bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonists of the stress and opioid systems restore the functional connectivity of the prefrontal cortex during alcohol withdrawal through divergent mechanisms
Authors: Carrette L.L.G. , Santos A. , Brennan M. , Othman D. , Collazo A. , George O. 
Published: October 2023

AbstractChronic alcohol consumption leads to dependence and withdrawal symptoms upon cessation, contributing to persistent use. However, the brain network mechanisms by which the brain orchestrates alcohol withdrawal and how these networks are affected by pharmacological treatments remain elusive. Recent work revealed that alcohol withdrawal produces a widespread increase in coordinated brain activity and a decrease in modularity of the whole-brain functional network using single-cell whole-brain imaging of immediate early genes. This decreased modularity and functional hyperconnectivity are hypothesized to be novel biomarkers of alcohol withdrawal in alcohol dependence, which could potentially be used to evaluate the efficacy of new medications for alcohol use disorder. However, there is no evidence that current FDA-approved medications or experimental treatments known to reduce alcohol drinking in animal models can normalize the changes in whole-brain functional connectivity. In this report, we tested the effect of R121919, a CRF1 antagonist, and naltrexone, an FDA-approved treatment for alcohol use disorder, on whole-brain functional connectivity using the cellular marker FOS combined with graph theory and advanced network analyses. Results show that both R121919 and naltrexone restored the functional connectivity of the prefrontal cortex during alcohol withdrawal, but through divergent mechanisms. Specifically, R121919 increased FOS activation in the prefrontal cortex, partially restored modularity, and normalized connectivity, particularly in CRF1-rich regions, including the prefrontal, pallidum, and extended amygdala circuits. On the other hand, naltrexone decreased FOS activation throughout the brain, decreased modularity, and increased connectivity overall except for the Mu opioid receptor-rich regions, including the thalamus. These results identify the brain networks underlying the pharmacological effects of R121919 and naltrexone and demonstrate that these drugs restored different aspects of functional connectivity of the prefrontal cortex, pallidum, amygdala, and thalamus during alcohol withdrawal. Notably, these effects were particularly prominent in CRF1-and Mu opioid receptors-rich regions highlighting the potential of whole-brain functional connectivity using FOS as a tool for identifying neuronal network mechanisms underlying the pharmacological effects of existing and new medications for alcohol use disorder.
Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development
Authors: Ryser Marc D. , Greenwald Matthew A. , Sorribes Inmaculada C. , King Lorraine M. , Hall Allison , Geradts Joseph , Weaver Donald L. , Mallo Diego , Holloway Shannon , Monyak Daniel , Gumbert Graham , Vaez-Ghaemi Shariar , Wu Ethan , Murgas Kevin , Grimm Lars J. , Maley Carlo C. , Marks Jeffrey R. , Shibata Darryl , Hwang E. Shelley 
Published: October 2023

ABSTRACTDuctal carcinoma in situ (DCIS) and invasive breast cancer share many morphologic, proteomic, and genomic alterations. Yet in contrast to invasive cancer, many DCIS tumors do not progress and may remain indolent over decades. To better understand the heterogenous nature of this disease, we reconstructed the growth dynamics of 18 DCIS tumors based on the geo-spatial distribution of their somatic mutations. The somatic mutation topographies revealed that DCIS is multiclonal and consists of spatially discontinuous subclonal lesions. Here we show that this pattern of spread is consistent with a new ‘Comet’ model of DCIS tumorigenesis, whereby multiple subclones arise early and nucleate the buds of the growing tumor. The discontinuous, multiclonal growth of the Comet model is analogous to the branching morphogenesis of normal breast development that governs the rapid expansion of the mammary epithelium during puberty. The branching morphogenesis-like dynamics of the proposed Comet model diverges from the canonical model of clonal evolution, and better explains observed genomic spatial data. Importantly, the Comet model allows for the clinically relevant scenario of extensive DCIS spread, without being subjected to the selective pressures of subclone competition that promote the emergence of increasingly invasive phenotypes. As such, the normal cell movement inferred during DCIS growth provides a new explanation for the limited risk of progression in DCIS and adds biologic rationale for ongoing clinical efforts to reduce DCIS overtreatment.
A Cross-sectional Feasibility Study to Evaluate the Usability and Efficacy of “Swaasa”: An AI-Platform for Rapid Respiratory Health Assessment
Authors: Lotheti Siva Kumar , Vissamsetti Haritha , Pamarthi kiran , Bhimarasetty Devi Madhavi , Rudraraju Gowrisree , Rao Sripada Narayana , Gottipulla Charishma , Firmal Priyanka , Mamidgi Baswaraj , Palreddy Shubha Deepti , Bhoge Nikhil kumar Reddy , Narreddy Harsha Vardhan Reddy , Yechuri Venkat , Jain Manmohan , Peddireddi Venkata Sudhakar , Joshi Niranjan , Vijayan Shibu , Turaga Sanchit , Avasarala Vardhan 
Published: October 2023

