bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zebrafishcarbohydrate sulfotransferase 6(chst6) mutants provide a preclinical model for macular corneal dystrophy
Authors: Ersoz-Gulseven Esra , Basol Merve , Özaktaş Helin , Kalyoncu Sibel , Utine Canan Asli , Cakan-Akdogan Gulcin 
Published: January 2024

AbstractMacular corneal dystrophy (MCD) is a rare congenital disease caused by mutations in thecarbohydrate sulfotransferase 6(chst6) gene. Patients suffer from opaque aggregates in the cornea leading to bilateral progressive vision loss by 4thdecade of life. Corneal transplantation is the only available treatment, which is invasive, not available to every patient and recurrence of the symptoms is common. Keratocytes in the cornea express thechst6gene, which encodes a golgi enzyme that is essential for sulfation of the keratan sulfate proteoglycans (KSPG). The loss of KS sulfation leads to defects in collagen fibril organization and aggregate formation in the corneal extracellular matrix. Lack of preclinical disease models is a major limitation for the development of accessible treatment strategies. Attempts to develop mouse MCD models have failed due to lack ofchst6gene in mice and difference in proteoglycan composition of the mouse cornea. The zebrafishchst6gene has not been studied previously. Zebrafish cornea structure is highly similar to humans, containing high levels of keratan sulfate proteoglycans in the stroma. Here, loss of functionchst6mutant zebrafish were generated with CRISPR/Cas9 mediated gene editing. Severalchst6alleles were obtained, and loss of KSPG sulfation in the eye stroma was shown. Mutant zebrafish developed age-dependent, alcian blue positive, opaque accumulates in the cornea. Degeneration of corneal structure and changes in epithelial thickness were observed. The zebrafish MCD model developed here is the firstin vivomodel of the disease and opens up possibilities to develop and screen treatment strategies.Significance StatementFirstin vivomodel of macular corneal dystrophy (MCD) is reported in this study. Zebrafish model developed here paves the way for modeling of other corneal dystrophies in this aquatic vertebrate which is easy to apply therapeutics and imagein vivo. The clinical symptoms of MCD are well reproduced in the zebrafish MCD model. Moreover, the authors showed thatchst6gene function is not restricted to cornea, and a fraction of mutant larvae have morphological defects. The mutants developed here provide a genetic model for understanding the highly complex roles of keratan sulfate proteoglycans.
Blood flow regulatesacvrl1transcription via ligand-dependent Alk1 activity
Authors: Anzell Anthony R. , Kunz Amy Biery , Donovan James P. , Tran Thanhlong G. , Lu Xinyan , Young Sarah , Roman Beth L. 
Published: January 2024

AbstractHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by the development of arteriovenous malformations (AVMs) that can result in significant morbidity and mortality. HHT is caused primarily by mutations in bone morphogenetic protein receptorsACVRL1/ALK1, a signaling receptor, or endoglin (ENG), an accessory receptor. Because overexpression ofAcvrl1prevents AVM development in bothAcvrl1andEngnull mice, enhancingACVRL1expression may be a promising approach to development of targeted therapies for HHT. Therefore, we sought to understand the molecular mechanism ofACVRL1regulation. We previously demonstrated in zebrafish embryos thatacvrl1is predominantly expressed in arterial endothelial cells and that expression requires blood flow. Here, we document that flow dependence exhibits regional heterogeneity and thatacvrl1expression is rapidly restored after reinitiation of flow. Furthermore, we find thatacvrl1expression is significantly decreased in mutants that lack the circulating Alk1 ligand, Bmp10, and that BMP10 microinjection into the vasculature in the absence of flow enhancesacvrl1expression in an Alk1-dependent manner. Using a transgenicacvrl1:egfpreporter line, we find that flow and Bmp10 regulateacvrl1at the level of transcription. Finally, we observe similar ALK1 ligand-dependent increases inACVRL1in human endothelial cells subjected to shear stress. These data suggest that Bmp10 acts downstream of blood flow to maintain or enhanceacvrl1expression via a positive feedback mechanism, and that ALK1 activating therapeutics may have dual functionality by increasing both ALK1 signaling flux andACVRL1expression.
Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression
Authors: Mozafari Negin , Milagres Salomé , Rocha S. J. , Vargiu Claudia Marina , Freyberger Fiona , Saher Osama , Umek Tea , Blomberg Pontus , Jørgensen Per T. , Edvard Smith C. I. , Wengel Jesper , Zain Rula 
Published: January 2024

