bluuebunny/crossref_metadata_2025_split huggingface dataset:
The specific AMPK activator A-769662 ameliorates pathological phenotypes following mitochondrial DNA depletion
Authors: Carvalho Gustavo , Repolês Bruno , Nguyen Tran V.H. , Forslund Josefin M.E. , Ranjbarian Farahnaz , Mendes Isabela C. , Falabella Micol , Doimo Mara , Wanrooij Sjoerd , Pitceathly Robert D.S. , Hofer Anders , Wanrooij Paulina H. 
Published: March 2024

AbstractAMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, it is currently unclear how severe of a mitochondrial dysfunction is required to trigger AMPK activation, and whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cell model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP+ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist was also observed in cells from patients suffering from mtDNA depletion. However, the positive effects of A-769662 in the two experimental cell models appeared to involve at least partially different mechanisms. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function, and suggest a potential utility for these compounds in disease states involving mtDNA depletion.
Early-life stress alters chromatin modifications in VTA to prime stress sensitivity
Authors: Geiger Luke T. , Balouek Julie-Anne , Farrelly Lorna A. , Chen Andy S. , Tang Megan , Bennett Shannon N. , Nestler Eric J. , Garcia Benjamin A. , Maze Ian , Peña Catherine Jensen 
Published: March 2024

ABSTRACTEarly-life stress increases sensitivity to subsequent stress, which has been observed among humans, other animals, at the level of cellular activity, and at the level of gene expression. However, the molecular mechanisms underlying such long-lasting sensitivity are poorly understood. We tested the hypothesis that persistent changes in transcription and transcriptional potential were maintained at the level of the epigenome, through changes in chromatin. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome-editing, behavioral quantification, and RNA-sequencing in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a brain region critically implicated in motivation, reward learning, stress response, and mood and drug disorders. We find that early-life stress in mice alters histone dynamics in VTA and that a majority of these modifications are associated with an open chromatin state that would predict active, primed, or poised gene expression, including enriched histone-3 lysine-4 methylation and the H3K4 monomethylase Setd7. Mimicking ELS through over-expression of Setd7 and enrichment of H3K4me1 in VTA recapitulates ELS-induced behavioral and transcriptional hypersensitivity to future stress. These findings enrich our understanding of the epigenetic mechanisms linking early-life environmental experiences to long-term alterations in stress reactivity within the brain’s reward circuitry, with implications for understanding and potentially treating mood and anxiety disorders in humans.
Identification of a new family of peptidoglycan transpeptidases reveals atypical crosslinking is essential for viability inClostridioides difficile
Authors: Bollinger Kevin W. , Müh Ute , Ocius Karl L. , Apostolos Alexis J. , Pires Marcos M. , Helm Richard F. , Popham David L. , Weiss David S. , Ellermeier Craig D. 
Published: March 2024

ABSTRACTClostridioides difficile, the leading cause of antibiotic-associated diarrhea, relies primarily on 3-3 crosslinks created by L,D-transpeptidases (LDTs) to fortify its peptidoglycan (PG) cell wall. This is unusual, as in most bacteria the vast majority of PG crosslinks are 4-3 crosslinks, which are created by penicillin-binding proteins (PBPs). Here we report the unprecedented observation that 3-3 crosslinking is essential for viability inC. difficile. We also report the discovery of a new family of LDTs that use a VanW domain to catalyze 3-3 crosslinking rather than a YkuD domain as in all previously known LDTs. Bioinformatic analyses indicate VanW domain LDTs are less common than YkuD domain LDTs and are largely restricted to Gram-positive bacteria. Our findings suggest that LDTs might be exploited as targets for antibiotics that killC. difficilewithout disrupting the intestinal microbiota that is important for keepingC. difficilein check.
Identification of novel evolutionarily conserved genes and pathways in human and mouse musculoskeletal progenitors
Authors: Saravanan S , Devika A. S , Pranty Abida Islam , Shaji R. V , Bhushan Raghu , Adjaye James , Sudheer Smita 
Published: March 2024