AbstractAnalysing cough sounds is vital in pulmonary medicine. Recently, AI tools are being trained to analyse the acoustic signals of cough sounds so that more cases can be quickly tested, thereby reducing the patient load on primary healthcare systems. In this paper, we evaluate ”Swaasa”, our AI-based platform for rapid respiratory screening, highlighting its efficacy and ease of use. We applied our trained classifier to catch underlying pathologies from cough sound data collected from diverse sources. We then used a pattern classifier to identify specific respiratory conditions based on cough sound patterns. We tested the robustness of our methods by comparing our results with that of a pulmonary physician in 355 cases and show that Swaasa correctly predicted associated risk in 87.32% of those cases. Our platform has a sensitivity of 97.27% with a Positive Predictive Value (PPV) of 88.54%, giving us the potential to revolutionise disease screening, especially for large populations and in isolated rural areas. Our rapid and easy-to-use Software as a Service (SaaS) solution efficiently diagnoses and conserves resources, improves patient outcomes, and establishes a comprehensive and accessible healthcare framework.
Heterogeneous Nuclear Ribonucleoprotein C is an Indispensable Target in Acute Myeloid Leukemia
Authors: Vijay Vindhya , Meacham Amy , Katzell Lauren M. , Winer Aaron J. , Terrell Jesse , Archibald Vincent L. , Vaughn Lauren T. , Drusbosky Leylah , Thach Emily , Welmaker Greg , Giulianotti Marcello , Brothers Shaun , Beurel Eleonore , Bubenik Jodi L. , Swanson Maurice S. , Riva Alberto , Elsayed Abdelrahman H. , Lamba Jatinder K. , Cogle Christopher R. 
Published: October 2023

ABSTRACTRefractory disease is the greatest challenge in acute myeloid leukaemia (AML). Previously, we found vascular-associated AML cells as a source for refractory disease. In this study we use a bioassay of AML cells co-cultured on bone marrow-derived endothelial cells (BMECs) to screen 31 million compounds within a mixture-based synthetic combinatorial library followed by deconvolution leading to the identification of a novel polyamine sulfonamide that is selectively toxic to AML. Using three distinct proteomics methods we identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as the compound target.Depleting HNRNPC reduces AML cell proliferation, viability, colony formation and fails to establish AML in mice. In contrast, no changes in cell proliferation, survival, or colony outgrowth were observed when depleting HNRNPC in normal hematopoietic or stromal cells. Clinical data show that lower HNRNPC expression independently associates with prolonged survival times in 554 adult and pediatric AML patients. We show that HNRNPC regulates DNA replication initiation and the Myc transcriptional program. Using differential isoform expression and differential alternative splicing analyses, we show significant alternative splicing of MAX after HNRNPC depletion, resulting in MAX transcript isoforms that lack Myc-interacting domains, which we term non-activating MAX isoforms. These Myc-interacting domains are necessary for the obligate heterodimerization of Myc and Max and are critical for Myc transcriptional activation. We further analyzed the alternative splicing landscapes of 538 AML patients and 33 specimens from healthy individuals and show substantial alternative splicing of mRNA in AML patients despite the absence of splicing factor gene mutations. Moreover, we found significantly high expression of non-activating MAX isoforms in healthy individuals, while AML patients highly expressed fully functional MAX isoforms, suggesting that MAX splicing may serve an important functional role in AML. Together, these data show HNRNPC as an indispensable splicing repressor in AML that is necessary for supporting deregulated Myc-Max activity and suggest HNRNPC as a potential therapeutic target for AML.
Investigating the Causal Role of Motor Brain Areas in Rhythm Reproduction: A Transcranial Direct Current Stimulation Study
Authors: Emerick Marina , Hoddinott Joshua , Grahn Jessica A. 
Published: October 2023

AbstractHumans have an intrinsic tendency to move to music. However, our understanding of the neural mechanisms underlying the music-movement connection remains limited, and most studies have used correlational methods. Here, we used transcranial direct current stimulation (tDCS) to investigate the causal role of four brain regions commonly involved in movement timing and beat perception: the supplementary motor area (SMA), left and right premotor cortices (PMC), and the right cerebellum. On three different days, subjects received anodal, cathodal, or sham stimulation while reproducing strong-beat, weak-beat, and non-beat rhythms via finger tapping. Each subject only received stimulation in one of the four brain regions. As the SMA appears to play a primary role in beat perception, while the premotor cortex and cerebellum appear to have a more general role in timing, we predicted that the SMA stimulation would affect reproduction of rhythms with a beat, whereas premotor and cerebellar stimulation would affect reproduction of sequences with no beat. As expected, reproduction accuracy depended on beat strength; strong-beat rhythms were more accurately reproduced than weak and non-beat rhythms. Unexpectedly, tDCS had no effect on reproduction accuracy in any brain region. Thus, we found no evidence that modulating brain excitability in SMA, PMC, or cerebellum altered accuracy of rhythm reproduction. We discuss the implications of these results and future perspectives for this research.
Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity
Authors: Liang Jiaxin , Vitale Tevis , Zhang Xixi , Jackson Thomas D. , Yu Deyang , Jedrychowski Mark , Gygi Steve P. , Widlund Hans R. , Wucherpfennig Kai W. , Puigserver Pere 
Published: October 2023

AbstractTargeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Here we provide evidence for a specific means of mitochondrial respiratory Complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of the CI subunitsNdufs4andNdufs6, but not other subunits, induces an immune-dependent tumor growth attenuation in mouse melanoma models. We show that deletion ofNdufs4induces expression of the transcription factorNlrc5and genes in the MHC class I antigen presentation and processing pathway. This induction of MHC-related genes is driven by an accumulation of pyruvate dehydrogenase-dependent mitochondrial acetyl-CoA downstream of CI subunit deletion. This work provides a novel functional modality by which selective CI inhibition restricts tumor growth, suggesting that specific targeting ofNdufs4, or related CI subunits, increases T-cell mediated immunity and sensitivity to ICB.
Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium
Authors: Sheth Anagha Inguva , Engel Krysta , Tolison Hunter , Althoff Mark J , Amaya Maria L. , Krug Anna , Young Tracy , Pei Shanshan , Patel Sweta B. , Minhajuddin Mohammad , Winters Amanda , Miller Regan , Shelton Ian , St-Germain Jonathan , Ling Tianyi , Jones Courtney , Raught Brian , Gillen Austin , Ransom Monica , Staggs Sarah , Smith Clayton A. , Pollyea Daniel A. , Stevens Brett M. , Jordan Craig T. 
Published: October 2023

AbstractWe previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.SignificanceWe identify increased utilization of mitochondrial calcium as distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.
MALDI-IM-MS Imaging of Brain Sterols and Lipids in a Mouse Model of Smith-Lemli-Opitz Syndrome
Authors: Li Amy , Xu Libin 
Published: October 2023

AbstractSmith-Lemli-Opitz syndrome (SLOS) is a neurodevelopmental disorder caused by genetic mutations in theDHCR7gene, encoding the enzyme 3β-hydroxysterol-Δ7-reductase (DHCR7) that catalyzes the last step of cholesterol synthesis. The resulting deficiency in cholesterol and accumulation of its precursor, 7-dehydrocholesterol (7-DHC), have a profound impact on brain development, which manifests as developmental delay, cognitive impairment, and behavioral deficits. To understand how the brain regions are differentially affected by the defective Dhcr7, we aim to map the regional distribution of sterols and other lipids in neonatal brains from aDhcr7-KO mouse model of SLOS, using mass spectrometry imaging (MSI). MSI enables spatial localization of biomoleculesin situon the surface of a tissue section, which is particularly useful for mapping the changes that occur within a metabolic disorder such as SLOS, and in an anatomically complex organ such as the brain. In this work, using MALDI-ion mobility (IM)-MSI, we successfully determined the regional distribution of features that correspond to cholesterol, 7-DHC/desmosterol, and the precursor of desmosterol, 7-dehydrodesmosterol, in WT andDhcr7-KO mice. Interestingly, we also observedm/zvalues that match the major oxysterol metabolites of 7-DHC (DHCEO and hydroxy-7-DHC), which displayed similar patterns as 7-DHC. We then identified brain lipids usingm/zand CCS at the Lipid Species-level and curated a database of MALDI-IM-MS-derived lipid CCS values. Subsequent statistical analysis of regions-of-interest allowed us to identify differentially expressed lipids betweenDhcr7-KO and WT brains, which could contribute to defects in myelination, neurogenesis, neuroinflammation, and learning and memory in SLOS.
Natural killer cell regulation of breast cancer stem cells mediates metastatic dormancy
Authors: Bushnell Grace G. , Sharma Deeksha , Wilmot Henry C. , Zheng Michelle , Fashina Toluwaleke D. , Hutchens Chloe M. , Osipov Samuel , Wicha Max S. 
Published: October 2023

