The miR-17-92 cluster: Yin and Yang in human cancers.

MicroRNAs (miRNAs) are non-coding RNAs which modulate gene expression via multiple post-transcriptional mechanisms. They are involved in a variety of biological processes, including cell proliferation, metastasis, metabolism, tumorigenesis, and apoptosis. Dysregulation of miRNA expression has been implicated in human cancers, and they may also serve as biomarkers of disease progression and prognosis. The miR-17-92 cluster is one of the most widely studied miRNA clusters, which was initially reported as an oncogene, but was later reported to exhibit tumour suppressive effects in some human cancers. This review summarizes the recent progress and context-dependant role of this cluster in various cancers. We summarize the known mechanisms which regulate miR-17-92 expression and molecular pathways that are in turn controlled by it. We discuss examples where it acts as an oncogene or a tumour suppressor along with key targets affecting hallmarks of cancer. We discuss how cellular contexts regulate the biological effects of miR-17-92. The plausible mechanisms of its paradoxical roles are explained, and mechanisms are described that may contribute to cell fate regulation by miR-17-92. Further, we discuss recently developed strategies to target miR-17-92 cluster in human cancers. MiR-17-92 may serve as a potential biomarker for prognosis and response to therapy as well as a target for cancer prevention and therapeutics.

Metagenomic Insights into Rhizospheric Microbiome Profiling in Lentil Cultivars Unveils Differential Microbial Nitrogen and Phosphorus Metabolism under Rice-Fallow Ecology.

The plant rhizosphere interfaces an array of microbiomes related to plant growth and development. Cultivar-specific soil microbial communities with respect to their taxonomic structure and specific function have not been investigated explicitly in improving the adaptation of lentil cultivars under rice-fallow ecology. The present study was carried out to decipher the rhizosphere microbiome assembly of two lentil cultivars under rice-fallow ecology for discerning the diversity of microbial communities and for predicting the function of microbiome genes related to nitrogen (N) and phosphorus (P) cycling processes deploying high-throughput whole (meta) genome sequencing. The metagenome profile of two cultivars detected variable microbiome composition with discrete metabolic activity. Cyanobacteria, Bacteroidetes, Proteobacteria, Gemmatimonadetes, and Thaumarchaeota were abundant phyla in the "Farmer-2" rhizosphere, whereas Actinobacteria, Acidobacteria, Firmicutes, Planctomycetes, Chloroflexi, and some incompletely described procaryotes of the "Candidatus" category were found to be robustly enriched the rhizosphere of "Moitree". Functional prediction profiles of the microbial metagenomes between two cultivars revealed mostly house keeping genes with general metabolism. Additionally, the rhizosphere of "Moitree" had a high abundance of genes related to denitrification processes. Significant difference was observed regarding P cycling genes between the cultivars. "Moitree" with a profuse root system exhibited better N fixation and translocation ability due to a good "foraging strategy" for improving acquisition of native P under the nutrient depleted rice-fallow ecology. However, "Farmer-2" revealed a better "mining strategy" for enhancing P solubilization and further transportation to sinks. This study warrants comprehensive research for explaining the role of microbiome diversity and cultivar-microbe interactions towards stimulating microbiome-derived soil reactions regarding nutrient availability under rice-fallow ecology.

S-allyl cysteine: A potential compound against skeletal muscle atrophy.

