The Mechanism of the Gastric Epithelial Stem Cell Response to Metaplastic Injury

Almost nothing is known about the identity of the epithelial stem cell of the gastric corpus, either during normal turnover or in response to injury. Our lab has shown that injection of the selective estrogen receptor modulator tamoxifen leads to near complete atrophy of parietal cells by 3 days and induces expansion of an undifferentiated cell population within the normal stem cell niche in the isthmus of the gastric unit. Here we show that CD44 labels the membranes of such undifferentiated isthmal cells, both in the normal gastric epithelium and when those cells expand fourfold upon injury with tamoxifen. Loss of CD44, either in knockout mice or by blocking its interaction with its ligand, leads to reduced proliferation. We found CD44 regulates proliferation by binding to active STAT3 and occupying the CyclinD1 promoter; accordingly, blocking STAT3 activity completely abrogates atrophy induced proliferation. We screened for signaling kinases potentially responsible for increased CD44 and/or proliferation and found only ERK MAPK was activated during early stages following injury: as few as 6 hours following tamoxifen injection). This burst of ERK activation is localized to non-differentiated cells of the isthmus, and blocking ERK activation with the inhibitor U0126 blocked the expansion of CD44-positive cells. To determine which cytokines induced ERK in progenitor cells, we assayed sera of mice treated with tamoxifen for 6h. Compared to control injected mice, tamoxifen treated mice have a significant increase in the STAT3-inducing cytokine IL-6 levels, correlating with increased F4/80+ macrophages in the gastric mesenchyme. Isolated peritoneal macrophages treated ex vivo with tamoxifen showed significantly increased IL-6 expression, and depletion of bone-marrow derived macrophages in vivo blocks tamoxifen induced metaplasia and increased progenitor cell proliferation. Depletion of macrophages also blocks activation of ERK and expression of the stress signal, iNOS, in parietal cells. Inhibition of iNOS and scavenging of nitric oxide blocks parietal cell atrophy and stem cell expansion. Taken together, our data suggest that CD44 marks a population of undifferentiated epithelial cells within the stem-cell niche of the gastric unit, which greatly expands on injury and is regulated by ERK-MAPK signaling. ERK, in turn, is potentially regulated by cytokines like IL-6 secreted by peritoneal and resident macrophages. Once induced, CD44 associates with pSTAT3 to increase Cyclin D1 expression and consequent stem/progenitor cell proliferation. In conclusion, this thesis identifies a marker and pathway for the presumptive stem cell of the gastric epithelium during response to atrophy and during normal homeostasis

Comprehensive mutations analyses of FTO (fat mass and obesity-associated gene) and their effects on FTO’s substrate binding implicated in obesity

An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity (FTO) gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the FTO gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the FTO gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders

Student's perception: A core indicator in building academia in today's world

Introduction: The perception of students considering their educational environment is a useful source to modify or to improve the quality of education. Whereas the education is a dynamic process, researches about this topic are important to improve education methods and strategies. Equally essential is to know opinion of the students about teachers and educational environment. Aim: The aim of this study is to assess students' perceptions of educational environment using Dundee ready education environment measure (DREEM) among four different health science courses. Materials and Methods: A cross-sectional survey design was conducted on 398 students enrolled in undergraduate health science programs offered at a multispecialty university in Haryana, whose courses consisted of traditional classes and clinical fieldwork. This comprised of students from bachelor degrees in Dental Sciences, Physiotherapy, Nursing, and Allied health sciences. The survey was conducted using a standardized self-report questionnaire DREEM, which is 50-item, close-ended, and scored on 5-point Likert scale. Results: The mean total DREEM score was 77.2 ± 13.07, which according to the interpretation guide was seen to be more positive than negative. More positive results were seen among students of dental sciences (76.7 ± 12.8) and physiotheray (78.06 ± 13.1). Statistical significant difference (P ≤ 0.05) was seen among all the courses in each subscale. Students' perception of teachers and students' self-perception showed statistically nonsignificant results when compared between gender. Conclusion: Students rated their learning environment as positive. This suggests a student-centered approach from the university and may lead to positive outcomes for the students

Varied manifestations of tuberous sclerosis

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disease. The prevalence of TSC is estimated to be 1 in 95,136 in general population and in those <6 years of age, it is 1 in 14,608. It is an autosomal dominant neurocutaenous disease and in about 80% of cases it is caused by a de novo mutation. The relationship between cardiac rhabdomyomas and TSC is well established. The cardiac rhabdomyomas may arise anywhere in the myocardium but are more commonly seen in the left ventricle. However, in our case an interventricular septal rhabdomyoma was seen. Angiomyolipomas (AMLs) occur in up to 80% of patients with TSC. Bilateral renal AMLs were seen in our case. There was evidence of systemic involvement in form of lymphangiomyomatosis and subependymal hamartomas

Evaluation of four-terminal-pair capacitance standards using electrical equivalent circuit model

The reported work has been performed in order to establish the measurement traceability of high frequency capacitance standards at CSIR-NPL. In this context, four-terminal-pair air capacitance standards of Agilent 16380A type with nominal values of 1 pF, 10 pF, 100 pF and 1000 pF have been evaluated at a set of frequencies ranging from 10 kHz to 30 MHz. The evaluation procedure involves the determination of capacitive and inductive residual components of an electrical equivalent circuit model of these standards. The versatile measurement automation program has been developed to control the evaluation procedure and the functionality of the same has been discussed in the paper

Effectiveness of oral health education program using braille text in a group of visually impaired children-before and after comparison trial

CONTEXT: Vision is the most important sense for interpreting the world and when sight is impaired, especially in childhood it can have detrimental effects on one's life. To maintain the oral health status of such group requires special approach. AIM: The aim of this study is to evaluate the impact of Braille text and verbal, oral hygiene instructions on the oral health status of visually impaired children. SETTINGS AND DESIGN: A prospective nonrandomized before and after comparison trial without any control group was conducted among 165 children aged 7–19 years residing in one of the blind schools in Delhi. MATERIALS AND METHODS: A questionnaire was developed to record the source of oral health knowledge and practices. Oral health status of the children was evaluated by recording plaque index (PI) and gingival index (GI) scores at 1, 3, and 5 months intervals. Periodic reinforcement of oral health education was performed with the help of instructions in Braille language. STATISTICAL ANALYSIS: Paired t-test and McNemar tests were used to assess the difference between the scores before and after oral health education. RESULTS: Among completely blind children, the mean difference of PI and GI score from baseline to the last evaluation was found to be 0.56 and 0.28, whereas among partially blind children, it was found to be 0.58 and 0.25, respectively. All the above values were statistically significant (P < 0.001). CONCLUSION: Visually impaired children irrespective of the degree of blindness could maintain an acceptable level of oral hygiene when taught using Braille text for instructions. However, continuous motivation and reinforcement at regular intervals are required for the maintenance of oral health status