectively, are thought to play differential roles in these behavioral responses, although it remains unclear if or how these neurons display differential responsivity to sensory stimuli. Here, we used whole-cell recordings in vivo and ex vivo to examine the strength of excitatory and inhibitory synaptic inputs onto D1 and D2 SPNs following the stimulation of upstream auditory pathways. While D1 and D2 SPNs both displayed stimulus-evoked depolarizations, D1 SPN responses were stronger and faster for all stimuli tested in vivo as well as in brain slices. This difference did not arise from differences in the strength of excitatory inputs but from differences in the strength of feed forward inhibition. Indeed, fast spiking interneurons, which are readily engaged by auditory afferents exerted stronger inhibition onto D2 SPNs compared to D1 SPNs. Our results support a model in which differences in feed forward inhibition enable the preferential recruitment of the direct pathway in response to auditory stimuli, positioning this pathway to initiate sound-driven actions.
Depression in Parkinson’s disease is associated with dopamine unresponsive reduced reward sensitivity during effort-based decision making
Authors: Costello Harry , Yamamori Yumeya , Kieslich Karel , Murphy Mackenzie , Bobyreva Kamilla , Schrag Anette-Eleonore , Howard Robert , Roiser Jonathan P 
Published: May 2024

AbstractWillingness to exert effort for a given goal is dependent on the magnitude of the potential rewards and effort costs of an action. Such effort-based decision making is an essential component of motivation, in which the dopaminergic system plays a key role. Depression in Parkinson’s disease (PD) is common, disabling and has poor outcomes. Motivational symptoms such as apathy and anhedonia, are prominent in PD depression and related to dopaminergic loss. We hypothesised that dopamine-dependent disruption in effort-based decision-making contributes to depression in PD.In the present study, an effort-based decision-making task was administered to 62 patients with PD, with and without depression, ON and OFF their dopaminergic medication across two sessions, as well as to 34 patients with depression and 29 matched controls on a single occasion. During the task, on each trial, participants decided whether to accept or reject offers of different levels of monetary reward in return for exerting varying levels of physical effort via grip force, measured using individually calibrated dynamometers. The primary outcome variable was choice (accept/decline offer), analysed using both logistic mixed-effects modelling and a computational model which dissected the individual contributions of reward and effort on depression and dopamine state in PD.We found PD depression was characterised by lower acceptance of offers, driven by markedly lower incentivisation by reward (reward sensitivity), compared to all other groups. Within-subjects analysis of the effect of dopamine medication revealed that, although dopamine treatment improves reward sensitivity in non-depressed PD patients, this therapeutic effect is not present in PD patients with depression.These findings suggest that disrupted effort-based decision-making, unresponsive to dopamine, contributes to PD depression. This highlights reward sensitivity as a key mechanism and treatment target for PD depression that potentially requires non-dopaminergic therapies.
Mitochondrial Phosphopantetheinylation is Required for Oxidative Function
Authors: Norden Pieter R. , Wedan Riley J. , Longenecker Jacob Z. , Preston Samuel E. J. , Graber Naomi , Pentecost Olivia A. , Canfield Morgan , McLaughlin Elizabeth , Nowinski Sara M. 
Published: May 2024

Abstract4’-phosphopantetheinyl (4’PP) groups are essential co-factors added to target proteins byphosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4’PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTaseaminoadipatesemialdehydedehydrogenasephosphopantetheinyltransferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4’-PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative function. We further identify two variants of uncertain significance inAASDHPPTthat are likely pathogenic in humans due to loss of mtFAS activity.
Yes Associated Transcriptional Regulator 1 (YAP1) and WW Domain Containing Transcription Regulator (WWTR1) are required for murine pregnancy initiation
Authors: Moldovan Genna E. , Massri Noura , Vegter Erin , Pauneto-Delgado Ivonne L , Burns Gregory W. , Joshi Niraj , Gu Bin , Arora Ripla , Fazleabas Asgerally T. 
Published: May 2024

AbstractEndometrial stromal cell decidualization is required for pregnancy success. Although this process is integral to fertility, many of the intricate molecular mechanisms contributing to decidualization remain undefined. One pathway that has been implicated in endometrial stromal cell decidualization in humansin vitrois the Hippo signaling pathway. Two previously conducted studies showed that the effectors of the Hippo signaling pathway, YAP1 and WWTR1, were required for decidualization of primary stromal cells in culture. To investigate thein vivorole of YAP1 and WWTR1 in decidualization and pregnancy initiation, we generated aProgesterone Cremediated partial double knockout (pdKO) ofYap1andWwtr1. Female pdKOs exhibited subfertility, a compromised decidualization response, partial interruption in embryo transport, blunted endometrial receptivity, delayed implantation and subsequent embryonic development, and a unique transcriptional profile. Bulk mRNA sequencing revealed aberrant maternal remodeling evidenced by significant alterations in extracellular matrix proteins at 7.5 days post-coitus in pdKO dams and enrichment for terms associated with fertility-compromising diseases like pre-eclampsia and endometriosis. Our results indicate a required role for YAP1 and WWTR1 for successful mammalian uterine function and pregnancy success.
Experimental parkinsonism induced by tetanus toxin injected into basal ganglia
Authors: Meglić Patrik , Šoštarić Petra , Habek Nikola , Virag Davor , Knezović Ana , Matak Ivica 
Published: May 2024