BACKGROUND: Oxidative stress is crucial player in skeletal muscle atrophy pathogenesis. S-allyl cysteine (SAC), an organosulfur compound of Allium sativum, possesses broad-spectrum properties including immuno- and redox-modulatory impact. Considering the role of SAC in regulating redox balance, we hypothesize that SAC may have a protective role in oxidative-stress induced atrophy. METHODS: C2C12 myotubes were treated with H2O2 (100 µM) in the presence or absence of SAC (200 µM) to study morphology, redox status, inflammatory cytokines and proteolytic systems using fluorescence microscopy, biochemical analysis, real-time PCR and immunoblotting approaches. The anti-atrophic potential of SAC was confirmed in denervation-induced atrophy model. RESULTS: SAC pre-incubation (4 h) could protect the myotube morphology (i.e. length/diameter/fusion index) from atrophic effects of H2O2. Lower levels of ROS, lipid peroxidation, oxidized glutathione and altered antioxidant enzymes were observed in H2O2-exposed cells upon pre-treatment with SAC. SAC supplementation also suppressed the rise in cytokines levels (TWEAK/IL6/myostatin) caused by H2O2. SAC treatment also moderated the degradation of muscle-specific proteins (MHCf) in the H2O2-treated myotubes supported by lower induction of diverse proteolytic systems (i.e. cathepsin, calpain, ubiquitin-proteasome E3-ligases, caspase-3, autophagy). Denervation-induced atrophy in mice illustrates that SAC administration alleviates the negative effects (i.e. mass loss, decreased cross-sectional area, up-regulation of proteolytic systems, and degradation of total/specific protein) of denervation on muscles. CONCLUSIONS: SAC exerts significant anti-atrophic effects to protect myotubes from H2O2-induced protein loss and myofibers from denervation-induced muscle loss, due to the prevention of elevated proteolytic systems and inflammatory/oxidative molecules. GENERAL SIGNIFICANCE: The results signify the potential of SAC against muscle atrophy.

Alarming India-wide phenomenon of antifungal resistance in dermatophytes: A multicentre study.

BACKGROUND: An alarming increase in recalcitrant dermatophytosis has been witnessed in India over the past decade. Drug resistance may play a major role in this scenario. OBJECTIVES: The aim of the present study was to determine the prevalence of in vitro resistance to terbinafine, itraconazole and voriconazole in dermatophytes, and to identify underlying mutations in the fungal squalene epoxidase (SQLE) gene. PATIENTS/METHODS: We analysed skin samples from 402 patients originating from eight locations in India. Fungi were identified by microbiological and molecular methods, tested for antifungal susceptibility (terbinafine, itraconazole, voriconazole), and investigated for missense mutations in SQLE. RESULTS: Trichophyton (T.) mentagrophytes internal transcribed spacer (ITS) Type VIII was found in 314 (78%) samples. Eighteen (5%) samples harboured species identified up to the T interdigitale/mentagrophytes complex, and T rubrum was detected in 19 (5%) samples. 71% of isolates were resistant to terbinafine. The amino acid substitution Phe397Leu in the squalene epoxidase of resistant T mentagrophytes was highly prevalent (91%). Two novel substitutions in resistant Trichophyton strains, Ser395Pro and Ser443Pro, were discovered. The substitution Ala448Thr was found in terbinafine-sensitive and terbinafine-resistant isolates but was associated with increased MICs of itraconazole and voriconazole. CONCLUSIONS: The high frequencies of terbinafine resistance in dermatophytes are worrisome and demand monitoring and further research. Squalene epoxidase substitutions between Leu393 and Ser443 could serve as markers of resistance in the future.

Disability and its association with sociodemographic factors among elderly persons residing in an urban resettlement colony, New Delhi, India.

Disability prevents an individual from performing to the fullest potential. It is multidimensional. Disability may be physical, mental, social, personal, and environmental or a combination of these. The elderly experience an increased burden of disability, especially in areas where there are limited resources and rapid urbanization. Comparison of reported disability is difficult because several definitions and scales are in use. We used the World Health Organization Disability Assessment Schedule version 2.0 (WHODAS 2.0) to study the prevalence of disability, and its association with sociodemographic factors among elderly persons residing in an urban resettlement colony, New Delhi, India. The WHODAS 2.0 provides continuous summary scores, where higher scores indicate higher disability, and vice versa. Elderly persons aged 60 years and above were selected by simple random sampling in this community-based cross-sectional study. Trained interviewers administered the semi-structured interview schedule and WHODAS 2.0. The prevalence of disability was 7.4% (5.8% - 9.3%) among the 931 participants. The prevalence was higher among females than males. Female sex, elderly aged 70 years and above, and those who were illiterate had increased risk of higher disability scores. Participants who were in government or private service had 50% decreased risk of having higher disability scores. The burden of disability was high among elderly persons residing in this resettlement colony. Community-based holistic interventions are required to mitigate the disability, and to improve the functioning of elderly persons.

