bluuebunny/crossref_metadata_2025_split huggingface dataset:
The causal role of thyroid hormones in bipolar disorders: a two-sample Mendelian Randomization study
Authors: Li James L. 
Published: September 2024

ABSTRACTIntroductionBipolar disorder is a complex psychiatric condition with distinctions between clinical subtypes including Type 1 and 2 disorders. Several studies have proposed thyroid hormones may be involved in the etiology of bipolar disorders.MethodsThis study employed a two-sample Mendelian Randomization (MR) approach to investigate the causal relationships between six thyroid hormone metrics (TSH, FT4, FT3, TT3, FT3/FT4, and TT3/FT4) and bipolar disorder, and Type 1 and 2 disorders, separately. Genome-wide association (GWAS) data from the Thyroidomics Consortium (up to 271,040 individuals of European ancestry) were used for thyroid function metrics. Bipolar disorder GWAS data included 41,917 cases and 371,549 controls (25,060 Type 1 and 6,781 Type 2 cases). We applied inverse variance weighted (IVW) methods for primary MR analysis, with MR Egger, weighted median, and weighted mode for sensitivity. Additional tests assessed horizontal pleiotropy and heterogeneity.ResultsHigher FT4 levels showed a protective causal effect against bipolar disorder (OR: 0.92, 95% CI: 0.86-0.97, p=4.58×10−3) and a suggestive effect on Type 1 disorders (OR: 0.92, 95% CI: 0.86-0.99, p=3.21×10−2). Elevated FT3 (OR: 1.18, 95% CI: 1.03-1.35, p=1.55×10−2) and FT3/FT4 ratio (OR: 1.97, 95% CI: 1.02-3.82, p=4.46×10−2) had suggestive harmful effects on Type 1 disorders. Sensitivity analyses showed consistent effects, with no significant horizontal pleiotropy or heterogeneity.ConclusionsThese findings highlight the protective role of FT4 and the potentially harmful effect of elevated FT3 in Type 1 bipolar disorder, highlighting the need for further research on thyroid hormone levels as a potential treatment strategy for Type 1 bipolar disorder.
Evaluation of the diagnostic accuracy and analytical sensitivity of the novel Xpert® Mpox (Cepheid®) and STANDARD™ M10 MPX/OPX (SD Biosensor) molecular point-of-care assays for the detection of Mpox virus in skin lesion swabs and upper-respiratory swab samples
Authors: Romero-Ramirez Alessandra , Somasundaran Anushri , Kontogianni Konstantina , Parkes Jacob , Hussain Yusra , Gould Susan , Williams Christopher T , Wooding Dominic , Body Richard , Hardwick Hayley E , Kenneth Baillie J , Dunning Jake , Semple Malcom G ,   CONDOR steering group,   ISARIC CCP UK investigators, Fletcher Tom E , Edwards Thomas , Emperador Devy , Cubas-Atienzar Ana I 
Published: September 2024

AbstractObjectivesEvaluation of diagnostic accuracy of two point-of-care (POC) molecular diagnostic tests for the detection of monkeypox virus (MPXV): Xpert® Mpox (Cepheid, Inc., USA) and STANDARD™ M10 MPX/OPX (SD Biosensor, Inc., Korea).MethodsDiagnostic accuracy of both platforms was evaluated using 53 upper-respiratory swabs (URS) and 32 skin lesions swabs (SS) collected from mpox and COVID-19 patients in the UK against the Sansure (Sansure Biotech Inc.) and the CDC reference qPCR tests. The analytical sensitivity of both platforms was assessed using a viral isolate from the lineage II, B.1.ResultsThe limit of detection was 1×101pfu/ml for both tests. The overall sensitivity and specificity of the Xpert® Mpox was 97.67% [95% CI 87.71–99.94%] and 88.57% [95% CI 73.26–96.80%] and 97.44% [95% CI 86.52–99.94%] and 74.42% [95% CI 58.83–86.48%] comparing the Sansure and CDC qPCR, respectively and for the M10 MPX/OPX was 87.80% [95% CI 73.80–95.92%] and 76.60% [95% CI 61.97–87.70%] and 94.29% [95% CI 80.84–99.30%] and 86.67% [95% CI 73.21–94.95%] with the Sansure and CDC qPCR.ConclusionThe Xpert® Mpox had good diagnostic accuracy for both sample types while the M10 MPX/OPX clinical accuracy was deficient with URS. Our data supports the use of URS during the first 3 days of symptoms onset for mpox diagnosis.HighlightsThe Xpert® Mpox detected Monkeypox virus (MPXV) DNA in more samples than the M10 MPX/OPX, CDC qPCR and Sansure qPCR suggesting higher sensitivity at lower viral loads.Xpert® Mpox fulfilled the performance requirements recommended in the World Health Organisation (WHO) target product profile (TPP) using upper-respiratory swabs (URS) and skin lesion swabs (SS) but M10 MPX/OPX performance was only met when using SS.MPXV DNA was reliably detectable in SS up to 5 days after onset of symptoms. with all PCR testsThe use of URS for mpox diagnosis is not recommended for use more than 3 days after onset of symptoms.
Role ofBAG3protein interactions in cardiomyopathies
Authors: Qu Hui-Qi , Wang JuFang , Rosa-Campos Alexandre , Hakonarson Hakon , Feldman Arthur M. 
Published: September 2024

AbstractBackgroundBcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3-protein interactions, it is important to understand these protein interactions given the importance of the multifunctional cochaperone BAG3 in cardiomyocytes, using an in vitro cardiomyocyte model.MethodsThe experimental assay was done using high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the human AC16 cardiomyocyte cell line with the BioID technology.ResultsProteins with BAG3-interaction were identified in all the 28 hallmark gene sets enriched in idiopathic cardiomyopathies and/or ischemic disease. Among the 24 hallmark gene sets enriched in both idiopathic cardiomyopathies and ischemic disease, 15 gene sets had at least 3 proteins with BAG3-interaction.ConclusionsThis study highlights BAG3 protein interactions, unveiling the key gene sets affected in cardiomyopathies, which help to explain the molecular mechanisms of the cardioprotective effects of BAG3. In addition, this study also highlighted the complexity of proteins with BAG3 interactions, implying unwanted effects of BAG3.
Excessive Corneal Endothelial Single Cell Loss Following Endothelial Injuries
Authors: Fu Yuan Kai , Lin Matthew , Hung Kuo-Hsuan , Yeh Lung-Kun , Tan Hsin-Yuan 
Published: September 2024

AbstractCorneal endothelial dysfunction is the main cause for more than 50% of corneal transplantations. Human corneal endothelial cells are generally viewed as non-proliferativein vivo. Any injury that results in endothelial loss exceeding the critical threshold can cause irreversible endothelial functional decompensation, leading to corneal edema and vision loss. Currently, the mainstay treatment for irreversible corneal dysfunction is corneal transplantation. In this work, using well-established imaging technique of specular microscopy, we revisited the endothelial damage following three common corneal endothelial injury scenarios: post-cataract surgery, endothelial dystrophy, and corneal penetrating injury. We identified unexpected, stochastic single-cell loss in the corneal endothelium following primary injuries, persisting well beyond the expected wound healing period, a phenomenon that has not been previously highlighted. This finding offers a potential explanation for the chronic endothelial cell loss following a primary injury. Further investigation could provide valuable insights for improving clinical management strategies for corneal endothelial dysfunction.
Letter: Cancer-independent, second somaticNF1mutation of normal tissues in neurofibromatosis type 1
Authors: Oliver Thomas R. W. , Lawson Andrew R. J. , Lee-Six Henry , Tollit Anna , Jung Hyunchul , Hooks Yvette , Sanghvi Rashesh , Young Matthew D. , Butler Timothy M. , Nicola Pantelis , Treger Taryn D. , Amos Burke G. A. , Aquilina Kristian , Löbel Ulrike , Cortes-Ciriano Isidro , Hargrave Darren , Jorgensen Mette , Jessop Flora A. , Coorens Tim H. H. , Flanagan Adrienne M. , Allinson Kieren , Martincorena Inigo , Jacques Thomas S. , Behjati Sam 
Published: September 2024