ABSTRACTFriedreich’s ataxia (FRDA) is a progressive, autosomal recessive ataxia caused, in the majority of cases, by homozygous expansion of GAA•TTC triplet-repeats in the first intron of thefrataxin(FXN) gene. GAA•TTC repeat expansion results in the formation of non-B DNA intramolecular triplex structure (H-DNA) as well as changes in the epigenetic landscape atFXNloci and heterochromatin formation. Expansion of intronic GAA•TTC repeats is associated with reduced levels ofFXNmRNA and protein resulting in disease development. Previously, we reported that DNA-binding anti-gene oligonucleotides (AGOs) targeting the GAA•TTC repeat expansion abolished H-DNA formation. Here, we demonstrate that targeting repeat-expanded chromosomal DNA using single-strand locked nucleic acid (LNA)-DNA mixmer AGOs increases FXN mRNA and protein expression in patient-derived cells. We examined numerous LNA-DNA AGOs and found that the design, length and their LNA composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed ONs targeting the GAA•TTC DNA repeats to upregulateFXNgene expression.
Broadly inhibitory antibodies against severe malaria virulence proteins
Authors: Reyes Raphael A. , Raghavan Sai Sundar Rajan , Hurlburt Nicholas K. , Introini Viola , Kana Ikhlaq Hussain , Jensen Rasmus W. , Martinez-Scholze Elizabeth , Gestal-Mato Maria , Bau Cristina Bancells , Fernández-Quintero Monica Lisa , Loeffler Johannes R. , Ferguson James Alexander , Lee Wen-Hsin , Martin Greg Michael , Theander Thor G. , Ssewanyana Isaac , Feeney Margaret E. , Greenhouse Bryan , Bol Sebastiaan , Ward Andrew B. , Bernabeu Maria , Pancera Marie , Turner Louise , Bunnik Evelien M. , Lavstsen Thomas 
Published: January 2024

AbstractPlasmodium falciparumpathology is driven by the accumulation of parasite-infected erythrocytes in microvessels. This process is mediated by the parasite’s polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. A subset of PfEMP1 variants that bind human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here, we describe two broadly reactive and binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies isolated from two different individuals exhibited a similar and consistent EPCR-binding inhibition of 34 CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins as well as parasite sequestration in bioengineered 3D brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with two different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies likely represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.
A method for separating bacterial cultures into single cells and defined size fractions of biofilm aggregates
Authors: Nielsen Regitze Lund , Bjarnsholt Thomas , Jakobsen Tim Holm , Lichtenberg Mads 
Published: January 2024

AbstractIn vitromicrobiological experiments that aim to describe differences between planktonic and biofilm aggregate populations are challenging since liquid batch cultures contain a mix of both. Here, we present a simple method for fractioning a bacterial liquid batch culture into aggregates and single cells.Stackable cell strainers with mesh sizes of 30 μm and 10 μm were used to filtrate 6 day old batch cultures ofPseudomonas aeruginosato produce size fractions of 0-10μm and >30μm. By confocal laser scanning microscopy measurements, we show that 95.5% of the total biomass was <10 μm in the “0-10μm size fraction” and that 92.5% of the total biomass was >30μm in the “>30μm size fraction”.Furthermore, the adjustment of bacterial concentration using CFU/ml was validated by quantifying the total DNA of viable bacteria in the two size fractions after DNase treatment to deplete eDNA and DNA from dead bacteria. Surprisingly, this showed that adjusting the bacterial concentration using CFU/ml was a valid method with no significant differences in total DNA from viable bacteria.
scMeFormer: a transformer-based deep learning model for imputing DNA methylation states in single cells enhances the detection of epigenetic alterations in schizophrenia
Authors: Zhou Jiyun , Luo Chongyuan , Liu Hanqing , Heffel Matthew G. , Straub Richard E. , Kleinman Joel E. , Hyde Thomas M. , Ecker Joseph R. , Weinberger Daniel R. , Han Shizhong 
Published: January 2024