Secretase inhibitors for the treatment of Alzheimer's disease: Long road ahead.

Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. The two protein structures in the brain i.e. neurofibrillary tangles and senile plaques are considered to hamper the normal cognitive activity of the brain. There are various therapeutic interpolations under investigation to thwart and treat AD. Secretases inhibitors are important agents that inhibit the development of senile plaques. ß-secretase (BACE) inhibitors are in lime light for the drug development of AD. BACE initiates the production of Aß, so its inhibition provides a valid target for the AD. BACE inhibitors viz. LY2811376, LY2886721, E2609 are in different phases of clinical trials. However, chemical study of MK8931 was discontinued due to lack of chances of finding a positive clinical effect. AREAS COVERED: The review incorporates exhaustive literature reports on secretase inhibitors, γ-secretase modulators (GSMs) and α-secretase enhancers. The recent studies on the natural products as GSMs have also been included.

S-allyl cysteine inhibits TNFα-induced skeletal muscle wasting through suppressing proteolysis and expression of inflammatory molecules.

BACKGROUND: Elevated levels of inflammatory molecules are key players in muscle wasting/atrophy leading to human morbidity. TNFα is a well-known pro-inflammatory cytokine implicated in the pathogenesis of muscle wasting under diverse clinical settings. S-allyl cysteine (SAC), an active component of garlic (Allium sativum), has established anti-oxidant and anti-inflammatory effects in various cell types. However, the impact of SAC on skeletal muscle pathology remains unexplored. Owing to the known anti-inflammatory properties of SAC, we investigated whether pre-treatment with SAC has a protective role in TNFα-induced atrophy in cultured myotubes. METHODS AND RESULTS: C2C12 myotubes were treated with TNFα (100ng/ml) in the presence or absence of SAC (0.01mM). TNFα treatment induced atrophy in myotubes by up-regulating various proteolytic systems i.e. cathepsin L, calpain, ubiquitin-proteasome E3-ligases (MuRF1/atrogin1), caspase 3 and autophagy (Beclin1/LC3B). TNFα also induced the activation of NFκB by stimulating the degradation of IκBα (inhibitor of NFκB), in myotubes. The alterations in proteolytic systems likely contribute to the degradation of muscle-specific proteins and reduce the myotube length, diameter and fusion index. The SAC supplementation significantly impedes TNFα-induced protein loss and protects myotube morphology by suppressing protein catabolic systems and endogenous level of inflammatory molecules namely TNFα, IL-6, IL-1ß, TNF-like weak inducer of apoptosis (TWEAK), fibroblast growth factor-inducible 14 (Fn14) and Nox. CONCLUSION AND GENERAL SIGNIFICANCE: Our findings reveal anti-atrophic role for SAC, as it prevents alterations in protein metabolism and protects myotubes by regulating the level of inflammatory molecules and multiple proteolytic systems responsible for muscle atrophy.

Use of traditional eye medicine and self-medication in rural India: A population-based study.

