A gut-derived hormone regulates cholesterol metabolism.

The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.

Mechanism of the cardioprotective effect of empagliflozin on diabetic nephropathy mice based on the basis of proteomics.

Diabetic nephropathy affects a significant proportion of individuals with diabetes, and its progression often leads to cardiovascular disease and infections before the need for renal replacement therapy arises. Empagliflozin has been shown to have various protective effects in cardiovascular disease studies, such as improving diabetic myocardial structure and function, and reducing myocardial oxidative stress. However, the impact of empagliflozin on cardiac protein expression and signaling pathways has not been comprehensively analyzed. To address this gap, we conducted proteome analysis to identify specific protein markers in cardiac tissue from the diabetes model group, including Myh7, Wdr37, Eif3k, Acot1, Acot2, Cat, and Scp2, in cardiac tissue from the diabetes model group. In our drug model, empagliflozin primarily modulates the fat-related metabolic signaling pathway within the heart. Empagliflozin downregulated the protein expression levels of ACOX1, ACADVL and CPT1A in the model group. Overall, our findings demonstrate that empagliflozin provides cardiac protection by targeting metabolic signaling pathways, particularly those related to fat metabolism. Moreover, the identification of cardiac biomarkers in a mouse model of diabetic nephropathy lays the foundation for further exploration of disease biomarkers in cardiac tissue.

Research Advances in Amorphous-Crystalline Heterostructures Toward Efficient Electrochemical Applications.

Interface engineering of heterostructures has proven a promising strategy to effectively modulate their physicochemical properties and further improve the electrochemical performance for various applications. In this context related research of the newly proposed amorphous-crystalline heterostructures have lately surged since they combine the superior advantages of amorphous- and crystalline-phase structures, showing unusual atomic arrangements in heterointerfaces. Nonetheless, there has been much less efforts in systematic analysis and summary of the amorphous-crystalline heterostructures to examine their complicated interfacial interactions and elusory active sites. The critical structure-activity correlation and electrocatalytic mechanism remain rather elusive. In this review, the recent advances of amorphous-crystalline heterostructures in electrochemical energy conversion and storage fields are amply discussed and presented, along with remarks on the challenges and perspectives. Initially, the fundamental characteristics of amorphous-crystalline heterostructures are introduced to provide scientific viewpoints for structural understanding. Subsequently, the superiorities and current achievements of amorphous-crystalline heterostructures as highly efficient electrocatalysts/electrodes for hydrogen evolution reaction, oxygen evolution reaction, supercapacitor, lithium-ion battery, and lithium-sulfur battery applications are elaborated. At the end of this review, future outlooks and opportunities on amorphous-crystalline heterostructures are also put forward to promote their further development and application in the field of clean energy.

Vitamin D Ameliorates Podocyte Injury by Enhancing Autophagy Activity in Diabetic Kidney Disease.

INTRODUCTION: Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the protective effect and potential mechanism of vitamin D on podocyte injury of DKD. METHODS: Type 2 diabetic db/db mice received intraperitoneal injections of vitamin D analog paricalcitol 400 ng/kg per day for 16 weeks. Immortalized mouse podocytes were cultured in high glucose (HG) medium with active vitamin D3 calcitriol or autophagy inhibitor 3-methyladenine. Renal function and urine albumin creatinine ratio were assessed at week 24. HE, PAS staining, and electron microscopy were used to evaluate renal histopathology and morphological changes. Immunohistochemistry, immunofluorescence, and Western blot were used to evaluate protein expression of nephrin and podocin in kidney tissue and podocytes. The expression of autophagy-related proteins (LC3, Beclin-1, Vps34) and apoptosis-related proteins (cleaved caspase-3, Bax) was determined by Western blotting. Podocyte apoptosis was further evaluated by using flow cytometer. RESULTS: Albuminuria in a db/db mouse model was markedly attenuated after treatment with paricalcitol. This was accompanied by alleviation of mesangial matrix expansion and podocyte injury. Besides, the impaired autophagy in podocytes under diabetic conditions was also markedly enhanced after paricalcitol or calcitriol treatment, accompanied by restored decreased podocyte slit diaphragm proteins podocin and nephrin. Furthermore, the protective effect of calcitriol against HG-induced podocyte apoptosis could be abated by autophagy inhibitor 3-methyladenine. CONCLUSION: Vitamin D ameliorates podocyte injury of DKD by enhancing podocyte autophagy activity, which may become a potential candidate autophagy activator for the therapeutic interventions for DKD.

