VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid–liquid phase separation

Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins, such as collagens. Humoral factors like TGF-β, and matrix stiffness are important for collagen production by myofibroblasts. However, the molecular mechanisms regulating their ability to produce collagen remain poorly characterised. Here, we show that vestigial-like family member 3 (VGLL3) is specifically expressed in myofibroblasts from mouse and human fibrotic hearts and promotes collagen production. Further, substrate stiffness triggers VGLL3 translocation into the nucleus through the integrin β1-Rho-actin pathway. In the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWS RNA-binding protein 1 (EWSR1). VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA. Consistently, cardiac fibrosis after myocardial infarction is significantly attenuated in Vgll3-deficient mice, with increased miR-29b expression. Overall, our results reveal an unrecognised VGLL3-mediated pathway that controls myofibroblasts’ collagen production, representing a novel therapeutic target for tissue fibrosis

(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice

Yokoyama R., Ago Y., Igarashi H., et al. (R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice. Molecular Psychiatry , (2024); https://doi.org/10.1038/s41380-024-02419-6.Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function

SAR-RARP50: Segmentation of surgical instrumentation and Action Recognition on Robot-Assisted Radical Prostatectomy Challenge

Surgical tool segmentation and action recognition are fundamental building blocks in many computer-assisted intervention applications, ranging from surgical skills assessment to decision support systems. Nowadays, learning-based action recognition and segmentation approaches outperform classical methods, relying, however, on large, annotated datasets. Furthermore, action recognition and tool segmentation algorithms are often trained and make predictions in isolation from each other, without exploiting potential cross-task relationships. With the EndoVis 2022 SAR-RARP50 challenge, we release the first multimodal, publicly available, in-vivo, dataset for surgical action recognition and semantic instrumentation segmentation, containing 50 suturing video segments of Robotic Assisted Radical Prostatectomy (RARP). The aim of the challenge is twofold. First, to enable researchers to leverage the scale of the provided dataset and develop robust and highly accurate single-task action recognition and tool segmentation approaches in the surgical domain. Second, to further explore the potential of multitask-based learning approaches and determine their comparative advantage against their single-task counterparts. A total of 12 teams participated in the challenge, contributing 7 action recognition methods, 9 instrument segmentation techniques, and 4 multitask approaches that integrated both action recognition and instrument segmentation. The complete SAR-RARP50 dataset is available at: https://rdr.ucl.ac.uk/projects/SARRARP50_Segmentation_of_surgical_instrumentation_and_Action_Recognition_on_Robot-Assisted_Radical_Prostatectomy_Challenge/19109

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

ATP-Sensitive Anion Channel from Rat Brain Synaptosomal Membranes Incorporated into Planar Lipid Bilayers

An anion channel was incorporated from rat brain synaptic plasma membrane fractions into planar lipid bilayers. The single-channel conductance was found to be 48.5 pS in choline-Cl solution (300 μM cis/100 μM trans). The anion selectivity of the channel was rather low (P(Cl)/P(choline) = 1.7). The gating rate of the channel did not change with membrane potential over the range of -50 mV to 50 mV. Several drugs, which are known as inhibitors of anion channels, were found to be efficient inhibitors for the synaptosomal anion channel. 4-Acetoamino-4′-isothiocyanostilbene-2,2′-disulfonic acid, ethacrynic acid, indanyloxyacetic acid, and 5-nitro-2-(3-phenylpropylamino) benzoic acid inhibited the channel from the cis side of the membrane, corresponding to the cytoplasmic side of the plasma membrane. We found that the channel is regulated by intracellular ATP at millimolar concentrations. Other nucleotides, ADP and GTP, inhibited the channel as well. Glibenclamide, which is known as an inhibitor of an ATP-regulated potassium channel, inhibited the channel at micromolar concentrations from the trans side of the membrane. It is likely that the synaptosomal anion channel is a member of the ATP-binding cassette superfamily