OBJECTIVE: To determine the type and nature of traditional eye medicine (TEM), their sources and use and practices related to self-medication for ophthalmic diseases in a rural Indian population. METHODS: A population-based, cross-sectional study was conducted in 25 randomly selected clusters of Rural Gurgaon, Haryana, India as part of CORE (Cornea Opacity Rural Epidemiological) study. In addition to comprehensive ophthalmic examination, health-seeking behavior and use of self-medication and TEM was assessed in the adult population using a semi-structured questionnaire. Physical verification of available ophthalmic medications in the enumerated households was conducted by the study team. Descriptive statistics were computed along with multivariable logistic regression analysis to determine associated factors for use of self-medication and TEM. RESULTS: Of the 2160 participants interviewed, 396 (18.2%) reported using ophthalmic medications without consulting an ophthalmologist, mainly for symptoms like watering (37.1%), redness (27.7%), itching (19.2%) and infection (13.6%). On physical verification of available eye drops that were being used without prescription, 26.4% participants were practicing self-medication. Steroid, expired/unlabeled and indigenous eye drops were being used by 151(26.5%), 120(21.1%) and 75 (13.2%) participants respectively. Additionally, 25.7% (529) participants resorted to home remedies like 'kajal'(61.4%), honey (31.4%), ghee (11.7%) and rose water (9.1%). CONCLUSION: Use of TEM is prevalent in this population. The rampant use of steroid eye drops without prescription along with use of expired or unlabelled eye drops warrants greater emphasis on safe eye care practices in this population. Public awareness and regulatory legislations must be implemented to decrease harmful effects arising due to such practices.

Unintentional Childhood Injuries in Urban Delhi: A Community-Based Study.

BACKGROUND: Childhood injuries claim around a million lives around the world each year. A community-based study on childhood injuries would provide valuable information on the epidemiology of injuries. OBJECTIVE: To assess the prevalence of unintentional childhood injuries in an urban locality and determine various sociodemo graphic factors associated with childhood injuries. METHODS: The study was done in urban Delhi among 1,639 children aged less than 18 years. Information on injuries in the last one year was collected. Only those injury episodes where treatment was sought or the child was left disabled after the injury were included. Treatment seeking behavior and the impact of injury on the child and the household were also assessed. RESULTS: Among 1,639 children, 102 children suffered 116 episodes of various types of injuries in the last one year. Prevalence of injuries was 7.1% (95% CI: 5.9-8.4). Mean age was 8.5 ± 5.1 years. Prevalence was more in boys (8.4%) than girls (5.1%). Accidental falls (37.1%), dog bites (25%), and road traffic injuries (18.9%) were the three most common modes of injury. Two-thirds of children with injuries were taken to the emergency facility for treatment while 40% resorted to home remedies. Treatment expenses in some families led to the need for borrowing money, additional employment by another family member, and selling of household assets. CONCLUSIONS: The prevalence of childhood injuries in the past one year was 7.1%. Maximum injuries occurred at home and were mostly accidental falls and dog bites. Childhood injuries caused loss of school attendance and financial burden to the family.

Demonstrating Potential of Cell Therapy for Wilson's Disease with the Long-Evans Cinnamon Rat Model.

Wilson's disease (WD) is characterized by the inability to excrete copper (Cu) from the body with progressive tissue injury, especially in liver and brain. The molecular defect in WD concerns mutations in ATP7B gene leading to loss of Cu transport from the hepatocyte to the bile canaliculus. While drugs, e.g., Cu chelators, have been available for several decades, these must be taken lifelong, which can be difficult due to issues of compliance or side effects. Many individuals may require liver transplantation, which can also be difficult due to donor organ shortages. Therefore, achieving permanent cures via cell or gene therapy are of great interest for WD. Cell therapy is feasible because transplanted hepatocytes can integrate in liver parenchyma and restore deficient functions, including transport of Cu into bile. The availability of authentic animal models that recapitulate hepatic WD, especially the Long-Evans Cinnamon (LEC) rat, has advanced cell transplantation research in WD. We describe requirements for cell therapy in animal models with several standardized methods for studies to test or refine cell therapy strategies in WD.

Dietary Calcium Intake, Serum Calcium Level, and their Association with Preeclampsia in Rural North India.

