bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral mutations underlie promiscuous transport of quaternary ammonium antiseptics by Small Multidrug Resistance transporters
Authors: Burata Olive E. , O’Donnell Ever , Hyun Jeonghoon , Lucero Rachael M. , Thomas Junius E. , Gibbs Ethan M. , Reacher Isabella , Carney Nolan A. , Stockbridge Randy B. 
Published: February 2024

AbstractThe mechanistic basis of transport promiscuity in multidrug exporters is not well understood. We examine this question using the Small Multidrug Resistance (SMR) transporters. We engineer a selective SMR protein to promiscuously export quaternary ammonium antiseptics, similar to multidrug exporters in this family. Using combinatorial mutagenesis and deep sequencing, we identify the necessary and sufficient molecular determinants of this new activity. Using x-ray crystallography, electrophysiology, and a novel proteoliposome-based antiseptic transport assay, we tease apart the mechanistic roles that these residues play in transport polyspecificity. We find that substrate preference changes not through modification of the residues that directly interact with the substrate, but through mutations peripheral to the binding pocket. Our new molecular insights into substrate promiscuity among the SMRs can be applied to understand multidrug export and the evolution of novel transport functions more generally.
Striatal dopamine contributions to skilled motor learning
Authors: Phillips Chris D. , Myers Courtney C. , Leventhal Daniel K. , Burgess Christian R. 
Published: February 2024

AbstractCoordinated multi-joint limb and digit movements - “manual dexterity” - underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson’s Disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that cortico-striatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release as mice learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In dorsolateral striatum, dopamine dynamics are faster than in dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.
Temporal dynamics of BMP/Nodal ratio drive tissue-specific gastrulation morphogenesis
Authors: Emig Alyssa A , Hansen Megan , Grimm Sandra , Coarfa Cristian , Lord Nathan D , Williams Margot Kossmann 
Published: February 2024

ABSTRACTAnteroposterior (AP) elongation of the vertebrate body plan is driven by convergence and extension (C&E) gastrulation movements in both the mesoderm and neuroectoderm, but how or whether molecular regulation of C&E differs between tissues remains an open question. Using a zebrafish explant model of AP axis extension, we show that C&E of the neuroectoderm and mesoderm can be uncoupledex vivo, and that morphogenesis of individual tissues results from distinct morphogen signaling dynamics. Using precise temporal manipulation of BMP and Nodal signaling, we identify a critical developmental window during which high or low BMP/Nodal ratios induce neuroectoderm- or mesoderm-driven C&E, respectively. Increased BMP activity similarly enhances C&E specifically in the ectoderm of intact zebrafish gastrulae, highlighting thein vivorelevance of our findings. Together, these results demonstrate that temporal dynamics of BMP and Nodal morphogen signaling activate distinct morphogenetic programs governing C&E gastrulation movements within individual tissues.SUMMARY STATEMENTUsing zebrafish embryo and explant models, we demonstrate that temporal dynamics of morphogen signaling ratios distinguish between tissue-specific morphogenetic programs during vertebrate body plan formation.
Disease Characteristics Influence the Privacy Calculus to adopt Electronic Health Records: A randomized controlled trial in Germany
Authors: von Kalckreuth Niklas , Feufel Markus 
Published: February 2024

AbstractBackgroundThe electronic health record (EHR) is integral to improving healthcare efficiency and quality. Its successful implementation hinges on patient willingness to use it, particularly in Germany where concerns about data security and privacy significantly influence usage intention. Little is known, however, about how specific characteristics of medical data influence patients’ intention to use the EHR.ObjectiveThis study aims to validate the Privacy Calculus Model (PCM) in the EHR context and to assess how personal and disease characteristics, namely disease-related stigma and disease time course, affect PCM predictions.MethodsAn online survey was conducted to empirically validate the PCM for EHR, incorporating a case vignette varying in disease-related stigma (high/low) and time course (acute/chronic), with 241 German participants. The data were analyzed using SEM-PLS.ResultsThe model explains R²=71.8% of the variance in intention to use. The intention to use is influenced by perceived benefits, data privacy concerns, trust in the provider, and social norms. However, only the disease’s time course, not stigma, affects this intention. For acute diseases, perceived benefits and social norms are influential, whereas for chronic diseases, perceived benefits, privacy concerns, and trust in the provider influence intention.ConclusionsThe PCM validation for EHRs reveals that personal and disease characteristics shape usage intention in Germany. This suggests the need for tailored EHR adoption strategies that address specific needs and concerns of patients with different disease types. Such strategies could lead to a more successful and widespread implementation of EHRs, especially in privacy-conscious contexts.
Neuropsychology of chronic back pain managed with long-term opioid use
Authors: Baliki Marwan N , Vigotsky Andrew D. , Rached Gaelle , Jabakhanji Rami , Huang Lejian , Branco Paulo , Cong Olivia , Griffith James , Wasan Ajay D. , Schnitzer Thomas J. , Apkarian A. Vania 
Published: February 2024