Annexin-1 is an oncogene in glioblastoma and causes tumour immune escape through the indirect upregulation of interleukin-8.

Annexin-1 (ANXA1) is widely reported to be deregulated in various cancers and is involved in tumorigenesis. However, its effects on glioblastoma (GBM) remain unclear. Using immunohistochemistry with tissue microarrays, we showed that ANXA1 was overexpressed in GBM, positively correlated with higher World Health Organization (WHO) grades of glioma, and negatively associated with poor survival. To further explore its role and the underlying molecular mechanism in GBM, we constructed ANXA1shRNA U87 and U251 cell lines for further experiments. ANXA1 downregulation suppressed GBM cell proliferation, migration, and invasion and enhanced their radiosensitivity. Furthermore, we determined that ANXA1 was involved in dendritic cell (DC) maturation in patients with GBM and that DC infiltration was inversely proportional to GBM prognosis. Considering that previous reports have shown that Interleukin-8 (IL-8) is associated with DC migration and maturation and is correlated with NF-κB transcriptional regulation, we examined IL-8 and p65 subunit expressions and p65 phosphorylation levels in GBM cells under an ANXA1 knockdown. These results suggest that ANXA1 significantly promotes IL-8 production and p65 phosphorylation levels. We inferred that ANXA1 is a potential biomarker and a candidate therapeutic target for GBM treatment and may mediate tumour immune escape through NF-kB (p65) activation and IL-8 upregulation.

Analyses of prognosis-related factors of intracranial solitary fibrous tumors and hemangiopericytomas help understand the relationship between the two sorts of tumors.

Increasing evidence has suggested a close relationship between solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) in the central nervous system (CNS). However, CNS SFTs differentiate from HPCs in their clinical behavior and patient prognoses. Analyses of prognosis-related factors can help clarify the relationship between SFT and HPC. The intracranial SFT and HPC cases treated in our departments from January 2002 to December 2012 were retrospectively reviewed. The SFT and HPC cases were also combined into an SFT/HPC group. The factors associated with patient progression-free survival (PFS) and overall survival (OS) were statistically analyzed using uni- and multivariate analyses. Fifty-eight intracranial SFT/HPC patients including 38 SFT patients and 20 HPC patients were treated during this period. The "Marseille grading" evaluated upon the histological aggressive phenotypes was applied in this study. The grading reflected a malignant progression ranging from "conventional" SFTs (grade I) to WHO III HPCs (grade III), and grade was negatively correlated with the PFS and OS of the SFT, HPC and SFT/HPC patients (P < 0.05).The multivariate analyses revealed that gross total resection (GTR) was significantly positively correlated with PFS and OS in the SFT, HPC and SFT/HPC patients and that radiotherapy was significantly positively correlated with PFS in the HPC and SFT/HPC patients (P < 0.05). In conclusion, the intracranial SFTs and HPCs share common prognostic factors including extent of surgery and pathology, moreover, the histological grading of the aggressive phenotypes supports the unifying of the CNS SFT and HPC into one tumor entity of SFT/HPC.

Wnt/ß-catenin pathway involvement in ionizing radiation-induced invasion of U87 glioblastoma cells.

