Effect of Benzothiazole based conjugates in causing apoptosis by Regulating p53, PTEN and MAP Kinase proteins affecting miR-195a and miR-101-1

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) accounts for majority of liver cancers and is the leading cause of cancer related death in Asia. Like any other cancer, HCC develops when there is a mutation to the cellular machinery that causes the cell to replicate at a higher rate and results in the loss of apoptosis. Therefore, a delicate balance between the expression of various genes involved in proliferation and apoptosis decide the ultimate fate of the cell to undergo rapid proliferation (cancer) or cell death.</p> <p>Results</p> <p>The benzothiazole based compounds exhibited effective cytotoxicity at 4 μM concentration and have shown G1 cell cycle arrest with decrease in levels of G1 cell cycle proteins such as cyclin D1 and Skp2. Involvement of tumour suppressor proteins such as PTEN and p53 was studied. Interestingly these compounds displayed decrease in the phosphorylated forms of AKT, p38 MAPK and ERK1/2 which play a vital role in cell proliferation. Compounds have exhibited strong and significant effect on the expression of micro RNAs such as miR-195a & miR-101-1 which regulate hepatic cell proliferation.</p> <p>Conclusions</p> <p>The cell cycle arrest and apoptotic inducing nature of these compounds was revealed by FACS, BrdU cell proliferation and tunel assays. Compounds affected both tumour suppressor proteins as well as proteins that are involved in active cell proliferation. Micro RNAs whose target is Cyclin D1 such as miR-195a and miR-101-1 that is required for growth of hepatoma cells was drastically affected. These compounds caused apoptosis by activating caspase-3 and PARP.</p

Reactive resource provisioning heuristics for dynamic dataflows on cloud infrastructure

The need for low latency analysis over high-velocity data streams motivates the need for distributed continuous dataflow systems. Contemporary stream processing systems use simple techniques to scale on elastic cloud resources to handle variable data rates. However, application QoS is also impacted by variability in resource performance exhibited by clouds and hence necessitates autonomic methods of provisioning elastic resources to support such applications on cloud infrastructure. We develop the concept of “dynamic dataflows” which utilize alternate tasks as additional control over the dataflow's cost and QoS. Further, we formalize an optimization problem to represent deployment and runtime resource provisioning that allows us to balance the application's QoS, value, and the resource cost. We propose two greedy heuristics, centralized and sharded, based on the variable-sized bin packing algorithm and compare against a Genetic Algorithm (GA) based heuristic that gives a near-optimal solution. A large-scale simulation study, using the linear road benchmark and VM performance traces from the AWS public cloud, shows that while GA-based heuristic provides a better quality schedule, the greedy heuristics are more practical, and can intelligently utilize cloud elasticity to mitigate the effect of variability, both in input data rates and cloud resource performance, to meet the QoS of fast data applications

A multi-ingredient nutritional supplement enhances exercise training-related reductions in markers of systemic inflammation in healthy older men

We evaluated whether twice daily consumption of a multi-ingredient nutritional supplement (SUPP) would reduce systemic inflammatory markers following 6wk of supplementation alone (Phase 1), and the subsequent addition of 12wk exercise training (Phase 2) in healthy older men, in comparison to a carbohydrate-based control (CON). Tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) concentrations were progressively reduced (P-time<0.05) SUPP group. No change in TNF-α or IL-6 concentrations was observed in the CON group

Prevalence and pattern of congenital heart diseases in Karimnagar, Andhra Pradesh, India: diagnosed clinically and by trans-thoracic-two-dimensional echocardiography

