Huntingtin contains an ubiquitin-binding domain and regulates lysosomal targeting of mitochondrial and RNA-binding proteins.

Understanding the normal function of the Huntingtin (HTT) protein is of significance in the design and implementation of therapeutic strategies for Huntington's disease (HD). Expansion of the CAG repeat in the HTT gene, encoding an expanded polyglutamine (polyQ) repeat within the HTT protein, causes HD and may compromise HTT's normal activity contributing to HD pathology. Here, we investigated the previously defined role of HTT in autophagy specifically through studying HTT's association with ubiquitin. We find that HTT interacts directly with ubiquitin in vitro. Tandem affinity purification was used to identify ubiquitinated and ubiquitin-associated proteins that copurify with a HTT N-terminal fragment under basal conditions. Copurification is enhanced by HTT polyQ expansion and reduced by mimicking HTT serine 421 phosphorylation. The identified HTT-interacting proteins include RNA-binding proteins (RBPs) involved in mRNA translation, proteins enriched in stress granules, the nuclear proteome, the defective ribosomal products (DRiPs) proteome and the brain-derived autophagosomal proteome. To determine whether the proteins interacting with HTT are autophagic targets, HTT knockout (KO) cells and immunoprecipitation of lysosomes were used to investigate autophagy in the absence of HTT. HTT KO was associated with reduced abundance of mitochondrial proteins in the lysosome, indicating a potential compromise in basal mitophagy, and increased lysosomal abundance of RBPs which may result from compensatory up-regulation of starvation-induced macroautophagy. We suggest HTT is critical for appropriate basal clearance of mitochondrial proteins and RBPs, hence reduced HTT proteostatic function with mutation may contribute to the neuropathology of HD.

An altered extracellular matrix-integrin interface contributes to Huntington's disease-associated CNS dysfunction in glial and vascular cells.

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may contribute to the dysfunction of the BBB in HD. This disruption has functional consequences since reducing ITG expression in glia in an HD Drosophila model suppressed disease-associated CNS dysfunction. Since ITGs can be targeted therapeutically and manipulating ITG signaling prevents neurodegeneration in other diseases, defining the role of ITGs in HD may provide a novel strategy of intervention to slow CNS pathophysiology to treat HD.

Dysregulation of protein SUMOylation networks in Huntington's disease R6/2 mouse striatum.

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat mutation in the Huntingtin (HTT) gene. The mutation impacts neuronal protein homeostasis and cortical/striatal circuitry. SUMOylation is a post-translational modification with broad cellular effects including via modification of synaptic proteins. Here, we used an optimised SUMO protein-enrichment and mass spectrometry method to identify the protein SUMOylation/SUMO interaction proteome in the context of HD using R6/2 transgenic and non-transgenic (NT) mice. Significant changes in enrichment of SUMOylated and SUMO-interacting proteins were observed, including those involved in presynaptic function, cytomatrix at the active zone scaffolding, cytoskeleton organization, and glutamatergic signaling. Mitochondrial and RNA-binding proteins also showed altered enrichment. Modified SUMO-associated pathways in HD tissue include clathrin-mediated endocytosis signaling, synaptogenesis signaling, synaptic long-term potentiation, and SNARE signaling. To evaluate how modulation of SUMOylation might influence functional measures of neuronal activity in HD cells in vitro, we utilised primary neuronal cultures from R6/2 and NT mice. A receptor internalization assay for the metabotropic glutamate receptor 7 (mGLUR7), a SUMO enriched protein in the mass spec, showed decreased internalization in R6/2 neurons compared to NT. siRNA-mediated knockdown of the E3 SUMO ligase Protein Inhibitor of Activated STAT1 (Pias1), which can SUMO modify mGLUR7, prevented this HD phenotype. In addition, microelectrode array analysis of primary neuronal cultures indicated early hyperactivity in HD cells, while later timepoints demonstrated deficits in several measurements of neuronal activity within cortical neurons. HD phenotypes were rescued at selected timepoints following knockdown of Pias1. Collectively, our results provide a mouse brain SUMOome resource and show that significant alterations occur within the post-translational landscape of SUMO-protein interactions of synaptic proteins in HD mice, suggesting that targeting of synaptic SUMO networks may provide a proteostatic systems-based therapeutic approach for HD and other neurological. Disorders.