AbstractChronic pain is commonly treated with long-term opioids, but the neuropsychological outcomes associated with stable long-duration opioid use remain unclear. Here, we contrasted the psychological profiles, brain activity, and brain structure of 70 chronic back pain patients on opioids (CBP+O, average opioid exposure 6.2 years) with 70 patients managing their pain without opioids. CBP+O exhibited moderately worse psychological profiles and small differences in brain morphology. However, CBP+O had starkly different spontaneous brain activity, dominated by increased mesocorticolimbic and decreased dorsolateral-prefrontal activity, even after controlling for pain intensity and duration. These differences strongly reflected cortical opioid and serotonin receptor densities and mapped to two antagonistic resting-state circuits. The circuits’ dynamics were explained by mesocorticolimbic activity and reflected negative affect. We reassessed a sub-group of CBP+O after they briefly abstained from taking opioids. Network dynamics, but not spontaneous activity, reflected exacerbated signs of withdrawal. Our results have implications for the management and tapering of opioids in chronic pain.
White matter microstructural changes in adult-onset idiopathic focal cervical dystonia using ultra-strong diffusion gradient MRI
Authors: MacIver CL , Jones DK , Green K , Szewczyk-krolikowski K , Doring A , Tax CMW , Peall KJ 
Published: February 2024

AbstractBackground and ObjectivesAdult-onset idiopathic focal cervical dystonia (AOIFCD) involves loss of co-ordinated contraction of the cervical musculature, resulting in pain, impaired function and in some individuals, an associated head tremor. Existing neuroimaging studies have implicated key motor networks. However, measures used to date lack specificity in detailing the underlying pathophysiological differences.MethodsA cohort of individuals diagnosed with AOIFCD and an age- and sex-matched control group were prospectively recruited. All participants underwent MRI using structural and diffusion sequences with multiple b-values up to 30,000 s/mm2, coupled with motor and non-motor clinical phenotyping. Tractography was performed assessing whole tract median values, while tractometry was used for along tract analysis. Key white matter motor pathways were assessed initially using general measures (DTI/DKI: FA-fractional anisotropy; MD-mean diffusivity; MK-mean kurtosis; AK-axial kurtosis; RK-radial kurtosis) with subsequent microstructural white matter modelling approaches (NODDI: ODI-orientation distribution index, NDI-neurite density index, FWF-free water fraction; and standard model:f-intra-axonal signal fraction, Da-intra axonal diffusivity, Depar-extra axonal parallel diffusivity, Deperp-extra axonal perpendicular diffusivity,p2-orientation coherence) and unconstrained high b-value zero-order spherical harmonic signal (R0, related to intra-axonal signal) to assess differences within these tracts. Subgroup analyses were undertaken comparing those with and without associated head tremor to the control cohort.Results50 AOIFCD and 30 healthy control participants underwent structural brain MRI, with 46 AOIFCD and 30 healthy controls included for analysis (33 without head tremor, 13 with head tremor). Significant differences were observed in the anterior thalamic radiations (lower mid tract FA, RK,fandp2and higher ODI), thalamopremotor tracts (mid tract higher MK and lower NDI, and distal tract lower ODI and higherf) and striatopremotor tracts (proximal lowerfand R0). These measures correlated with symptom severity across the spectrum with clinical measures, including psychiatric symptoms, sleep quality, pain and cognitive functioning.DiscussionOverall, localised microstructural differences were identified within tracts linking the prefrontal cortex and premotor cortex with basal ganglia regions, suggesting microstructural aberrances of motor system modulatory pathways, particularly in relation to intra-axonal and fibre orientation dispersion measures.
Reliance on vision for walking balance is related to somatosensory deficits in individuals with cerebral palsy
Authors: Sansare Ashwini , Reimann Hendrik , Bodt Barry , Arcodia Maelyn , Verma Khushboo , Jeka John , Lee Samuel C.K. 
Published: February 2024

