bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crispant analysis in zebrafish as a tool for rapid functional screening of disease-causing genes for bone fragility
Authors: Debaenst Sophie , Jarayseh Tamara , de Saffel Hanna , Bek Jan Willem , Boone Matthieu , Josipovic Ivan , Kibleur Pierre , Kwon Ronald Young , Coucke Paul J. , Willaert Andy 
Published: June 2024

AbstractHeritable Fragile Bone Disorders (FBDs) encompass a spectrum of conditions, from widespread multifactorial to rare monogenic diseases, all characterized by an elevated risk of fractures. The process of validating causative genes and elucidating their pathogenic mechanisms remains a daunting and resource-intensive task. In this study, we evaluated the feasibility of a semi-high throughput zebrafish screening platform for rapid validation andin vivofunctional testing and validation of candidate disease-causing genes for a wide range of heritable FBDs. Six genes associated with severe recessive forms of Osteogenesis Imperfecta (OI) and four genes associated with bone mineral density (BMD), a key osteoporosis indicator, identified through genome-wide association studies (GWAS) were selected. The crispant screening approach, based on CRISPR/Cas9 technology, was used to phenotype directly in F0 mosaic founder zebrafish. Next-Generation Sequencing (NGS) analysis revealed a mean indel efficiency of 88% across ten different crispants, indicating a high proportion of knock-out alleles and thus resembling stable knock-out models. We applied multiple techniques to evaluate skeletal characteristics at 7, 14 and 90 days post-fertilization (dpf), including microscopy for osteoblast reporter visualization and mineralization by Alizarin Red S staining, and microCT for quantitative skeletal analysis. While larval crispants exhibited variable differences in osteoblast-positive and mineralized surface areas, adult-stage crispants displayed more pronounced and consistent skeletal phenotypes. Notably, all crispants developed malformed neural and haemal arches, with a majority presenting vertebral fractures and fusions, and some showing significant alterations in vertebral bone volume and density. In addition,aldh7a1andmbtps2crispants experienced increased mortality due to severe skeletal deformities. RT-qPCR analysis of osteoblast differentiation and bone formation markers at larval stages indicated differential expression of osteogenic markersbglapandcol1a1ain a substantial portion of the crispants, hinting at their utility as biomarkers for FBD crispant screening. In summary, our findings demonstrate that crispant screening in zebrafish offers a viable and efficient strategy for the functional assessment of FBD genes. We advocate for a novel comprehensive approach that integrates various techniques and evaluates distinct skeletal and molecular profiles across different developmental and adult stages. This methodology has the potential to provide new insights into the role of these genes in skeletal biology.
Integrative Transcriptomics Reveals Layer 1 Astrocytes Altered in Schizophrenia
Authors: Leon Julio , Yoshinaga Satoshi , Hino Mizuki , Nagaoka Atsuko , Ando Yoshinari , Moody Jonathan , Kojima Miki , Kitazawa Ayako , Hayashi Kanehiro , Nakajima Kazunori , Condello Carlo , Carninci Piero , Kunii Yasuto , Hon Chung Chau , Shin Jay W. , Kubo Ken-ichiro 
Published: June 2024

AbstractSchizophrenia is one of the most prevalent psychiatric disorders with unclear pathophysiology despite a century-long history of intense research. Schizophrenia affects multiple networks across different brain regions. The anterior cingulate cortex (ACC) is the region that connects the limbic system to cognitive areas such as the prefrontal cortex and represents a pivotal region for the etiology of schizophrenia; however, the molecular pathology, considering its cellular and anatomical complexity, is not well understood. Here, we performed an integrative analysis of spatial and single-nucleus transcriptomics of the postmortem ACC of people with schizophrenia, together with a thorough histological analysis. The data revealed major transcriptomics signatures altered in schizophrenia, pointing at the dysregulation of glial cells, primarily in astrocytes. We further discovered a decrease in the cellular density and abundance of processes of interlaminar astrocytes, a subpopulation of astrocytes specific to primates that localize in the layer 1 and influence the superficial cortical microenvironment across layer 1 and layers 2/3 of the cortex. Our study suggests that aberrant changes in interlaminar astrocytes could explain the cell-to-cell circuit alterations found in schizophrenia and represent novel therapeutic targets to ameliorate schizophrenia-associated dysfunction.
Regulation of intracellular cAMP levels in osteocytes by mechano-sensitive focal adhesion kinase via PDE8A
Authors: Papaioannou Garyfallia , Sato Tadatoshi , Houghton Caroline , Kotsalidis Parthena E , Strauss Katelyn E , Dean Thomas , Nelson Alissa J. , Stokes Matthew , Gardella Thomas J , Wein Marc N 
Published: June 2024