Prevalence of Chronic liver disease in Cholangiocarcinoma: a Meta-Analysis.

INTRODUCTION: Chronic liver disease is a known risk factor for cholangiocarcinoma (CCA), but the proportion of people with CCA who have concurrent chronic liver disease is unclear. We aimed to evaluate the prevalence of chronic liver diseases in people with cholangiocarcinoma. METHODS: In this single-arm meta-analysis, we searched MEDLINE and EMBASE from inception to 10 August 2024 for articles in English containing data for cholangiocarcinoma with and without chronic liver diseases. Data were pooled to obtain the prevalence of different chronic liver diseases, with further stratification by geographical location and tumor location. RESULTS: In total, 118068 individuals diagnosed with cholangiocarcinoma were included, of whom 16771 had chronic liver diseases. A pooled analysis of 109 studies determined that the prevalence of chronic liver disease was 25.23% (95% CI: 20.82% - 30.23%; I2=99.0%), and 10.21% (7.75% - 13.35%; I2=98.6%) of CCA patients had cirrhosis. Chronic liver diseases were associated more with intrahepatic CCAs, compared to extrahepatic CCAs (RR: 2.46, CI: 2.37 - 2.55, p < 0.0001). This was observed across all etiologies of liver disease, except for primary sclerosing cholangitis which was associated with extrahepatic CCAs (RR: 0.49; CI: 0.43 - 0.57, p < 0.0001). CONCLUSION: Around one in four people with cholangiocarcinoma have chronic liver diseases, and one in ten have cirrhosis.

Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum.

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease.

DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease.

Pediatric hand fractures detection on radiographs: do localization cues improve diagnostic performance?

OBJECTIVE: To compare the diagnostic accuracy and interpretation time for detection of pediatric fractures on hand radiographs with and without localization cues. MATERIALS AND METHODS: Consecutive children, who underwent radiographic examinations after injury, over 2 years (2019-2021) and with > 2 weeks of follow-up to confirm the presence or absence of a fracture, were included. Four readers, blinded to history and diagnosis, retrospectively reviewed all images twice, without and with cue, at least 1 week apart and after randomization, to determine the presence or absence of a fracture, and if present, anatomic location and diagnostic confidence were recorded. Interpretation time for each study was also recorded and averaged across readers. Inter-reader agreement was calculated using Fleiss' kappa. Diagnostic accuracy and interpretation time were compared between examinations using sensitivity, specificity, and Mann-Whitney U correlation. RESULTS: Study group included 92 children (61 boys, 31 girls; 10.8 ± 3.4 years) with and 40 (31 boys, 9 girls; 10.9 ± 3.7 years) without fractures. Cue improved inter-reader agreement (κ = 0.47 to 0.62). While the specificity decreased (63 to 62%), sensitivity (75 to 78%), diagnostic accuracy (71 to 73%), and confidence improved (78 to 87%, p < 0.01), and interpretation time (median: 40 to 22 s, p < 0.001) reduced with examinations with localization cue. Specifically, examinations with fracture and cue had the shortest interpretation time (median: 16 s), whereas examinations without fracture and without cue had the longest interpretation time (median: 48 s). CONCLUSION: Localization cues increased inter-reader agreement and diagnostic confidence, reduced interpretation time in the detection of fractures on pediatric hand radiographs, while maintaining diagnostic accuracy.

Treatment with JQ1, a BET bromodomain inhibitor, is selectively detrimental to R6/2 Huntington's disease mice.

Transcriptional and epigenetic alterations occur early in Huntington's disease (HD), and treatment with epigenetic modulators is beneficial in several HD animal models. The drug JQ1, which inhibits histone acetyl-lysine reader bromodomains, has shown promise for multiple cancers and neurodegenerative disease. We tested whether JQ1 could improve behavioral phenotypes in the R6/2 mouse model of HD and modulate HD-associated changes in transcription and epigenomics. R6/2 and non-transgenic (NT) mice were treated with JQ1 daily from 5 to 11 weeks of age and behavioral phenotypes evaluated over this period. Following the trial, cortex and striatum were isolated and subjected to mRNA-seq and ChIP-seq for the histone marks H3K4me3 and H3K27ac. Initially, JQ1 enhanced motor performance in NT mice. In R6/2 mice, however, JQ1 had no effect on rotarod or grip strength but exacerbated weight loss and worsened performance on the pole test. JQ1-induced gene expression changes in NT mice were distinct from those in R6/2 and primarily involved protein translation and bioenergetics pathways. Dysregulation of HD-related pathways in striatum was exacerbated by JQ1 in R6/2 mice, but not in NTs, and JQ1 caused a corresponding increase in the formation of a mutant huntingtin protein-dependent high molecular weight species associated with pathogenesis. This study suggests that drugs predicted to be beneficial based on their mode of action and effects in wild-type or in other neurodegenerative disease models may have an altered impact in the HD context. These observations have important implications in the development of epigenetic modulators as therapies for HD.

