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Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets. Michel et al. report unique localization of non-canonical BAF to CTCF sites and promoters, which confers synthetic lethality in canonical BAF-perturbed synovial sarcoma and malignant rhabdoid tumour cells.

To develop an effective and sustainable cell therapy for sickle cell disease (SCD), we investigated the feasibility of targeted disruption of the gene, either within exon 2 or at the GATAA motif in the intronic erythroid-specific enhancer, using zinc finger nucleases in human bone marrow (BM) CD34 hematopoietic stem and progenitor cells (HSPCs). Both targeting strategies upregulated fetal globin expression in erythroid cells to levels predicted to inhibit hemoglobin S polymerization. However, complete inactivation of resulting from bi-allelic frameshift mutations in exon 2 adversely affected erythroid enucleation. In contrast, bi-allelic disruption of the GATAA motif in the erythroid enhancer of did not negatively impact enucleation. Furthermore, exon 2-edited BM-CD34 cells demonstrated a significantly reduced engraftment potential in immunodeficient mice. Such an adverse effect on HSPC function was not observed upon erythroid-enhancer GATAA motif editing, because enhancer-edited CD34 cells achieved robust long-term engraftment and gave rise to erythroid cells with elevated levels of fetal globin expression when chimeric BM was cultured ex vivo. Altogether, our results support further clinical development of the erythroid-specific enhancer editing in BM-CD34 HSPCs as an autologous stem cell therapy in SCD patients.

The false discovery proportion (FDP), the proportion of incorrect rejections among all rejections, is a direct measure of abundance of false positive findings in multiple testing. Many methods have been proposed to control FDP, but they are too conservative to be useful for power analysis. Study designs for controlling the mean of FDP, which is false discovery rate, have been commonly used. However, there has been little attempt to design study with direct FDP control to achieve certain level of efficiency. We provide a sample size calculation method using the variance formula of the FDP under weak-dependence assumptions to achieve the desired overall power. The relationship between design parameters and sample size is explored. The adequacy of the procedure is assessed by simulation. We illustrate the method using estimated correlations from a prostate cancer dataset.

Protein kinase A (PKA) silences the Hedgehog (Hh) pathway in Drosophila in the absence of ligand by phosphorylating the pathway's transcriptional effector, Cubitus interruptus (Ci). Smoothened (Smo) is essential for Hh signal transduction but loses activity if three specific PKA sites or adjacent PKA-primed casein kinase 1 (CK1) sites are replaced by alanine residues. Conversely, Smo becomes constitutively active if acidic residues replace those phosphorylation sites. These observations suggest an essential positive role for PKA in responding to Hh. However, direct manipulation of PKA activity has not provided strong evidence for positive effects of PKA, with the notable exception of a robust induction of Hh target genes by PKA hyperactivity in embryos. Here we show that the latter response is mediated principally by regulatory elements other than Ci binding sites and not by altered Smo phosphorylation. Also, the failure of PKA hyperactivity to induce Hh target genes strongly through Smo phosphorylation cannot be attributed to the coincident phosphorylation of PKA sites on Ci. Finally, we show that Smo containing acidic residues at PKA and CK1 sites can be stimulated further by Hh and acts through Hh pathways that both stabilize Ci-155 and use Fused kinase activity to increase the specific activity of Ci-155.