INTRODUCTIONCancer predisposition syndromes mediated by recessive cancer genes generate tumours via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here, we performed whole genome and exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multi-system cancer-predisposing syndrome mediated by constitutive monoallelicNF1inactivation. We identified multiple independentNF1driver variants in histologically normal tissues, but not in 610 biopsies from two non-predisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncatingNF1mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbour second hits inNF1, the extent and pattern of which may underpin the syndrome’s cancer phenotype.
Kinbiont: From time series to ecological and evolutionary responses in microbial systems
Authors: Angaroni Fabrizio , Peruzzi Alberto , Alvarenga Edgar Z. , Pinheiro Fernanda 
Published: September 2024

AbstractMicrobial behavior is quantitatively characterized by observables inferred from kinetics experiments. Growth rate and biomass yield, for example, are used to map response patterns across different conditions including antibiotic growth inhibition and yield dependence on substrate. As microbial kinetics datasets grow, there is immense potential to advance our understanding of ecological and evolutionary processes. But how can we turn these data into actionable insights about microbial responses? Here we introduce Kinbiont – an ecosystem of numerical methods integrating advanced ordinary differential equation solvers, non-linear optimization, signal processing, and interpretable machine learning algorithms. Kinbiont offers a model-based data analysis pipeline covering all aspects of microbial kinetics, from pre-processing to result interpretation. We demonstrate Kinbiont’s performance using synthetic and real datasets, including bacterial growth, diauxic curves, phage-bacteria co-cultures, and ecotoxicological responses. Kinbiont can aid biological discovery through data-driven generation of hypotheses that can be tested in targeted experiments.
How a pathogenic mutation impairs Hsp60 functional dynamics from monomeric to fully assembled states
Authors: Torielli Luca , Guarra Federica , Shao Hao , Gestwicki Jason E. , Serapian Stefano A. , Colombo Giorgio 
Published: September 2024

AbstractHeat Shock Protein 60 kDa (Hsp60) is a mitochondrial chaperonin that cooperates with Hsp10 to drive the correct folding of client proteins. MonomersMof Hsp60 (featuring equatorial, intermediate, and apical domains) first assemble into 7-meric Single rings (S), then pairs ofSinterface equatorially to form 14-meric Double rings (D) that accommodate clients into their lumen. Recruitment of 7 Hsp10 molecules per pole turnsDinto a 28-meric Football-shaped complex (F). Sequential hydrolysis of ATP present in each Hsp60 unit ofFfinally drives client folding andFdisassembly. Equatorial domain mutation V72I occurs in SPG13, a form of hereditary spastic paraplegia: while distal to the active site, this severely impairs the chaperone cycle and stability. To understand the molecular bases of this impairment we have run atomistic molecular dynamics (MD) simulations ofM,S,D, andFfor both WT and mutant Hsp60, with two catalytically relevant Hsp60 aspartates inDandFmodelled in three different protonation states. Additionally,Din one protonation state was modelled post-hydrolysis (total production time: 36 µs). By combining complementary experimental and computational approaches for the analysis of functional dynamics and allosteric mechanisms, we consistently find that mutation V72I significantly rewires allosteric routes present in WT Hsp60 across its complexes, from isolatedMunits right up toF, rigidifying them—as observed experimentally—by introducing a direct allosteric link between equatorial and apical Hsp60 domains that bypasses the ATP binding site (wherein we observe the alteration of mechanisms driving reactivity). Our results reveal a multiscale complexity of functional mechanisms for Hsp60 and its pathogenic mutant, and may lay the foundation for the design of experiments to fully understand both variants.
Elucidating the Differential Impacts of Equivalent Gating-Charge Mutations in Voltage-Gated Sodium Channels
Authors: Elhanafy Eslam , Akbari Ahangar Amin , Roth Rebecca , Gamal El-Din Tamer M. , Bankston John R , Li Jing 
Published: September 2024