IKKß slows Huntington's disease progression in R6/1 mice.

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKß, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington's disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKß on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKß phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKß to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKß knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKß in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKß knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKß is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKß is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKß may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

Is it time to switch your T1W sequence? Assessing the impact of prospective motion correction on the reliability and quality of structural imaging.

New large neuroimaging studies, such as the Adolescent Brain Cognitive Development study (ABCD) and Human Connectome Project (HCP) Development studies are adopting a new T1-weighted imaging sequence with prospective motion correction (PMC) in favor of the more traditional 3-Dimensional Magnetization-Prepared Rapid Gradient-Echo Imaging (MPRAGE) sequence. Here, we used a developmental dataset (ages 5-21, N = 348) from the Healthy Brain Network (HBN) Initiative to directly compare two widely used MRI structural sequences: one based on the Human Connectome Project (MPRAGE) and another based on the ABCD study (MPRAGE+PMC). We aimed to determine if the morphometric measurements obtained from both protocols are equivalent or if one sequence has a clear advantage over the other. The sequences were also compared through quality control measurements. Inter- and intra-sequence reliability were assessed with another set of participants (N = 71) from HBN that performed two MPRAGE and two MPRAGE+PMC sequences within the same imaging session, with one MPRAGE (MPRAGE1) and MPRAGE+PMC (MPRAGE+PMC1) pair at the beginning of the session and another pair (MPRAGE2 and MPRAGE+PMC2) at the end of the session. Intraclass correlation coefficients (ICC) scores for morphometric measurements such as volume and cortical thickness showed that intra-sequence reliability is the highest with the two MPRAGE+PMC sequences and lowest with the two MPRAGE sequences. Regarding inter-sequence reliability, ICC scores were higher for the MPRAGE1 - MPRAGE+PMC1 pair at the beginning of the session than the MPRAGE1 - MPRAGE2 pair, possibly due to the higher motion artifacts in the MPRAGE2 run. Results also indicated that the MPRAGE+PMC sequence is robust, but not impervious, to high head motion. For quality control metrics, the traditional MPRAGE yielded better results than MPRAGE+PMC in 5 of the 8 measurements. In conclusion, morphometric measurements evaluated here showed high inter-sequence reliability between the MPRAGE and MPRAGE+PMC sequences, especially in images with low head motion. We suggest that studies targeting hyperkinetic populations use the MPRAGE+PMC sequence, given its robustness to head motion and higher reliability scores. However, neuroimaging researchers studying non-hyperkinetic participants can choose either MPRAGE or MPRAGE+PMC sequences, but should carefully consider the apparent tradeoff between relatively increased reliability, but reduced quality control metrics when using the MPRAGE+PMC sequence.

Measurement reliability for individual differences in multilayer network dynamics: Cautions and considerations.