AbstractBackground and ObjectivesLocal inhibitory circuits and long-range inhibitory projections within the interconnected basal ganglia nuclei are critical for control of voluntary movement and pathophysiology of different extrapyramidal movement disorders. Herein, we examined the major motor effects of tetanus neurotoxin (TeNT), a presynaptic neurotoxin that selectively targets the GABA-ergic synaptic transmission, when injected into individual basal ganglia nuclei.MethodsThe rats were injected with low-dose TeNT (0.4-0.8 ng) unilaterally into globus pallidus internus (GPi), substantia nigra (SN), or caudate putamen (CPu). The effects of TeNT-induced disinhibition were characterized by repeated assessments of motor coordination, gait, and rotational behavior, followed by measurement of regional protein content of major neuronal monoaminergic, GABA-ergic and glutamatergic population markers.ResultsIn the beamwalk test, the CPu injection of TeNT induced contralateral plantar misplacement. TeNT injections into GPi and CPu were associated with decreased stride length and increased duration of step cycle and induced a slight ipsiversive circling during open field observation, and more intensive rotational behavior during swimming, differentially affected by D-amphetamine. Unlike rotational behavior, the gait and motor control deficits during beamwalk recovered promptly by day 14 post TeNT, which, along with the lack of reduced neuronal marker protein contents, suggested the reversibility and lack of neuronal degeneration.Conclusion and ImplicationsTetanus toxin injected into basal ganglia evokes transient hypokinetic motor dysfunctions consistent with experimental parkinsonism, with differential occurrence of individual motor symptoms depending on the region targeted. These results suggest that TeNT might be a useful non-neurodegenerative pharmacological agent for investigating the motor control abnormalities involving GABA-ergic basal ganglia circuits.
Evolutionary Insights from the Mitochondrial Genome ofOikopleura dioica: Sequencing Challenges, RNA Editing, Gene Transfers to the Nucleus, and tRNA Loss
Authors: Klirs Yael , Novosolov Maria , Gissi Carmela , Garic Rade , Pupko Tal , Stach Thomas , Huchon Dorothée 
Published: May 2024

AbstractSequencing the mitochondrial genome of the tunicateOikopleura dioicais a challenging task due to the presence of long poly-A/T homopolymer stretches, which impair sequencing and assembly. Here, we report on the sequencing and annotation of the majority of the mitochondrial genome ofO. dioicaby means of combining several DNA and amplicon reads obtained by Illumina and MinIon Oxford Nanopore Technologies (ONT) with public RNA sequences. We document extensive RNA editing, since all homopolymer stretches present in the mitochondrial DNA correspond to 6U-regions in the mitochondrial RNA. Out of the 13 canonical protein-coding genes, we were able to detect eight, plus an unassigned ORF that lacked sequence similarity to canonical mitochondrial protein-coding genes. We show that thenad3gene has been transferred to the nucleus and acquired a mitochondria-targeting signal. In addition to two very short rRNAs, we could only identify a single tRNA (tRNA-Met), suggesting multiple losses of tRNA genes, supported by a corresponding loss of mitochondrial aminoacyl-tRNA synthetases in the nuclear genome. Based on the eight canonical protein-coding genes identified, we reconstructed maximum likelihood and Bayesian phylogenetic trees and inferred an extreme evolutionary rate of this mitochondrial genome. The phylogenetic position of appendicularians among tunicates, however, could not be accurately determined.SignificanceSequencing and annotating the mitochondrial genome of fast-evolving organisms is difficult because they often present unusual characteristics. The tunicateOikopleura dioicais a model species for understanding tunicate and chordate genome evolution. However, no complete annotated mitochondrial genome for this species has been published to date. Here, we determined the major part of the mitochondrial genome ofO. dioica. Our results indicate the presence of highly modified rRNA genes and the absence of all tRNAs except tRNA-Met. Moreover, we show that the mitochondrial genome undergoes editing at the RNA level. Our study demonstrates that utilizing a combination of public RNA data and DNA from long-and short-read sequencing platforms significantly improves our ability to study mitochondrial genomes with atypical characteristics.
Histone Modifications and miRNA Perturbations Contribute to Transcriptional Dysregulation of Hypertrophy in Obstructive Hypertrophic Cardiomyopathy
Authors: Garmany Ramin , Dasari Surendra , Bos J. Martijn , Kim Evelyn T. , Tester David J. , Remedios Cristobal dos , Maleszewski Joseph J. , Robertson Keith D. , Dearani Joseph A. , Ommen Steve R. , Giudicessi John R. , Ackerman Michael J. 
Published: May 2024