AbstractVoltage-gated sodium (Nav) channels are pivotal for cellular signaling and mutations in Navchannels can lead to excitability disorders in cardiac, muscular, and neural tissues. A major cluster of pathological mutations localizes in the voltage-sensing domains (VSDs), resulting in either gain-of-function (GoF), loss-of-function (LoF) effects, or both. However, the mechanism behind this functional divergence of mutations at equivalent positions remains elusive. Through hotspot analysis, we identified three gating charges (R1, R2, and R3) as major mutational hotspots in VSDs. The same amino-acid substitutions at equivalent gating-charge positions in VSDIand VSDIIof the cardiac sodium channel Nav1.5 show differential gating-property impacts in electrophysiology measurements. We conducted 120 µs molecular dynamics (MD) simulations on wild-type and six mutants to elucidate the structural basis of their differential impacts. Our μs-scale MD simulations with applied external electric fields captured VSD state transitions and revealed the differential structural dynamics between equivalent R-to-Q mutants. Notably, we observed transient leaky conformations in some mutants during structural transitions, offering a detailed structural explanation for gating-pore currents. Our salt-bridge network analysis uncovered VSD-specific and state-dependent interactions among gating charges, countercharges, and lipids. This detailed analysis elucidated how mutations disrupt critical electrostatic interactions, thereby altering VSD permeability and modulating gating properties. By demonstrating the crucial importance of considering the specific structural context of each mutation, our study represents a significant leap forward in understanding structure- function relationships in Navchannels. Our work establishes a robust framework for future investigations into the molecular basis of ion channel-related disorders.
CRISPR-CLEAR: Nucleotide-Resolution Mapping of Regulatory Elements via Allelic Readout of Tiled Base Editing
Authors: Becerra Basheer , Wittibschlager Sandra , Patel Zain M. , Kutschat Ana P. , Delano Justin , Che Eric , Karjalainen Anzhelika , Wu Ting , Starrs Marlena , Jankowiak Martin , Bauer Daniel E. , Seruggia Davide , Pinello Luca 
Published: September 2024

ABSTRACTCRISPR tiling screens have advanced the identification and characterization of regulatory sequences but are limited by low resolution arising from the indirect readout of editing via guide RNA sequencing. This study introducesCRISPR-CLEAR, an end-to-end experimental assay and computational pipeline, which leverages targeted sequencing of CRISPR-introduced alleles at the endogenous target locus following dense base-editing mutagenesis. This approach enables the dissection of regulatory elements at nucleotide resolution, facilitating a direct assessment of genotype-phenotype effects.
A secondary β-hydroxybutyrate metabolic pathway linked to energy balance
Authors: Moya-Garzon Maria Dolores , Wang Mengjie , Li Veronica L. , Lyu Xuchao , Wei Wei , Tung Alan Sheng-Hwa , Raun Steffen H. , Zhao Meng , Coassolo Laetitia , Islam Hashim , Oliveira Barbara , Dai Yuqin , Spaas Jan , Delgado-Gonzalez Antonio , Donoso Kenyi , Alvarez-Buylla Aurora , Franco-Montalban Francisco , Letian Anudari , Ward Catherine , Liu Lichao , Svensson Katrin J. , Goldberg Emily L. , Gardner Christopher D. , Little Jonathan P. , Banik Steven M. , Xu Yong , Long Jonathan Z. 
Published: September 2024

Summaryβ-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.
CRISPRoff epigenetic editing for programmable gene silencing in human cells without DNA breaks
Authors: Pattali Rithu K. , Ornelas Izaiah J. , Nguyen Carolyn D. , Xu Da , Divekar Nikita S. , Nuñez James K. 
Published: September 2024

AbstractThe advent of CRISPR-based technologies has enabled the rapid advancement of programmable gene manipulation in cells, tissues, and whole organisms. An emerging platform for targeted gene perturbation is epigenetic editing, the direct editing of chemical modifications on DNA and histones that ultimately results in repression or activation of the targeted gene. In contrast to CRISPR nucleases, epigenetic editors modulate gene expression without inducing DNA breaks or altering the genomic sequence of host cells. Recently, we developed the CRISPRoff epigenetic editing technology that simultaneously establishes DNA methylation and repressive histone modifications at targeted gene promoters. Transient expression of CRISPRoff and the accompanying single guide RNAs in mammalian cells results in transcriptional repression of targeted genes that is memorized heritably by cells through cell division and differentiation. Here, we describe our protocol for the delivery of CRISPRoff through plasmid DNA transfection, as well as the delivery of CRISPRoff mRNA, into transformed human cell lines and primary immune cells. We also provide guidance on evaluating target gene silencing and highlight key considerations when utilizing CRISPRoff for gene perturbations. Our protocols are broadly applicable to other CRISPR-based epigenetic editing technologies, as programmable genome manipulation tools continue to evolve rapidly.
Addressing Inconsistency in Functional Neuroimaging: A Replicable Data-Driven Multi-Scale Functional Atlas for Canonical Brain Networks
Authors: Jensen Kyle M. , Turner Jessica A. , Uddin Lucina Q. , Calhoun Vince D. , Iraji Armin 
Published: September 2024

