The matrilineal ancestry of Nepali populations.

The Tibetan plateau and high mountain ranges of Nepal are one of the challenging geographical regions inhabited by modern humans. While much of the ethnographic and population-based genetic studies were carried out to investigate the Tibetan and Sherpa highlanders, little is known about the demographic processes that enabled the colonization of the hilly areas of Nepal. Thus, the present study aimed to investigate the past demographic events that shaped the extant Nepalese genetic diversity using mitochondrial DNA (mtDNA) variations from ethnic Nepalese groups. We have analyzed mtDNA sequences of 999 Nepalese and compared data with 38,622 published mtDNA sequences from rest of the world. Our analysis revealed that the genomic landscapes of prehistoric Himalayan settlers of Nepal were similar to that of the low-altitude extant Nepalese (LAN), especially Newar and Magar population groups, but differ from contemporary high-altitude Sherpas. LAN might have derived their East Eurasian ancestry mainly from low-altitude Tibeto-Burmans, who likely have migrated from East Asia and assimilated across the Eastern Himalayas extended from the Eastern Nepal to the North-East of India, Bhutan, Tibet and Northern Myanmar. We also identified a clear genetic sub-structure across different ethnic groups of Nepal based on mtDNA haplogroups and ectodysplasin-A receptor (EDAR) gene polymorphism. Our comprehensive high-resolution mtDNA-based genetic study of Tibeto-Burman communities reconstructs the maternal origins of prehistoric Himalayan populations and sheds light on migration events that have brought most of the East Eurasian ancestry to the present-day Nepalese population.

Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with preserved or increased ejection fraction in the absence of secondary causes. Mutations in the sarcomeric protein-encoding genes predominantly cause HCM. However, relatively little is known about the genetic impact of signalling proteins on HCM. METHODS AND RESULTS: Here, using exome and targeted sequencing methods, we analysed two independent cohorts comprising 401 Indian patients with HCM and 3521 Indian controls. We identified novel variants in ribosomal protein S6 kinase beta-1 (RPS6KB1 or S6K1) gene in two unrelated Indian families as a potential candidate gene for HCM. The two unrelated HCM families had the same heterozygous missense S6K1 variant (p.G47W). In a replication association study, we identified two S6K1 heterozygotes variants (p.Q49K and p.Y62H) in the UK Biobank cardiomyopathy cohort (n=190) compared with matched controls (n=16 479). These variants are neither detected in region-specific controls nor in the human population genome data. Additionally, we observed an S6K1 variant (p.P445S) in an Arab patient with HCM. Functional consequences were evaluated using representative S6K1 mutated proteins compared with wild type in cellular models. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6 and ERK1/2 signalling cascades, suggesting a gain-of-function effect. CONCLUSIONS: Our study demonstrates for the first time that the variants in the S6K1 gene are associated with HCM, and early detection of the S6K1 variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of S6K1 gene variants.

Paddy-Straw-Derived Graphene Quantum Dots Reinforced Vertical Aligned Zinc Oxide Nanosheet-Based Flexible Triboelectric Nanogenerator for Self-Powered UV Sensors and Tribotronics Application.

Herein, we report the paddy-straw-derived graphene quantum dots (GQDs)-reinforced vertical-aligned two-dimensional (2D) ZnO nanosheet-based flexible triboelectric nanogenerator (FTNG) for scavenging mechanical energy for the first time. The GQDs (diameter ∼5-7 nm) and ZnO nanosheets were grown using a hydrothermal method and seed-assisted chemical route, respectively. The X-ray diffraction and electron microscopy results confirmed the formation of a hexagonal wurtzite crystal structure and vertical-aligned morphology of 2D ZnO nanosheets. The GQD-reinforced ZnO-nanosheet-based FTNG device generated an output voltage of 40 V and current density of 2 µA/cm2, respectively, whereas pristine vertical-aligned ZnO-nanosheet-based device produced an output voltage of only 16 V and a current density of 0.36 µA/cm2, respectively. The performance of the GQD-ZnO nanosheet FTNG device was also measured under illumination of the UV light, and a drastic increase in the output voltage is observed as compared to a pristine ZnO-nanosheet-based device. The GQD-reinforced ZnO nanosheets exhibited very high dielectric constant of 40 at low frequency side. The current finding suggested a novel approach to efficiently harvest mechanical energy and a novel method to fabricate the self-powered UV sensors and tribotronics devices using agrowaste-derived GQDs and ZnO nanosheets.

Mindin (SPON2) Is Essential for Cutaneous Fibrogenesis in a Mouse Model of Systemic Sclerosis.

Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis.

A review of chemical and biological profile of genus Michelia.

The genus Michelia, belonging to family Magnoliaceae, consists of about 80 plant species mainly distributed in South Asian countries. The plants of this genus have been traditionally used in curing various diseases like fever, colic, leprosy, eye disorders, inflammation, antidote for scorpion, etc. Ninety-four compounds isolated from nine species of the genus Michelia like sesquiterpenes, steroids, flavonoids, aporphines, phenols, esters, benzenoid and alkaloids have antibacterial, anticancer and antiplasmodial activities. This review presents first time detailed information on chemical and biological properties of constituents isolated from the genus Michelia.

Extremely Reduced Dielectric Constant and Band Gap Enhancement in Few-Layered Tungsten Disulfide Nanosheets.