AbstractBreast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cells display “stem like” properties (CSCs), which may be regulated by the immune system. Although many studies have examined tumor cell intrinsic characteristics of dormancy, the role of the immune system in controlling dormancy and its escape is not well understood. This scientific gap is due, in part, to a lack of immunocompetent mouse models of breast cancer dormancy with many studies involving human xenografts in immunodeficient mice. To overcome this limitation, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. We find that PyMT, Met-1 and D2.0R cell lines contain CSCs that display both short- and long-term metastatic dormancyin vivo, which is dependent on the host immune system. Natural killer cells were key for the metastatic dormancy phenotype observed for D2.0R and the role of NK cells in regulating CSCs was further investigated. Quiescent D2.0R CSC are resistant to NK cytotoxicity, while proliferative D2.0R CSC were sensitive to NK cytotoxicity bothin vitroandin vivo. This resistance was mediated, in part, by the expression of Bach1 and Sox2 transcription factors. NK killing was enhanced by the STING agonist MSA-2. Collectively, our findings demonstrate the important role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon.
Dry surface biofilm formation byCandida aurisfacilitates persistence and tolerance to sodium hypochlorite
Authors: Ware Alicia , Johnston William , Delaney Christopher , Butcher Mark , Ramage Gordon , Price Lesley , Butcher John , Kean Ryan 
Published: October 2023

ABSTRACTCandida aurisis an enigmatic fungal pathogen, recently elevated to the critical priority group of pathogens by the World Health Organization. Of key concern is its ability to cause outbreaks within intensive and chronic care units, facilitated through its environmental persistence. We investigated the susceptibility of phenotypically distinctC. aurisisolates to sodium hypochlorite (NaOCl) disinfection, and the subsequent role of biofilms in surviving disinfection using a dry-surface biofilm (DSB) model and transcriptomic profiling. Planktonic cells were tested for susceptibility to NaOCl in suspension, with biofilm formation using the DSB model consisting of consecutive 48 hr cycles with/without media across a 12-day period, assessed using viable counts, biomass assays, and microscopy. Disinfection efficacy was assessed using clinically relevant protocols of 500-1000ppm for 1-5min. RNA-sequencing was performed on untreated DSBs in comparison to planktonic cells. Isolates were found to be sensitive to NaOCl planktonically at concentrations ≤62.5 ppm, and grew robust biofilms using the DSB protocol. Biofilms developed tolerance to all NaOCl treatment parameters, with only 2-4 log10-reductions in viable cells observed at highest concentrations. Transcriptomics identified ABC transporters and iron acquisition pathways as strongly upregulated in DSBs relative to planktonic cells. Our novel findings have optimised a DSB protocol in whichC. aurisbiofilms can mediate tolerance to adverse conditions such as NaOCl disinfection, suggesting a lifestyle through which this problematic yeast can environmentally persist and transmit. Mechanistically it has been shown for the first time that upregulation of small-molecule and iron transport pathways are potential facilitators of environmental survival.IMPORTANCECandida aurisis a pathogenic yeast that has been responsible for outbreaks in healthcare facilities across the globe, predominantly affecting vulnerable patients. This organism displays a concerning ability to persist within the healthcare environment that is likely facilitated by attaching onto surfaces and developing protective microbial communities knows as biofilms. These communities allow cells to survive and tolerate disinfection with bleach. In this study, we show thatC. aurisforms robust biofilms on surfaces which promote survival up to 12 days, even with prolonged drying periods. We also demonstrate that development of these biofilms over time significantly reduces the efficacy of hypochlorite disinfection. By investigating the molecular mechanisms of biofilms, we have shown that these biofilms express efflux pumps, which may actively remove hypochlorite molecules from cells, allowing them to tolerate disinfection, and that uptake of iron from the external environment is also important for survival of these communities.
Axonal selectivity of myelination by single oligodendrocytes established during development in mouse cerebellar white matter
Authors: Battulga Batpurev , Osanai Yasuyuki , Yamazaki Reiji , Shinohara Yoshiaki , Ohno Nobuhiko 
Published: October 2023

AbstractMyelin formation by oligodendrocytes regulates conduction velocity and functional integrity of neuronal axons. While individual oligodendrocytes form myelin sheaths around multiple axons and control the functions of neural circuits in the brains, it remains unclear if oligodendrocytes selectively form myelin sheaths around the specific types of axons. In this study, we developed a method for observing a single oligodendrocyte and its myelin sheaths around different types of axons in the mouse cerebellar white matter. This was achieved by combining sparse fluorescent labeling of oligodendrocytes by attenuated rabies virus and subsequent immunostaining for axonal markers along with tissue clearing. We revealed that approximately half of the oligodendrocytes showed a preferential myelination of axons originating from Purkinje cells in the adult mice. The preference for Purkinje cell axons was more pronounced during development, when the process of myelination within cerebellar white matter was initiated; over 90% of oligodendrocytes preferentially myelinated the Purkinje cell axons. The transgenic mice that label early born oligodendrocytes showed that their myelin sheaths were predominantly formed around Purkinje cell axons in the adult cerebellar white matter. These results suggest that a significant proportion of oligodendrocytes preferentially myelinate functionally distinct axons in the cerebellar white matter, and the axonal preference of myelination is established during development.