Obesity-induces Organ and Tissue Specific Tight Junction Restructuring and Barrier Deregulation by Claudin Switching

Obesity increases susceptibility to multiple organ disorders, however, underlying mechanisms remain unclear. The subclinical inflammation assisted by obesity-induced gut permeability may underlie obesity-associated co-morbidities. Despite eminent clinical significance of the obesity led gut barrier abnormalities, its precise molecular regulation remains unclear. It is also unknown whether barrier deregulations, similar to the gut, characterize other vital organs in obese individuals. The claudin family of proteins is integral to the tight junction (TJ), the apical cell-cell adhesion and a key regulator of the epithelial barrier. Using comprehensive physiological and biochemical analysis of intestinal and renal tissues from high-fat diet fed mice, critical for maintaining metabolic homeostasis, this study demonstrates that profound TJ-restructuring by organ and tissue-specific claudin switching characterize obese organs. Protein expression and cellular distribution were examined. In-silico analysis further highlighted potential association of select claudins, modulated by the obesity, with signaling and metabolic pathways of pathological significance. In vitro studies using Leptin or DCA-treatment suggested causal significance of obesity-induced changes in tissue microenvironment in regulating barrier deregulations in tissue-specific manner. Overall, current findings advances our understanding of the molecular undertakings of obesity associated changes that help predispose to specific diseases and also identifies novel windows of preventive and/or therapeutic interventions

Ultraviolet radiation-induced tumor necrosis factor alpha, which is linked to the development of cutaneous SCC, modulates differential epidermal microRNAs expression

Chronic exposure to ultraviolet radiation (UVR) is linked to the development of cutaneous squamous cell carcinoma (SCC), a non-melanoma form of skin cancer that can metastasize. Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, is linked to UVR-induced development of SCC. To find clues about the mechanisms by which TNFα may promote UVR-induced development of SCC, we investigated changes in the expression profiling of microRNAs (miRNA), a novel class of short noncoding RNAs, which affects translation and stability of mRNAs. In this experiment, TNFα knockout (TNFα KO) mice and their wild type (WT) littermates were exposed to acute UVR (2.0 kJ/m2) and the expression profiling of epidermal miRNA was determined 4hr post UVR exposure. TNFα deletion in untreated WT mice resulted in differential expression (log fold change\u3e1) of seventeen miRNA. UVR exposure in WT mice induced differential expression of 22 miRNA. However, UVR exposure in TNFα KO mice altered only two miRNAs. Four miRNA, were differentially expressed between WT+UVR and TNFα KO+UVR groups. Differentially expressed selected miRNAs were further validated using real time PCR. Few of the differentially expressed miRNAs (miR-31-5p, miR-196a-5p, miR-127-3p, miR-206-3p, miR-411-5p, miR-709, and miR-322-5p) were also observed in UVR-induced SCC. Finally, bio-informatics analysis using DIANA, MIRANDA, Target Scan, and miRDB algorithms revealed a link with major UVR-induced pathways (MAPK, PI3K-Akt, transcriptional mis-regulation, Wnt, and TGF-beta)

Tissue-specific conditional PKCε knockout mice: a model to precisely reveal PKCε functional role in initiation, promotion and progression of cancer

PKCε is a transforming oncogene and a predictive biomarker of various human cancers. However, a precise in vivo link of PKCε to cancer induction, progression and metastasis remain undefined. To achieve these goals, we generated tissue specific conditional PKCε knockout mice (PKCε-CKO) using cre-lox technology. Homozygous PKCεLoxP/LoxP mice have normal body weight and phenotype. To determine what effect loss of PKCε would have on the prostate, the PKCεLoxP/LoxP mice were bred to probasin cre (PB-Cre4+) mice which express cre specifically in the prostate epithelium of postnatal mice. Western blot and immunohistochemical analyses showed reduced levels of PKCε specifically in the prostate of PKCε-CKO mice. Histopathological analyses of prostate from both PKCεLoxP/LoxP and prostate PKCε-CKO mice showed normal pathology. To determine the functional impact of prostate specific deletion of PKCε on prostate tumor growth, we performed an orthotopic xenograft study. Transgenic adenocarcinoma of the mouse prostate (TRAMP) cells (TRAMPC1, 2×106) were implanted in the prostate of PKCε-CKO mice. Mice were sacrificed at 6th week post-implantation. Results demonstrated a significant (P\u3c0.05) decrease in the growth of TRAMPC1 cells-derived xenograft tumors in PKCε-CKO mice compared to wild type. To determine a link of PKCε to ultraviolet radiation (UVR) exposure-induced epidermal Stat3 phosphorylation, PKCεLoxP/LoxP mice were bred to tamoxifen-inducible K14 Cre mice. PKCε deletion in the epidermis resulted in inhibition of UVR-induced Stat3 phosphorylation. In summary, our novel PKCεLoxP/LoxP mice will be useful for defining the link of PKCε to various cancers in specific organ, tissue, or cells

