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Molecular chaperones regulate quality control in the human proteome, pathways that have been implicated in many diseases, including heart failure. Mutations in the BAG3 gene, which encodes a co-chaperone protein, have been associated with heart failure due to both inherited and sporadic dilated cardiomyopathy. Familial BAG3 mutations are autosomal dominant and frequently cause truncation of the coding sequence, suggesting a heterozygous loss-of-function mechanism. However, heterozygous knockout of the murine BAG3 gene did not cause a detectable phenotype. To model BAG3 cardiomyopathy in a human system, we generated an isogenic series of human induced pluripotent stem cells (iPSCs) with loss-of-function mutations in BAG3. Heterozygous BAG3 mutations reduced protein expression, disrupted myofibril structure, and compromised contractile function in iPSC-derived cardiomyocytes (iPS-CMs). BAG3-deficient iPS-CMs were particularly sensitive to further myofibril disruption and contractile dysfunction upon exposure to proteasome inhibitors known to cause cardiotoxicity. We performed affinity tagging of the endogenous BAG3 protein and mass spectrometry proteomics to further define the cardioprotective chaperone complex that BAG3 coordinates in the human heart. Our results establish a model for evaluating protein quality control pathways in human cardiomyocytes and their potential as therapeutic targets and susceptibility factors for cardiac drug toxicity.

Autoimmune neutropenia (AIN) in early childhood is characterized by chronic neutropenia and positivity for human neutrophil antibodies (HNA), resulting in the excessive destruction of neutrophils. The association between regulatory T cells (Tregs) and AIN has been described, and in this study, we investigated three Treg‐associated genes, IL‐2, IL‐10 and FOXP3. The frequencies of three single nucleotide polymorphisms (SNPs) in IL‐2 −330T>G (rs2069762), +114G>T (rs2069763) and IVS3‐116 A>G (rs2069772), four SNPs in IL‐10 −3575T>A (rs1800890), −1082G>A (rs1800896), −819 C>T (rs1800871) and −592 C>A (rs1800872) and three SNPs in FOXP3 –3499 A>G (rs3761547), −3279 C>A (rs3761548) and −924 A>G (rs2232365) were compared between 166 Danish AIN patients and 358 healthy controls. Disease association was observed for IL‐2 IVS3‐116 GG (p = 0.0081, OR = 0.35 [0.15–0.80]), IL‐10 −3575 TT (p = 0.0078, OR = 1.71 [1.16–2.54]) and IL‐10 −1082 AA (p = 0.014, OR = 1.76 [1.14–2.72]) in all patients and FOXP3 –924 (p = 0.0005, A OR = 0.41 [0.25–0.68] and G OR = 2.42 [1.46–4.01]) in male patients. None of the associations were linked to antibody specificity. Disease‐associated haplotypes were observed in IL‐2 and FOXP3. IL‐2 −330T/+114 T/IVS3‐116A was associated with anti‐FcγRIIIb‐positive patients (p = 0.012, OR = 2.07 [1.18–3.62]). FOXP3 –3499A/–3279C/−924A was associated with anti‐HNA‐1a‐positive male patients (p = 0.016, OR = 0.41 [0.20–0.83]), and ACG was associated with female patients, both in the combined group (p = 0.006, OR = NA) and the anti‐FcγRIIIb‐positive group (p = 0.002, OR = NA). We conclude that our findings reveal a correlation between SNP in Treg‐associated genes and AIN, indicating that AIN could be driven by dysfunction of immune homeostatic‐evolving Tregs. [ABSTRACT FROM AUTHOR]

Background and Purpose: Diseases of raised intracranial pressure (ICP) cause severe morbidity and mortality. Multiple drugs are utilised to lower ICP including acetazolamide and topiramate. However, the evidence for their use is unclear. We aimed to assess the ICP modulatory effects and molecular effects at the choroid plexus (CP) of acetazolamide and topiramate. Experimental Approach: Female rats were implanted with telemetric ICP probes for physiological, freely moving 24/7 ICP recordings. Randomised cross‐over studies were performed, where rats received acute (24 h) high doses of acetazolamide and topiramate, and chronic (10 days) clinically equivalent doses of acetazolamide and topiramate, all via oral gavage. Cerebrospinal fluid (CSF) secretion assays, and RT‐qPCR and western blots on in vitro and in vivo CP, were used to investigate drug actions. Key Results: We demonstrate that acetazolamide and topiramate achieved maximal ICP reduction within 120 min of administration, and in combination doubled the ICP reduction over a 24‐h period. Chronic administration of acetazolamide or topiramate lowered ICP by 25%. Topiramate decreased CSF secretion by 40%. Chronic topiramate increased the gene expression of Slc12a2 and Slc4a10 and protein expression of the sodium‐dependent chloride/bicarbonate exchanger (NCBE), whereas chronic acetazolamide did not affect the expression of assessed genes. Conclusions and Implications: Acetazolamide and topiramate are effective at lowering ICP at therapeutic levels. We provide the first evidence that topiramate lowers CSF secretion and that acetazolamide and topiramate may lower ICP via distinct molecular mechanisms. Thus, the combination of acetazolamide and topiramate may have utility for treating raised ICP. [ABSTRACT FROM AUTHOR]

