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Recent discoveries have underscored the cross-talk between intestinal microbes and their hosts. Notably, intestinal microbiota impacts the development, physiological function and social behavior of hosts. This influence usually revolves around the microbiota-gut-brain axis (MGBA). In this review, we firstly outline the impacts of the host on colonization of intestinal microorganisms, and then highlight the influence of intestinal microbiota on hosts focusing on short-chain fatty acid (SCFA) and tryptophan metabolite-mediated MGBA. We also discuss the intervention of intestinal microbial metabolism by dietary supplements, which may provide new strategies for improving the welfare and production of pigs. Overall, we summarize a state-of-the-art theory that gut microbiome affects brain functions via metabolites from dietary macronutrients.

Placental growth factor (PlGF or PGF) is a member of the VEGF (vascular endothelial growth factor) family. It plays a pathological role in inflammation, vascular permeability, and pathological angiogenesis. The molecular signaling by which PlGF mediates its effects in nonproliferative diabetic retinopathy (DR) remains elusive. This study aims to characterize the transcriptome changes of human retinal endothelial cells (HRECs) with the presence and the absence of PlGF signaling. Primary HRECs were treated with the PlGF antibody (ab) to block its activity. The total RNA was isolated and subjected to deep sequencing to quantify the transcripts and their changes in both groups. We performed transcriptome-wide analysis, gene ontology, pathway enrichment, and gene-gene network analyses. The results showed that a total of 3760 genes were significantly differentially expressed and were categorized into cell adhesion molecules, cell junction proteins, chaperone, calcium-binding proteins, and membrane traffic proteins. Functional pathway analyses revealed that the TGF-β pathway, pentose phosphate pathway, and cell adhesion pathway play pivotal roles in the blood-retina barrier (BRB) and antioxidant defense system. Collectively, the data provide new insights into the molecular mechanisms of PlGF’s biological functions in HRECs relevant to DR and diabetic macular edema (DME). The newly identified genes and pathways may act as disease markers and target molecules for therapeutic interventions for the patients with DR and DME refractory to the current anti-VEGF therapy.

We report that placental growth factor (PlGF) negatively affects the endothelial cell (EC) barrier function through a novel regulatory mechanism. The PlGF mAb promotes (but recombinant protein disrupts) EC barrier function, thus affecting the barrier-forming protein levels, membrane distribution, and EC monolayer impedance by the electrical cell-impedance sensing system, Western blot, and immunofluorescence staining. RNA sequencing–based transcriptome analysis identified the up-regulation of the pentose phosphate pathway (PPP) and the antioxidant defense protein by PlGF blockade. The PlGF and PlGF/VEGF dimers (but not VEGF-A) down-regulated the protein expression of glucose-6-phosphate dehydrogenase (G6PD) and peroxiredoxin (PRDX). G6PD inhibition and gene silencing (small interfering RNA) abolished the beneficial effects of PlGF inhibition on EC barrier function and PRDX3/6 protein expression. VEGF receptor (VEGFR)1 or VEGFR2 blockade prevented the inhibitory effect of PlGF on G6PD protein expression and EC barrier function. The PRDX6 played dual roles in EC barrier function through glutathione peroxidase and phospholipase A(2) activity. In sum, PlGF negatively regulates EC barrier function through the activation of VEGFR1 and VEGFR2 and the suppression of the G6PD/PPP and the antioxidant pathways.—Huang, H., Lennikov, A., Saddala, M. S., Gozal, D., Grab, D. J., Khalyfa, A., Fan, L. Placental growth factor negatively regulates endothelial cell barrier function through suppression of glucose-6-phosphate dehydrogenase and antioxidant defense systems.