Reproductive biology of Withania ashwagandha sp. novo (Solanaceae)

Withania ashwagandha Kaul (Solanaceae) is an annual plant species of immense medicinal importance. It is a repository of a large number of pharmacologically active secondary metabolites known as withanolides. Evidence for the delimitation of the species from W. somnifera has been provided by our group using multidisciplinary approaches. Knowledge of reproductive biology of medicinal plants is crucial for improvement, effective conservation and management plans to evolve genetically superior varieties. The present paper reports our findings on the floral biology, pollination behavior and breeding system of W. ashwagandha in natural populations grown at our experimental field under near natural conditions. Flowering (peak) takes place during April–July and anthesis occurs between 08:00 and 11:00 h. The period of stigma receptivity coincides with anther dehiscence. Fruit set on pollination treatments ranged from 90.8% (passive autogamy), 72% (assisted autogamy), 30.30% (xenogamy), and 56.50% (geitonogamy) through 50.40% (open pollination). Xenogamy brings about very low fruit set, seed-set and seed germination percentages. It is inferred that W. ashwagandha is predominantly an autogamous and self-compatible species. Self-compatibility is mainly accomplished due to close proximity of stigma and anthers. This work is the first report on the reproductive biology of W. ashwagandha and will be useful for conservation and development of improved varieties of this multipurpose herb.The author acknowledge the University of Pretoria for providing Vice-Chancellors Post Doctoral Fellowship.http://www.elsevier.com/locate/indcrophb201

Innføring av standardiserte evidensbaserte rettningslinjer for behandling av fibromyalgi i allmennpraksis

Bakgrunn/emne: Norge er det landet i verden med høyest forekomst av fibromyalgi i forhold til befolkningen. Det finnes ikke standardiserte oppdaterte evidensbaserte retningslinjer for behandling av fibromyalgi i allmennpraksis i Norge. Studier har vist at systematisk bruk av evidensbaserte retningslinjer for behandling av fibromyalgi kan redusere pasientenes plager, legenes frustrasjoner og samfunnets utgifter. Kunnskapsgrunnlag: Vi har gått gjennom evidensbasert litteratur på feltet, plukket ut de studiene vi anså som viktigst og fått ekspertuttalelse av overlege dr. Wigers ved Jeløya kurbad. Vi fant evidens for følgende tiltak: Informasjon/ undervisning, kondisjonstrening, kognitiv atferdsterapi, flerdimensjonal rehabilitering, lav kveldsdose TCA, Tramadol ved behov. Begrunnet tiltak og metode: Implementere en sjekkliste i allmennpraksis som inneholder hva som er evidensbasert kunnskap om behandling av fibromyalgipasienter, og hvilke tiltak som ikke er evidensbaserte. Slik får allmennpraktikeren et standardisert opplegg å følge for hver fibromyalgipasient. Vi evaluerer prosjektet ved hjelp av et skåringsskjema som besvares av allmennlegene. Indikator er andelen fastleger som gjennomfører våre tiltak, som igjen er et indirekte mål på forbedringen i håndtering av fibromyalgipasienter. Organisering: Fase 1: Forberede: Vi har funnet evidens i kunskapsgrunnlaget for at standardiserte retningslinjer kan bedre praksis for allmennlegenes håndtering av fibromyalgipasienter. Allmennleger og spesialist vi har vært i kontakt med har bekreftet et behov for slike retningslinjer. Fase 2: Planlegge: Vi ønsker å innføre en sjekkliste som tiltak og benytte et skåringsskjema for evaluering av tiltaket. Indikatoren vår er hvor stor andel av allmenpraktikerne som som etter en tid fortsatt benytter sjekklisten. Fase 3: Utføre: Informasjon om effekt av sjekklisten og distribusjon av den. Fase 4: Kontrollere: Evaluere bruken av sjekklisten ved hjelp av et skåringsskjema og benytte indikator som mål på resultat. Fase 5: Standardisere og følge opp: Følge opp allmenpraksisene i henhold til evalueringene. Resultater /Vurdering: Vi mener det er et behov for tiltaket. Det lar seg gjennomføres på en kostnadseffektiv måte og det vil ha konsekvenser for et stort antall pasienter og allmennleger. Kvalitetsforbedringstiltaket bør utføres

