bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decellularization of Rat Gracilis Muscle Flap as a Potential Scaffold For Skeletal Muscle Composite Allotransplantation
Authors: Dong Chenhui , Sarcon Aida K. , Zhao Chunfeng 
Published: April 2024

ABSTRACTThere are limited biomaterials for skeletal muscle regeneration. This study aimed to apply a decellularization protocol in a muscle flap model and investigate its patency. Twenty-six gracilis-muscle (GM) flaps were harvested from 13 rats. GMs were divided into groups of either 1) normal (control), 2) perfusion with 1% sodium dodecyl sulfate or SDS for 48h, followed by Triton X-100 or TX100, or lastly, 3) perfusion with SDS for 72h, followed by TX100. The morphology, microcirculatory network patency, and residual DNA content (DNAC) were evaluated. Decellularized muscle (DM) for 72h was more translucent than DM-48h. Despite longer decellularization, the DM-72h microcirculatory network maintained its integrity, except when the dye infiltrated from the muscle edges. Compared to normal, all DM had significantly lower DNAC (normal of 1.44 μg/mgvs. DM-48h of 0.37 μg/mgvs. DM-72h of 0.089 μg/mg; P < 0.001). The DNAC of the DM-72h group was significantly lower than DM-48h (P< 0.001). We report successful GM flap decellularization. Longer decellularization led to lower DNAC, which did not compromise circulation. Our protocol may be applicable as a free-flap scaffold model for transplantation in the future.Statement of clinical significanceThe impact of our work involves a reproducible skeletal muscle decellularization protocol to later apply in translational research.
IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history
Authors: Bongartz H. , Bradfield C. , Gross J. , Fraser I.D.C. , Nita-Lazar A. , Meier-Schellersheim M. 
Published: April 2024

AbstractDuring an infection, innate immune cells must adjust nature and strength of their responses to changing pathogen abundances. To determine how stimulation of the pathogen sensing TLR4 shapes subsequent macrophage responses, we systematically varied priming and restimulation concentrations of its ligand KLA. We find that different priming strengths have very distinct effects at multiple stages of the signaling response, including receptor internalization, MAPK activation, cytokine and chemokine production, and nuclear translocation and chromatin association of NFκB and IκB members. In particular, restimulation-induced TNF-α production required KLA doses equal to or greater than those used for prior exposure, indicating that macrophages can detect and adaptively respond to changing TLR4 stimuli. Interestingly, while such adaptation was dependent on the anti-inflammatory cytokine IL-10, exogenous concentrations of IL-10 corresponding to those secreted after strong priming did not exert suppressive effects on TNF-α without such prior priming, confirming the critical role of TLR4 stimulation history.
Labels as a Feature: Network Homophily for Systematically Discovering human GPCR Drug-Target Interactions
Authors: Hansson Frederik G. , Madsen Niklas Gesmar , Hansen Lea G. , Jakočiūnas Tadas , Lengger Bettina , Keasling Jay D. , Jensen Michael K. , Acevedo-Rocha Carlos G. , Jensen Emil D. 
Published: April 2024

AbstractMachine learning (ML) has revolutionized drug discovery by enabling the exploration of vast, uncharted chemical spaces essential for discovering novel patentable drugs. Despite the critical role of human G protein-coupled receptors (hGPCRs) in FDA-approved drugs, exhaustive in-distribution drug-target interaction (DTI) testing across all pairs of hGPCRs and known drugs is rare due to significant economic and technical challenges. This often leaves off-target effects unexplored, which poses a considerable risk to drug safety. In contrast to the traditional focus on out-of-distribution (OOD) exploration (drug discovery), we introduce a neighborhood-to-prediction model termed Chemical Space Neural Networks (CSNN) that leverages network homophily and training-free graph neural networks (GNNs) with Labels as Features (LaF). We show that CSNN’s ability to make accurate predictions strongly correlates with network homophily. Thus, LaFs strongly increase a ML model’s capacity to enhance in-distribution prediction accuracy, which we show by integrating labeled data during inference. We validate these advancements in a high-throughput yeast biosensing system (3773 DTIs, 539 compounds, 7 hGPCRs) to discover novel DTIs for FDA-approved drugs and to expand the general understanding of how to build reliable predictors to guide experimental verification.
TET2 regulates early and late transitions in exhausted CD8+T-cell differentiation and limits CAR T-cell function
Authors: Dimitri Alexander J. , Baxter Amy E. , Chen Gregory M. , Hopkins Caitlin R. , Rouin Geoffrey T. , Huang Hua , Kong Weimin , Holliday Christopher H. , Wiebking Volker , Bartoszek Robert , Drury Sydney , Dalton Katherine , Koucky Owen M. , Chen Zeyu , Giles Josephine R. , Jung In-Young , O’Connor Roddy , Collins Sierra , Everett John K. , Amses Kevin , Sherrill-Mix Scott , Chandra Aditi , Goldman Naomi , Vahedi Golnaz , Jadlowsky Julie K. , Young Regina M. , Melenhorst Jan Joseph , Maude Shannon L. , Levine Bruce L. , Frey Noelle V. , Berger Shelley L. , Grupp Stephan A. , Porter David L. , Herbst Friederike , Porteus Matthew H. , Bushman Frederic D. , Weber Evan W. , Wherry E. John , Jordan Martha S. , Fraietta Joseph A. 
Published: April 2024