BACKGROUND: Radiotherapy has been reported to promote the invasion of glioblastoma cells; however, the underlying mechanisms remain unclear. Here, we investigated the role of the Wnt/ß-catenin pathway in radiation-induced invasion of glioblastoma cells. METHODS: U87 cells were irradiated with 3 Gy or sham irradiated in the presence or absence of the Wnt/ß-catenin pathway inhibitor XAV 939. Cell invasion was determined by an xCELLigence real-time cell analyser and matrigel invasion assays. The intracellular distribution of ß-catenin in U87 cells with or without irradiation was examined by immunofluorescence and Western blotting of nuclear fractions. We next investigated the effect of irradiation on Wnt/ß-catenin pathway activity using TOP/FOP flash luciferase assays and quantitative polymerase chain reaction analysis of ß-catenin target genes. The expression levels and activities of two target genes, matrix metalloproteinase (MMP)-2 and MMP-9, were examined further by Western blotting and zymography. RESULTS: U87 cell invasiveness was increased significantly by ionizing radiation. Interestingly, ionizing radiation induced nuclear translocation and accumulation of ß-catenin. Moreover, we found increased ß-catenin/TCF transcriptional activities, followed by up-regulation of downstream genes in the Wnt/ß-catenin pathway in irradiated U87 cells. Importantly, inhibition of the Wnt/ß-catenin pathway by XAV 939, which promotes degradation of ß-catenin, significantly abrogated the pro-invasion effects of irradiation. Mechanistically, XAV 939 suppressed ionizing radiation-triggered up-regulation of MMP-2 and MMP-9, and inhibited the activities of these gelatinases. CONCLUSION: Our data demonstrate a pivotal role of the Wnt/ß-catenin pathway in ionizing radiation-induced invasion of glioblastoma cells, and suggest that targeting ß-catenin is a promising therapeutic approach to overcoming glioma radioresistance.

Hyperthermia improves immune function and radiotherapy efficacy in patients with post-operative recurrent gastric cancer.

BACKGROUND/AIMS: Hyperthermia has long been used in combination with radiation for the treatment of cancers. This study aimed to investigate the efficacy safety and impact on the immune function of the abdominal hyperthermia combining with radiotherapy. METHODOLOGY: Sixty-eight patients with post-operative local recurrent gastric carcinoma were divided randomly into two groups. Patients in 3DCRT+HT group received three-dimensional conformal radio therapy combined with abdominal hyperthermia while patients from 3DCRT group only received the three-dimensional conformal radiation therapy. The differences of efficacy, toxicity and the impact on immune function between two kinds of therapies were compared. RESULTS: Response rate in 3DCRT+HT group was 57.2%, which was significant higher than that in 3DCRT group (47.1%) (P=0.04). Median local progression-free survival time of 3DCRT+HT group (14 months) was significantly longer than 3DCRT group (11 months). The peripheral blood T lymphocyte subsets analyses showed that, after the treatment, CD3+, CD4+, NK level and CD4+/CD8+ ratio increased significantly, while there was no significant alterations for those immunological parameters in 3DCRT group. CONCLUSION: Abdominal hyperthermia combined with three-dimensional conformal radiotherapy could gain higher response rate, prolong median local progression-free survival time and improve immune function for the post-operative recurrentgastric cancer.

Integrated bioinformatics analysis and experimental validation reveal the relationship between ALOX5AP and the prognosis and immune microenvironment in glioma.

BACKGROUND: Treatment of gliomas, the most prevalent primary malignant neoplasm of the central nervous system, is challenging. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) is crucial for converting arachidonic acid into leukotrienes and is associated with poor prognosis in multiple cancers. Nevertheless, its relationship with the prognosis and the immune microenvironment of gliomas remains incompletely understood. METHODS: The differential expression of ALOX5AP was evaluated based on public Databases. Kaplan-Meier, multivariate Cox proportional hazards regression analysis, time-dependent receiver operating characteristic, and nomogram were used to estimate the prognostic value of ALOX5AP. The relationship between ALOX5AP and immune infiltration was calculated using ESTIMATE and CIBERSORT algorithms. Relationships between ALOX5AP and human leukocyte antigen molecules, immune checkpoints, tumor mutation burden, TIDE score, and immunophenoscore were calculated to evaluate glioma immunotherapy response. Single gene GSEA and co-expression network-based GO and KEGG enrichment analysis were performed to explore the potential function of ALOX5AP. ALOX5AP expression was verified using multiplex immunofluorescence staining and its prognostic effects were confirmed using a glioma tissue microarray. RESULT: ALOX5AP was highly expressed in gliomas, and the expression level was related to World Health Organization (WHO) grade, age, sex, IDH mutation status, 1p19q co-deletion status, MGMTp methylation status, and poor prognosis. Single-cell RNA sequencing showed that ALOX5AP was expressed in macrophages, monocytes, and T cells but not in tumor cells. ALOX5AP expression positively correlated with M2 macrophage infiltration and poor immunotherapy response. Immunofluorescence staining demonstrated that ALOX5AP was upregulated in WHO higher-grade gliomas, localizing to M2 macrophages. Glioma tissue microarray confirmed the adverse effect of ALOX5AP in the prognosis of glioma. CONCLUSION: ALOX5AP is highly expressed in M2 macrophages and may act as a potential biomarker for predicting prognosis and immunotherapy response in patients with glioma.