AbstractOsteocytes are the primary mechano-sensitive cell type in bone. Mechanical loading is sensed across the dendritic projections of osteocytes leading to transient reductions in focal adhesion kinase (FAK) activity. Knowledge regarding the signaling pathways downstream of FAK in osteocytes is incomplete. We performed tyrosine-focused phospho-proteomic profiling in osteocyte-like Ocy454 cells to identify FAK substrates. Gsα, parathyroid hormone receptor (PTH1R), and phosphodiesterase 8A (PDE8A), all proteins associated with cAMP signaling, were found as potential FAK targets based on their reduced tyrosine phosphorylation in both FAK- deficient or FAK inhibitor treated cells. Real time monitoring of intracellular cAMP levels revealed that FAK pharmacologic inhibition or gene deletion increased basal and GPCR ligand-stimulated cAMP levels and downstream phosphorylation of protein kinase A substrates. Mutating FAK phospho-acceptor sites in Gsα and PTH1R had no effect on PTH- or FAK inhibitor-stimulated cAMP levels. Since FAK inhibitor treatment augmented cAMP levels even in the presence of forskolin, we focused on potential FAK substrates downstream of cAMP generation. Indeed, PDE8A inhibition mimicked FAK inhibition at the level of increased cAMP, PKA activity, and expression of cAMP-regulated target genes.In vitrokinase assay showed that PDE8A is directly phosphorylated by FAK while immunoprecipitation assays revealed intracellular association between FAK and PDE8A. Thus, FAK inhibition in osteocytes acts synergistically with signals that activate adenylate cyclase to increase intracellular cAMP. Mechanically-regulated FAK can modulate intracellular cAMP levels via effects on PDE8A. These data suggest a novel signal transduction mechanism that mediates crosstalk between mechanical and cAMP-linked hormonal signaling in osteocytes.
Proteomic analysis of isolated nerve terminals from NaV1.9 knockout mice reveals pathways relevant for neuropathic pain signalling
Authors: Rawat Ankita , Vu Duc Tung , Erbacher Christoph , Stigloher Christian , Üçeyler Nurcan , Mann Matthias , Briese Michael , Sendtner Michael 
Published: June 2024

AbstractNeuropathic pain substantially affects the mental and physical well-being of patients and magnifies the socio-economic burden on the healthcare system. It is important to understand the molecular mechanisms underlying chronic pain to effectively target it. To investigate peripheral mechanisms relevant to pain signaling, we isolated nerve terminals from mouse footpads. The isolated peripheral terminals contain both pre- and post-synaptic proteins and are deficient in keratin and histone in both mice and humans. We detected the protein translational machinery and mitochondria in nerve terminals and observed that they were capable of endocytosis. An unbiased proteomic analysis of nerve terminals from footpads of NaV1.9 knockout mice shows dysregulation of the p38 mitogen-activated protein kinase (MAPK) and extracellular regulated kinase 1/2 (ERK1/2) pathways, and of protein components involved in translation and energy metabolism. Isolation of human nerve terminals from skin punch biopsies, validated by proteomic analysis, highlights the broad and translational value of our approach. Our study thus reveals peripheral signaling mechanisms implicated in pain perception.
RFC1regulates the expansion of neural progenitors in the developing zebrafish cerebellum
Authors: Nobilleau Fanny , Audet Sébastien , Turk Sanaa , Zaouter Charlotte , Liao Meijiang , Pilon Nicolas , Tétreault Martine , Patten Shunmoogum A. , Samarut Éric 
Published: June 2024