Background: To find the prevalence and pattern of congenital heart diseases (CHD) at a Semi-Urban teaching hospital in Karimnagar, Andhra Pradesh, India.Methods: A thorough history, clinical examination and Trans-Thoracic-Two-Dimensional Echocardiography (TTE) was done for all the live birth, children up to 18years of age and patients between 18 to 25 years, who were referred or presented to the Department of Medicine, Chalmeda Anand Rao Institute of Medical Sciences, Bommakal, Karimnagar (AP), over a period of 5 years from July 2008 through June 2013. Those suspected to having a CHD or referred in our department, were further evaluated with: Clinically, Twelve-Lead-Surface Electrocardiography, Chest Radiography and the diagnosis was confirmed by TTE. Trans-Thoracic-Two-Dimensional Echocardiography, M-Mode, Color flow doppler and Spectral doppler echocardiography was done in all patients in the various views.Results: Total 13,554 patients were examined and underwent TTE. Out of 13,554 patients 116 were identified as having congenital heart diseases, thus giving a prevalence of 8.55 per 1,000 live births. Isolated Ventricular septal defect (28.44%), isolated atrial septal defect (18.10%), Patent ductus arteriosus (10.34%), isolated congenital pulmonary stenosis (6.03%) and tetralogy of Fallot’s (6.03%), were the commonest defects observed and confirmed by TTE. TOF was the main cyanotic CHD (6.03%), with the prevalence of 0.51% per 1,000 live births. VSD, ASD and PDA were more prevalent in males. TOF and Complete A.V. Canal defect was prevalent in females. All small size muscular and perimembranous VSD was closed spontaneously. Spontaneous closure rate of 75.00% in Muscular VSD and 52.17% in perimembranous VSD was observed. Spontaneous closure rate of Ostium secundum type ASD was 53.33%. Conclusions: The prevalence of CHD at a tertiary teaching hospital (CAIMS, Bommakal, Karimnagar, AP, India), is 8.55 per 1,000 live births. VSD, ASD, PDA are the most common acyanotic and TOF was the commonest cyanotic congenital heart defects respectively. Non-Invasive Cardiac diagnostic technique (like TTE) plays major in the diagnosis of CHD. When clinical evidences lead to suspicion of congenital heart defect, an echocardiography should be performed immediately.

Digital Therapeutics Care Utilizing Genetic and Gut Microbiome Signals for the Management of Functional Gastrointestinal Disorders: Results From a Preliminary Retrospective Study

Diet and lifestyle-related illnesses including functional gastrointestinal disorders (FGIDs) and obesity are rapidly emerging health issues worldwide. Research has focused on addressing FGIDs via in-person cognitive-behavioral therapies, diet modulation and pharmaceutical intervention. Yet, there is paucity of research reporting on digital therapeutics care delivering weight loss and reduction of FGID symptom severity, and on modeling FGID status and symptom severity reduction including personalized genomic SNPs and gut microbiome signals. Our aim for this study was to assess how effective a digital therapeutics intervention personalized on genomic SNPs and gut microbiome signals was at reducing symptomatology of FGIDs on individuals that successfully lost body weight. We also aimed at modeling FGID status and FGID symptom severity reduction using demographics, genomic SNPs, and gut microbiome variables. This study sought to train a logistic regression model to differentiate the FGID status of subjects enrolled in a digital therapeutics care program using demographic, genetic, and baseline microbiome data. We also trained linear regression models to ascertain changes in FGID symptom severity of subjects at the time of achieving 5% or more of body weight loss compared to baseline. For this we utilized a cohort of 177 adults who reached 5% or more weight loss on the Digbi Health personalized digital care program, who were retrospectively surveyed about changes in symptom severity of their FGIDs and other comorbidities before and after the program. Gut microbiome taxa and demographics were the strongest predictors of FGID status. The digital therapeutics program implemented, reduced the summative severity of symptoms for 89.42% (93/104) of users who reported FGIDs. Reduction in summative FGID symptom severity and IBS symptom severity were best modeled by a mixture of genomic and microbiome predictors, whereas reduction in diarrhea and constipation symptom severity were best modeled by microbiome predictors only. This preliminary retrospective study generated diagnostic models for FGID status as well as therapeutic models for reduction of FGID symptom severity. Moreover, these therapeutic models generate testable hypotheses for associations of a number of biomarkers in the prognosis of FGIDs symptomatology

Aerobic conditioning augments the satellite cell and ribosome response to acute eccentric contractions in young men and women