In traditional medical school curriculum of cancer education in China, there is a very limited amount of teaching about breast cancer. The current situation may result in indifference to breast cancer education among medical students. Case-based learning (CBL) is a popular teaching method based on clinical cases. To date, there are few research reports about the application and research of CBL in breast cancer education. The aim of this study is to explore the teaching effect about CBL combined with lecture-based learning (LBL) in breast cancer education. Questions of breast cancer in National Medical Licensing Examination (NMLE) from 2011 to 2018 were analyzed. The questions about breast cancer were used as the evaluation criteria for this study. In this pilot study, a total of 140 students were randomly divided into a lecture only group (control group) and a lecture plus CBL group (observation group). The students in the observation group had better academic performances and abilities of memory, understanding, and application. They also had higher favorable impressions of the learning experience. In conclusion, more active approaches yield more learning and are viewed more favorably. CBL plus lecture can significantly improve education about breast cancer among medical students, which may be an important message for the evolution of curriculum in Chinese medical schools.

Background Age-related macular degeneration (AMD) is the most common, progressive, and polygenic cause of irreversible visual impairment in the world. The molecular pathogenesis of the primary events of AMD is poorly understood. We have investigated a transcriptome-wide analysis of differential gene expression, single-nucleotide polymorphisms (SNPs), indels, and simple sequence repeats (SSRs) in datasets of the human peripheral retina and RPE-choroid-sclera control and AMD. Methods and results Adaptors and unbiased components were removed and checked to ensure the quality of the data sets. Molecular function, biological process, cellular component, and pathway analyses were performed on differentially expressed genes. Analysis of the gene expression datasets identified 5011 upregulated genes, 11,800 downregulated genes, 42,016 SNPs, 1141 indels, and 6668 SRRs between healthy controls and AMD donor material. Enrichment categories for gene ontology included chemokine activity, cytokine activity, cytokine receptor binding, immune system process, and signal transduction respectively. A functional pathways analysis identified that chemokine receptors bind chemokines, complement cascade genes, and create cytokine signaling in immune system pathway genes (p value

Introduction: O'Donnell-Luria-Rodan syndrome was recently identified as an autosomal dominant systemic disorder caused by variants in KMT2E. It is characterized by global developmental delay, some patients also exhibit autism, seizures, hypotonia, and/or feeding difficulties.Methods: Whole-exome sequencing of family trios were performed for two independent children with unexplained recurrent seizures and developmental delay. Both cases were identified as having de novo variants in KMT2E. We also collected and summarized the clinical data and diagnosed them with O'Donnell-Luria-Rodan syndrome. Structural-prediction programs were used to draw the variants' locations.Results: A 186 G>A synonymous variant [NM_182931.3:exon4: c.186G>A (p.Ala62=)] was found in one family, resulting in alternative splicing acid. A 5417 C>T transition variant [NM_182931.3:exon27: c.5417C>T (p.Pro1806Leu)] was found in another family, resulting in 1806 Pro-to-Leu substitution. Both variants were classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines and verified by Sanger sequencing.Conclusion: To date, three studies of O'Donnell-Luria-Rodan syndrome have been reported with heterogeneous clinical manifestations. As a newly recognized inherited systemic disorder, O'Donnell-Luria-Rodan syndrome needs to be paid more attention, especially in gene testing.

To evaluate the diagnostic performance of fractional flow reserve (FFR) derived from coronary computed tomography angiography (CCTA; CT-FFR) and combined plaque characteristics for ischemia in different CCTA stenosis levels.This clinical trial analyzed 317 patients with 30 %-90 % coronary stenosis in 366 vessels from 5 centers undergoing CCTA and invasive FFR. 366 vessels were assigned into50 % (nonobstructive) and ≥ 50 % (obstructive) stenosis groups. Lesion length (LL), plaque burden (PB), diameter stenosis (DS), volume ratio of plaque subcomponents30 HU (VR 30HU), and high-risk features were analyzed. Logistic regression models were used to identify plaque characteristic predictors for lesion-specific ischemia in different stenosis grades. The area under receiver operating characteristics curve (AUC) of integrated plaque characteristics and CT-FFR were calculated and compared.In50 % stenosis lesions, PB (OR: 1.296, p = 0.002), LL (OR:1.075, p = 0.020), and DS (OR:1.085, p = 0.031) were independent predictors of ischemia. In ≥ 50 % stenosis lesions, VR 30HU (OR:1.031, p = 0.005) and DS (OR: 1.020, p = 0.044) were independent predictors for ischemia. AUC of plaque characteristic (VR30HU plus DS) for ischemia was 0.67 (95 % CI: 0.61-0.72) in ≥ 50 % stenosis level, which was significantly lower than CT-FFR (AUC=0.90; 95 % CI: 0.86-0.93) (p 0.001). For lesions causing50 % stenosis, AUC of combined plaque model (VR30HU plus DS) was 0.88 (95 % CI: 0.80-0.95), equivalent to AUC of CT-FFR (AUC = 0.88; 95 % CI: 0.80-0.96; p = 0.957).CT-FFR is a powerful functional assessment tool for both obstructive and nonobstructive diseases. However, for nonobstructive CAD confirmed by CCTA, a model of a combination of plaque characteristics could be a valuable alternative to CT-FFR.