METTL3 restricts RIPK1-dependent cell death via the ATF3-cFLIP axis in the intestinal epithelium.

Intestinal epithelial cells (IECs) are pivotal for maintaining intestinal homeostasis through self-renewal, proliferation, differentiation, and regulated cell death. While apoptosis and necroptosis are recognized as distinct pathways, their intricate interplay remains elusive. In this study, we report that Mettl3-mediated m6A modification maintains intestinal homeostasis by impeding epithelial cell death. Mettl3 knockout induces both apoptosis and necroptosis in IECs. Targeting different modes of cell death with specific inhibitors unveils that RIPK1 kinase activity is critical for the cell death triggered by Mettl3 knockout. Mechanistically, this occurs via the m6A-mediated transcriptional regulation of Atf3, a transcription factor that directly binds to Cflar, the gene encoding the anti-cell death protein cFLIP. cFLIP inhibits RIPK1 activity, thereby suppressing downstream apoptotic and necroptotic signaling. Together, these findings delineate the essential role of the METTL3-ATF3-cFLIP axis in homeostatic regulation of the intestinal epithelium by blocking RIPK1 activity.

Lymphoepithelial carcinoma of the head and neck: a SEER analysis of prognostic factors for survival.

OBJECTIVE: To explore the epidemiological characteristics of patients with lymphoepithelial carcinoma (LEC) of the head and neck and the prognostic factors. METHODS: We conducted a retrospective cohort study of cases of head and neck LEC retrieved from the Surveillance, Epidemiology and End Results database. Kaplan-Meier survival analysis and the log-rank test were employed to assess overall survival (OS) and cancer-specific survival (CSS). Univariate and multivariate analyses were used to construct Cox regression models. We established nomograms to predict OS and CSS among patients with nasopharyngeal LEC, who were divided into high- and low-risk groups based on the OS nomograms to compare the effects of treatment using the restricted mean survival time (RMST). RESULTS: The 5-year OS and CSS rates of the cohort were 70.8% and 74.8%, respectively. Advanced age, unmarried status, black race, distant metastasis, and the absence of surgical treatment were significantly associated with decreased survival rates. RMST did not differ between the combined treatment (radiotherapy and chemotherapy) and radiotherapy monotherapy groups, but chemotherapy alone displayed poor efficacy. CONCLUSIONS: Head and neck LEC is associated with a favorable prognosis. Radiotherapy plays a significant role in managing patients with nasopharyngeal LEC, which is influenced by multiple prognostic factors.

Development of a 32-gene signature using machine learning for accurate prediction of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by multiple genetic and environmental factors. Numerous genes are implicated in the etiology of IBD, but the diagnosis of IBD is challenging. Here, XGBoost, a machine learning prediction model, has been used to distinguish IBD from healthy cases following elaborative feature selection. Using combined unsupervised clustering analysis and the XGBoost feature selection method, we successfully identified a 32-gene signature that can predict IBD occurrence in new cohorts with 0.8651 accuracy. The signature shows enrichment in neutrophil extracellular trap formation and cytokine signaling in the immune system. The probability threshold of the XGBoost-based classification model can be adjusted to fit personalized lifestyle and health status. Therefore, this study reveals potential IBD-related biomarkers that facilitate an effective personalized diagnosis of IBD.

Cross-species single-cell transcriptomic analysis of animal gastric antrum reveals intense porcine mucosal immunity.