Satellite cells (SC) and ribosomes are key determinants of the skeletal muscle adaptive response. Both are thought to increase acutely after resistance exercise and chronically with resistance training. However, the acute SC and ribosome exercise response with prior aerobic conditioning is unknown. Fourteen young men and women underwent 6 weeks of single-legged aerobic conditioning followed by an acute bout of 300 eccentric contractions. Muscle biopsies were taken from the vastus lateralis of the aerobically conditioned (AC) and the control (CTL) legs before (Pre), 24 (24h) and 48 (48h) hours post-contractions. SC pool expansion (PAX7+ cells/100 fibres) was greater in type-I (1.3-fold) and mixed-fibres (1.2-fold) in the AC leg compared to the CTL. Pax7 (1.2-fold) and MyoD1 (1.4-fold) mRNA expression was also greater in the AC leg compared to the CTL. AC had greater RNA concentration (1.2-fold) and mRNA expression of Ubf (1.2-fold) and Tif-1a (1.3-fold) compared to CTL. Only the AC leg increased (Pre-48h) c-Myc (3.0-fold), (Pre-24h) 45S pre-rRNA (2.6-fold), 5.8S ITS (2.1-fold) and 28S ITS (2.0-fold) following eccentric contractions. We discovered that aerobic conditioning augmented type-I SC pool expansion and ribosome content following an acute bout of eccentric contractions

Integrated Myofibrillar Protein Synthesis in Recovery From Unaccustomed and Accustomed Resistance Exercise With and Without Multi-ingredient Supplementation in Overweight Older Men

Background: We previously showed that daily consumption of a multi-ingredient nutritional supplement increased lean mass in older men, but did not enhance lean tissue gains during a high-intensity interval training (HIIT) plus resistance exercise training (RET) program. Here, we aimed to determine whether these divergent observations aligned with the myofibrillar protein synthesis (MyoPS) response to acute unaccustomed and accustomed resistance exercise.Methods: A sub-sample of our participants were randomly allocated (n = 15; age: 72 ± 7 years; BMI: 26.9 ± 3.1 kg/m2 [mean ± SD]) to ingest an experimental supplement (SUPP, n = 8: containing whey protein, creatine, vitamin D, and n-3 PUFA) or control beverage (CON, n = 7: 22 g maltodextrin) twice per day for 21 weeks. After 7 weeks of consuming the beverage alone (Phase 1: SUPP/CON only), subjects completed 12 weeks of RET (twice per week) + HIIT (once per week) (Phase 2: SUPP/CON + EX). Orally administered deuterated water was used to measure integrated rates of MyoPS over 48 h following a single session of resistance exercise pre- (unaccustomed) and post-training (accustomed).Results: Following an acute bout of accustomed resistance exercise, 0–24 h MyoPS was 30% higher than rest in the SUPP group (effect size: 0.86); however, in the CON group, 0–24 h MyoPS was 0% higher than rest (effect size: 0.04). Nonetheless, no within or between group changes in MyoPS were statistically significant. When collapsed across group, rates of MyoPS in recovery from acute unaccustomed resistance exercise were positively correlated with training-induced gains in whole body lean mass (r = 0.63, p = 0.01).Conclusion: There were no significant between-group differences in MyoPS pre- or post-training. Integrated rates of MyoPS post-acute exercise in the untrained state were positively correlated with training-induced gains in whole body lean mass. Our finding that supplementation did not alter 0–48 h MyoPS following 12 weeks of training suggests a possible adaptive response to longer-term increased protein intake and warrants further investigation. This study was registered at ClinicalTrials.gov.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT0228133

Age‐related changes to the satellite cell niche are associated with reduced activation following exercise

Skeletal muscle satellite cell (SC) function and responsiveness is regulated, in part, through interactions within the niche, in which they reside. Evidence suggests that structural changes occur in the SC niche as a function of aging. In the present study, we investigated the impact of aging on SC niche properties. Muscle biopsies were obtained from the vastus lateralis of healthy young (YM; 21 ± 1 yr; n = 10) and older men (OM; 68 ± 1 yr; n = 16) at rest. A separate group of OM performed a single bout of resistance exercise and additional muscle biopsies were taken 24 and 48 hours post‐exercise; this was performed before and following 12 wks of combined exercise training (OM‐Ex; 73 ± 1; n = 24). Muscle SC niche measurements were assessed using high resolution immunofluorescent confocal microscopy. Type II SC niche laminin thickness was greater in OM (1.86 ± 0.06 µm) as compared to YM (1.55 ± 0.09 µm, P < .05). The percentage of type II‐associated SC that were completely surrounded by laminin was greater in OM (13.6%±4.2%) as compared to YM (3.5%±1.5%; P < .05). In non‐surrounded SC, the proportion of active MyoD+/Pax7+ SC were higher compared to surrounded SC (P < .05) following a single bout of exercise. This “incarceration” of the SC niche by laminin appears with aging and may inhibit SC activation in response to exercise

Prognostic factors for recovery following acute lateral ankle ligament sprain: a systematic review.