AbstractThe advent of multiple neuroimaging methodologies has greatly aided in the conceptualization of large-scale functional brain networks in the field of cognitive neuroscience. However, there is inconsistency across studies in both nomenclature and the functional entities being described. There is a need for a unifying framework that standardizes terminology across studies while also bringing analyses and results into the same reference space. Here we present a whole-brain atlas of canonical functional brain networks derived from more than 100,000 resting-state fMRI datasets. These data-driven functional networks are highly replicable across datasets and capture information from multiple spatial scales. We have organized, labeled, and described the networks with terms familiar to the fields of cognitive and affective neuroscience in order to optimize their utility in future neuroimaging analyses and enhance the accessibility of new findings. The benefits of this atlas are not limited to future template-based or reference-guided analyses, but also extend to other data-driven neuroimaging approaches across modalities, such as those using blind independent component analysis (ICA). Future studies utilizing this atlas will contribute to greater harmonization and standardization in functional neuroimaging research.
In cell NMR reveals cells selectively amplify and structurally remodel amyloid fibrils
Authors: Ansari Shoyab , Lagasca Dominique , Dumarieh Rania , Xiao Yiling , Krishna Sakshi , Li Yang , Frederick Kendra K. 
Published: September 2024

AbstractAmyloid forms of α-synuclein adopt different conformations depending on environmental conditions. Advances in structural biology have accelerated fibril characterization. However, it remains unclear which conformations predominate in biological settings because current methods typically not only require isolating fibrils from their native environments, but they also do not provide insight about flexible regions. To address this, we characterized α-syn amyloid seeds and used sensitivity enhanced nuclear magnetic resonance to investigate the amyloid fibrils resulting from seeded amyloid propagation in different settings. We found that the amyloid fold and conformational preferences of flexible regions are faithfully propagatedin vitroand in cellular lysates. However, seeded propagation of amyloids inside cells led to the minority conformation in the seeding population becoming predominant and more ordered, and altered the conformational preferences of flexible regions. The examination of the entire ensemble of protein conformations in biological settings that is made possible with this approach may advance our understanding of protein misfolding disorders and facilitate structure-based drug design efforts.
Disrupted Development of the mPFC-Thalamic Circuit in the Mouse Shank3−/−model of Autism
Authors: Devienne Gabrielle , Vantomme Gil , Huguenard John R 
Published: September 2024

AbstractAutism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders with heterogeneous causes, and are characterized by communication deficits, impaired social interactions, and repetitive behaviors. Despite numerous studies in mouse models focused on pathophysiological circuit mechanisms of ASD in mature animals, little is known regarding ASD onset and its evolution through development. The medial prefrontal cortex (mPFC) is crucial for higher-order cognitive functions and social behavior, thus key to understanding ASD pathology. To explore early developmental disruptions in the mPFC, we used theShank3knockout (Shank3−/−) mouse model. SHANK3 is crucial for glutamatergic synapse maturation, and the Shank3−/−mouse has been well-characterized for displaying ASD-related behavioral phenotypes. We investigated network, cellular, and synaptic changes within the mPFC and in its projections to the mediodorsal thalamus (MD) at two developmental stages, preweaning (P14) and adulthood (>P55). Our findings reveal early synaptic deficits at P14 both within the mPFC and in its projections to the MD accompanied by alterations in mPFC network activity and reduced excitability of excitatory neurons, overall suggesting hypofunction. Interestingly, behavioral deficits were already detectable by P11, preceding the observation of synaptic changes at P14. By adulthood, these early synaptic and cellular alterations progressed to global dysfunction, characterized by mPFC network hyperfunction and layer 5 pyramidal cell hyperexcitability, accompanied by augmented glutamatergic signaling to MD with enhanced action potential production. These results suggest that early synaptic changes may precede and interact with behavioral deficits, potentially leading to compensatory mechanisms that contribute to more pronounced mPFC dysfunction later in development. This study highlights the complex dynamic progression of mPFC deficits in ASD and emphasizes the potential impact of targeting early synaptic alterations to mitigate later behavioral and cognitive deficits.