BACKGROUND: Preeclampsia in pregnancy has been shown to be associated with low serum calcium level. Though the evidence is abundant, it is equivocal. OBJECTIVES: The study aimed to estimate the dietary calcium intake and serum calcium status among pregnant women, and to document the association of the dietary calcium intake and serum calcium status with incidence of preeclampsia in the 3rd trimester of pregnancy. MATERIALS AND METHODS: A community-based cross-sectional study was conducted in the Health and Demographic Surveillance System (HDSS) site, Ballabgarh, Haryana, India. All pregnant women between 28 weeks and 36 weeks of gestation were interviewed. A semi-structured interview schedule and a 24-h dietary recall questionnaire were administered to assess the dietary calcium intake. AutoAnalyser (Biolis 24i) was used for measuring serum calcium. RESULTS: We enrolled 217 pregnant women. The mean [standard deviation (SD)] dietary calcium intake was 858 (377) mg/day. The mean (SD) serum calcium level was 9.6 mg/dL (0.56). Incidence of preeclampsia was 13.4%. Preeclampsia was not associated with hypocalcemia [odds ratio (OR) = 1.2 95% confidence interval (CI); 0.27-3.98]. CONCLUSION: The majority of pregnant women had inadequate dietary calcium intake. The prevalence of hypocalcemia was low. Low serum calcium level was not associated with preeclampsia. Calcium supplementation may not reduce preeclampsia in this population.

Models for primary eye care services in India.

Blindness and visual impairment continues to be a major public health problem in India. Availability and easy access to primary eye care services is essential for elimination of avoidable blindness. 'Vision 2020: The Right to Sight - India' envisaged the need for establishing primary eye care units named vision centers for every 50,000 population in the country by the year 2020. The government of India has given priority to develop vision centers at the level of community health centers and primary health centers under the 'National Program for Control of Blindness'. NGOs and the private sector have also initiated some models for primary eye care services. In the current situation, an integrated health care system with primary eye care promoted by government of India is apparently the best answer. This model is both cost effective and practical for the prevention and control of blindness among the underprivileged population. Other models functioning with the newer technology of tele-ophthalmology or mobile clinics also add to the positive outcome in providing primary eye care services. This review highlights the strengths and weaknesses of various models presently functioning in the country with the idea of providing useful inputs for eye care providers and enabling them to identify and adopt an appropriate model for primary eye care services.

Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection.

The aim of the present research was to study the prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. Patients were enrolled in two groups: diabetic patients with foot infection (n 125) as cases and diabetic patients without the infection as controls (n 164). Serum 25-hydroxyvitamin D (25(OH)D) was measured by RIA. Data were presented as means and standard deviations unless otherwise indicated and were analysed by SPSS. Results revealed that 25(OH)D (nmol/l) was significantly lower (40·25 (sd 38·35) v. 50·75 (sd 33·00); P < 0·001) in cases than in controls. Vitamin D inadequacy (25(OH)D < 75 nmol/l) was equally common in cases and controls (OR 1·45, 95 % CI 0·8, 3·0; P = 0·32), but cases had a greater risk of vitamin D deficiency (25(OH)D < 50 nmol/l) than controls (OR 1·8, 95 % CI 1·1, 3·0; P = 0·02). Risk of severe vitamin D deficiency (25(OH)D < 25 nmol/l) was significantly higher in cases than in controls (OR 4·0, 95 % CI 2·4, 6·9; P < 0·0001). Age, duration of diabetes and HbA1c were significantly higher in cases than in controls and therefore adjusted to nullify the effect of these variables, if any, on study outcome. The study concluded that vitamin D deficiency was more prevalent and severe in patients with diabetic foot infection. This study opens up the issue of recognising severe vitamin D deficiency (< 25 nmol/l) as a possible risk factor for diabetic foot infections and the need for vitamin D supplementation in such patients for a better clinical outcome. This could be substantiated by similar data from future studies.

Long-term Vihangam Yoga meditation and scores on tests of attention.