AbstractBackgroundRecently, we demonstrated transcriptional downregulation of hypertrophy pathways in myectomy tissue derived from patients with obstructive hypertrophic cardiomyopathy (HCM) despite translational activation of hypertrophy pathways. The mechanisms and modifiers of this transcriptional dysregulation in HCM remain unexplored. We hypothesized that miRNA and post-translational modifications of histones contribute to transcriptional dysregulation in HCM.MethodsFirst, miRNA-sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) were performed on HCM myectomy tissue and control donor hearts to characterize miRNA and differential histone marks across the genome. Next, the differential miRNA and histone marks were integrated with RNA-sequencing (RNA-seq) data. Finally, the effects of miRNA and histones were removedin silicoto determine their necessity for transcriptional dysregulation of pathways.ResultsmiRNA-analysis identified 19 differentially expressed miRNA. ChIP-seq analysis identified 2,912 (7%) differential H3K4me3 peaks, 23,339 (21%) differential H3K9ac peaks, 33 (0.05%) differential H3K9me3 peaks, 58,837 (42%) differential H3K27ac peaks, and 853 (3%) differential H3K27me3 peaks. Univariate analysis of concordance between H3K9ac with RNA-seq data showed activation of cardiac hypertrophy signaling, while H3K27me showed downregulation of cardiac hypertrophy signaling. Similarly, miRNAs were predicted to result in downregulation of cardiac hypertrophy signaling.In silicoknock-out that effects either miRNA or histones attenuated transcriptional downregulation while knocking out both abolished downregulation of hypertrophy pathways completely.ConclusionMyectomy tissue from patients with obstructive HCM shows transcriptional dysregulation, including transcriptional downregulation of hypertrophy pathways mediated by miRNA and post-translational modifications of histones. Cardiac hypertrophy loci showed activation via changes in H3K9ac and a mix of activation and repression via H3K27ac.
Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism
Authors: Dierks David , Shachar Ran , Nir Ronit , Garcia-Campos Miguel Angel , Uzonyi Anna , Wiener David , Toth Ursula , Rossmanith Walter , Lasman Lior , Slobodin Boris , Hanna Jacob H. , Antebi Yaron , Scherz-Shouval Ruth , Schwartz Schraga 
Published: May 2024

Abstractm6A is the most widespread mRNA modification and is primarily implicated in controlling mRNA stability. Fundamental questions pertaining to m6A are the extent to which it is dynamically modulated within cells and across stimuli, and the forces underlying such modulation. Prior work has focused on investigatingactivemechanisms governing m6A levels, such as recruitment of m6A writers or erasers leading to either ‘global’ or ‘site-specific’ modulation. Here, we propose that changes in m6A levels across subcellular compartments and biological trajectories may result frompassivechanges in gene-level mRNA metabolism. To predict the intricate interdependencies between m6A levels, mRNA localization, and mRNA decay, we establish a differential model ‘m6ADyn’ encompassing mRNA transcription, methylation, export, and m6A-dependent and independent degradation. We validate the predictions of m6ADyn in the context of intracellular m6A dynamics, where m6ADyn predicts associations between relative mRNA localization and m6A levels, which we experimentally confirm. We further explore m6ADyn predictions pertaining to changes in m6A levels upon controlled perturbations of mRNA metabolism, which we also experimentally confirm. Finally, we demonstrate the relevance of m6ADyn in the context of cellular heat stress response, where genes subjected to altered mRNA product and export also display predictable changes in m6A levels, consistent with m6ADyn predictions. Our findings establish a framework for dissecting m6A dynamics and suggest the role of passive dynamics in shaping m6A levels in mammalian systems.
Mammalian RNAi represses pericentromeric lncRNAs to maintain genome stability
Authors: Sandoval Rafael , Dilsavor Corinne N. , Grishanina Nadia R. , Patel Vandan , Zamudio Jesse R. 
Published: May 2024