AbstractCD8+T-cell exhaustion hampers disease control in cancer and chronic infections and limits efficacy of T-cell−based therapies, such as CAR T-cells. Epigenetic reprogramming of CAR T-cells by targeting TET2, a methylcytosine dioxygenase that mediates active DNA demethylation, has shown therapeutic potential; however, the role of TET2 in exhausted T-cell (TEX) development is unclear. In CAR T-cell exhaustion models and chronic LCMV infection, TET2 drove the conversion from stem cell-like, self-renewing TEXprogenitors towards terminally differentiated and effector (TEFF)-like TEX. In mouse T-cells,TET2-deficient terminally differentiated TEXretained aspects of TEXprogenitor biology, alongside decreased expression of the transcription factor TOX, suggesting that TET2 potentiates terminal exhaustion. TET2 also enforced a TEFF-like terminally differentiated CD8+T-cell state in the early bifurcation between TEFFand TEX, indicating a broad role for TET2 in mediating the acquisition of an effector biology program that could be exploited therapeutically. Finally, we developed a clinically actionable strategy forTET2-targeted CAR T-cells, using CRISPR/Cas9 editing and site-specific adeno-associated virus transduction to simultaneously knock-in a CAR at theTRAClocus and a functional safety switch withinTET2. Disruption ofTET2with this safety switch in CAR T-cells restrained terminal TEXdifferentiationin vitroand enhanced anti-tumor responsesin vivo. Thus, TET2 regulates pivotal fate transitions in TEXdifferentiation and can be targeted with a safety mechanism in CAR T-cells for improved tumor control and risk mitigation.One Sentence SummaryModulation of exhausted CD8+T-cell differentiation by targeting TET2 improves therapeutic potential of CAR T-cells in cancer.
Laminin Receptor Characterization in Acute Myeloid Leukemia: Integrin α7β1 Defines non-Leukemic Stem Cells with Migratory Potential
Authors: Görsch Elsa , Arnone Marlon , Klimiankou Maksim , Weller Jan , Rudat Saskia , Klein Gerd , Lengerke Claudia 
Published: April 2024

ABSTRACTInteractions with the bone marrow (BM) niche are crucial for promoting self-renewal and survival of acute myeloid leukemia (AML) cells. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, including laminins. Despite the association of laminin receptor expression with stemness in healthy hematopoiesis, the role of laminin receptors in AML remains poorly understood. In this study, we present a comprehensive examination of the laminin receptors integrin α3β1, α6β1, α7β1 and basal cell adhesion molecule (BCAM) in AML. We demonstrate that high mRNA expression of all four laminin receptors correlates with poor overall survival. Notably, integrin α6 and α7 display the highest cell surface presentation among the examined laminin receptors and are higher expressed on AML cells compared to healthy controls. Moreover, our results indicate that integrin α7 expression allows to distinguish between leukemic stem cells (LSC) and non-LSC populations. Specifically, integrin α7 appears to mark non-LSC with enhanced migratory potential. Together, our results confirm the association of high laminin receptor expression with poor prognosis and establish integrin α7 as marker of high migratory non-LSC.Abstract Figure
Premeiotic 24-nt phasiRNAs are present in theZeagenus and unique in biogenesis mechanism and molecular function
Authors: Zhan Junpeng , Bélanger Sébastien , Lewis Scott , Teng Chong , McGregor Madison , Beric Aleksandra , Schon Michael A. , Nodine Michael D. , Meyers Blake C. 
Published: April 2024