SummaryDNA replication and repair are basic yet essential molecular processes for all cells.RFC1encodes the largest subunit of the Replication Factor C (RFC), which is a clamp-loader during DNA replication and repair. Intronic repeat expansion inRFC1has recently been associated with so-calledRFC1-related disorders, which mainly encompass late-onset cerebellar ataxias. However, the mechanisms that make certain tissues more susceptible to defects in these universal pathways remain mysterious. In this study, we provide the first investigation ofRFC1gene functionin vivousing zebrafish. We showed thatRFC1is expressed in neural progenitor cells within the developing cerebellum and that it is necessary to maintain these cells’ genomic integrity during neurogenic maturation. Accordingly,RFC1loss-of-function leads to a severe cerebellar phenotype due to impaired neurogenesis of both Purkinje and granule cells. Our data thus point to a specific role ofRFC1in the developing cerebellum, paving the way for a better understanding of the pathogenic mechanisms underlyingRFC1-related disorders.
Layer Va neurons, as major presynaptic partners of corticospinal neurons, play critical roles in skilled movements
Authors: Imai Fumiyasu , Matsuura Ken , Yang Emily , Klinefelter Kelsey , Alexandrou Gabriella , Letelier Agustín , Takatani Hirohide , Osakada Fumitaka , Yoshida Yutaka 
Published: June 2024

AbstractCorticospinal neurons (CSNs) are located in the cortex and projecting into the spinal cord. The activation of CSNs, which is associated with skilled motor behaviors, induces the activation of interneurons in the spinal cord. Eventually, motor neuron activation is induced by corticospinal circuits to coordinate muscle activation. Therefore, elucidating how the activation of CSNs in the brain is regulated is necessary for understanding the roles of CSNs in skilled motor behaviors. However, the presynaptic partners of CSNs in the brain remain to be identified. Here, we performed transsynaptic rabies virus-mediated brain-wide mapping to identify presynaptic partners of CSNs (pre-CSNs). We found that pre-CSNs are located in all cortical layers, but major pre-CSNs are located in layer Va. A small population of pre-CSNs are also located outside the cortex, such as in the thalamus. Inactivation of layer Va neurons inTlx3-Cremice results in deficits in skilled reaching and grasping behaviors, suggesting that, similar to CSNs, layer Va neurons are critical for skilled movements.Finally, we examined whether the connectivity of CSNs is altered after spinal cord injury (SCI). We found that unlike connections between CNSs and postsynaptic neurons, connections between pre-CSNs and CSNs do not change after SCI.
Axial asymmetry organizes division plane orthogonality inNeisseria gonorrhoeae
Authors: Bandekar Aditya C. , Ramirez-Diaz Diego A. , Palace Samantha G. , Wang Yi , Garner Ethan C. , Grad Yonatan H. 
Published: June 2024

AbstractFor rod-shaped bacterial model organisms, the division plane is defined by the geometry of the cell. However, forNeisseria gonorrhoeae, a coccoid organism that most commonly exists as a diplococcus and that possesses genes coding for rod-based cell division systems, the relationship between cell geometry and division is unclear. Here, we characterized the organization ofN. gonorrhoeaedivision using a combination of fluorescent probes, genetics, and time-lapse microscopy. We found that the planes of successive cell divisions are orthogonal and temporally overlapping, thereby maintaining diplococcal morphology. Division takes place perpendicular to a subtle long-axis in each coccus. In keeping with the ParABS and the MinCDE systems reading the long-axis of rod-shaped bacteria, in the coccoidN. gonorrhoeae, ParB segregates along this subtle long-axis and cells lackingminCDEhave severe morphological consequences, including an inability to perform orthogonal division and aberrant assembly of the division plane at the cell poles. Taken together, this stresses the central role of even slight dimensional asymmetry as a general organizational principle in bacterial cell division.
PP2A-B56 regulates Mid1 protein levels for proper cytokinesis in fission yeast
Authors: Chrupcala Madeline L. , Moseley James B. 
Published: June 2024