Although the literature indicates that meditation has beneficial effects on several aspects of human functioning, few studies have specifically investigated the effects of meditation on various domains of attention. This study was conducted to examine the differences in various domains of attention between long-term concentrative meditators versus matched controls. 15 practitioners of Vihangam Yoga (> 10 yr. experience) were enrolled in the study. Controls matched on age, sex, and years of education were recruited. Both groups were administered the Stroop, Trail-Making, and Digit Symbol Substitution tests as well as the Digit Forward and Digit Backward tests. The group of Vihangam Yogis had significantly better mean performance on all tests of attention. Long-term Vihangam Yoga meditation improves attention span, processing speed, attention alternation ability, and performance in interference tests.

Development of cell therapy strategies to overcome copper toxicity in the LEC rat model of Wilson disease.

AIMS: Therapeutic replacement of organs with healthy cells requires disease-specific strategies. As copper toxicosis due to ATP7B deficiency in Wilson disease produces significant liver injury, disease-specific study of transplanted cell proliferation will offer insights into cell and gene therapy mechanisms. MATERIALS & METHODS: We used Long-Evans Cinnamon (LEC) rats to demonstrate the effects of liver preconditioning with radiation and ischemia reperfusion, followed by transplantation of healthy Long-Evans Agouti rat hepatocytes and analysis of hepatic atp7b mRNA, bile copper, liver copper and liver histology. RESULTS: LEC rats without cell therapy or after transplantation of healthy cells without liver conditioning accumulated copper and showed liver disease during the study period. Liver conditioning incorporating hepatic radiation promoted transplanted cell proliferation and reversed Wilson disease parameters, although with interindividual variations and time lags for improvement, which were different from previous results of liver repopulation in healthy animals. CONCLUSION: Cell therapy will correct genetic disorders characterized by organ damage. However, suitable mechanisms for inducing transplanted cell proliferation will be critical for therapeutic success.

Catastrophic flooding origin of shelf valley systems in the English Channel.

Megaflood events involving sudden discharges of exceptionally large volumes of water are rare, but can significantly affect landscape evolution, continental-scale drainage patterns and climate change. It has been proposed that a significant flood event eroded a network of large ancient valleys on the floor of the English Channel-the narrow seaway between England and France. This hypothesis has remained untested through lack of direct evidence, and alternative non-catastrophist ideas have been entertained for valley formation. Here we analyse a new regional bathymetric map of part of the English Channel derived from high-resolution sonar data, which shows the morphology of the valley in unprecedented detail. We observe a large bedrock-floored valley that contains a distinct assemblage of landforms, including streamlined islands and longitudinal erosional grooves, which are indicative of large-scale subaerial erosion by high-magnitude water discharges. Our observations support the megaflood model, in which breaching of a rock dam at the Dover Strait instigated catastrophic drainage of a large pro-glacial lake in the southern North Sea basin. We suggest that megaflooding provides an explanation for the permanent isolation of Britain from mainland Europe during interglacial high-sea-level stands, and consequently for patterns of early human colonisation of Britain together with the large-scale reorganization of palaeodrainage in northwest Europe.

Withania somnifera (Ashwagandha) attenuates antioxidant defense in aged spinal cord and inhibits copper induced lipid peroxidation and protein oxidative modifications.

Withania somnifera is classified in Ayurveda, the ancient Indian system of medicine, as a rasayana, a group of plant-derived drugs which promote physical and mental health, augment resistance of the body against disease and diverse adverse environmental factors, revitalize the body in debilitated conditions and increase longevity. We investigated the effects of Withania somnifera on copper-induced lipid peroxidation and antioxidant enzymes in aging spinal cord of Wistar rats. The activity of glutathione peroxidase (GPx) decreased significantly in the spinal cord from adult to aged mice. Treatment with Withania somnifera successfully attenuated GPx activity and inhibited lipid peroxidation in a dose dependent manner. Withania somnifera inhibited both the lipid peroxidation and protein oxidative modification induced by copper. These effects were similar to those of superoxide dismutase and mannitol. The results indicate the therapeutic potential of Withania somnifera in aging and copper-induced pathophysiological conditions.