As an important part of the stomach, gastric antrum secretes gastrin which can regulate acid secretion and gastric emptying. Although most cell types in the gastric antrum are identified, the comparison of cell composition and gene expression in the gastric antrum among different species are not explored. In this study, we collected antrum epithelial tissues from human, pig, rat and mouse for scRNA-seq and compared cell types and gene expression among species. In pig antral epithelium, we identified a novel cell cluster, which is marked by high expression of AQP5, F3, CLCA1 and RRAD. We also discovered that the porcine antral epithelium has stronger immune function than the other species. Further analysis revealed that this may be due to the insufficient function of porcine immune cells. Together, our results replenish the information of multiple species of gastric antral epithelium at the single cell level and provide resources for understanding the homeostasis maintenance and regeneration of gastric antrum epithelium.

Spatial-temporal analysis of pulmonary tuberculosis in Hubei Province, China, 2011-2021.

BACKGROUND: Pulmonary tuberculosis (PTB) is an infectious disease of major public health problem, China is one of the PTB high burden counties in the word. Hubei is one of the provinces having the highest notification rate of tuberculosis in China. This study analyzed the temporal and spatial distribution characteristics of PTB in Hubei province for targeted intervention on TB epidemics. METHODS: The data on PTB cases were extracted from the National Tuberculosis Information Management System correspond to population in 103 counties of Hubei Province from 2011 to 2021. The effect of PTB control was measured by variation trend of bacteriologically confirmed PTB notification rate and total PTB notification rate. Time series, spatial autonomic correlation and spatial-temporal scanning methods were used to identify the temporal trends and spatial patterns at county level of Hubei. RESULTS: A total of 436,955 cases were included in this study. The total PTB notification rate decreased significantly from 81.66 per 100,000 population in 2011 to 52.25 per 100,000 population in 2021. The peak of PTB notification occurred in late spring and early summer annually. This disease was spatially clustering with Global Moran's I values ranged from 0.34 to 0.63 (P< 0.01). Local spatial autocorrelation analysis indicated that the hot spots are mainly distributed in the southwest and southeast of Hubei Province. Using the SaTScan 10.0.2 software, results from the staged spatial-temporal analysis identified sixteen clusters. CONCLUSIONS: This study identified seasonal patterns and spatial-temporal clusters of PTB cases in Hubei province. High-risk areas in southwestern Hubei still exist, and need to focus on and take targeted control and prevention measures.

Digitizing tuberculosis treatment monitoring in Wuhan city, China, 2020-2021: Impact on medication adherence.

Introduction: Digital technologies can improve adherence to tuberculosis (TB) treatment. We studied the impact of digitizing TB treatment monitoring on adherence among TB patients in Wuhan, China, during 2020-2021. Methods: We compared an electronic system introduced to monitor TB medication adherence (e-Patient Service System; e-PSS) with the p paper-based standard of care (TB Control Information System; TCIS) in terms of prescribed TB treatment doses taken by patients and patient outcome after six months of follow up. We designed a cross sectional study using retrospective data for all drug susceptible pulmonary TB patients recorded on both systems. The main indicators were: compliant first follow up visit (within 3 days of start of treatment); medication adherence (80% or more of monthly doses taken); and end of treatment success ratio. Results: A total of 1,576 TB patients were recorded in TCIS in July September, 2020 and 1,145 TB cases were included in e-PSS in January March, 2021. The distribution of patient demographic and clinical features was similar between the two groups. A larger proportion from the e-PSS group visited the community doctor in the first three days compared with the TCIS group (48.91 versus 29. 76 % respectively). Medication adherence was also higher in the e-PSS group during the 6 months of treatment than in the TCIS group (84. 28 versus 80.3 3 % respectively). Treatment success was 92.52% in the e-PSS group and 92.07% in the TCIS group. Multivariate logistic regress ion analysis demonstrated that adjusted odds ratios for compliant first follow up visit, medication adherence and favorable treatment outcome in the e-PSS versus TCIS groups were 2.94 (95% 2.47 3.50), 1.33 (95% 1.08 1.63), and 1. 12 (95% CL: 0.79 1.57) respectively. Discussion: This study revealed improvements in TB care following an intervention to monitor treatment digitally in patients in Wuhan, China.

Corrigendum: Digitizing tuberculosis treatment monitoring in Wuhan city, China, 2020-2021: Impact on medication adherence.

[This corrects the article DOI: 10.3389/fpubh.2023.1033532.].

The cyclooxygenase-expressing mesenchyme resists intestinal epithelial injury by paracrine signaling.

Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.

