FOXO inhibition rescues α-defensin expression in human intestinal organoids.

To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring DEFA5 and DEFA6 to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.

Biochar enhances the growth and physiological characteristics of Medicago sativa, Amaranthus caudatus and Zea mays in saline soils.

Biochar is a promising solution to alleviate the negative impacts of salinity stress on agricultural production. Biochar derived from food waste effect was investigated on three plant species, Medicago sativa, Amaranthus caudatus, and Zea mays, under saline environments. The results showed that biochar improved significantly the height by 30%, fresh weight of shoot by 35% and root by 45% of all three species compared to control (saline soil without biochar adding), as well as enhanced their photosynthetic pigments and enzyme activities in soil. This positive effect varied significantly between the 3 plants highlighting the importance of the plant-biochar interactions. Thus, the application of biochar is a promising solution to enhance the growth, root morphology, and physiological characteristics of plants under salt-induced stress.

Exocrine pancreatic insufficiency after bariatric surgery: a bariatric surgery center of excellence experience.

INTRODUCTION: Gastrointestinal symptoms such as diarrhea, bloating, abdominal pain, and nausea are common after bariatric surgery (BS) and can lead to significant morbidity. While many diagnoses can explain these symptoms, post-bariatric exocrine pancreatic insufficiency (EPI) is becoming increasingly recognized as contributor to gastrointestinal symptoms. The frequency and outcomes of EPI after BS are not well understood. We investigated the prevalence and outcomes of EPI over 18 years at a tertiary bariatric referral center. METHODS: A retrospective review of patients who underwent primary or revisional BS from 2002 to 2020 was performed. Patients were included if they were suspected of having EPI or underwent fecal elastase testing (FE-1). EPI diagnosis was defined as positive FE-1 testing or improvement with empiric pancreatic enzyme replacement therapy (PERT). RESULTS: EPI was suspected in 261 patients, and 190 were tested via FE-1 (89.5%) or empirically treated (10.5%). EPI was diagnosed in 79 (41.6%) patients and was associated with older age and lower BMI. Therapeutic PERT was given to 65 patients diagnosed with EPI, and 56 (86.2%) patients reported improved symptoms. Patients who underwent RYGB and BPD-DS were more likely to have EPI than those after SG (47.9% and 70.0% vs 17.4%, p < 0.01). EPI diagnosis was associated with a history chronic pancreatitis. While diarrhea and abdominal pain were the most common symptoms prompting FE-1 testing, no symptoms were significantly associated with EPI. EPI was also associated with abnormal fecal fat results and treatment with bile acid sequestrants, but not small intestinal bacterial overgrowth. CONCLUSION: This study highlights that exocrine pancreatic insufficiency can account to for previously unexplained GI complaints after bariatric surgery. Therefore, bariatric surgery programs should consider this diagnosis in symptomatic patients, especially following RYGB and BPD-DS. Further work to define patient factors that should prompt evaluation, optimal treatment, and prevention is necessary.

A mathematical model of coronavirus transmission by using the heuristic computing neural networks.

In this study, the nonlinear mathematical model of COVID-19 is investigated by stochastic solver using the scaled conjugate gradient neural networks (SCGNNs). The nonlinear mathematical model of COVID-19 is represented by coupled system of ordinary differential equations and is studied for three different cases of initial conditions with suitable parametric values. This model is studied subject to seven class of human population N(t) and individuals are categorized as: susceptible S(t), exposed E(t), quarantined Q(t), asymptotically diseased IA (t), symptomatic diseased IS (t) and finally the persons removed from COVID-19 and are denoted by R(t). The stochastic numerical computing SCGNNs approach will be used to examine the numerical performance of nonlinear mathematical model of COVID-19. The stochastic SCGNNs approach is based on three factors by using procedure of verification, sample statistics, testing and training. For this purpose, large portion of data is considered, i.e., 70%, 16%, 14% for training, testing and validation, respectively. The efficiency, reliability and authenticity of stochastic numerical SCGNNs approach are analysed graphically in terms of error histograms, mean square error, correlation, regression and finally further endorsed by graphical illustrations for absolute errors in the range of 10-05 to 10-07 for each scenario of the system model.

Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease.

Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S-adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx-j) mouse model of WD corrected higher thioredoxin 1 (TNX1) transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS). Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of TXN1 and peroxiredoxin 1 (Prdx1) were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A WGBS comparison of human WD liver and tx-j mouse liver demonstrated a significant overlap of differentially methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin (TXN) pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on TXN system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.

The Ring-Type E3 Ubiquitin Ligase JUL1 Targets the VQ-Motif Protein JAV1 to Coordinate Jasmonate Signaling.

Jasmonates regulate plant defense and development. In Arabidopsis (Arabidopsis thaliana), JASMONATE-ASSOCIATED VQ-MOTIF GENE1 (JAV1/VQ22) is a repressor of jasmonate-mediated defense responses and is degraded through the ubiquitin-26S proteasome system after herbivory. We found that JAV1-ASSOCIATED UBIQUITIN LIGASE1 (JUL1), a RING-type E3 ubiquitin ligase, interacted with JAV1. JUL1 interacted with JAV1 in the nucleus to ubiquitinate JAV1, leading to proteasomal degradation of JAV1. The transcript levels of JUL1 and JAV1 were coordinately and positively regulated by the CORONATINE INSENSITIVE1-dependent signaling pathway in the jasmonate signaling network, but in a manner that was not dependent on CORONATINE INSENSITIVE1-mediated signaling upon herbivory by Spodoptera litura Gain or loss of function of JUL1 modulated the expression levels of the defensin gene PDF1.2 in leaves, conferring on the plants various defense properties against the generalist herbivore S. litura Because neither the JUL1 mutant nor overexpression lines showed any obvious developmental defects, we concluded that the JAV1/JUL1 system functions as a specific coordinator of reprogramming of plant defense responses. Altogether, our findings offer insight into the mechanisms by which the JAV1/JUL1 system acts specifically to coordinate plant defense responses without interfering with plant development or growth.

Tricalcium silicate cements: osteogenic and angiogenic responses of human bone marrow stem cells.

Tricalcium silicate cements (TSCs) are used in endodontic procedures to promote wound healing and hard tissue formation. The aim of this study was to evaluate and compare the effect of commonly used TSCs [mineral trioxide aggregate (MTA), Biodentine, and TotalFill] on cellular metabolism and osteogenic/angiogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) in vitro. We tested the null hypothesis of no difference between MTA, Biodentine, and TotalFill in stem cell responses. Cells were subjected to eluates of the tested materials for up to 14 d. Cell viability was evaluated using the 3-(4,5-dimethyl-thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Real-time PCR was used to determine the levels of expression of the osteogenic factors alkaline phosphatase (ALP), osteoprotegerin (OPG), osteocalcin (OC), and collagen 1A (COL1A1), and the angiogenic factors vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1). ELISAs were used to measure the levels of VEGFA and ALP in culture supernatants. Mineralization in vitro of hBMSCs was assessed using Alizarin Red staining. The hBMSCs tolerated exposure to TSCs well, with Biodentine showing the most favorable effect on cell viability. Expression of ALP, COL1A1, OPG, and VEGFA were differentially affected by the materials, with Biodentine and TotalFill inducing earlier changes at gene level. Increased mineralization was observed with time, after exposure to all TSCs tested, with MTA showing the greatest effect. The results revealed different responses of hBMSCs to TSCs in vitro.

Body Image & Quality of Life: Changes With Gastric Bypass and Body Contouring.