AbstractThe axial skeletal system and skeletal muscles of the vertebrates arise from somites, the blocks of tissues flanking both sides of the neural tube. The progenitors of Somites, called the Presomitic Mesoderm (PSM) reside at the posterior end of a developing embryo. Most of our understanding about these two early developmental stages comes from the studies on chick and mouse, and in the recent past, there have been a few studies on human. Here, we have analysed and compared the RNA-sequencing data of PSM and somite tissues from Mouse and Human. The functional and pathway enrichment analysis identified the key Hub-genes that are evolutionarily conserved in the PSM and the somites of both the organisms that include 23 multifunctional genes likely to be associated with different developmental disorders in humans. Our analysis revealed that NOTCH, WNT, MAPK, BMP, Calcium, ErbB, cGMP-PKG, RAS and RAP1 signaling pathways are conserved in both human and mouse during the development of PSM and Somites. Furthermore, we validated the expression of representative conserved candidates in the hESCs-derived PSM and somite cells (NOG,BMP2,BMP7,BMP5,HES5andMEF2C). Taken together, our study identifies putative gene interactions and pathways that are conserved across the mouse and human genomes, which may potentially have crucial roles in human PSM and somite development.
Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression
Authors: Pizzirusso Giusy , Preka Efthalia , Goikolea Julen , Aguilar-Ruiz Celia , Rodriguez Patricia Rodriguez , Cabrera Guillermo Vazquez , Laterza Simona , Leal Maria Latorre , Eroli Francesca , Blomgren Klas , Maioli Silvia , Nilsson Per , Fragkopoulou Adamantia , Fisahn André , Arroyo-García Luis Enrique 
Published: March 2024

AbstractAlzheimer’s disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer’s disease onset and progression. Characterizing the initial phase of Alzheimer’s disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used theAppNL-G-Fknock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer’s disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis-and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network’s functionality. These results suggest that the early loss of microglia could be a pivotal event in the progression of Alzheimer’s disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.
The Dystrophin-Dystroglycan complex ensures cytokinesis efficiency inDrosophilaepithelia
Authors: Gonçalves Margarida , Lopes Catarina , Alégot Hervé , Osswald Mariana , Bosveld Floris , Ramos Carolina , Richard Graziella , Bellaiche Yohanns , Mirouse Vincent , Morais-de-Sá Eurico 
Published: March 2024

ABSTRACTCytokinesis physically separates daughter cells at the end of cell division. This step is particularly challenging for epithelial cells, which are connected to their neighbors and to the extracellular matrix by transmembrane protein complexes. To systematically evaluate the impact of the cell adhesion machinery on epithelial cytokinesis efficiency, we performed an RNAi-based modifier screen in theDrosophilafollicular epithelium. Strikingly, this unveiled adhesion molecules and transmembrane receptors that facilitate cytokinesis completion. Among these is Dystroglycan, which connects the extracellular matrix to the cytoskeleton via Dystrophin. Live imaging revealed that Dystrophin and Dystroglycan become enriched in the ingressing membrane, below the cytokinetic ring, during and after ring constriction. Using multiple alleles, including Dystrophin isoform-specific mutants, we show that Dystrophin/Dystroglycan localization is linked with unanticipated roles in regulating cytokinetic ring contraction and in preventing membrane regression during the abscission period. Altogether, we provide evidence that, rather than opposing cytokinesis completion, the machinery involved in cell-cell and cell-matrix interactions has also evolved functions to ensure cytokinesis efficiency in epithelial tissues.
Optimal motion-in-depth estimation with natural stimuli
Authors: Herrera-Esposito Daniel , Burge Johannes 
Published: March 2024

AbstractEstimating the motion of objects in depth is important for behavior, and is strongly supported by binocular visual cues. To understand both how the brain should estimate motion in depth and how natural constraints shape and limit performance, we develop image-computable ideal observer models from naturalistic binocular video clips of two 3D motion tasks. The observers spatio-temporally filter the videos, and non-linearly decode 3D motion from the filter responses. The optimal filters and decoder are dictated by the task-relevant natural image statistics, and are specific to each task. Multiple findings emerge. First, two distinct filter types are spontaneously learned for each task. For 3D speed estimation, filters emerge for processing either changing disparities over time (CDOT) or interocular velocity differences (IOVD), cues used by humans. For 3D direction estimation, filters emerge for discriminating either left-right or towards-away motion. Second, the filter responses, conditioned on the latent variable, are well-described as jointly Gaussian, and the covariance of the filter responses carries the information about the task-relevant latent variable. Quadratic combination is thus necessary for optimal decoding, which can be implemented by biologically plausible neural computations. Finally, the ideal observer yields non-obvious–and in some cases counter-intuitive–patterns of performance like those exhibited by humans. Important characteristics of human 3D motion processing and estimation may therefore result from optimal information processing in the early visual system.Significance statementHumans and other animals extract and process features of natural images that are useful for estimating motion-in-depth, an ability that is crucial for successful interaction with the environment. But the enormous diversity of natural visual inputs that are consistent with a given 3D motion–natural stimulus variability–presents a challenging computational problem. The neural populations that support the estimation of motion-in-depth are under active investigation. Here, we study how to optimally estimate local 3D motion with naturalistic stimulus variability. We show that the optimal computations are biologically plausible, and that they reproduce sometimes counterintuitive performance patterns independently reported in the human psychophysical literature. Novel testable hypotheses for future neurophysiological and psychophysical research are discussed.
Astrocyte CCN1 stabilizes neural circuits in the adult brain
Authors: Sancho Laura , Boisvert Matthew M. , Dawoodtabar Trinity , Burgado Jillybeth , Wang Ellen , Allen Nicola J. 
Published: March 2024