AbstractDNA methylation (DNAm), a crucial epigenetic mark, plays a key role in gene regulation, mammalian development, and various human diseases. Single-cell technologies enable the profiling of DNAm states at cytosines within the DNA sequence of individual cells, but they often suffer from limited coverage of CpG sites. In this study, we introduce scMeFormer, a transformer-based deep learning model designed to impute DNAm states for each CpG site in single cells. Through comprehensive evaluations, we demonstrate the superior performance of scMeFormer compared to alternative models across four single-nucleus DNAm datasets generated by distinct technologies. Remarkably, scMeFormer exhibits high-fidelity imputation, even when dealing with significantly reduced coverage, as low as 10% of the original CpG sites. Furthermore, we applied scMeFormer to a single-nucleus DNAm dataset generated from the prefrontal cortex of four schizophrenia patients and four neurotypical controls. This enabled the identification of thousands of differentially methylated regions associated with schizophrenia that would have remained undetectable without imputation and added granularity to our understanding of epigenetic alterations in schizophrenia within specific cell types. Our study highlights the power of deep learning in imputing DNAm states in single cells, and we expect scMeFormer to be a valuable tool for single-cell DNAm studies.
m6A-dependent circular RNA formation mediates tau-induced neurotoxicity
Authors: Atrian Farzaneh , Ramirez Paulino , De Mange Jasmine , Marquez Marissa , Gonzalez Elias M. , Minaya Miguel , Karch Celeste M. , Frost Bess 
Published: January 2024

ABSTRACTCircular RNAs (circRNAs), covalently closed RNA molecules that form due to back-splicing of RNA transcripts, have recently been implicated in Alzheimer’s disease and related tauopathies. circRNAs are regulated by N6-methyladenosine (m6A) RNA methylation, can serve as “sponges” for proteins and RNAs, and can be translated into protein via a cap-independent mechanism. Mechanisms underlying circRNA dysregulation in tauopathies and causal relationships between circRNA and neurodegeneration are currently unknown. In the current study, we aimed to determine whether pathogenic forms of tau drive circRNA dysregulation and whether such dysregulation causally mediates neurodegeneration. We identify circRNAs that are differentially expressed in the brain of aDrosophilamodel of tauopathy and in induced pluripotent stem cell (iPSC)-derived neurons carrying a tau mutation associated with autosomal dominant tauopathy. We leverageDrosophilato discover that depletion of circular forms ofmuscleblind(circMbl), a circRNA that is particularly abundant in brains of tau transgenicDrosophila, significantly suppresses tau neurotoxicity, suggesting that tau-inducedcircMblelevation is neurotoxic. We detect a general elevation of m6A RNA methylation and circRNA methylation in tau transgenicDrosophilaand find that tau-induced m6A methylation is a mechanistic driver ofcircMblformation. Interestingly, we find that circRNA and m6A RNA accumulate within nuclear envelope invaginations of tau transgenicDrosophilaand in iPSC-derived cerebral organoid models of tauopathy. Taken together, our studies add critical new insight into the mechanisms underlying circRNA dysregulation in tauopathy and identify m6A-modified circRNA as a causal factor contributing to neurodegeneration. These findings add to a growing literature implicating pathogenic forms of tau as drivers of altered RNA metabolism.
Degenerative and regenerative peripheral processes are associated with persistent painful chemotherapy-induced neuropathies in males and females
Authors: Naratadam George T. , Mecklenburg Jennifer , Shein Sergey A. , Zou Yi , Lai Zhao , Tumanov Alexei V. , Price Theodor J. , Akopian Armen N. 
Published: January 2024