AbstractMammalian pericentromeric tandem repeats produce long noncoding RNAs (lncRNAs) that are dysregulated in cancer and linked to genomic instability. Identifying the basic molecular characteristics of these lncRNAs and their regulation is important to understanding their biological function. Here, we determine that the Argonaute (Ago) proteins of the RNA interference (RNAi) pathway directly and uniformly repress bidirectional pericentromeric lncRNAs in a Dicer-dependent manner in mouse embryonic and adult stem cells. Ago-dependent and Dicer-dependent autoregulatory small RNAs were identified within pericentromeric lncRNA degradation intermediates. We develop an RNase H cleavage assay to determine the relative proportions and lengths of the pericentromeric lncRNA targets. We find that 5’-phosphate and non-polyadenylated bidirectional pericentromeric lncRNAs are expressed at similar proportions. These lncRNAs can span up to 9 repeats, with transcription from the reverse strand template yielding the longer products. Using pericentromeric repeat RNA reporters, we determine that Ago represses pericentromeric lncRNAs after S phase transcription. Upon loss of Ago, pericentromeric lncRNA dysregulation results in delayed cell cycle progression, a defective mitotic spindle assembly checkpoint (SAC) and genomic instability. These results show that an evolutionarily conserved Ago activity at pericentromeres contributes to mammalian genome stability.
Assessing the Impact of Valve Sizing and Orientation on Bioprosthetic Pulmonary Valve Hemodynamics Using In Vitro 4D-Flow MRI
Authors: Schiavone Nicole K. , Nair Priya J. , Elkins Christopher J. , McElhinney Doff B. , Ennis Daniel B. , Eaton John K. , Marsden Alison L. 
Published: May 2024

AbstractPurposePulmonary valve replacement (PVR) using bioprosthetic valves is a common procedure performed in patients with repaired Tetralogy of Fallot and other conditions, but these valves frequently become dysfunctional within 15 years of implantation. Since PVR is often performed in adolescence, valves are typically oversized to account for somatic growth. However, the contribution of oversizing to early valve failure are not clearly understood. The purpose of this study was to explore the impact of valve sizing and orientation on local hemodynamics and valve performance.MethodsDifferent valve sizes were represented by changing the cardiac output through a 25 mm bioprosthetic valve implanted in an idealized 3D-printed model of the right ventricular outflow tract (RVOT). The local hemodynamics at three valve sizes and two valve orientations were assessed using 4D-Flow MRI and high-speed camera imaging.ResultsNoticeable differences in jet asymmetry, the amount of recirculation, leaflet opening patterns, as well as the size and location of reversed flow regions were observed with varying valve sizes. Rotation of the valve resulted in drastic differences in reversed flow regions, but not forward flow.ConclusionFlow features observed in the oversized valve in this study have previously been correlated with calcification, hemolysis, and leaflet fatigue. Therefore, valve oversizing can negatively impact local hemodynamics and leaflet performance.
Oxysterol accumulation in aging cells alters GPCR signalling
Authors: Asthana Suramya , Verma Anant , Bhattacharya Baivabi , Nath Arnab , Sajeev Nithin , Maan Kiran , Nair Raji R. , Ayappa K. Ganapathy , Saini Deepak K. 
Published: May 2024

AbstractOrganismal aging is accompanied by the accumulation of senescent cells in the body, which drives tissue dysfunction. Senescent cells have a distinctive profile, including proliferation arrest, resistance to apoptosis, altered gene expression, and high inflammation. Despite global signalling and metabolic dysregulation during senescence, the underlying reasons for changes in signalling remain unclear. GPCRs are pivotal in cellular signalling, dynamically mediating the complex interplay between cells and their surrounding environment to maintain cellular homeostasis. The chemokine receptor CXCR4 plays a crucial role in modulating immune responses and inflammation. It has been shown that expression of CXCR4 increases in cells undergoing senescence, which enhances inflammation post-activation. Here we examine CXCR4 signalling in deeply senescent cells, where cholesterol and its oxidized derivatives, oxysterols, affect receptor function. We report elevated oxysterol levels in senescent cells, which altered classical CXCL12-mediated CXCR4 signalling. Tail-oxidized sterols disrupted signalling more than ring-oxidized counterparts. Molecular dynamics simulations revealed that 27-hydroxycholesterol displaces cholesterol and binds strongly to alter the conformation of critical signalling residues to modify the sterol-CXCR4 interaction landscape. Our study provides a molecular view of the observed mitigated GPCR signalling in the presence of oxysterols, which switched G-protein signalling from Gαi/oto Gαsclass. Overall, we present an altered paradigm of GPCR signalling where cholesterol oxidation alters the signalling outcome in aged cells.Significance StatementOur study brings to light a novel and significant discovery in aged cells: the accumulation of oxysterols, oxidized forms of cholesterol, critically impairs CXCR4-dependent signalling and alters G-protein coupling specificity. This effect of oxysterols is demonstrated for the first time in aged cellular models, providing a molecular basis for a multitude of observed alterations in senescence, such as compromised immune functions and a decline in cellular responsiveness with age. Our research not only fills a crucial gap in understanding the aging process at the molecular level but also identifies potential targets for therapeutic interventions aimed at mitigating age-related cellular dysfunctions and diseases.