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Abstract Chordin-like 1 (CHRDL1) is a secreted protein that serves as an endogenous antagonist of bone morphogenetic proteins (BMPs). In the developing retina, Bmp4 has been demonstrated to be essential for sustaining the proliferation of progenitor cells and facilitating the differentiation of glial cells. Despite these efforts, the precise effects of Bmp4 inhibition on the developing retina are yet to be fully understood. We sought to address this question by overexpressing Chrdl1 in the developing retina. In this study, we explored the impact of Bmp4 inhibition on the developing mouse retina by conditionally overexpressing the Bmp4 inhibitor Chrdl1. Initially, we characterized the expression patterns of Bmp4 and Chrdl1 in the developing mouse retina from E10.5 to P12.5. Additionally, we utilized various molecular markers to demonstrate that Bmp4 inhibition disrupts both neuronal and Müller glial differentiation in the developing mouse retina. Moreover, through the application of RNA-seq analysis, distinctively expressed retinal genes under the modulation of Bmp4 signaling were discerned, encompassing the upregulation of Id1/2/3/4 and Hes1/5, as well as the downregulation of Neurod1/2/4 and Bhlhe22/23. Lastly, electroretinogram (ERG) and optomotor response (OMR) assays were conducted to illustrate that Bmp4 inhibition impairs the functional connectivity of various cells in the retina and consequently affects visual function. Collectively, this study demonstrates that inhibiting Bmp4 promotes the differentiation of retinal neurons over Müller glia by activating the expression of genes associated with neuron specification. These findings offer molecular insights into the role of Bmp4 signaling in mammalian retinal development.

Microphthalmia, mostly an autosomal dominant disorder, is a worldwide severe congenital ocular malformation that causes visual impairment. Our investigation unveiled a total of 30 genes associated with microphthalmia. Employing the CytoHubba and PPI network, we identified Bmp4 as the most pivotal hub gene. Subsequently, the conditional overexpression of Bmp4 in the retina caused highly distinctive microphthalmia, manifested by retinal disorganization with ganglion cell misalignment. Significant reduction in the number and abnormal distribution location of retinal cells in microphthalmia model mice. Elevated Bmp4 was associated with an increase in retinal apoptosis and a decrease in proliferating cells, which exacerbates the development of microphthalmia. Here we identify Bmp4 as an extremely important gene responsible for microphthalmia and the involved mechanisms. Overexpression of Bmp4 induces retinal cell ectopic expression and developmental defects, highlighting the importance of a well-balanced Bmp4 level in shaping the embryonic retina during early development.

Abstract Background Ketone body β-hydroxybutyrate (BHB) has received more and more attentions, because it possesses a lot of beneficial, life-preserving effects in the fields of clinical science and medicine. However, the role of BHB in intestinal inflammation has not yet been investigated. Methods Colonic mucosa of inflammatory bowel disease (IBD) patients and healthy controls were collected for evaluation of BHB level. Besides, the therapeutic effect of exogenous BHB in a murine model of acute dextran sulfate sodium (DSS)-induced colitis were assessed by body weight change, colon length, disease activity index, and histopathological sections. The regulatory effectors of BHB were analyzed by RT-qPCR, immunofluorescence, and microbe analysis in vivo. Moreover, the molecular mechanism of BHB was further verified in bone marrow-derived macrophages (BMDMs). Results In this study, significantly reduced BHB levels were found in the colonic mucosa from IBD patients and correlated with IBD activity index. In addition, we demonstrated that the administration of exogenous BHB alleviated the severity of acute experimental colitis, which was characterized by less weight loss, disease activity index, colon shortening, and histology scores, as well as decreased crypt loss and epithelium damage. Furthermore, BHB resulted in significantly increased colonic expression of M2 macrophage-associated genes, including IL-4Ra, IL-10, arginase 1 (Arg-1), and chitinase-like protein 3, following DSS exposure, suggesting an increased M2 macrophage skewing in vivo. Moreover, an in vitro experiment revealed that the addition of BHB directly promoted STAT6 phosphorylation and M2 macrophage-specific gene expression in IL-4-stimulated macrophages. Besides, we found that BHB obviously increased M2 macrophage-induced mucosal repair through promoting intestinal epithelial proliferation. However, the enhancement effect of BHB on M2 macrophage-induced mucosal repair and anti-inflammation was completely inhibited by the STAT6 inhibitor AS1517499. Conclusions In summary, we show that BHB promotes M2 macrophage polarization through the STAT6-dependent signaling pathway, which contributes to the resolution of intestinal inflammation and the repair of damaged intestinal tissues. Our finding suggests that exogenous BHB supplement may be a useful therapeutic approach for IBD treatment.