Hedgehog (Hh) signaling regulates cell fate and proliferation in development, cancer and stem cells by altering the activity of Ci/Gli-family transcription factors. Hh signal transduction is conveniently studied in Drosophila wing discs, where anterior (A) cells respond to Hh produced from posterior (P) cells. In A cells that are not exposed to Hh, full-length Cubitus interruptus (Ci-155) is maintained in an inactive form through interactions with the kinesin family protein Costal 2 (Cos2), a Serine/Threonine kinase Fused (Fu) and Suppressor of fused (Su(fu)). Those interactions also result in proteolytic processing of Ci-155 to a repressor form, Ci-75. At the AP border, Hh acts via its receptor Patched (Ptc) and the seven trans-membrane protein Smoothened (Smo) to inhibit Ci-155 processing and to stimulate transcriptional activation of Hh target genes, including ptc and engrailed ( en), in a dose-dependent manner. Fused (Fu) protein kinase activity is essential for En and strong ptc-lacZ induction but is not essential for Hh to regulate Ci-155 processing. Fu kinase is thought primarily to inactivate Su(fu), whose phosphorylation is dependent on Fu kinase activity. Fu kinase can also phosphorylate Cos2. Both Fu and Su(fu) are hyper-phosphorylated in response to Hh, suggesting that phosphorylation may regulate their activities. How Hh-induced activation of Smo reverses Ci-155 silencing by Su(fu) and Cos2 binding partners is a major unanswered question. Here we show that Hh acts via Smo and Cos2 to stimulate inter-molecular auto-phosphorylation and consequent activation of the Fused (Fu) protein kinase. We specifically identified several Hh stimulated auto-phosphorylation sites in the Fu kinase activation loop and also in its regulatory domain. Altering those sites to Alanines and Valines compromised Fu kinase activity, while changing two key sites to acidic residues to mimic phosphorylation resulted in a constitutively active Fu, manifest by ectopic induction of ptc-lacZ and en in anterior wing discs. Additionally, activated Fu surprisingly recapitulated a full Hh response. It stabilized full-length Ci-155 in anterior wing discs by phosphorylating Cos2 at serine 572. It also activated Ci-155 in the absence of Su(fu). Finally, activated Fu antagonized Su(fu), although not by phosphorylating Su(fu) at prominent sites. Mouse SUFU is an essential negative regulator of the mammalian Hh pathway, but there is no identified functional counterpart of Fu in the mammalian Hh pathway. We found that Fu could antagonize Ci-155 silencing by mouse SUFU in flies. These findings reveal the central role of Fu in Drosophila Hh signaling and predict a key role for an analogous activity in mammalian Hh signaling. Earlier, we examined the mechanism by which Ci-155 is processed to Ci-75 in the absence of Hh. This was known to involve Cos2 binding to Ci-155 and to three protein kinases (Protein kinase A (PICA), Casein Kinase 1 (CK1), Glycogen Synthase Kinase 3 (GSK3)), which phosphorylate Ci-155 to create a binding site for an E3 ubiquitin ligase component, Slimb. We found that the two known binding sites on Ci-155 for Cos2 (CDN and CORD) were dispensable. We identified the Zinc fingers as a third Cos2 interaction region, which acts redundantly with the CORD domain. We also found that the CORD-Cos2 interaction can be regulated by nucleotides and likely serves to alter Ci accessibility to phosphorylation as well as contributing to Cos2 recruitment. We also showed that a previous reported role for excess PKA in promoting Hh signaling did not involve the core Hh signaling pathway and did not result from hyper-phosphorylation of known required PKA and CK1 sites in Smo. We also showed that Smo phosphorylation at these sites was sufficient to activate all downstream aspects of Hh signaling, but could be activated further by Hh.

Metabolic reprogramming shapes the tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. \"Immune cold\" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of protumor macrophages, and reduced cytotoxic T cells in the TME. Analysis of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of endosulfine α (ENSA-K63la), a crucial step that triggers STAT3/CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. A therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

Bioretention systems effectively capture rubber particles and other microplastics in stormwater runoff. However, it is uncertain whether long-term particle accumulation affects pollutant removal efficacy. This study investigated the impact of various concentrations of ethylene-propylene-diene-monomer (EPDM) particles (0, 50, 100, and 400 mg/L) on bioretention system nitrogen removal performance. The input of EPDM during short-duration (2 h) rainfall favored the removal of nitrogen, and the total nitrogen effluent concentration of the bioretention system with EPDM was reduced by 0.59–1.52 mg/L compared with that of the system without EPDM. In addition, the input of EPDM reduced the negative effects of drought. During long-duration (24 h) rainfall, higher concentrations of EPDM led to lower nitrate–nitrogen concentrations in the effluent. The bioretention system with EPDM required less time for nitrate–nitrogen removal to reach 50% than that without EPDM input. Microbial community analysis showed that EPDM increased the relative total abundance of denitrifying bacteria (such as Dechloromonas, Zoogloea, Ramlibacter, and Aeromonas) by 7.25–10.26%, which improved the denitrification capacity of the system.