ABSTRACTReproductive phasiRNAs are broadly present in angiosperms and play crucial roles in sustaining male fertility. While the premeiotic 21-nt phasiRNAs and meiotic 24-nt phasiRNA pathways have been extensively studied in maize (Zea mays) and rice (Oryza sativa), a third putative category of reproductive phasiRNAs–named premeiotic 24-nt phasiRNAs–have recently been reported in barley (Hordeum vulgare) and wheat (Triticum aestivum). To determine whether premeiotic 24-nt phasiRNAs are also present in maize and related species and begin to characterize their biogenesis and function, we performed a comparative transcriptome and degradome analysis of premeiotic and meiotic anthers from five maize inbred lines and three teosinte species/subspecies. Our data indicate that a substantial subset of the 24-nt phasiRNA loci in maize and teosinte are already highly expressed at premeiotic phase. The premeiotic 24-nt phasiRNAs are similar to meiotic 24-nt phasiRNAs in genomic origin and dependence on DCL5 for biogenesis, however, premeiotic 24-nt phasiRNAs are unique in that they are likely (i) not triggered by microRNAs, (ii) not loaded by AGO18 proteins, and (iii) not capable of mediatingcis-cleavage. In addition, we also observed a group of premeiotic 24-nt phasiRNAs in rice using previously published data.Together, our results indicate that the premeiotic 24-nt phasiRNAs constitute a unique class of reproductive phasiRNAs and are present more broadly in the grass family (Poaceae) than previously known.SIGNIFICANCEWe previously reported two classes of reproductive phasiRNAs in maize, the premeiotic 21-nt phasiRNAs and the meiotic 24-nt phasiRNAs. Here we report a third class of reproductive phasiRNAs – premeiotic 24-nt phasiRNAs – that are present in theZeagenus, including all five maize inbred lines and three teosinte species/subspecies that we examined, plus rice.We show that in theZeagenus the premeiotic 24-nt phasiRNAs are distinct from the meiotic 24-nt phasiRNAs in triggering mechanism, effector protein, and molecular function.
fMROI: a simple and adaptable toolbox for easy region-of-interest creation
Authors: Peres André , Valério Daniela , Vaz Igor , Mahdiani Morteza , Walbrin Jon , Almeida Jorge 
Published: April 2024

ABSTRACTThis study introduces fMROI, an open-source software designed for creating regions-of-interest (ROIs) and visualizing magnetic resonance imaging data. fMROI offers a user-friendly graphical interface that simplifies the creation of complex ROIs. It is compatible with various operating systems and enables the integration of user-specified algorithms. Comparative analysis against popular neuroimaging software demonstrates the feasibility, applicability, and ease of use of fMROI. Notably, fMROI’s interactive graphical interface with a real-time viewer allows users to identify inconsistencies and design more accurate ROIs, saving significant time by avoiding errors before storing ROIs as NIfTI files. Additionally, fMROI supports automation through command-line accessibility, making it ideal for large-scale analyses. As an open-source platform, fMROI provides a valuable resource for researchers in the neuroimaging community, facilitating efficient ROI creation and streamlining neuroimage analysis.
Relationships between balance performance and connectivity of motor cortex with primary somatosensory cortex and cerebellum in middle aged and older adults
Authors: Sansare Ashwini , Magalhaes Thamires N.C. , Bernard Jessica A. 
Published: April 2024

AbstractConnectivity of somatosensory cortex (S1) and cerebellum with the motor cortex (M1) is critical for balance control. While both S1-M1 and cerebellar-M1 connections are affected with aging, the implications of altered connectivity for balance control are not known. We investigated the relationship between S1-M1 and cerebellar-M1 connectivity and standing balance in middle-aged and older adults. Our secondary objective was to investigate how cognition affected the relationship between connectivity and balance. Our results show that greater S1-M1 and cerebellar-M1 connectivity was related to greater postural sway during standing. This may be indicative of an increase in functional recruitment of additional brain networks to maintain upright balance despite differences in network connectivity. Also, cognition moderated the relationship between S1-M1 connectivity and balance, such that those with lower cognition had a stronger relationship between connectivity and balance performance. It may be that individuals with poor cognition need increased recruitment of brain regions (compensation for cognitive declines) and in turn, higher wiring costs, which would be associated with increased functional connectivity.
Neurofilament accumulation disrupts autophagy in giant axonal neuropathy
Authors: Paumier Jean-Michel , Zewe James , Pergande Melissa R , Venkatesan Meghana , Israeli Eitan , Panja Chiranjit , Snider Natasha , Savas Jeffrey , Opal Puneet 
Published: April 2024

