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Trial registration ClinicalTrials.gov, Identifier NCT01357772 .The levels of nuclear protein Lamin A/C are crucial for nuclear mechanotransduction. Lamin A/C levels are known to scale with tissue stiffness and extracellular matrix levels in mesenchymal tissues. But in epithelial tissues, where cells lack a strong interaction with the extracellular matrix, it is unclear how Lamin A/C is regulated. Here, we show in epithelial tissues that Lamin A/C levels scale with apico-basal cell compression, independent of tissue stiffness. Using genetic perturbations in Drosophila epithelial tissues, we show that apico-basal cell compression regulates the levels of Lamin A/C by deforming the nucleus. Further, in mammalian epithelial cells, we show that nuclear deformation regulates Lamin A/C levels by modulating the levels of phosphorylation of Lamin A/C at Serine 22, a target for Lamin A/C degradation. Taken together, our results reveal a mechanism of Lamin A/C regulation which could provide key insights for understanding nuclear mechanotransduction in epithelial tissues.The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are "addicted" to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.Electrocatalytic conversion of nitrogen oxides to value-added chemicals is a promising strategy for mitigating the human-caused unbalance of the global nitrogen-cycle, but controlling product selectivity remains a great challenge. Here we show iron-nitrogen-doped carbon as an efficient and durable electrocatalyst for selective nitric oxide reduction into hydroxylamine. Using in operando spectroscopic techniques, the catalytic site is identified as isolated ferrous moieties, at which the rate for hydroxylamine production increases in a super-Nernstian way upon pH decrease. Computational multiscale modelling attributes the origin of unconventional pH dependence to the redox active (non-innocent) property of NO. This makes the rate-limiting NO adsorbate state more sensitive to surface charge which varies with the pH-dependent overpotential. Guided by these fundamental insights, we achieve a Faradaic efficiency of 71% and an unprecedented production rate of 215 μmol cm-2 h-1 at a short-circuit mode in a flow-type fuel cell without significant catalytic deactivation over 50 h operation.Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of this global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of "stemness" and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. https://www.selleckchem.com/products/raptinal.html We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.It is important to evaluate the durability of the protective immune response elicited by primary infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we systematically evaluated the SARS-CoV-2-specific memory B cell and T cell responses in healthy controls and individuals recovered from asymptomatic or symptomatic infection approximately 6 months prior. Comparatively low frequencies of memory B cells specific for the receptor-binding domain (RBD) of spike glycoprotein (S) persisted in the peripheral blood of individuals who recovered from infection (median 0.62%, interquartile range 0.48-0.69). The SARS-CoV-2 RBD-specific memory B cell response was detected in 2 of 13 individuals who recovered from asymptomatic infection and 10 of 20 individuals who recovered from symptomatic infection. T cell responses induced by S, membrane (M), and nucleocapsid (N) peptide libraries from SARS-CoV-2 were observed in individuals recovered from coronavirus disease 2019 (COVID-19), and cross-reactive T cell responses to SARS-CoV-2 were also detected in healthy controls.
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