AbstractNeural circuits in many brain regions are refined by experience. Sensory circuits support higher plasticity at younger ages during critical periods - times of circuit refinement and maturation - and limit plasticity in adulthood for circuit stability. The mechanisms underlying these differing plasticity levels and how they serve to maintain and stabilize the properties of sensory circuits remain largely unclear. By combining a transcriptomic approach withex vivoelectrophysiology andin vivoimaging techniques, we identify that astrocytes release cellular communication network factor 1 (CCN1) to maintain synapse and circuit stability in the visual cortex. By overexpressing CCN1 in critical period astrocytes, we find that it promotes the maturation of inhibitory circuits and limits ocular dominance plasticity. Conversely, by knocking out astrocyte CCN1 in adults, binocular circuits are destabilized. These studies establish CCN1 as a novel astrocyte-secreted factor that stabilizes neuronal circuits. Moreover, they demonstrate that the composition and properties of sensory circuits require ongoing maintenance in adulthood, and that these maintenance cues are provided by astrocytes.
A random mutagenesis screen enriched for missense mutations in bacterial effector proteins
Authors: Urbanus Malene L. , Zheng Thomas M. , Khusnutdinova Anna N. , Banh Doreen , Mount Harley O’Connor , Gupta Alind , Stoigos Peter J. , Savchenko Alexei , Isberg Ralph R. , Yakunin Alexander F. , Ensminger Alexander W. 
Published: March 2024

AbstractTo remodel their hosts and escape immune defenses, many pathogens rely on large arsenals of proteins (effectors) that are delivered to the host cell using dedicated translocation machinery. Effectors hold significant insight into the biology of both the pathogens that encode for them and the host pathways that they manipulate. One of the most powerful systems biology tools for studying effectors is the model organism,Saccharomyces cerevisiae. For many pathogens, the heterologous expression of effectors in yeast is growth inhibitory at a frequency much higher than housekeeping genes, an observation ascribed to targeting conserved eukaryotic proteins. Abrogation of yeast growth inhibition has been used to identify bacterial suppressors of effector activity, host targets, and functional residues and domains within effector proteins. We present here a yeast-based method for enriching for informative, in-frame, missense mutations in a pool of random effector mutants. We benchmark this approach against three effectors fromLegionella pneumophila, an intracellular bacterial pathogen that injects a staggering >330 effectors into the host cell. For each protein, we show howin silicoprotein modeling (AlphaFold2) and missense- directed mutagenesis can be combined to reveal important structural features within effectors. We identify known active site residues within the metalloprotease RavK, highly conserved residues in SdbB, and previously unidentified functional motifs within the C-terminal domain of SdbA. We show that this domain has structural similarity with glycosyltransferases and exhibitsin vitroactivity consistent with this predicted function.
YTHDC1 cooperates with the THO complex to prevent RNA damage-induced DNA breaks
Authors: Tsao Ning , Olabode Jennifer , Rodell Rebecca , Sun Hua , Brickner Joshua R. , Tsai Miaw-Sheue , Pollina Elizabeth A. , Chen Chun-Kan , Mosammaparast Nima 
Published: March 2024

SummaryCertain environmental toxins are nucleic acid damaging agents, as are many chemotherapeutics used for cancer therapy. These agents induce various adducts in DNA as well as RNA. Indeed, most of the nucleic acid adducts (>90%) formed due to these chemicals, such as alkylating agents, occur in RNA1. However, compared to the well-studied mechanisms for DNA alkylation repair, the biological consequences of RNA damage are largely unexplored. Here, we demonstrate that RNA damage can directly result in loss of genome integrity. Specifically, we show that a human YTH domain-containing protein, YTHDC1, regulates alkylation damage responses in association with the THO complex (THOC)2. In addition to its established binding toN6-methyladenosine (m6A)-containing RNAs, YTHDC1 binds toN1-methyladenosine (m1A)-containing RNAs upon alkylation. In the absence of YTHDC1, alkylation damage results in increased alkylation damage sensitivity and DNA breaks. Such phenotypes are fully attributable to RNA damage, since an RNA-specific dealkylase can rescue these phenotypes. TheseRNAdamage-induced DNAbreaks (RDIBs) depend on R-loop formation, which in turn are processed by factors involved in transcription-coupled nucleotide excision repair. Strikingly, in the absence of YTHDC1 or THOC, an RNA m1A methyltransferase targeted to the nucleus is sufficient to induce DNA breaks. Our results uncover a unique role for YTHDC1-THOC in base damage responses by preventing RDIBs, providing definitive evidence for how damaged RNAs can impact genomic integrity.
Quantum Simulation of the First-Quantized Pauli-Fierz Hamiltonian
Authors: Mukhopadhyay Priyanka , Stetina Torin F. , Wiebe Nathan 
Published: March 2024