ABSTRACTNeurofilament accumulation is a marker of several neurodegenerative diseases, but it is the primary pathology in Giant Axonal Neuropathy (GAN). This childhood onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that is essential for neurofilament degradation. Using a combination of genetic and RNA interference (RNAi) approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through two mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations sequester the chaperone 14-3-3, a protein responsible for the localization of the transcription factor EB (TFEB), a key regulator of autophagy. This dual disruption of autophagy likely contributes to the pathogenesis of other neurodegenerative diseases with neurofilament accumulations.
Dendrite injury, but not axon injury, triggers neuroprotection in Drosophila models of neurodegenerative disease
Authors: Prange Sydney E. , Bhakta Isha N. , Sysoeva Daria , Jean Grace E. , Madisetti Anjali , Duong Ly U. , Hwu Patrick T. , Melton Jaela G. , Le Hieu H. N. , Thompson-Peer Katherine L. 
Published: April 2024

SUMMARYDendrite defects and loss are early cellular alterations observed across neurodegenerative diseases that play a role in early disease pathogenesis. Dendrite degeneration can be modeled by expressing pathogenic polyglutamine disease transgenes inDrosophilaneuronsin vivo. Here, we show that we can protect against dendrite loss in neurons modeling neurodegenerative polyglutamine diseases through injury to a single primary dendrite branch. We find that this neuroprotection is specific to injury-induced activation of dendrite regeneration: neither injury to the axon nor injury just to surrounding tissues induces this response. We show that the mechanism of this regenerative response is stabilization of the actin (but not microtubule) cytoskeleton. We also demonstrate that this regenerative response may extend to other neurodegenerative diseases. Together, we provide evidence that activating dendrite regeneration pathways has the potential to slow–or even reverse–dendrite loss in neurodegenerative disease.
Genomic evolution and rearrangement of CTX-Φ prophage elements in Vibrio cholerae during the 2018-2022 cholera outbreaks in The Democratic Republic of Congo
Authors: Irenge Leonid M. , Ambroise Jérôme , Bearzatto Bertrand , Durant Jean-François , Wimba Louisette K. , Gala Jean-Luc 
Published: April 2024

AbstractBetween 2018 and 2022, we conducted whole-genome sequencing and phylogenomic analysis on 173Vibrio choleraebacteria (172V. choleraeO1 and 1V. choleraenon-O1/non-O139 isolates) from cholera patients across four provinces in the Democratic Republic of Congo (North-Kivu, South-Kivu, Tanganyika, and Kasai Oriental). AllV. choleraeO1 isolates were classified into the AFR10d and AFR10e sublineages of AFR10 lineage, originating from the third wave of the seventh El Tor cholera pandemic (7PET). Compared to the strains analysed between 2014 and 2017, we observed only limited genetic changes in the core genome of both sublineages. However, AFR10e expanded across the four provinces, whereas AFR10d appeared to become extinct by the end of 2020. TheV. choleraeisolates from 2022 exhibited significant rearrangement in the CTX prophage and associated phage satellites. Notably, this included the tandem repeat of a novel environmental satellite phage RS1 downstream thectxB toxin gene of the CTX-Φ-3 prophage on the large chromosome, and two tandemly arrayed copies of the pre-CTX-Φ prophage precursor on the small chromosome. In conclusion, while the core genome ofV. choleraeO1 AFR10d and AFR10e sublineages showed minimal changes, significant alterations in the content and organisation of elements associated with the CTX-Φ and pre-CTX prophages were identified in AFR10eV. choleraeO1 isolated in 2022.
A Deep Learning Approach for Automated Extraction of Functional Status and New York Heart Association Class for Heart Failure Patients During Clinical Encounters
Authors: Adejumo Philip , Thangaraj Phyllis , Dhingra Lovedeep Singh , Aminorroaya Arya , Zhou Xinyu , Brandt Cynthia , Xu Hua , Krumholz Harlan M , Khera Rohan 
Published: April 2024