Multilayer network models have been proposed as an effective means of capturing the dynamic configuration of distributed neural circuits and quantitatively describing how communities vary over time. Beyond general insights into brain function, a growing number of studies have begun to employ these methods for the study of individual differences. However, test-retest reliabilities for multilayer network measures have yet to be fully quantified or optimized, potentially limiting their utility for individual difference studies. Here, we systematically evaluated the impact of multilayer community detection algorithms, selection of network parameters, scan duration, and task condition on test-retest reliabilities of multilayer network measures (i.e., flexibility, integration, and recruitment). A key finding was that the default method used for community detection by the popular generalized Louvain algorithm can generate erroneous results. Although available, an updated algorithm addressing this issue is yet to be broadly adopted in the neuroimaging literature. Beyond the algorithm, the present work identified parameter selection as a key determinant of test-retest reliability; however, optimization of these parameters and expected reliabilities appeared to be dataset-specific. Once parameters were optimized, consistent with findings from the static functional connectivity literature, scan duration was a much stronger determinant of reliability than scan condition. When the parameters were optimized and scan duration was sufficient, both passive (i.e., resting state, Inscapes, and movie) and active (i.e., flanker) tasks were reliable, although reliability in the movie watching condition was significantly higher than in the other three tasks. The minimal data requirement for achieving reliable measures for the movie watching condition was 20 min, and 30 min for the other three tasks. Our results caution the field against the use of default parameters without optimization based on the specific datasets to be employed - a process likely to be limited for most due to the lack of test-retest samples to enable parameter optimization.

Evaluating fMRI-Based Estimation of Eye Gaze During Naturalistic Viewing.

The collection of eye gaze information during functional magnetic resonance imaging (fMRI) is important for monitoring variations in attention and task compliance, particularly for naturalistic viewing paradigms (e.g., movies). However, the complexity and setup requirements of current in-scanner eye tracking solutions can preclude many researchers from accessing such information. Predictive eye estimation regression (PEER) is a previously developed support vector regression-based method for retrospectively estimating eye gaze from the fMRI signal in the eye's orbit using a 1.5-min calibration scan. Here, we provide confirmatory validation of the PEER method's ability to infer eye gaze on a TR-by-TR basis during movie viewing, using simultaneously acquired eye tracking data in five individuals (median angular deviation < 2°). Then, we examine variations in the predictive validity of PEER models across individuals in a subset of data (n = 448) from the Child Mind Institute Healthy Brain Network Biobank, identifying head motion as a primary determinant. Finally, we accurately classify which of the two movies is being watched based on the predicted eye gaze patterns (area under the curve = 0.90 ± 0.02) and map the neural correlates of eye movements derived from PEER. PEER is a freely available and easy-to-use tool for determining eye fixations during naturalistic viewing.

Functional brain networks involved in lexical decision.

Functional magnetic resonance imaging (fMRI)5 studies on lexical decision (LD)6 attempting to isolate the brain network underlying access to lexical representations can be confounded by attentional and response processes. However, manipulating the "wordlikeness" of the LD stimuli can facilitate functional interpretation of each emerging brain network, providing principles for separation of attentional demand from linguistic processing. This is because activation of difficult-to-access lexical representations (for obscure real words), and avoidance of interfering word properties (for wordlike non-words), are both generally attentionally demanding. Therefore, congruent patterns of activation would be predicted for general-attention-responsive networks, but opposing patterns for language-responsive networks. 59 healthy adults performed a LD task, and multidimensional functional connectivity analysis was used to extract three functional brain networks. A linguistic processing network (LPN) was separated from attention/response networks anatomically (LPN included Broca's and Wernicke's areas), but also temporally by showing reduced activation for the most attentionally demanding condition (i.e., wordlike non-words). This demonstrated that during LD in fMRI a network involved in linguistic processing can be disentangled from attention- and response-specific networks, using a combination of experimental design and multidimensional analysis methods.

HIV glycoprotein gp120 enhances mesenchymal stem cell migration by upregulating CXCR4 expression.

BACKGROUND: HIV infection and/or the direct pathogenic effects of circulating HIV proteins impairs the physiological function of mesenchymal stem cells (MSCs), and contribute to the pathogenesis of age-related clinical comorbidities in people living with HIV. The SDF-1/CXCR4 pathway is vital for modulating MSC proliferation, migration and differentiation. HIV glycoprotein gp120 inhibits SDF-1 induced chemotaxis by downregulating the expression and function of CXCR4 in monocytes, B and T cells. The influence of gp120 on CXCR4 expression and migration in MSCs is unknown. METHODS: We investigated CXCR4 expression and SDF-1/CXCR4-mediated MSC migration in response to gp120, and its effect on downstream signaling pathways: focal adhesion kinase (FAK)/Paxillin and extracellular signal-regulated kinase (ERK). RESULTS: Gp120 upregulated MSC CXCR4 expression. This potentiated the effects of SDF-1 in inducing chemotaxis; FAK/Paxillin and ERK pathways were over-activated, thereby facilitating actin stress fiber reorganization. CXCR4 blockage or depletion abrogated the observed effects. CONCLUSION: Gp120 from both T- and M- tropic HIV strains upregulated CXCR4 expression in MSCs, resulting in enhanced MSC chemotaxis in response to SDF-1. GENERAL SIGNIFICANCE: HIV infection and its proteins are known to disrupt physiological differentiation of MSC; increased gp120-driven migration amplifies the total MSC population destined for ineffective and inappropriate differentiation, thus contributing to the pathogenesis of HIV-related comorbidities. Additionally, given that MSCs are permissive to HIV infection, initial cellular priming by gp120 results in increased expression of CXCR4 and could lead to co-receptor switching and cell tropism changes in chronic HIV infection and may have implications against CCR5-knockout based HIV cure strategies.