AbstractThis study aimed to investigate the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hind paws and dorsal root ganglia (DRG). Bulk RNA-seq was used to investigate the gene expression changes in the paw and DRG collected at 1, 16, and 31 days post-PTX. At these time points, differentially expressed DEGs were predominantly related to reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes were accompanied by regulation of DEGs related to cytoskeleton, extracellular matrix organization and cellular energy production. This gene plasticity during persistent painful neuropathy progression likely represents biological processes linked to tissue regeneration and degeneration. Unlike regeneration/degeneration, gene plasticity related to immune processes was minimal at 1–31 days post-PTX. It was also noted that despite similarities in biological processes and pain chronicity in males and females, specific DEGs showed dramatic sex-dependency. The main conclusions of this study are that gene expression plasticity in paws and DRG during PTX neuropathy progression relates to tissue regeneration and degeneration, minimally affects the immune system processes, and is heavily sex-dependent at the individual gene level.
Amplifying post-stimulation oscillatory dynamics by engaging synaptic plasticity with periodic stimulation: a modelling study
Authors: Lefebvre Jeremie , Pariz Aref 
Published: January 2024

AbstractPeriodic brain stimulation (PBS) techniques, either intracranial or non-invasive, electrical or magnetic, represent promising neuromodulatory tools for the treatment of neurological and neuropsychiatric disorders. Through the modulation of endogenous oscillations, PBS may engage synaptic plasticity, hopefully leading to persistent lasting effects. However, stabilizing such effects represents an important challenge: the interaction between induced electromagnetic fields and neural circuits may yield highly variable responses due to heterogeneous neuronal and synaptic biophysical properties, limiting PBS clinical potential. In this study, we explored the conditions on which PBS leads to amplified post-stimulation oscillatory power, persisting once stimulation has been turned off. We specifically examined the effects of heterogeneity in neuron time scales on post-stimulation dynamics in a population of balanced leaky-integrated and fire (LIF) neurons that exhibit synchronous-irregular spiking activity. Our analysis reveals that such heterogeneity enables PBS to engage synaptic plasticity, amplifying post-stimulation power. Our results show that such post-stimulation aftereffects result from selective frequency- and cell-type-specific synaptic modifications. We evaluated the relative importance of stimulation-induced plasticity amongst and between excitatory and inhibitory populations. Our results indicate that heterogeneity in neurons’ time scales and synaptic plasticity are both essential for stimulation to support post-stimulation aftereffects, notably to amplify the power of endogenous rhythms.
Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries
Authors: Criado-Marrero Marangelie , Ravi Sakthivel , Bhaskar Ekta , Barroso Daylin , Pizzi Michael A. , Williams Lakiesha , Wellington Cheryl L. , Febo Marcelo , Abisambra Jose Francisco 
Published: January 2024

AbstractTraumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific signs and vulnerabilities. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following repetitive mild traumatic brain injuries (rmTBIs). In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and Neurite Orientation Dispersion and Density Imaging (NODDI). Utilizing the CHIMERA model, we conducted rmTBIs or sham (control) procedures on young (2.5-3 months old) and aged (22-month-old) male and female mice to model high risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposing effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean, radial, axial diffusivity, fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Inflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in aged animals. These findings provide a comprehensive understanding of the intricate interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBIs.
Hippocampal reactive neural stem cells are able to phagocytose and have an immunological molecular signature
Authors: Abiega Oihane , Senovilla-Ganzo Rodrigo , El-Ouraoui Maroua , Muro-García Teresa , Ruiz-Clavijo Lorena , García-Moreno Fernando , Fitzsimons Carlos , Martín-Suárez Soraya , Encinas Juan M. 
Published: January 2024