Pyroptosis is a type of programmed cell death that is mediated by both typical and atypical pathways and ultimately leads to the lysis and rupture of cell membranes and the release of proinflammatory factors, triggering an intense inflammatory response. Heart failure (HF) is a serious and terminal stage of various heart diseases. Myocardial hypertrophy, myocardial fibrosis, ventricular remodeling, oxidative stress, the inflammatory response and cardiomyocyte ionic disorders caused by various cardiac diseases are all risk factors for and aggravate HF. Numerous studies have shown that pyroptosis can induce and exacerbate these reactions, causing progression to HF. Therefore, targeting pyroptosis is a promising strategy to treat HF. This paper summarizes the role of pyroptosis in the development of HF and the underlying mechanism involved. Recent research progress on the ability of traditional Chinese medicine (TCM) extracts and formulas to inhibit pyroptosis and treat HF was summarized, and some traditional Chinese medicine extracts and formulas can alleviate different types of HF, including heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with midrange ejection fraction (HFmrEF), by targeting pyroptosis. These findings may provide new ideas and evidence for the treatment or adjuvant treatment of HF by targeting pyroptosis.

To evaluate the efficacy and safety of Shenmai injection for the treatment of viral myocarditis (VMS) through systematic evaluation and meta-analysis. Seven databases were searched to identify randomized controlled trials that examined the use of Shenmai injection for the treatment of VMS. The databases were searched from inception to 20 January 2024. The quality of the included studies was evaluated via the Cochrane risk of bias tool (RoB 2) version 2. Data analysis was performed using Review Manager 5.4 and Stata 16. In total, 18 randomized controlled trials were included. The trials were conducted in 2006-2024 and included 1,661 patients with VMS. The results reveal that Shenmai injection combined with conventional treatment was superior to conventional treatment alone in terms of the following outcomes: total effective rate [RR = 1.22, 95% CI (1.16, 1.28)], CKMB [SMD = -3.33, 95% CI (-4.85, -1.81)], electrocardiogram (ECG) efficacy [RR = 1.30, 95% CI (1.20, 1.40)], AST [SMD = -0.70, 95% CI (-1.28, -0.11)], LDH [SMD = -1.17, 95% CI (-1.37, -0.97], < 0.00001], CK [SMD = -1.74, 95% CI (-2.34, -1.13)], TNF-α [SMD = -1.35, 95% CI (-1.85, -0.84)], and IL-6 [SMD = -1.40, 95% CI (-1.76, -1.05)]. There were no significant differences in the incidence of adverse reactions [RR = 1.56, 95% CI (0.73, 3.33), = 0.25] or cTnI levels [SMD = -3.35, 95% CI (-6.81, 0.11)] between the groups. Shenmai injection with conventional treatment can reduce the degree of myocardial injury in patients with VMS, weaken the inflammatory response and improve the clinical efficacy of the conventional treatment. This approach was found to be safe. However, additional high-quality studies are necessary to confirm the reliability of this treatment method. https://www.crd.york.ac.uk/PROSPERO/logout.php, identifier PROSPERO (CRD42024518665).

The Pelton turbine has been widely applied for the advantages of its simple structure, flexible mass flow rate, wide range of applicable heads and high efficiency. The nozzle and needle are a core part of the Pelton turbine injector. In this paper, the VOF (Volume of Fluid) model was used to simulate the jet flow behaviors and hydraulic performance for a Pelton injector with a needle tip with different breakage losses. Three types of needle tip breakage loss combined with normal needle tip were selected for numerical calculation and analysis, focusing on the influence of needle tip on the high-speed jet flow characteristics. An injector with normal needle tip hydraulic performance is compared with the model test. Finally, the injector hydraulic performance and the jet flow behavior changes with the needle tip shape were comprehensively analyzed. Results show that the needle tip shape almost does not affect the flow rate; when the tip breakage loss is larger than 0.1 of nozzle diameter, the jet efficiency will decrease rapidly and the jet will diffuse rapidly after outflow from the injector. The investigation provides a basis for the operation, maintenance and stability of the Pelton turbine.