The digestion ability of pigs to dietary fiber is derived from their intestinal microbiota, especially hindgut microbiota. However, tolerance of pigs to high dietary fiber and the changes of microbiota profile with fiber levels are still unclear. To investigate the changes of gut microbiota with dietary fiber and its relationship with fiber digestibility, we conducted comparative analyses of growth rate, apparent fiber digestibility, gut microbiota and volatile fatty acid (VFA) profiles in Chinese Suhuai pigs feeding diets with different defatted rice bran (DFRB) fiber levels. We found that dietary fiber level had no effect on the growth rate of Suhuai pigs. Although the apparent digestibility of Cellulose, insoluble dietary fiber (IDF) and total dietary fiber (TDF) decreased with dietary fiber level, we found that the apparent digestibility of Cellulose, IDF and TDF of Suhuai pigs was not changed when provided with diet containing 19.10% TDF (as feed basis). The pigs provided with diet containing 19.10% TDF had higher microbial richness, proportions of several fiber-degrading bacteria taxa at genus level and predicted microbial functions (such as carbohydrate metabolism, energy metabolism) in cecum compared to those fed with basal diet. In addition, the fiber-induced increasing of fiber-degrading bacteria promoted the VFAs metabolism, which potentially helped Suhuai pigs to maintain growth rate. However, as TDF reached to 24.11% (as feed basis), the apparent digestibility of fiber decreased and the positive effect on intestine microbiota in caecum were absent. Together, our data suggest that appropriate fiber level could increase the diversity and metabolic capacity of distal gut microbiota to improve the utilization efficiency of fiber resources without altering the growth rate of pigs.

Background Virulence factors of Helicobacter pylori including cagA, vacA, iceA and their association with clinical manifestation varied widely with different subpopulations. The objective of the study was to determine the prevalence of cagA, iceA1, iceA2, vacA, vacA s1/s2, vacA m1/m2, Western type cagA and East Asian type cagA virulence genes in H. pylori isolated from gastric ulcer patients and evaluate the association of these genes with gender, age, smoking and alcohol consumption. Methods Gastric biopsy samples from 172 patients were collected. H. pylori virulence genes, cagA, vacA, iceA1, iceA2, vacA s1/s2, vacA m1/m2, Western type cagA and East Asian type cagA were detected using polymerase chain reaction (PCR). Results Of the gastric biopsy samples collected, 48.3% of samples grew H. pylori. The vacA (68.7%) was the predominant virulence gene detected and associated with male patients and patients within the age group of 31–40 years. The cagA was the second most common gene detected and significantly associated with alcoholic patients. Conclusions H. pylori infection rate was 48.3% and was associated with patients who were smokers or had a history of smoking. The majority of our isolates were positive for any one of the virulence genes tested indicating that these isolates were highly virulent in nature.