ABSTRACTProtein phosphorylation regulates many steps in the cell division process including cytokinesis. In fission yeast cells, the anillin-like protein Mid1 sets the cell division plane and is regulated by phosphorylation. Multiple protein kinases act on Mid1, but no protein phosphatases have been shown to regulate Mid1. Here, we discovered that the conserved protein phosphatase PP2A-B56 is required for proper cytokinesis by promoting Mid1 protein levels. We find thatpar1Δcells lacking the primary B56 subunit divide asymmetrically due to the assembly of misplaced cytokinetic rings that slide towards cell tips. Thesepar1Δmutants have reduced whole-cell levels of Mid1 protein, leading to reduced Mid1 at the cytokinetic ring. Restoring proper Mid1 expression suppressespar1Δcytokinesis defects. This work identifies a new PP2A-B56 pathway regulating cytokinesis through Mid1, with implications for control of cytokinesis in other organisms.
Tax avoidance and tax evasion: current insights and future research directions from an emerging economy
Authors: Hossain Md Shamim , Ali Md. Sobhan , Ling Chui Ching , Fung Chorng Yuan 
Published: June 2024

PurposeThis study aims to identify factors affecting tax avoidance and tax evasion in Bangladesh and propose a future research agenda.Design/methodology/approachThis paper reviewed 423 articles published between 2010 and 2023 using a systematic literature review (SLR) approach.FindingsThe review classified the factors into three categories, namely individual taxpayers, corporate taxpayers and tax administration. Income level, tax penalty, tax morale, inefficient tax return system and tax assessment process are associated with the individual’s tax avoidance and tax evasion activities. Profitability, corporate governance and financial restrictions are key factors influencing corporate taxpayers’ involvement in tax avoidance and tax evasion. Factors related to tax administration include lack of social interaction, distrust of national officials, complexities of policies, politicisation of tax authority, lack of political stability, incompetent auditing, insufficient recording, lack of administrative cooperation, lack of accountability, insufficient counselling and compromising in tax prosecution cases.Practical implicationsThis paper provides tax regulators with insights to improve regulations and lessen tax avoidance and tax evasion activities.Originality/valueThis paper is the first attempt to provide guidance for academics when examining tax avoidance and tax evasion in Bangladesh.
Determinants of behavior towards hemp-based products: an application of the theory of planned behavior
Authors: Lacasse Hannah , Buzas Jeffrey , Kolodinsky Jane , Mark Tyler , Hill Rebecca , Snell William , Darby Heather 
Published: June 2024

PurposeThis paper examines how U.S. consumer intentions to adopt hemp vary across product types using the theory of planned behavior (TPB).Design/methodology/approachData were collected via an online survey of U.S. residents in 2022 (n = 1,948). Two-step structural equation modeling is used to examine how TPB constructs and background factors influence intent to use five different hemp-based products: cannabidiol (CBD), clothing, food, personal care products, and pet products. Data are analyzed using R.FindingsPositive attitudes towards all categories of hemp-based products increase the probability of adoption, while subjective norm and perceived behavioral control have limited and varied significant influence across product models. Age has a consistent significant and negative influence on adoption.Research limitations/implicationsFindings highlight consumer segmentation and marketing opportunities, inform hemp stakeholder decision-making, and provide directions for future research. Given the absence of explanatory power of SN and PBC on most product models and the diversity of products and nuanced U.S. hemp policy, future research could investigate expanded iterations of TPB. Using revealed behavior could also highlight potential intention-behavior gaps and offer more robust insights for hemp stakeholders.Originality/valueFindings contribute to a limited body of information on markets and consumer demand for hemp in the U.S.
A stochastic technique to solve interval non-linear programming problems using GH-difference
Authors: Kumari Shaveta , Srivastava Saurabh 
Published: June 2024

PurposeA stochastic technique for solving interval non-linear problems using generalized Hukuhara (GH)-difference is proposed. The non-linear programming problem in interval form is transformed into an equivalent non-linear programming problem with real coefficients by associating a Gaussian random variable to the interval and the six-sigma rule. The conceptualized idea eliminates the decision maker’s instinctive selection of weight functions and provides an alternative to the order relation method, max-min criteria-based methods and bi-level approaches for representing intervals as real numbers. To demonstrate a coherent understanding, numerical examples have been used.Design/methodology/approachA stochastic approach has been used to develop a solution technique for solving interval nonlinear programming problems which arise in the modeling of scientific and engineering problems under uncertain environments.FindingsThe proposed idea eliminates the decision maker’s instinctive selection of weight functions and provides an alternative to the order relation method, max-min criteria-based methods and bi-level approaches for representing intervals as real numbers. This method provides specific results rather than in the interval form, which are more practical and implementable by the decision maker.Originality/valueThis is to certify, that the research paper submitted is an outcome of original work. I have duly acknowledged all the sources from which the ideas and extracts have been taken. This article has not been submitted elsewhere for publication.
Effect of polygenic scores of telomere length alleles on telomere length in newborns and parents
Authors: Lee Yunsung , Jugessur Astanand , Gjessing Håkon K. , Harris Jennifer R. , Susser Ezra , Magnus Per , Aviv Abraham 
Published: June 2024