Sepsis Reduces Bone Strength Before Morphologic Changes Are Identifiable.

OBJECTIVES: Survivors of critical illness have an increased prevalence of bone fractures. However, early changes in bone strength, and their relationship to structural changes, have not been described. We aimed to characterize early changes in bone functional properties in critical illness and their relationship to changes in bone structure, using a sepsis rodent model. DESIGN: Experimental study. SETTING: Animal research laboratory. SUBJECTS: Adult Sprague-Dawley rats. INTERVENTIONS: Forty Sprague-Dawley rats were randomized to cecal ligation and puncture or sham surgery. Twenty rodents (10 cecal ligation and puncture, 10 sham) were killed at 24 hours, and 20 more at 96 hours. MEASUREMENTS AND MAIN RESULTS: Femoral bones were harvested for strength testing, microCT imaging, histologic analysis, and multifrequency scanning probe microscopy. Fracture loads at the femoral neck were significantly reduced for cecal ligation and puncture-exposed rodents at 24 hours (83.39 ± 10.1 vs 103.1 ± 17.6 N; p = 0.014) and 96 hours (81.60 ± 14.2 vs 95.66 ± 14.3 N; p = 0.047). Using multifrequency scanning probe microscopy, collagen elastic modulus was lower in cecal ligation and puncture-exposed rats at 24 hours (1.37 ± 0.2 vs 6.13 ± 0.3 GPa; p = 0.001) and 96 hours (5.57 ± 0.5 vs 6.13 ± 0.3 GPa; p = 0.006). Bone mineral elastic modulus was similar at 24 hours but reduced in cecal ligation and puncture-exposed rodents at 96 hours (75.34 ± 13.2 vs 134.4 ± 8.2 GPa; p < 0.001). There were no bone architectural or bone mineral density differences by microCT. Similarly, histologic analysis demonstrated no difference in collagen and elastin staining, and C-X-C chemokine receptor type 4, nuclear factor kappa beta, and tartrate-resistant acid phosphatase immunostaining. CONCLUSIONS: In a rodent sepsis model, trabecular bone strength is functionally reduced within 24 hours and is associated with a reduction in collagen and mineral elastic modulus. This is likely to be the result of altered biomechanical properties, rather than increased bone mineral turnover. These data offer both mechanistic insights and may potentially guide development of therapeutic interventions.

Latest Advances in Chondrocyte-Based Cartilage Repair.

Chondrocyte-based cell therapy has been used for more than 30 years and is still considered to be a promising method of cartilage repair despite some limitations. This review introduces the latest developments of four generations of autologous chondrocyte implantation and current autologous chondrocyte products. The regeneration of cartilage from adult chondrocytes is limited by culture-induced dedifferentiation and patient age. Cartibeads is an innovative three-step method to produce high-quality hyaline cartilage microtissues, and it is developed from adult dedifferentiated chondrocytes with a high number of cell passages. In addition, allogeneic chondrocyte therapies using the Quantum hollow-fiber bioreactor and several signaling pathways involved in chondrocyte-based cartilage repair are mentioned, such as WNT signaling, the BMP-2/WISP1 pathway, and the FGF19 pathway.

Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers.

The high heritability of amyotrophic lateral sclerosis (ALS) contrasts with its low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. To aid the exploration of these factors, we introduced EpiOut, an algorithm to identify chromatin accessibility outliers that are regions exhibiting divergent accessibility from the population baseline in a single or few samples. Annotation of accessible regions with histone chromatin immunoprecipitation sequencing and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is available at github.com/uci-cbcl/EpiOut.