Background: The inflammatory milieu in the liver as determined by histopathology is different in individual patients undergoing autologous islet cell transplantation. We hypothesized that inflammation related to fatty-liver adversely impacts islet survival. To test this hypothesis, we used a mouse model of fatty-liver to determine the outcome of syngeneic islet transplantation after chemical pancreatectomy. Methods: Mice (C57BL/6) were fed a high-fat-diet from 6 weeks of age until attaining a weight of ≥28 grams (6–8 weeks) to produce a fatty liver (histologically > 30% fat);steatosis was confirmed with lipidomic profile of liver tissue. Islets were infused via the intra-portal route in fatty-liver and control mice after streptozotocin induction of diabetes. Outcomes were assessed by the rate of euglycemia, liver histopathology, evaluation of liver inflammation by measuring tissue cytokines IL-1β and TNF-α by RT-PCR and CD31 expression by immunohistochemistry. Results: The difference in the euglycemic fraction between the normal liver group (90%, 9/10) and the fatty-liver group (37.5%, 3/8) was statistically significant at the 18th day post- transplant and was maintained to the end of the study (day 28) (p = 0.019, X2 = 5.51). Levels of TNF–α and IL-1β were elevated in fatty-liver mice (p = 0.042, p = 0.037). Compared to controls cytokine levels were elevated after islet cell transplantation and in transplanted fatty-liver mice as compared to either fatty- or islet transplant group alone (p = NS). A difference in the histochemical pattern of CD31 could not be determined. Conclusion: Fatty-liver creates an inflammatory state which adversely affects the outcome of autologous islet cell transplantation.

Background Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare urea cycle disorder. The aim of this study was to present the clinical findings, management, biochemical data, molecular genetic analysis, and short‐term prognosis of five children with CPS1D. Methods The information of five CPS1D patients was retrospectively studied. We used targeted next‐generation sequencing to identify carbamoyl phosphate synthetase 1 (CPS1) variants in patients suspected to have CPS1D. Candidate mutations were validated by Sanger sequencing. In silico and structure analyses were processed for the pathogenicity predictions of the identified mutations. Results The patients had typically clinical manifestations and biochemical data of CPS1D. Genetic analysis revealed nine mutations in the CPS1 gene, including recurrence of c.1145C > T, five of which were firstly reported. Seven mutations were missense changes, while the remaining two were predicted to create premature stop codons. In silico and structure analyses showed that these genetic lesions were predicted to affect the function or stability of the enzyme. Conclusion We reported five cases of CPS1D. Five novel mutations of CPS1 gene were found. Mutations of CPS1 have private nature, and most of them are missense compound heterozygous. The mutation affecting residue predicted to interfere the catalytic sites, the internal tunnel, or the regulatory domain results in severe phenotype.

Placental growth factor (PlGF or PGF) is a member of the VEGF family, which is known to play a critical role in pathological angiogenesis, inflammation, and endothelial cell barrier function. However, the molecular mechanisms by which PlGF mediates its effects in non-proliferative diabetic retinopathy (DR) remain elusive. In this study, we performed transcriptome-wide profiling of differential gene expression for human retinal endothelial cells (HRECs) treated with PlGF antibody. The effect of antibody treatment on the samples was validated using trans-endothelial electric resistance (TEER), and western blot. A total of 3760 genes (1750 upregulated and 2010 downregulated) were found to be differentially expressed between the control and PlGF antibody treatment group. These differentially expressed genes (DEGs) were used for gene ontology and enrichment analysis to identify gene function, signal pathway, and interaction networks. The gene ontology results revealed that catalytic activity (GO:0003824) of molecular function, cell (GO:0005623) of the cellular component, and cellular process (GO:0009987) were among the most enriched biological processes. Pathways such as TGF-β, VEGF-VEGFR2, p53, apoptosis, pentose phosphate pathway, and ubiquitin-proteasome pathway, were among the most enriched, and TGF-β1 was identified as a primary upstream regulator. These data provide new insights into the underlying molecular mechanisms of PlGF in mediating biological functions, in relation to DR.