AbstractIn adults, polygenic scores (PGSs) of telomere length (TL) alleles explain about 4.5% of the variance in TL, as measured by quantitative polymerase chain reaction (qPCR). Yet, these PGSs strongly infer a causal role of telomeres in aging‐related diseases. To better understand the determinants of TL through the lifespan, it is essential to examine to what extent these PGSs explain TL in newborns. This study investigates the effect of PGSs on TL in both newborns and their parents, with TL measured by Southern blotting and expressed in base‐pairs (bp). Additionally, the study explores the impact of PGSs related to transmitted or non‐transmitted alleles on TL in newborns. For parents and newborns, the PGS effects on TL were 172 bp (p =  2.03 × 10−15) and 161 bp (p =  3.06 × 10−8), explaining 6.6% and 5.2% of the TL variance, respectively. The strongest PGS effect was shown for maternally transmitted alleles in newborn girls, amounting to 214 bp (p =  3.77 × 10−6) and explaining 7.8% of the TL variance. The PGS effect of non‐transmitted alleles was 56 bp (p = 0.0593) and explained 0.6% of the TL variance. Our findings highlight the importance of TL genetics in understanding early‐life determinants of TL. They point to the potential utility of PGSs composed of TL alleles in identifying susceptibility to aging‐related diseases from birth and reveal the presence of sexual dimorphism in the effect of TL alleles on TL in newborns. Finally, we attribute the higher TL variance explained by PGSs in our study to TL measurement by Southern blotting.
Periodontitis and the risk of oral, gastric and esophageal cancers: a two‐sample Mendelian randomization study
Authors: Sheng C , Han XX , Li MY , Jia XX , Wang KJ 
Published: June 2024

AbstractBackgroundPeriodontitis is a common oral disease and the chronic inflammation caused by it may influence the development of cancers in the upper gastrointestinal tract. Many observational studies have established a relationship between the two, but the results are not entirely consistent.MethodsTwo‐sample MR was performed using publicly available genome‐wide association studies data for periodontitis, oral, gastric and oesophagal cancers. The Inverse Variance Weighting (IVW) method serves as the primary method, with MR Egger, Weighted Median, Simple Model and Weighted Model Algorithm methods as complementary methods to assess genetic causal associations. Cochran Q‐test, MR‐Egger regression and MR polytropic residuals and outliers were used to assess heterogeneity and horizontal pleiotropy.ResultsIVW results did not support a causal association between periodontitis and oral (OR = 1.00, 95% CI: 1.00, 1.00) and oesophagal cancer (OR = 1.00, 95% CI: 1.00, 1.00). Similarly, there was again no causal association between periodontitis and gastric cancer, which was integrated with an OR of 1.04 (95% CI: 0.97, 1.12). Complementary method results were consistent with IVW and heterogeneity and horizontal pleiotropy were not found in most studies.ConclusionsThe findings of our MR study do not support a causal relationship between periodontitis and oral, gastric and oesophagal cancers.
Loneliness and socioemotional memory
Authors: Igarashi Tasuku 
Published: June 2024

AbstractDo chronically high‐lonely individuals exhibit specific memory biases when recalling past social episodes? We explored negative memory biases, focusing on the recall of unfavourable social experiences and social memory biases, emphasizing the recall of social experiences irrespective of emotional valence. We conducted a dictionary‐based semantic analysis of autobiographical episodes obtained from 4095 participants via four datasets. Participants recalled a positive, negative or emotionally neutral episode from their recent past. High‐lonely individuals predominantly exhibited a decline in recalling positive social episodes, providing partial support for negative memory biases. However, both high‐ and low‐lonely individuals were similarly inclined to recall negative social episodes. These results suggest that the primary issue among high‐lonely individuals is the limited recall of positive social experiences rather than the general negativity in memory biases or the hypersensitivity to general social memories.