ABSTRACTIntroductionSerial functional status assessments are critical to heart failure (HF) management but are often described narratively in documentation, limiting their use in quality improvement or patient selection for clinical trials. We developed and validated a deep learning-based natural language processing (NLP) strategy to extract functional status assessments from unstructured clinical notes.MethodsWe identified 26,577 HF patients across outpatient services at Yale New Haven Hospital (YNHH), Greenwich Hospital (GH), and Northeast Medical Group (NMG) (mean age 76.1 years; 52.0% women). We used expert annotated notes from YNHH for model development/internal testing and from GH and NMG for external validation. The primary outcomes were NLP models to detect (a) explicit New York Heart Association (NYHA) classification, (b) HF symptoms during activity or rest, and (c) functional status assessment frequency.ResultsAmong 3,000 expert-annotated notes, 13.6% mentioned NYHA class, and 26.5% described HF symptoms. The model to detect NYHA classes achieved a class-weighted AUROC of 0.99 (95% CI: 0.98-1.00) at YNHH, 0.98 (0.96-1.00) at NMG, and 0.98 (0.92-1.00) at GH. The activity-related HF symptom model achieved an AUROC of 0.94 (0.89-0.98) at YNHH, 0.94 (0.91-0.97) at NMG, and 0.95 (0.92-0.99) at GH. Deploying the NYHA model among 166,655 unannotated notes from YNHH identified 21,528 (12.9%) with NYHA mentions and 17,642 encounters (10.5%) classifiable into functional status groups based on activity-related symptoms.ConclusionsWe developed and validated an NLP approach to extract NYHA classification and activity-related HF symptoms from clinical notes, enhancing the ability to track optimal care and identify trial-eligible patients.
Comparative effectiveness of non-pharmacological interventions for primary dysmenorrhea: A protocol for a systematic review and network meta-analysis
Authors: Bao Qiong-Nan , Yao Jin , Li Ya-Qin , Zhang Xin-Yue , Chen Zheng-Hong , Xia Man-Ze , Zhong Wan-Qi , Wu Ke-Xin , Yin Zi-Han , Liang Fan-Rong 
Published: April 2024

ABSTRACTIntroductionPrimary dysmenorrhea (PD) is the most common gynecological condition among young women. Although several non-pharmacological interventions have proven effective in relieving pain in patients with PD, the optimal treatment remains unknown. This systematic review and network meta-analysis (NMA) will aim to compare and rank the analgesic effects of different non-drug interventions for PD.Methods and analysisRandomized controlled trials of non-pharmacological interventions for PD will be identified via a search of the PubMed, Cochrane Library, Web of Science, and Embase databases until May 2024. The primary outcome will be change in pain intensity among patients with PD, while the secondary outcomes include health-related quality of life and symptoms of depression and anxiety. Two independent reviewers will perform document screening, study selection, and data extraction. The methodological quality of the included studies will be assessed using the Cochrane Risk of Bias tool (V. 2). The RevMan, Stata, and Aggregate Data Drug Information System software will be used to perform a pairwise meta-analysis and Bayesian NMA in a random-effects model. The certainty of the evidence will be rated using the Grading of Recommendations, Assessment, Development, and Evaluation System.Ethics and disseminationEthical approval will not be required for this study because all data will be obtained from published research. The findings will be published in a peer-reviewed journal.STRENGTHS AND LIMITATIONS OF THIS STUDYThis will be the first study to comprehensively compare the efficacy of non-pharmacological interventions for primary dysmenorrhea using network meta-analysis.The study will assess both short- and long-term efficacies of various non-pharmacological interventions in mitigating pain intensity among patients with primary dysmenorrhea.This systematic review will be conducted in compliance with the Cochrane Handbook guidelines, which will ensure methodological rigor.Only trials from English databases will be included, which may lead to omission of eligible studies in other languages.The efficacy of different regimens of the same non-pharmacological intervention will not be investigated in this study.
Multiple molecular links between the circadian clock and memory centers in honey bees
Authors: Roy Tiyasa , Jain Rikesh , Brockmann Axel 
Published: April 2024

AbstractTime and memory are intimately linked: the capability to learn and recall varies over the day and humans and many animals can associate important events with the time of day. However, how the circadian clock and memory centers are connected is not well understood. We time-trained honey bee foragers and used RNA-sequencing and RNAscope imaging to analyze gene expression changes in focal populations of mushroom body neurons. Thus, we identified three candidate functional modules of time-memory: synchronized peak-level expression of memory-related genes during training time, anticipatory activation of transcription inpdfr-expressing neurons, andcry2andperco-expressing neurons that might represent local clocks. The complex interactions between the clock and memory centers, which appear to be more similar to mammals than other insects, might have been facilitated to optimize social foraging in honey bees.