Effect of Different Levels of Phosphorus and Sulphur on Seed & Stover Yield of Soybean (Glycine max L. Merill) under 'Eutrochrepts'

A field experiment was conducted at KVK, Srinagar during two consecutive kharif seasons of 2010 and 2011 to study the “Effect of phosphorus and sulphur on yield and quality of soybean (Glycine max L. Merill) under Eutrochrepts”. The experiment was laid down under 16 treatment combinations viz four levels of phosphorus (0, 30, 60, 90 kg P2O5 ha-1) and four levels of sulphur (0,15, 30, 45 kg S ha-1) in randomized complete block design with three replications .The soil of the experimental site was typic Eutrochrepts, silty clay loam in texture having pH 7.18, EC 0.18 dSm-1, organic carbon 0.74 per cent, available N, P, K 250.52, 11.45, 120.62, kg ha-1, respectively. Soil was sufficient in available Fe, Cu, Mn and deficient in available Zn and sulphur. Total and organic phosphorus content in soil was 345 and 173 ppm, respectively while as total and organic sulphur content was 232 and 162 ppm, respectively. Both seed and stover yield of soybean increased significantly due to individual as well as combined application of phosphorus and sulphur. Combined application of 45 kg S with 90 kg P2O5 produced highest seed (24.39 q ha-1) and stover (43.51 q ha-1) yield of soybean. Application of increasing levels of both phosphorus and sulphur resulted in a significant increase in macro and micronutrient content of soybean seed. With application of 90 kg P2O5 ha-1, maximum nutrient content of N, P, K, Ca, Mg and S in seed was 6.42, 0.56, 1.876, 0.324 0.440, 0.466 per cent, respectively while as Fe, Cu, Mn was 100.01, 2.86 and 3.74 mg kg-1, respectively

On energy consumption of switch-centric data center networks

Data center network (DCN) is the core of cloud computing and accounts for 40% energy spend when compared to cooling system, power distribution and conversion of the whole data center (DC) facility. It is essential to reduce the energy consumption of DCN to esnure energy-efficient (green) data center can be achieved. An analysis of DC performance and efficiency emphasizing the effect of bandwidth provisioning and throughput on energy proportionality of two most common switch-centric DCN topologies: three-tier (3T) and fat tree (FT) based on the amount of actual energy that is turned into computing power are presented. Energy consumption of switch-centric DCNs by realistic simulations is analyzed using GreenCloud simulator. Power related metrics were derived and adapted for the information technology equipment (ITE) processes within the DCN. These metrics are acknowledged as subset of the major metrics of power usage effectiveness (PUE) and data center infrastructure efficiency (DCIE), known to DCs. This study suggests that despite in overall FT consumes more energy, it spends less energy for transmission of a single bit of information, outperforming 3T

A Reconsideration of the Diagnosis and Management of Gastrointestinal Bleeding Based on its Epidemiology and Outcomes Analysis