AbstractAimTo investigate the relationship between somatosensory deficits, specifically ankle and hip joint position sense, two-point discrimination, and vibration on the (1) responses to visual perturbations during walking and (2) response improvements to visual perturbations while receiving a sensory-centric treatment, i.e., stochastic resonance (SR) stimulation, in individuals with and without cerebral palsy (CP).MethodsTwenty-eight individuals (14 CP, 14 age-and sex-matched controls) walked in a virtual reality cave while receiving visual perturbations. We applied SR to the ankle and hip joints. Data analysis consisted of bivariate correlations, and multiple regression analysis (MRA) using all four sensory tests as predictors with the responses to visual perturbation and the improvements in the responses when SR is applied as outcomes.ResultsWe found significant and strong correlations between performance on sensory tests and the responses to visual perturbations, and improvements in the responses with SR. Only one predictor could be entered into the MRA, indicating that performance on any of the sensory tests could predict the responses to visual perturbation and the improvements with SR.InterpretationIndividuals with sensory deficits are more responsive to sensory-centric interventions. This study is an initial step in identifying potential “responders” to sensory therapies in individuals with CP.
Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1
Authors: Khamrui Susmita , Dodatko Tetyana , Wu Ruoxi , Leandro João , Sabovic Amanda , Violante Sara , Cross Justin R. , Marsan Eric , Kumar Kunal , DeVita Robert J. , Lazarus Michael B. , Houten Sander M. 
Published: February 2024

AbstractGlutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or non-toxic metabolites. Here, we report a novel target, SUGCT, which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA. We report the structure of SUGCT, the first eukaryotic structure of a type III CoA transferase, develop a high-throughput enzyme assay and a cell-based assay, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme validating the screening approach. These results may form the basis for future development of new pharmacological intervention to treat GA1.
ASPYRE-Lung: Validation of a simple, fast, robust and novel method for multi-variant genomic analysis of actionable NSCLC variants in tissue
Authors: Evans Ryan T , Gillon-Zhang Elizabeth , Brown Julia N. , Knudsen Katherine E. , King Candace , Green Amanda S , Silva Ana-Luisa , Mordaka Justyna M. , Palmer Rebecca N. , Tomassini Alessandro , Collazos Alejandra , Xyrafaki Christina , Turner Iyelola , Ho Chau Ha , Nugent Dilyara , Jose Jinsy , Andreazza Simonetta , von Bargen Kristine , Gray Eleanor R. , Stolarek-Januszkiewicz Magdalena , Cooke Aishling , Reddi Honey , Balmforth Barnaby W , Osborne Robert J 
Published: February 2024

AbstractGenomic variant testing of tumors is a critical gateway for patients to access the full potential of personalized oncology therapeutics. Current methods such as next-generation sequencing are costly and challenging to interpret, while PCR assays are limited in the number of variants they can cover. We developed ASPYRE® (Allele-Specific PYrophosphorolysis REaction) technology to address the urgent need for rapid, accessible and affordable diagnostics informing actionable genomic target variants of a given cancer. The targeted ASPYRE-Lung panel for non-small cell carcinoma covers 114 variants in 11 genes (ALK, BRAF, EGFR, ERBB2, KRAS, RET, ROS1, MET & NTRK1/2/3) to robustly inform clinical management. The assay detects single nucleotide variants, insertions, deletions, and gene fusions from tissue-derived DNA and RNA simultaneously. We tested the limit of detection, specificity, analytical accuracy and analytical precision of ASPYRE-Lung using FFPE lung tissue samples from patients with non-small cell lung carcinoma, variant-negative FFPE tissue from healthy donors, and FFPE-based contrived samples with controllable variant allele fractions. The sensitivity of ASPYRE-Lung was determined to be ≤ 3% variant allele fraction for single nucleotide variants and insertions or deletions, 100 copies for fusions, and 200 copies for MET exon 14 skipping. The specificity was 100% with no false positive results. The analytical accuracy test yielded no discordant calls between ASPYRE-Lung and expected results for clinical samples (via orthogonal testing) or contrived samples, and results were replicable across operators, reagent lots, runs, and real-time PCR instruments with a high degree of precision. The technology is simple and fast, requiring only four reagent transfer steps using standard laboratory equipment (PCR and qPCR instruments) with analysis via a cloud-based analysis algorithm. The ASPYRE-Lung assay has the potential to be transformative in facilitating access to rapid, actionable molecular profiling of tissue for patients with non-small cell carcinoma.
Huntingtin is an RNA-binding protein and participates in NEAT1-mediated paraspeckles
Authors: Yadav Manisha , Harding Rachel J. , Li Tiantian , Xu Xin , Gall-Duncan Terence , Khan Mahreen , Bardile Costanza Ferrari , Sequiera Glen L. , Duan Shili , Chandrasekaran Renu , Pan Anni , Bu Jiachuan , Yamazaki Tomohiro , Hirose Tetsuro , Prinos Panagiotis , Tippett Lynette , Turner Clinton , Curtis Maurice A. , Faull Richard L.M. , Pouladi Mahmoud A. , Pearson Christopher E. , He Housheng Hansen , Arrowsmith Cheryl H. 
Published: February 2024