SUMMARYHippocampal neural stem cells (NSCs) are the drivers of neurogenesis in the dentate gyrus (DG) of most mammals including humans. During neuronal hyperactivity NSCs become reactive NSCs (react-NSCs), characterized by their activation, morphological changes, and symmetric division, abandoning their neurogenic programme and transforming into reactive astrocytes. Here, using different pathological models that induce react-NSCs in the DG, we looked for novel features of react-NSCs both histologically and by total RNA sequencing. We report that in two pathological models were react-NSCs emerge (mesial temporal lobe epilepsy (MTLE) and traumatic brain injury (TBI)) react-NSCs are capable of phagocytosis of dead cells, a typical immunological function carried out mainly by microglia in the brain. Importantly, MTLE-induced react-NSCs show phagocytic function in tissue and a predominantly immunological molecular signature, with a broad upregulation of phagocytosis-related gene expression. Our results describe a new function of react-NSCs as phagocytic and immunologically active cells in the hippocampal neurogenic niche.
Optogenetic silencing hippocampal inputs to the retrosplenial cortex causes a prolonged disruption of spatial working memory
Authors: Pinto-Correia Bárbara , Caldeira-Bernardo Patricia , Remondes Miguel 
Published: January 2024

SummaryWorking memory allows us to keep information in memory for the time needed to perform a given task. Such fundamental cognitive ability relies on a neural circuit including the retrosplenial cortex (RSC), connected to several cortical areas, functionally and anatomically, namely primary visual areas, and higher cognitive areas such as the cingulate, midcingulate, and subicular cortices. RSC bears intimate anatomical and functional connections with the hippocampus, and has been implicated in integrating and translating spatial-temporal contextual information between ego- and allocentric reference frames, to compute predictions about goals in goal-directed behaviors. The relative contribution of the hippocampus and retrosplenial cortex in working memory-guided behaviors remains unclear due to the lack of studies reversibly interfering with synapses connecting the two regions during such behaviors. We here used eArch3.0, a hyperpolarizing proton pump, to silence hippocampal axon terminals in RSC while animals perform a standard delayed non-match to place task. We found that such manipulation impairs memory retrieval, significantly decreasing performance and hastening decision-making. Furthermore, we found that such impairment outlasts light-activation of the opsin, its effects being noticed up to 3 subsequent trials.
Corporate index: bridging the academic–practitioner gap
Authors: Mendis Trevor 
Published: January 2024

PurposeThe academic–practitioner gap has been a widely discussed and well-established issue. Despite numerous studies conducted in this area, empirical evidence reveals that the gap is widening and also emphasizes the exigency to bridge this gap. Hence, the purpose of this study is to propose an acceptable solution that will fill this lacuna.Design/methodology/approachThe study adopts the qualitative research methodology and was based on the system theory (ST) and the institutional theory (IT). Interviews, based on a semi-structured questionnaire, were conducted, focusing on three categories, namely individuals with solely academic experience, individuals with both academic and industrial exposure and business leaders. The unit of analysis was the individual.FindingsThe study, which unearthed some rich and challenging evidence from the respondents, reveals that gaining industrial exposure and working on continuous professional development are vital for academics to narrow or even close this gap. In addition, serving as apex members at board level or in professional bodies, serving global organizations as lead consultants and working on research collaborations are other important dimensions for academics.Practical implicationsThis study introduces an emerging model named the “Pentagon Model” and develops a corporate index (C-index) for academics to earn, similar to the h-index. The study also explains the operationalization of the C-index based on the proposed algorithm. Hence, it is the envisaged that this study will change the landscape of the academic sphere in practical terms.Originality/valueThis study was carried out with the sole intention of bridging the gap between academics and practitioners. The proposed model and the index, which were developed by the author purely based on the outcome of this study, pave the way for many future research studies, not only to further improve the C-index but also to minimize disparities in transdisciplinary work between academics and practitioners.