Molecular and immune pathobiology of human angiosarcoma.

Angiosarcoma is a rare endothelial-derived malignancy that is extremely diverse in anatomy, aetiology, molecular and immune characteristics. While novel therapeutic approaches incorporating targeted agents and immunotherapy have yielded significant improvements in patient outcomes across several cancers, their impact on angiosarcoma remains modest. Contributed by its heterogeneous nature, there is currently a lack of novel drug targets in this disease entity and no reliable biomarkers that predict response to conventional treatment. This review aims to examine the molecular and immune landscape of angiosarcoma in association with its aetiology, anatomical sites, prognosis and therapeutic options. We summarise current efforts to characterise angiosarcoma subtypes based on molecular and immune profiling. Finally, we highlight promising technologies such as single-cell spatial "omics" that may further our understanding of angiosarcoma and propose strategies that can be similarly applied for the study of other rare cancers.

Chemical and Electrochemical Characterization of Hot-Pressed Li6PS5Cl Solid State Electrolyte: Operating Pressure-Invariant High Ionic Conductivity.

Sulfide solid state electrolytes (SSE) are among the most promising materials in the effort to replace liquid electrolytes, largely due to their comparable ionic conductivities. Among the sulfide SSEs, Argyrodites (Li6PS5X, X=Cl, Br, I) further stand out due to their high theoretical ionic conductivity (~1×10-2 S cm-1) and interfacial stability against reactive metal anodes such as lithium. Generally, solid state electrolyte pellets are pressed from powder feedstock at room temperature, however, pellets fabricated by cold pressing consistently result in low bulk density and high porosity, facilitating interfacial degradation reactions and allowing dendrites to propagate through the pores and grain boundaries. Here, we demonstrate the mechanical and electrochemical implications of hot-pressing standalone LPSCl SSE pellets with near-theoretical ionic conductivity, superior cycling performance, and enhanced mechanical stability. X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and x-ray diffraction spectroscopy (XRD) analysis reveal no chemical changes to the Argyrodite surface after hot pressing up to 250 °C. Moreover, we use electrochemical impedance spectroscopy (EIS) to understand mechanical stability of Argyrodite SSE pellets as a function of externally applied pressure, demonstrating for the first time pressed standalone Argyrodite pellets with near-theoretical conductivities at external pressures below 14 MPa.

Simultaneous detection of pathogens and antimicrobial resistance genes with the open source, cloud-based, CZ ID pipeline.

Antimicrobial resistant (AMR) pathogens represent urgent threats to human health, and their surveillance is of paramount importance. Metagenomic next generation sequencing (mNGS) has revolutionized such efforts, but remains challenging due to the lack of open-access bioinformatics tools capable of simultaneously analyzing both microbial and AMR gene sequences. To address this need, we developed the CZ ID AMR module, an open-access, cloud-based workflow designed to integrate detection of both microbes and AMR genes in mNGS and whole-genome sequencing (WGS) data. It leverages the Comprehensive Antibiotic Resistance Database and associated Resistance Gene Identifier software, and works synergistically with the CZ ID short-read mNGS module to enable broad detection of both microbes and AMR genes. We highlight diverse applications of the AMR module through analysis of both publicly available and newly generated mNGS and WGS data from four clinical cohort studies and an environmental surveillance project. Through genomic investigations of bacterial sepsis and pneumonia cases, hospital outbreaks, and wastewater surveillance data, we gain a deeper understanding of infectious agents and their resistomes, highlighting the value of integrating microbial identification and AMR profiling for both research and public health. We leverage additional functionalities of the CZ ID mNGS platform to couple resistome profiling with the assessment of phylogenetic relationships between nosocomial pathogens, and further demonstrate the potential to capture the longitudinal dynamics of pathogen and AMR genes in hospital acquired bacterial infections. In sum, the new AMR module advances the capabilities of the open-access CZ ID microbial bioinformatics platform by integrating pathogen detection and AMR profiling from mNGS and WGS data. Its development represents a critical step toward democratizing pathogen genomic analysis and supporting collaborative efforts to combat the growing threat of AMR.