AbstractHuntingtin protein, mutated in Huntington disease, is implicated in nucleic acid- mediated processes, yet evidence for direct huntingtin-nucleic acid interaction is limited. Here we show wildtype and mutant huntingtin co-purify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wildtype and mutant huntingtin revealed NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntington’s disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin co-localized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a novel huntingtin interactor, demonstrating huntingtin’s involvement in RNA-mediated functions and paraspeckle regulation.One-Sentence SummaryHTT is an RNA-binding protein that interacts with G-rich sequences, including those in the paraspeckle lncRNA NEAT1.
vmTracking: Virtual Markers Overcome Occlusion and Crowding in Multi-Animal Pose Tracking
Authors: Azechi Hirotsugu , Takahashi Susumu 
Published: February 2024

AbstractIn multi-animal tracking, addressing occlusion and crowding is crucial for accurate behavioral analysis. However, in situations where occlusion and crowding generate complex interactions, achieving accurate pose tracking remains challenging. Therefore, we introduced Virtual marker tracking (vmTracking), which uses virtual markers for individual identification. Virtual markers are labels derived from conventional markerless multi-animal tracking tools, such as multi-animal DeepLabCut (maDLC) and Social LEAP Estimate Animal Poses (SLEAP). Unlike physical markers, virtual markers exist only within the video and attribute features to individuals, enabling consistent identification throughout the entire video while keeping the animals markerless in reality. Using these markers as cues, annotations were applied to multi-animal videos, and tracking was conducted with single-animal DeepLabCut (saDLC) and SLEAP’s single-animal method. vmTracking minimized manual corrections and annotation frames needed for training, efficiently tackling occlusion and crowding. Experiments tracking multiple mice, fish, and human dancers confirmed vmTracking’s variability and applicability. These findings could enhance the precision and reliability of tracking methods used in the analysis of complex naturalistic and social behaviors in animals, providing a simpler yet more effective solution.
Lack of rhythmicity in Bmal1 deficient mice impairs motivation towards natural stimuli
Authors: Berbegal-Sáez Paula , Gallego-Landin Ines , Macía Javier , Alegre-Zurano Laia , Castro-Zavala Adriana , Welz Patrick-Simon , Benitah Salvador A , Valverde Olga 
Published: February 2024

ABSTRACTMaintaining appropriate circadian rhythmicity is essential for coordinating the activity of biological functions in mammalian organisms. A variety of physiological and behavioral changes have been associated with disturbances of this complex clock mechanism.In the present study, we delve into the consequences of circadian arrhythmia using the Bmal1-knockout (KO) mouse line aiming to explore potential behavioral and motivational implications. We were able to identify the intricate activity patterns that define circadian disturbance in Bmal1-KO mice by utilizing a new analysis model based on entropy divergence.Alterations in locomotor activity were accompanied by disruptions of circadian expression patterns in various clock genes as revealed by gene expression analysis. Additionally, we found a dysregulated gene expression profile in Bmal1-KO mice regarding genes related to circadian control in various brain nuclei. Specifically, the ventral striatum exhibited a dysregulation in the expression levels of genes modulating reward and motivation.Further investigation revealed that BMAL1 deficient mice showed a sustained rise in motivation and seeking behavior for food and water reinforcers in the self-administration paradigm, independently of the caloric content of the reward. Together, our data reveal that disruptions in circadian rhythmicity, induced by alterations in the molecular clock, also impact the gene expression regulating the reward system. This, in turn, can lead to altered seeking behavior and motivation for natural rewards. In summary, the present study contributes to our understanding of how reward processing is under the regulation of circadian clock machinery.
Adult neurogenesis through glial transdifferentiation in a CNS injury paradigm
Authors: Casas-Tintó Sergio , García-Guillen Nuria , Losada-Pérez Maria 
Published: February 2024

AbstractAs the global population ages, the prevalence of neurodegenerative disorders is fast increasing. This neurodegeneration as well as other CNS injuries cause permanent disabilities. Thus, generation of new neurons is the rosetta stone in contemporary neuroscience.Glial cells support central nervous system (CNS) homeostasis through evolutionary conserved mechanisms. Upon damage, glial cells activate an immune and inflammatory response to clear the injury site from debris, and proliferate to restore cell number. This glial regenerative response (GRR) is mediated by the neuropil associated glia (NG) inDrosophila, equivalent to vertebrate astrocytes, oligodendrocytes (OL) and oligodendrocyte progenitor cells (OPCs). Here, we examine the contribution of NG lineages and the GRR in response to injury. The results indicate that NG exchanges identities between ensheathing glia (EG) and astrocyte like glia (ALG). Additionally, we found that NG cells undergo transdifferentiation to yield neurons. Moreover, this transdifferentiation increases in injury conditions. Thus, these data demonstrate that glial cells are able to generate new neurons through direct transdifferentiation. The present work makes a fundamental contribution to the CNS regeneration field and describes a new physiological mechanism to generate new neurons.