Background: Traditionally, gastrointestinal bleeding (GIB) has been divided into upper and lower GIB with little consideration of the small bowel as a source. Furthermore, melena is generally included in the upper category, despite its poor localization value. We analyzed 341 consecutive GIB patients to see if those presenting with melena/hematocheiza have less efficient evaluations then when compared to those presenting with hematemesis. Methods: A retrospective analysis was performed for 341 consecutive patients admitted to our ED with GIB over a year. Cohorts were separated based on presenting symptom to the ED, hematemesis (G1) and non-hematemesis (G2). Data obtained included demographics, diagnosis, number and type of procedure, diagnostic yield of each procedure, hours to diagnosis, ICU days, and total hospital days. Results: G1 (n=105, 62%M) was younger than G2 (n=231, 53%M) with a mean age of 54 vs. 66, p≤0.001. 78% and 98% of patients were admitted to the hospital in G1 and G2 respectively (p=0.02). Median time to diagnosis was 14.0 hours and 20.0 hours for G1 and G2 respectively (p≤0.001). Median number of days in the ICU was 3.0 in both groups, and median number of hospital days was 3.0 for G1 vs. 4.0 for G2 (p=0.267). In G1, the 1st procedure was diagnostic 69% of the time vs 54% for G2 (p=0.07). The overall diagnostic yield for EGDs in G1 was 58% vs. 51% in G2 (p=0.279). Colonoscopies overall were diagnostic 39% of the time in G2 and, interestingly, VCEs were the most diagnostic, yielding a diagnosis 74% of the time in G2 (n= 34). Unexpectedly, those admitted in G1 had a confirmed diagnosis only 61% of the time compared to 62% in G2. Conclusion: Our data suggests that a portion of patients presenting with non-hematemesis (G2) are inefficiently managed and a search for an alternative strategy is warranted. Early deployment of VCE may be a more efficient and economic option, although prospective evaluation of this concept is needed

A triphenylethylene nonsteroidal SERM attenuates cervical cancer growth

Selective estrogen receptor modulator drug molecules of triphenylethylene family have gained considerable attention as anti-cancer agents. Despite recent advances in screening and development of HPV vaccines, cervical cancer remains one of the deadliest malignancies as advanced stage metastatic disease is mostly untreatable, thus warrants newer therapeutic strategies. Ormeloxifene (ORM) is a well-known SERM of triphenylethylene family that has been approved for human use, thus represents an ideal molecule for repurposing. In this study, we for the first time have demonstrated the anti-cancerous properties of ormeloxifene in cervical cancer. Ormeloxifene efficiently attenuated tumorigenic and metastatic properties of cervical cancer cells via arresting cell cycle at G1-S transition, inducing apoptosis, decreasing PI3K and Akt phosphorylation, mitochondrial membrane potential, and modulating G1-S transition related proteins (p21, cyclin E and Cdk2). Moreover, ORM repressed the expression of HPV E6/ E7 oncoproteins and restored the expression of their downstream target tumor suppressor proteins (p53, Rb and PTPN 13). As a result, ormeloxifene induces radio-sensitization in cervical cancer cells and caused potent tumor growth inhibition in orthotopic mouse model. Taken together, ormeloxifene represents an alternative therapeutic modality for cervical cancer which may have rapid clinical translation as it is already proven safe for human use

Real time endobronchial ultrasound guided transbronchial needle aspiration of intrathoracic lymphadenopathy: an initial experience

Background: Conventional TBNA has been used in the evaluation of intrathoracic lymphadenopathy with varied success rates depending upon size, site and aetiology of the node. Although mediastinoscopy has higher successes but it comes at the cost of general anaesthesia, more complications and limited access to the inferior and posterior mediastinum. Endobronchial ultrasound guided transbronchial needle aspiration has the advantage of real time nodal sampling with good success rates and minimal complications. The aim of our study was to assess the diagnostic yield and safety of EBUS TBNA in the evaluation of intrathoracic lymphadenopathy.Methods: This prospective observational study was conducted at government chest diseases hospital Srinagar over a period of two years from January 2016-December 2018 on 100 consecutive patients who underwent EBUS TBNA procedure for evaluation mediastinal and hilar lymphadenopathy. The data was collected and analysed for diagnostic yield and safety profile.Results: Out of the 100 subjects included in the study 52% were males and 48% were females. Mean age of the study population was 48.5±16.65 years. Most of the nodes sampled were subcarinal in location followed by paratracheal and hilar group. Granulomatous pathology (tuberculosis and sarcoidosis) was present in 41 patients followed by malignancy in 39 patients. Anthracosis was the cause of lymphadenopathy in 4 of the patients. There were no major complications in our study.Conclusions: EBUS TBNA is an effective and safe procedure for evaluation of mediastinal and hilar lymphadenopathy