We provide an explicit recursive divide-and-conquer approach for simulating quantum dynamics and derive a discrete first-quantized nonrelativistic QED Hamiltonian based on the many-particle Pauli-Fierz Hamiltonian. We apply this recursive divide-and-conquer algorithm to this Hamiltonian and compare it to a concrete simulation algorithm that uses qubitization. Our divide-and-conquer algorithm, using lowest-order Trotterization, scales for fixed grid spacing as O~(ΛN2η2t2/ϵ) for grid size N, η particles, simulation time t, field cutoff Λ, and error ϵ. Our qubitization algorithm scales as O~(N(η+N)(η+Λ2)tlog﻿(1/ϵ)). This shows that even a naive partitioning and low-order splitting formula can yield, through our divide-and-conquer formalism, superior scaling to qubitization for large Λ. We compare the relative costs of these two algorithms on systems that are relevant for applications such as the spontaneous emission of photons and the photoionization of electrons. We observe that for different parameter regimes, one method can be favored over the other. Finally, we give new algorithmic and circuit-level techniques for gate optimization, including a new way of implementing a group of multicontrolled-X gates that can be used for better analysis of circuit cost.

Published by the American Physical Society
2024
The determinants of corporate anti-corruption disclosures: evidence from construction companies in the Asia-Pacific
Authors: Utami Evy Rahman , Barokah Zuni 
Published: March 2024

Purpose
This study aims to investigate the determinants of anti-corruption disclosures by construction firms in Asia-Pacific countries.

Design/methodology/approach
The sample comprises construction companies from seven Asia-Pacific countries from 2015 to 2019. The authors hand-collected data on anti-corruption disclosures by using content analysis.

Findings
This study provides empirical evidence that government ownership, country-level accounting competence and high-quality auditors increase companies’ anti-corruption disclosures. Meanwhile, this study finds that uncertainty avoidance does not affect companies’ anti-corruption disclosures.

Practical implications
This study has a number of implications. First, government and professional accountant organizations need to improve accountants’ knowledge and competence through education, training and continuous professional development. Second, public accounting firms need to ensure the quality of their auditors, particularly in the technical competence in financial and nonfinancial reporting. Finally, universities must improve and update their curriculum regarding nonfinancial reporting issues.

Originality/value
This study is among the first to examine anti-corruption disclosure practices in the most corrupted settings, i.e. the construction industry in Asia-Pacific countries. It uses the isomorphism perspective to explain the influence of government ownership, country-level accounting competence and high-quality auditors on anti-corruption disclosure transparency. The number of prior studies investigating this association is very limited. Moreover, disclosures of anti-corruption information are complex and sensitive; thus, coercive, normative and mimetic pressures are required to achieve higher transparency and sustainability.
How supervisors and coworkers enable workplace practices to foster success for employees with mental health and/or addiction challenges
Authors: Packalen Kelley A. , Sobchuk Kaitlyn , Qin-Wang Kelly , Cheetham Jenelle , Hildebrand Jaclyn , Fecica Agnieszka , Lysaght Rosemary 
Published: March 2024

PurposeThe goal of this study was to understand which employee-focused workplace practices and priorities – more formally known as human resource (HR) practices and priorities – employees with mental health and/or addiction challenges (MHAC) valued and how they perceived the day-to-day implementation of those practices and priorities in the workplace integration social enterprises (WISEs) that employed them.Design/methodology/approachTwenty-two WISE workers who self-identified as having serious MHAC participated in semi-structured interviews. Interviews were transcribed and coded to identify ways that employees did or did not feel supported in their WISEs.FindingsParticipants identified three HR practices and two HR priorities as important to establishing an inclusive workplace that accommodated their MHAC. The extent to which individual participants felt included and accommodated, however, was shaped by interactions with their supervisors and coworkers.Originality/valueBy evaluating the salience of WISEs’ employee-focused workplace practices and priorities through the lens of the employees themselves, our study articulates the critical role that interactions with coworkers and supervisors have in determining whether HR practices and priorities have the intended effect on worker experience.