The instantaneous acceleration affects the performance of the water-jet pump obviously. Here, based on the user-defined function, the method to simulate the inner flow in water-jet pumps under acceleration conditions was established. The effects of two different acceleration modes (linear acceleration and exponential acceleration) and three kinds of different acceleration time (0.5s, 1s and 2s) on the performance of the water-jet pump were analyzed. The results show that the thrust and the pressure pulsation under exponential acceleration are lower than that under linear acceleration at the same time; the vapor volume fraction in the impeller under linear acceleration is 27.3% higher than that under exponential acceleration. As the acceleration time increases, the thrust gradually increases and the pressure pulsation amplitude at the impeller inlet and outlet gradually decreases, while the law of pressure pulsation is the opposite at the diffuser outlet. The main frequency of pressure pulsation at the impeller outlet is different under different acceleration time. The research results can provide some reference for the optimal design of water-jet pumps.

Abstract Background Pyroptosis is a form of proinflammatory gasdermin-mediated programmed cell death. Abnormal mucosal inflammation in the intestine is a critical risk factor for colitis-associated colorectal cancer (CAC). However, it is unknown whether pyroptosis participates in the development of CAC. Methods To investigate the role of gasdermin E (GSDME)-mediated pyroptosis in the development of CAC, Gsdme −/− mice and their wild-type (WT) littermate controls were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce a CAC model. Neutralizing antibodies against high-mobility group box protein 1 (HMGB1) were used to determine the role of HMGB1 in CAC. To identify the role of ERK1/2 in HMGB1-induced colon cancer cell proliferation, we performed western blotting and CCK8 assays using the ERK1/2-specific inhibitor U0126 in CT26 colon cancer cells. Results In the CAC model, Gsdme −/− mice exhibited reduced weight loss and colon shortening, attenuated rectal prolapse, and reduced tumor numbers and sizes compared to WT littermates. Furthermore, treatment with neutralizing anti-HMGB1 antibodies decreased the numbers and sizes of tumors, ERK1/2 activation and proliferating cell nuclear antigen (PCNA) expression in AOM/DSS-challenged WT mice. In addition, our in vitro experiments demonstrated that HMGB1 induced proliferation and PCNA expression in CT26 colon cancer cells through the ERK1/2 pathway. Conclusion GSDME-mediated pyroptosis promotes the development of CAC by releasing HMGB1, which induces tumor cell proliferation and PCNA expression through the ERK1/2 pathway. This finding reveals a previously unrecognized link between pyroptosis and CAC tumorigenesis and offers new insight into CAC pathogenesis.

Turning has a significant effect on the performance of water-jet pump. Here, the axial flow water-jet pump was used as the research object, the performance and inner flow characteristics of water-jet pump under different turning angle were simulated through numerical simulation. The thrust, vorticity, bubbles in impeller, vapor volume fraction and surface load of blade were analyzed in detail when the turning angles were ±10°, ±20°, and ±30°, respectively. The results demonstrate that the thrust of the water-jet pump decreases linearly with the increase of the turning angle. At the same angle, the thrust of the water-jet pump when turning right is larger than that when turning left, and the maximum thrust difference is 9.14% of that without the turning angle. As the turning angle increases, the overall pressure of the water-jet pump decreases and the streamline distribution gets turbulent gradually. The vortex direction is the same as the turning direction basically. And the vortex distribution range is smaller when turning right under the same turning angle. The cavitation bubbles in the impeller occur firstly at the rim of the blade inlet and develop to the middle of the blade as the turning angle increases. The cavitation area is concentrated on the blade at turning side and the cavitation area when turning right is smaller than that when turning left.

Summary: Crohn’s disease (CD) is a kind of refractory intestinal inflammatory diseases. Pyroptosis was recently identified as a gasdermin-mediated proinflammatory cell death. However, it is unclear whether gasdermin-mediated pyroptosis participates in the pathogenesis of CD. Here, we show that the pyroptosis-inducing fragment GSDME N-terminal is obviously detected in the inflamed colonic mucosa but not in the uninflamed mucosa of patients with CD, suggesting that GSDME-mediated pyroptosis may be correlated with intestinal mucosal inflammation in CD. To investigate the role of GSDME in colitis development, Gsdme−/− mice and wild-type (WT) littermate controls were treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis. We found that Gsdme−/− mice exhibit less-severe intestinal inflammation than WT controls do. Furthermore, our results indicate that GSDME-mediated epithelial-cell pyroptosis induces intestinal inflammation through the release of proinflammatory intracellular contents. In summary, we show that GSDME participates in the pathogenesis of CD through GSDME-mediated pyroptosis to release proinflammatory cytokines.