Cancer‐associated fibroblasts (CAFs) deposit and remodel collagens in the tumor stroma, impacting cancer progression and efficacy of interventions. CAFs are the focus of new therapeutics with the aim of normalizing the tumor microenvironment. To do this, a better understanding of CAF heterogeneity and collagen composition in cancer is needed. In this study, we sought to profile the expression of collagens at multiple levels with the goal of identifying cancer biomarkers. We investigated the collagen expression pattern in various cell types and CAF subtypes in a publicly available single‐cell RNA sequencing (RNA‐seq) dataset of pancreatic ductal adenocarcinoma. Next, we investigated the collagen expression profile in tumor samples across cancer types from The Cancer Genome Atlas (TCGA) database and evaluated if specific patterns of collagen expression were associated with prognosis. Finally, we profiled circulating collagen peptides using a panel of immunoassays to measure collagen fragments in the serum of cancer patients. We found that pancreatic stellate cells and fibroblasts were the primary producers of collagens in the pancreas. COL1A1, COL3A1, COL5A1, COL6A1 were expressed in all CAF subtypes, whereas COL8A1, COL10A1, COL11A1, COL12A1 were specific to myofibroblast CAFs (myCAF) and COL14A1 specific to inflammatory CAFs (iCAF). In TCGA database, myCAF collagens COL10A1 and COL11A1 were elevated across solid tumor types, and multiple associations between high expression and worse survival were found. Finally, circulating collagen biomarkers were elevated in the serum of patients with cancer relative to healthy controls with COL11A1 (myCAF) having the best diagnostic accuracy of the markers measured. In conclusion, CAFs express a noncanonical collagen profile with specific collagen subtypes associated with iCAFs and myCAFs in PDAC. These collagens are deregulated at the cellular, tumor, and systemic levels across different solid tumors and associate with survival. These findings could lead to new discoveries such as novel biomarkers and therapeutic targets. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Studies report an elevated risk of maltreatment in children with attention deficit/hyperactivity disorder (ADHD), and elevated levels of ADHD in people who suffered childhood maltreatment (CM). However, the direction(s) of causality between CM and ADHD remain unclear—does ADHD create a context for CM, does CM cause ADHD, or both? Objective: This study systematically reviews and qualitatively synthesizes the research evidence relating to this question using Bradford‐Hill criteria for establishing causality—strength, temporality, dose‐response and plausibility. Methods: We conducted a systematic review, following PRISMA guidelines, of prospective longitudinal studies examining both CM and ADHD. We then used Bradford‐Hill criteria to assess the quality of evidence for a causal link between CM and ADHD. Results: All 11 included studies demonstrated an association between CM and ADHD. Seven included evidence for temporality: five suggesting that CM precedes ADHD in the lifespan; two suggesting ADHD precedes CM. Four studies demonstrated a dose response relationship in which greater CM exposure was associated with elevated risk of ADHD. Studies presented a range of plausible mechanisms, including CM causing ADHD through biological programming, versus ADHD causing CM through parental stress. Conclusions: The high quality prospective longitudinal studies reviewed confirm the association between ADHD and CM, but present conflicting evidence about the direction of causality and mechanisms underpinning this association. To better understand the complex interplay between CM and ADHD, more studies using new research designs will be required that can partition effects by type of CM and account for bidirectional effects and other complexities. [ABSTRACT FROM AUTHOR]

Few studies investigate what members of the general population know about individuals with autism. Only one study has previously investigated how beliefs about autism differ from those about other psychiatric disorders. This study surveyed a convenience sample of the general adult population, within the Northern Region of Denmark, about their knowledge, attitudes and beliefs about individuals with autism and schizophrenia. The respondents (N = 440) possessed basic knowledge and were able to differentiate between the two disorders. Schizophrenia was associated with perceived danger (32.8%), while autism was associated with high intelligence (40.1%) and creativity (27.3%). Respondents were more positive towards interacting with individuals with autism (p < 0.001), but desire for social distancing was pronounced for both disorders in more intimate relationships. Significantly, more respondents reported that they would find it difficult and feel ashamed with regard to being diagnosed with schizophrenia (p < 0.001). Conversely, respondents significantly reported being more likely to elaborate on their diagnosis of autism to their colleagues (p < 0.001). Perceived dangerousness decreased the willingness for social interactions, while knowing someone with autism or schizophrenia increased the willingness to socially interact. Misconceptions and stigma must be addressed in order to minimize the social stigma and rejection associated with these disorders and ultimately improve the quality of life and psychological well-being of affected individuals and their families.