Highly crystalline few-layered tungsten disulfide (WS2) nanosheets were synthesized via a cost-effective, low-temperature hydrothermal route. X-ray diffraction and HR-TEM analysis confirmed the formation of hexagonal nanosheets with thickness of ∼6-8 nm. Raman analysis and AFM results confirmed the few-layered 2H phase of WS2 nanosheets. The UV-vis study shows absorption peaks at 219 and 271 nm with large band gap value of ∼3.12 eV for WS2 nanosheets. Surprisingly, WS2 nanosheets show a dielectric constant of approximately ε' ≈ 5245, whereas bulk WS2 material exhibits a dielectric constant of 7482373. An almost 1426-fold decrease in the value of dielectric constant for the WS2 nanosheet is observed. Such an extreme reduction in dielectric constant and observance of large band gap in WS2 nanosheet were observed for the first time. The present study reveals the excellent and unusual optical and dielectric properties for their potential application in optoelectronic, dielectric, solar, phosphor, and various nanoelectronic devices.

Generation of a new human induced pluripotent stem cell (hiPSC) line from a South Asian Indian with a MYBPC3Δ25bp variant.

Myosin binding protein C3 (MYBPC3) is a thick filament contractile protein that interacts with myosin, titin and actin and regulates cardiac muscle contraction. Genetic variations in the MYBPC3 gene are known causal factors for cardiomyopathy and heart failure. Previously, we identified a recurrent MYBPC3 deletion (25 base pairs) among South Asians associated with cardiomyopathy and heart failure. Here, we generated an induced pluripotent stem cell (iPSC) line using peripheral blood mononuclear cells (PBMC) from an Indian harboring MYBPC3 deletion. This iPSC line displayed embryonic stem cell morphology, expressed pluripotency markers, differentiated into three germ layers and exhibited normal karyotype.

Adiponectin receptor 1 variants contribute to hypertrophic cardiomyopathy that can be reversed by rapamycin.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart muscle disease characterized by hypertrophy with preserved or increased ejection fraction in the absence of secondary causes. However, recent studies have demonstrated that a substantial proportion of individuals with HCM also have comorbid diabetes mellitus (~10%). Whether genetic variants may contribute a combined phenotype of HCM and diabetes mellitus is not known. Here, using next-generation sequencing methods, we identified novel and ultrarare variants in adiponectin receptor 1 (ADIPOR1) as risk factors for HCM. Biochemical studies showed that ADIPOR1 variants dysregulate glucose and lipid metabolism and cause cardiac hypertrophy through the p38/mammalian target of rapamycin and/or extracellular signal-regulated kinase pathways. A transgenic mouse model expressing an ADIPOR1 variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that ADIPOR1 variants can cause HCM and provide new insights into ADIPOR1 regulation.

A data parsimonious model for capturing snapshots of groundwater pollution sources.

Presented herein is a data parsimonious model for identification of regional and local groundwater pollution sources at a reference time employing corresponding fields of head, concentration and its time derivative. The regional source flux, assumed to be uniformly distributed, is viewed as the causative factor for the widely prevalent background concentration. The localized concentration-excesses are attributed to flux from local sources distributed around the respective centroids. The groundwater pollution is parameterized by flux from regional and local sources, and distribution parameters of the latter. These parameters are estimated by minimizing the sum of squares of differences between the observed and simulated concentration fields. The concentration field is simulated by a numerical solution of the transient solute transport equation. The equation is solved assuming the temporal derivative term to be known a priori and merging it with the sink term. This strategy circumvents the requirement of dynamic concentration data. The head field is generated using discrete point head data employing a specially devised interpolator that controls the numerical-differentiation errors and simultaneously ensures micro-level mass balance. This measure eliminates the requirement of flow modeling without compromising the sanctity of head field. The model after due verification has been illustrated employing available and simulated data from an area lying between two rivers Yamuna and Krishni in India.

Antifertility effect of hydroalcoholic leaves extract of Michelia champaca L.: an ethnomedicine used by Bhatra women in Chhattisgarh state of India.

ETHNOPHARMACOLOGICAL RELEVANCE: Michelia champaca L. (family: Magnoliaceae), commonly known as Champa [Hindi], is traditionally used for fertility regulation by the women of Chhattisgarh state in India. No scientific evidence regarding the antifertility effect of this plant is available till date. AIM OF THE STUDY: To study the anti-fertility effect of hydroalcoholic leaf extract of Michelia champaca Linn. in female rats. MATERIALS AND METHODS: The antifertility activity of the extract (HAEMC) administered at dose levels (100 and 200mg/kg body weight, p.o.) was evaluated in two experimental animal models i.e. antiimplantation activity in female wistar rats and esterogenic/antiestrogenic activity in ovariectomized female rats. In anti-implantation activity, the extract (200 and 400mg/kg body weight, p.o.) was administered to female rats from 1 to 7 days of pregnancy and on 10th day, laprotomy was performed to count the no. of implants. For estrogenic/anti-estrogenic activity, ovariectomized female rats were administered with the extract at both the doses alone as well as along with 17α-ethinyl estradiol (1 µ/rat/day) for 7 consecutive days. On the 8th day, all animals were sacrificed and blood serum was further processed for the estimation of biochemical parameters such as estrogen level, alkaline phosphates, cholesterol, tryglycerides, total protein etc. RESULTS: The extract (HAEMC) showed significant (p<0.01) 49.95% and 71.03% antiimplantation activities at 100 and 200mg/kg doses respectively. The extract also exhibited significant (p<0.01) estrogenic activity as evidenced by increase in body weight, uterine weight, increased thickness and height of endometrium, vaginal cornification and significant (p<0.01) increase in estrogen, cholesterol, alkaline phosphate and triglycerides levels at higher dose when administered alone as well as along with ethinyl estradiol. Phytochemical screening showed the presence of steroids, flavonoids and alkaloids in the extract. CONCLUSIONS: Hydroalchoholic extract of Michelia champaca leaves possesses significant antifertility effect which might be due to the inhibition of implantation and estrogenic effect which in turn might be due to the presence of some phytoconstituents in the plant.