Westgottlieb3831

Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Treg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Treg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3-5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients-emanating from vascular endothelial cells outwards-in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.Achieving high levels of neutralizing antibodies to the spike protein of SARS-CoV-2 in a safe manner is likely to be crucial for an effective vaccine. Here, we propose that aluminium-based adjuvants might hold the key to this.An amendment to this paper has been published and can be accessed via a link at the top of the paper.The heavily industrialised Kanpur region is the most polluted stretch of the Ganga river because of excessive pollutant discharge from the industries. Agricultural runoff along with climate change further adds to the pollution risk in this industrialised stretch of Ganga. In this paper, we analyse the potential impacts of climate change and land use change on the water quality in this stretch under hypothetical scenarios using the water quality model, QUAL2K. Water quality indicators of Dissolved Oxygen (DO), Biochemical Oxygen Demand, ammonia, nitrate, total nitrogen, organic-, inorganic- and total phosphorous and faecal coliform are assessed for eight climate change and six land use land cover scenarios. Eutrophic conditions are observed in this stretch of the river for all scenarios, implying severe impacts on aquatic life. DO is identified as the most sensitive indicator to the climate change scenarios considered, while nutrients and faecal coliform are more sensitive to the land use scenarios. Increase in agricultural land area leads to larger nutrient concentration while increase in built-up area causes an increase in faecal coliform concentration. Results from this hypothetical study could provide valuable guidance for improving the water quality of the Ganges in future climate change and land use change scenarios.Recent studies suggested that an association exists between vision loss and cognitive impairment, although it is still vague whether there are causal relationships or direct association between low vision and dementia. We were to investigate the association between low vision and dementia in the Korean population using the National Health Insurance Service (NHIS) database. We analyzed the data of 6,029,657 subjects aged ≥40 years, drawn from Korea National Health Insurance Service. The hazard ratio (HRs) and 95% confidence interval (CIs) of dementia, Alzheimer's disease (AD), and Vascular dementia (VD) were estimated using multivariable Cox proportional hazards regression models. Statistical analysis showed that subjects with more severe visual impairments have a higher risk of dementia, AD, and VD after adjusting for compounding variables. The HRs of dementia increased significantly as visual acuity worsened (HRs 1.444 [95% CIs 1.415-1.473] for visual acuity (VA) less then 1.0, 1.734 [1.693-1.777] for VA less then 0.3, 1.727 [1.686-1.770] for VA less then 0.1 and 1.991[1.902-2.085] for visual loss). Baseline visual loss and visual impairment were positively associated with the risk of dementia, AD, and VD. From the results of this nationwide population-based cohort study, we suggest that there is a significant increase in the incidence of dementia in subjects with low vision.An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Acute encephalopathy with reduced subcortical diffusion (AED), characterised by seizure onset and widespread reduced apparent diffusion coefficient in the cortex/subcortical white matter, is one of the most common acute encephalopathies in children in East Asia. This 14-year single-centre retrospective study on 34 patients with AED showed that therapeutic hypothermia was used for patients with more severe consciousness disturbance after the first seizure or second phase initiation, extrapolating from neonatal hypoxic encephalopathy and adult post-cardiac arrest syndrome. The basal ganglia/thalamus lesions and the Tada score were the poor outcome determinants in the multivariate analysis. The correlation between the worse outcomes and the duration from the first seizure to the initiation of therapeutic hypothermia was observed only in the patients with AED cooled before the second phase. This correlation was not observed in the overall AED population. There was a moderate negative association between the worse outcomes and the duration between the first seizure and the second phase. Therefore, the basal ganglia/thalamus lesions and the Tada score were the outcome determinants for patients with AED. Further investigation is required to examine the efficacy of therapeutic hypothermia in this population while considering the timing of the therapeutic hypothermia initiation and the second phase.Vasopressin receptor 2 (V2R) mutations causing the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) can generate two constitutively active receptor phenotypes. PIM447 mouse One type results from residue substitutions in several V2R domains and is sensitive to vaptan inverse agonists. The other is only caused by Arg 137 replacements and is vaptan resistant. We compared constitutive and agonist-driven interactions of the vaptan-sensitive F229V and vaptan-resistant R137C/L V2R mutations with β-arrestin 1, β-arrestin 2, and Gαs, using null fibroblasts reconstituted with individual versions of the ablated transduction protein genes. F229V displayed very high level of constitutive activation for Gs but not for β-arrestins, and enhanced or normal responsiveness to agonists and inverse agonists. In contrast, R137C/L mutants exhibited maximal levels of constitutive activation for βarrestin 2 and Gs, minimal levels for β-arrestin 1, but a sharp decline of ligands sensitivity at all transducer interactions. The enhanced constitutive activity and reduced ligand sensitivity of R137 mutants on cAMP signaling persisted in cells lacking β-arrestins, indicating that these are intrinsic molecular properties of the mutations, not the consequence of altered receptor trafficking. The results suggest that the two groups of NSIAD mutations represent two distinct molecular mechanisms of constitutive activation in GPCRs.An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Investigations into the nature of platelet functional variety and consequences for homeostasis require new methods for resolving single platelet phenotypes. Here we combine droplet microfluidics with flow cytometry for high throughput single platelet function analysis. A large-scale sensitivity continuum was shown to be a general feature of human platelets from individual donors, with hypersensitive platelets coordinating significant sensitivity gains in bulk platelet populations and shown to direct aggregation in droplet-confined minimal platelet systems. Sensitivity gains scaled with agonist potency (convulxin > TRAP-14>ADP) and reduced the collagen and thrombin activation threshold required for platelet population polarization into pro-aggregatory and pro-coagulant states. The heterotypic platelet response results from an intrinsic behavioural program. The method and findings invite future discoveries into the nature of hypersensitive platelets and how community effects produce population level responses in health and disease.Photoacoustic endoscopy (PAE) is a method of in-vivo imaging that uses tissue absorption properties. In PAE, the main tools used to detect the acoustic signal are mechanical ultrasound transducers, which require direct contact and which are difficult to miniaturize. All-optic photoacoustic sensors can challenge this issue as they can provide contact-free sensing. Here, we demonstrate sensing of photo-acoustic signals through a multimode fiber (MMF) which can provide an ultra-thin endoscopic photoacoustic sensor. Furthermore, we show the advantage of using the optical-flow method for speckle sensing and extract the photoacoustic signal despite the mode-mixing along the MMF. Moreover, it is demonstrated for the first time that the speckle reconstruction method can be used without the need for imaging of the speckles as this enables the use of multimode fibers for the speckle method.