BACKGROUND: One-third of individuals who sustain an acute lateral ankle ligament sprain suffer significant disability due to pain, functional instability, mechanical instability or recurrent sprain after recovery plateaus at 1 to 5 years post injury. The identification of early prognostic factors associated with poor recovery may provide an opportunity for early-targeted intervention and improve outcome. METHODS: We performed a comprehensive search of AMED, EMBASE, Psych Info, CINAHL, SportDiscus, PubMed, CENTRAL, PEDro, OpenGrey, abstracts and conference proceedings from inception to September 2016. Prospective studies investigating the association between baseline prognostic factors and recovery over time were included. Two independent assessors performed the study selection, data extraction and quality assessment of the studies. A narrative synthesis is presented due to inability to meta-analyse results due to clinical and statistical heterogeneity. RESULTS: The search strategy yielded 3396 titles/abstracts after duplicates were removed. Thirty-six full text articles were then assessed, nine of which met the study inclusion criteria. Six were prospective cohorts, and three were secondary analyses of randomised controlled trials. Results are presented for nine studies that presented baseline prognostic factors for recovery after an acute ankle sprain. Age, female gender, swelling, restricted range of motion, limited weight bearing ability, pain (at the medial joint line and on weight-bearing dorsi-flexion at 4 weeks, and pain at rest at 3 months), higher injury severity rating, palpation/stress score, non-inversion mechanism injury, lower self-reported recovery, re-sprain within 3 months, MRI determined number of sprained ligaments, severity and bone bruise were found to be independent predictors of poor recovery. Age was one prognostic factor that demonstrated a consistent association with outcome in three studies, however cautious interpretation is advised. CONCLUSIONS: The associations between prognostic factors and poor recovery after an acute lateral ankle sprain are largely inconclusive. At present, there is insufficient evidence to recommend any factor as an independent predictor of outcome. There is a need for well-conducted prospective cohort studies with adequate sample size and long-term follow-up to provide robust evidence on prognostic factors of recovery following an acute lateral ankle sprain. TRIAL REGISTRATION: Prospero registration: CRD42014014471

A whey protein-based multi-ingredient nutritional supplement stimulates gains in lean body mass and strength in healthy older men: A randomized controlled trial

Protein and other compounds can exert anabolic effects on skeletal muscle, particularly in conjunction with exercise. The objective of this study was to evaluate the efficacy of twice daily consumption of a protein-based, multi-ingredient nutritional supplement to increase strength and lean mass independent of, and in combination with, exercise in healthy older men. Forty-nine healthy older men (age: 73 ± 1 years [mean ± SEM]; BMI: 28.5 ± 1.5 kg/m2) were randomly allocated to 20 weeks of twice daily consumption of either a nutritional supplement (SUPP; n = 25; 30 g whey protein, 2.5 g creatine, 500 IU vitamin D, 400 mg calcium, and 1500 mg n-3 PUFA with 700 mg as eicosapentanoic acid and 445 mg as docosahexanoic acid); or a control (n = 24; CON; 22 g of maltodextrin). The study had two phases. Phase 1 was 6 weeks of SUPP or CON alone. Phase 2 was a 12 week continuation of the SUPP/CON but in combination with exercise: SUPP + EX or CON + EX. Isotonic strength (one repetition maximum [1RM]) and lean body mass (LBM) were the primary outcomes. In Phase 1 only the SUPP group gained strength (Σ1RM, SUPP: +14 ± 4 kg, CON: +3 ± 2 kg, P < 0.001) and lean mass (LBM, +1.2 ± 0.3 kg, CON: -0.1 ± 0.2 kg, P < 0.001). Although both groups gained strength during Phase 2, upon completion of the study upper body strength was greater in the SUPP group compared to the CON group (Σ upper body 1RM: 119 ± 4 vs. 109 ± 5 kg, P = 0.039). We conclude that twice daily consumption of a multi-ingredient nutritional supplement increased muscle strength and lean mass in older men. Increases in strength were enhanced further with exercise training