Abstract Background Gastric cancer (GC) is one of the most frequent malignant tumors and the molecular mechanism underlying its proliferation remains far from completely understood. Although accumulating evidence shows that abnormal expression of microRNA (miRNA) is involved in tumorigenesis, the role of specific miRNAs involved in GC remains elusive. MiR-199a/b-3p functions as a tumor suppressor in diverse cancers, but its expression, function, and mechanism in GC remain unclear. Our aim is to explore miR-199a/b-3p expression and its role in regulating GC cell proliferation. Methods Real-time PCR was performed to determine miR-199a/b-3p expression in GC tissues and normal adjacent tissues as well as normal gastric mucosal cell line GES-1 and GC cell lines MGC-803 and SGC-7901. MTT assay and Western blot were performed to determine cell proliferation and expression of PAK4, p-MEK and p-ERK, respectively. MiR-199a/b-3p mimics-transfected assay and PAK-specific siRNA assay were performed to determine their function in cell proliferation, respectively. GC xenograft nude mice were used to determine miR-199a/b-3p function in cell proliferation. Results MiR-199a/b-3p expression was significantly decreased in GC tissues and GC cell lines MGC-803 and SGC-7901. MiR-199a/b-3p over-expression and PAK4 silencing inhibited cell proliferation and diminished the activation of p-MEK and p-ERK in MGC-803 and SGC-7901 cells, and miR-199a/b-3p over-expression reduced PAK4 expression. MiR-199a/b-3p over-expression suppressed MGC-803 cell growth and PAK4 expression in nude mice. Conclusions miR-199a/b-3p inhibits GC cell proliferation via down-regulating PAK4/MEK/ERK signaling pathway and may be a novel prognostic biomarker and a potential therapeutic target for GC patients.

The intricate web of cancer biology is governed by the active participation of long non-coding RNAs (lncRNAs), playing crucial roles in cancer cells' proliferation, migration, and drug resistance. Pioneering research driven by machine learning algorithms has unveiled the profound ability of specific combinations of lncRNAs to predict the prognosis of cancer patients. These findings highlight the transformative potential of lncRNAs as powerful therapeutic targets and prognostic markers. In this comprehensive review, we meticulously examined the landscape of lncRNAs in predicting the prognosis of the top five cancers and other malignancies, aiming to provide a compelling reference for future research endeavours. Leveraging the power of machine learning techniques, we explored the predictive capabilities of diverse lncRNA combinations, revealing their unprecedented potential to accurately determine patient outcomes. lncRNAs play crucial roles in cancer biology, regulating proliferation, migration, and drug resistance. Emerging evidence suggests that machine learning can predict cancer prognosis using specific lncRNA combinations. Comprehensive information on the predictive abilities of lncRNA combinations in oncology concerning machine learning is lacking. This review offers up-to-date vital references on diverse lncRNA combinations pertinent to future research and clinical trials. [ABSTRACT FROM AUTHOR]

Radial diffusers can improve the flow uniformity in pumps and affect the hydraulic performance of centrifugal pumps directly. The diffusion coefficient d is an important parameter in fluid machinery but it has seldom been used in the diffuser design of single-stage centrifugal pumps. To improve the design method of radial diffuser use in centrifugal pumps, the diffusion coefficient was introduced into the design of radial diffusers based on a single-arc hydraulic design method and it was found that the vane outlet angle, vane outlet thickness and vane number have a significant impact on the design results. A single-stage centrifugal pump with a radial diffuser was selected as the research model. The inner flow was simulated using the commercial computational fluid dynamics (CFD) program CFX and verified by experiment. The results indicate that the head and efficiency of the pump are best when the vane outlet angle is 6°. The flow area decreases and the flow velocity at radial diffuser outlet increase when the outlet thickness is greater than 2 mm. The hydraulic loss is minimum and the head and efficiency are better when the vane number is 8 at different flow rates. So, the optimal range of the diffusion coefficient for the model pump is around 1.6 to 2. The study indicates that it is feasible to design radial diffusers according to the diffusion coefficient.