INTRODUCTION: Bariatric surgery has emerged as an effective method of combating the morbid obesity epidemic. However, the massive weight loss that follows may result in contour changes that can affect body image and quality of life. Our study examines the effects and consequences of bariatric surgery and subsequent body contouring on body image and quality of life. METHODS: Patients were prospectively followed up through their experience with bariatric surgery and subsequent body contouring surgery. Using 2 validated survey instruments, the Multidimensional Body-Self Relations Questionnaire and the Short Form 36 (SF-36), patients completed questionnaires preoperatively and at 6, 12, and 24 months postoperatively. Mean scores were determined by repeated measures analyses of variance F tests. RESULTS: One hundred seventy-five patients were surveyed before bariatric surgery, with noted declines in survey completion at 6, 12, and 24 months. Appearance Evaluation scores improved significantly at all intervals (P = 0.0033), as did Body Area Satisfaction Scale and Appearance Orientation scores (P = 0.0079 and P = 0.044, respectively). While Overweight Preoccupation and Self-Classified Weight scores decreased over time, only the latter was significant (P < 0.0001). The composite SF-36 score for patients awaiting bariatric surgery (54.1%) with postoperative scores at 6 (67.6%,), 12 (at 74.0%), and 24 (76.7%) months being significantly higher (P < 0.0001). The body contouring group consisted of 41 patients who primarily had lower body procedures, with 31 patients surveyed at 6 months and 27 patients at 12 months. For this cohort, Appearance Evaluation and Body Area Satisfaction Scale scores both improved significantly (P = 0.0001 and P = 0.0005, respectively) whereas Appearance Orientation scores declined significantly (P = 0.0055). Both Overweight Preoccupation and Self-Classified Weight scores decreased with only the latter being statistically significant (P = 0.0286). Postoperative SF-36 scores at 6 (72.9%) and 12 (64.5%) months were no different than patients awaiting body contouring (71.3%). CONCLUSIONS: Using 2 validated survey instruments, we show that patients undergoing bariatric surgery have improvements in body image and quality of life. Subsequent postbariatric body contouring surgery results in further improvements in body image. Our findings provide measurable evidence for the value of body contouring after significant weight loss, which may favor greater insurance coverage for this patient population.

Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity.

The extracellular matrix (ECM) plays an important role in the maintenance of white adipose tissue (WAT) architecture and function, and proper ECM remodeling is critical to support WAT malleability to accommodate changes in energy storage needs. Obesity and adipocyte hypertrophy place a strain on the ECM remodeling machinery, which may promote disordered ECM and altered tissue integrity and could promote proinflammatory and cell stress signals. To explore these questions, new methods were developed to quantify omental and subcutaneous WAT tensile strength and WAT collagen content by three-dimensional confocal imaging, using collagen VI knockout mice as a methods validation tool. These methods, combined with comprehensive measurement of WAT ECM proteolytic enzymes, transcript, and blood analyte analyses, were used to identify unique pathophenotypes of metabolic syndrome and type 2 diabetes mellitus in obese women, using multivariate statistical modeling and univariate comparisons with weight-matched healthy obese individuals. In addition to the expected differences in inflammation and glycemic control, approximately 20 ECM-related factors, including omental tensile strength, collagen, and enzyme transcripts, helped discriminate metabolically compromised obesity. This is consistent with the hypothesis that WAT ECM physiology is intimately linked to metabolic health in obese humans, and the studies provide new tools to explore this relationship.

Single-site robotic cholecystectomy in a broadly inclusive patient population: a prospective study.

OBJECTIVES: To describe our initial experience with single-site robotic cholecystectomy (SSRC) and its applicability to a broad segment of patients. BACKGROUND: At the initiation of our study, there were only 3 published reports on SSRC. These initial studies had limited inclusion criteria. We present our experience with the technical aspects and patient outcomes of SSRC in a broadly inclusive patient population. METHODS: Prospective cohort study from January 2012 to January 2013, in which 95 patients underwent SSRC. Procedural times, postoperative complications, delayed hospital discharges, and re-admissions were evaluated. RESULTS: Patients were predominantly female (71.6%) had mean age of 45.2 ± 6.1 years and mean body mass index (BMI) of 30.1 ± 7.1 kg/m. Overall, mean total operative time (TOT) for all patients (n = 95) was 88.63 ± 32.0 (range: 49-220) minutes. SSRC was not completed in 8 (8.42%) patients: 6 conversions to laparoscopy, 1 conversion to open, and 1 aborted case. The group of patients who were able to complete SSRC (n = 87) had a mean TOT of 83.5 ± 24.5 minutes and mean operative robotic time (RT) of 39.6 ± 15.2 minutes. RT was longer in patients with intra-abdominal adhesions (P = 0.0139) and higher BMI (P = 0.03). A minority of patients required hospital admission (11.6%), readmission (6.3%), or reoperation (1.1%). No bile duct injury or death occurred. CONCLUSIONS: SSRC is safe and has a manageable learning curve. Patient factors, such as obesity, did not significantly affect conversion rates or TOTs. SSRC is a promising new technique, which can be offered to a wide array of patients.