Using Machine Learning Techniques to Develop Risk Prediction Models for the Risk of Incident Diabetic Retinopathy Among Patients With Type 2 Diabetes Mellitus: A Cohort Study.

Objective: To construct and validate prediction models for the risk of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus. Methods: Patients with type 2 diabetes mellitus hospitalized over the period between January 2010 and September 2018 were retrospectively collected. Eighteen baseline demographic and clinical characteristics were used as predictors to train five machine-learning models. The model that showed favorable predictive efficacy was evaluated at annual follow-ups. Multi-point data of the patients in the test set were utilized to further evaluate the model's performance. We also assessed the relative prognostic importance of the selected risk factors for DR outcomes. Results: Of 7943 collected patients, 1692 (21.30%) developed DR during follow-up. Among the five models, the XGBoost model achieved the highest predictive performance with an AUC, accuracy, sensitivity, and specificity of 0.803, 88.9%, 74.0%, and 81.1%, respectively. The XGBoost model's AUCs in the different follow-up periods were 0.834 to 0.966. In addition to the classical risk factors of DR, serum uric acid (SUA), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), estimated glomerular filtration rate (eGFR), and triglyceride (TG) were also identified to be important and strong predictors for the disease. Compared with the clinical diagnosis method of DR, the XGBoost model achieved an average of 2.895 years prior to the first diagnosis. Conclusion: The proposed model achieved high performance in predicting the risk of DR among patients with type 2 diabetes mellitus at each time point. This study established the potential of the XGBoost model to facilitate clinicians in identifying high-risk patients and making type 2 diabetes management-related decisions.

Cross-species single-cell transcriptomic analysis reveals divergence of cell composition and functions in mammalian ileum epithelium.

Animal models are widely used for biomedical studies and drug evaluation. The small intestine plays key roles in nutrient absorption, hormone secretion, microbiota defense and drug absorption and metabolism. Although the intestinal structure of mammals is conserved, the differences on epithelial cell composition, functional assignments and drug absorption among mammals are largely unknown. Here, cross-species analysis of single-cell transcriptomic atlas of the ileum epithelium from mouse, rat, pig, macaque and human reveals the conserved and differential cell types and functions among species, identifies a new CA7+ cell type in pig, macaque and human ileum, uncovers the distinct expression pattern in enterocytes, enteroendocrine cells and Paneth cells, and defines the conserved and species-specific intestinal stem cell signature genes. The examination of drug absorption across species suggests that drug metabolism in mouse ileum is closer to human while drug transport in macaque ileum is more similar to human. Together, our data provide the comprehensive information about cell composition and functional assignments in five species, and offer the valuable guidance for animal model selection and drug testing.

The Intron Retention Variant CsClpP3m Is Involved in Leaf Chlorosis in Some Tea Cultivars.

Tea products made from chlorotic or albino leaves are very popular for their unique flavor. Probing into the molecular mechanisms underlying the chlorotic leaf phenotype is required to better understand the formation of these tea cultivars and aid in future practical breeding. In this study, transcriptional alterations of multiple subunit genes of the caseinolytic protease complex (Clp) in the chlorotic tea cultivar 'Yu-Jin-Xiang' (YJX) were found. Cultivar YJX possessed the intron retention variant of ClpP3, named as CsClpP3m, in addition to the non-mutated ClpP3. The mutated variant results in a truncated protein containing only 166 amino acid residues and lacks the catalytic triad S182-H206-D255. Quantitative analysis of two CsClpP3 variants in different leaves with varying degrees of chlorosis in YJX and analyses of different chlorotic tea cultivars revealed that the transcript ratios of CsClpP3m over CsClpP3 were negatively correlated with leaf chlorophyll contents. The chlorotic young leaf phenotype was also generated in the transgenic tobacco by suppressing ClpP3 using the RNAi method; complementation with non-mutated CsClpP3 rescued the wild-type phenotype, whereas CsClpP3m failed to complement. Taken together, CsClpP3m is involved in leaf chlorosis in YJX and some other tea cultivars in a dose-dependent manner, likely resulting from the failure of Clp complex assembly due to the truncated sequence of CsClpP3m. Our data shed light on the mechanisms controlling leaf chlorosis in tea plants.