The present cross-sectional study aimed to assess hepatic fibrosis in chronic hepatitis B (CHB) patients with abdominal obesity and to explore the associated indicators. A total of 615 CHB patients were enrolled and 287 of them had abdominal obesity. The liver stiffness value was measured using Fibroscan. The diagnosis of liver fibrosis was confirmed by a liver stiffness value of >7.4 kPa, and a value of >10.6 kPa was considered to indicate advanced liver fibrosis. The Fibroscan results suggested that the liver stiffness value in patients with abdominal obesity was significantly higher than that in patients without abdominal obesity (9.94±11.59 vs. 7.47±7.58 kPa; P=0.002). The proportions of patients with liver fibrosis and advanced liver fibrosis among patients with abdominal obesity were significantly higher than those among patients without abdominal obesity (P=0.011). Multivariate logistic regression analysis indicated that a high aspartate aminotransferase (AST) level [odds ratio (OR)=2.991; P

Ovate Family Protein1 (OFP1) is a regulator, and it is suspected to be involved in plant growth and development. Meanwhile, Arabidopsis Thaliana Homeobox (ATH1), a BEL1-like homeodomain (HD) transcription factor, is known to be involved in regulating stem growth, flowering time and flower basal boundary development in Arabidopsis. Previous large-scale yeast two-hybrid studies suggest that ATH1 possibly interact with OFP1, but this interaction is yet unverified. In our study, the interaction of OFP1 with ATH1 was verified using a directional yeast two-hybrid system and bimolecular fluorescence complementation (BiFC). Our results also demonstrated that the OFP1-ATH1 interaction is mainly controlled by the HD domain of ATH1. Meanwhile, we found that ATH1 plays the role of transcriptional repressor to regulate plant development and that OFP1 can enhance ATH1 repression function. Regardless of the mechanism, a putative functional role of ATH1-OFP1 may be to regulate the expression of the both the GA20ox1 gene, which is involved in gibberellin (GA) biosynthesis and control of stem elongation, and the Flowering Locus C (FLC) gene, which inhibits transition to flowering. Ultimately, the regulatory functional mechanism of OFP1-ATH1 may be complicated and diverse according to our results, and this work lays groundwork for further understanding of a unique and important protein&ndash, protein interaction that influences flowering time, stem development, and flower basal boundary development in plants.

Gastric cancer has high incidence and mortality, and the mortality ranks second only to lung cancer. Downregulation of miR-133a has been observed in certain types of tumors, and it is involved in gastric cancer. The aim of the present study was to explore the molecular mechanisms of miR-133a and ubiquitin-specific protease 39 (USP39) in gastric cancer. Western blot analysis and RT-PCR were employed to measure miR-133a and USP39 expression. To confirm whether miR-133a targeted USP39, we conducted a luciferase reporter assay. We utilized 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay to detect the effects of miR-133a on gastric cell proliferation. miR-133a was significantly downregulated in cancer tissues and cell lines (HGC-27 and MGC-803), while the expression level of USP39 was higher in tumor tissues than in paracancerous tissues. Upregulated expression of miR-133a and/or USP39 downregulation could inhibit cell proliferation in gastric cancer cells. Furthermore, USP39 was identified as a direct target of miR-133a and the inverse relationship between them was also observed. USP39 was a firsthand target of miR-133a and there was a negative correlation between them. In addition, a low expression of miR-133a or overexpression of USP39 predicted poor prognosis. In conclusion, miR-133a may be a novel therapeutic target of microRNA-mediated suppression of cell proliferation in CC, but the role of the miR-133a/USP39 axis in CC progression needs further study.

Male breast cancer (MBC) is uncommon in clinical practice. Using the 21-gene assay to facilitate decision-making on comprehensive treatment of MBC is rarely reported. This study reports the case of a 53-year-old man with left breast cancer. Modified radical mastectomy was performed. Endocrine treatment was chosen for the patient according to the result of the 21-gene assay, a recommended genomic test of breast cancer. The patient remained in good health without evidence of recurrence at 18-month follow-up. This case provides a reference mode for the comprehensive management of early-stage, estrogen receptor-expressing and lymph node-negative MBC patients.

Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P