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Background & aimsStunting in children is a comorbid condition in undernutrition that may be ameliorated by the provision of high-quality foods that provide protein and micronutrients. Addressing this problem in lower social economic environments requires, in part, affordable and scalable food-based solutions with efficacious food products. Towards this end, biochemical/metabolic indicators for fast-throughput screening of foods and their components are desired. A highly acceptable and economical micronutrient-fortified food product with different levels of legume protein was provided to stunted Indian children for one month, to determine change in their linear growth and explore associated biochemical, metabolomic and microbiome indicators.MethodsA randomized controlled pilot trial was conducted with 100 stunted children (6-10 years of age) to elucidate metabolic and microbiome-based biomarkers associated with linear growth. They were randomized into 4 groups receiving 6, 8, 10 or 12 g of legume-based protein for one month. Anthropometry, blood biochemistry, aminoacidomics, acylcarnitomics and fecal microbiome were measured before and after feeding.ResultsNo significant differences were observed between groups in height, height-for-age Z-score (HAZ) or BMI-for-age Z-score (BAZ); however, 38 serum metabolites were altered significantly (Bonferroni adjusted P  0.2, P = 0.02), while serine and ornithine (ρ  1.5) were significantly correlated with change in height.ConclusionsIn this pilot trial, a number of fasting serum metabolomic and fecal microbiome signatures were associated with linear growth after a short-term dietary intervention. The alterations of these markers should be validated in long-term dietary intervention trials as potential screening indicators towards the development of food products that favor growth. This trial was registered at www.ctri.nic.in as CTRI/2016/12/007564.

Background and Aims: Hirschsprung disease (HSCR) is a congenital disorder of unknown etiology affecting the enteric nervous system (ENS). Since the early gestational development of the ENS is dependent on the prenatal maternal metabolic environment, the objective of this pilot study was to explore the role of specific maternal plasma metabolites in the etiology of HSCR. Methods: In this cross sectional study, postnatal (as a surrogate for prenatal) plasma samples were obtained from mothers of children diagnosed with HSCR (n = 7) and age-matched mothers of normal children (n = 6). The plasma metabolome was analyzed by ultra high pressure liquid chromatography and mass spectrometry. Metabolites were identified by mzCloud using Compound Discoverer software. Using an untargeted metabolomics workflow, metabolites with case versus control group differences were identified. Results: A total of 268 unique plasma metabolites were identified and annotated in maternal plasma. Of these, 57 were significantly different between case and control groups (P < 0.05, t-test). Using a false discovery rate corrected cutoff of 10% to adjust for multiple comparisons, 19 metabolites were significantly different in HSCR cases, including carnitines, medium-chain fatty acids, and glutamic acid. Pathways affected were for amino acid and lipid metabolism. Conclusion: Disordered prenatal metabolic pathways may be involved in the etiopathogenesis of HSCR in the developing fetus. This is the first study to assess maternal plasma metabolomics in HSCR. [ABSTRACT FROM AUTHOR]

Introduction Effective stimulation of arteriogenesis has long been an important therapeutic aim in clinical medicine. Attempts at stimulating it using various growth factors have failed largely because of impaired signaling [...], Arterial morphogenesis is an important and poorly understood process. In particular, the signaling events controlling arterial formation have not been established. We evaluated whether alterations in the balance between ERK1/2 and PI3K signaling pathways could stimulate arterial formation in the setting of defective arterial morphogenesis in mice and zebrafish. Increased ERK1/2 activity in mouse ECs with reduced VEGF responsiveness was achieved in vitro and in vivo by downregulating PI3K activity, suppressing Akt1 but not Akt2 expression, or introducing a constitutively active ERK1/2 construct. Such restoration of ERK1/2 activation was sufficient to restore impaired arterial development and branching morphogenesis in synectin-deficient mice and synectin-knockdown zebrafish. The same approach effectively stimulated arterial growth in adult mice, restoring arteriogenesis in mice lacking synectin and in atherosclerotic mice lacking both LDL-R and ApoB48. We therefore conclude that PI3K-ERK1/2 crosstalk plays a key role in the regulation of arterial growth and that the augmentation of ERK signaling via suppression of the PI3K signaling pathway can effectively stimulate arteriogenesis.

The belief that the divine is embedded in nature is part of the spiritual discourse of the religions of antiquity. Nature has been worshipped in one form or the other in different cultures of the world. In India, rivers are considered sacred, purifying, life-giving, and redeeming. The corporeality of the rivers is subsumed and often modified by its metaphorical, mystical, and transcendental associations. The Ganga (Ganges), the Yamuna, the Sarasvati, the Narmada, and other major and minor rivers of India are narrativized within a sacred discourse. The myths, rituals, and belief systems surrounding river worship in India are woven into the syncretic and composite cultural mosaic. However, the contemporary realities of globalization and environmental crises raise quite a few questions regarding the paradoxical nature of this sacred discourse. This essay explores the cultures of river worship in India in its scriptural as well as quotidian forms and attempts to understand the tangible and intangible issues contributing to its continuance and to locate the interface between religious discourse and environmental ethics. [ABSTRACT FROM AUTHOR]

Gut microbiota has been implicated as a modifier of childhood growth. Here, 16S rRNA sequencing-based fecal microbiota profiles of 18–24 month old Indian children were evaluated (n = 41), in relation to their anthropometric parameters, intestinal permeability, body composition and total energy expenditure. Pathway analyses were conducted to assess microbial functions related to stunting, underweight and wasting. The fecal microbiota was enriched in Prevotella 9, Bifidobacterium and Escherichia-Shigella. Weight, weight-for-age Z-scores (WAZ) and weight-for-length Z-scores (WLZ), along with age, acted as covariates of microbiota variation specifically in boys (n = 23). Bifidobacterium longum subsp longum abundance was positively associated with WAZ while Bifidobacterium bifidum and Bifidobacterium breve abundances were negatively associated with age. The lipopolysaccharide biosynthesis pathway was upregulated in stunted (n = 16) and wasted (n = 8) children. Findings from this study indicate that child sex may be a critical modifier of the role of gut microbiota on childhood growth. [ABSTRACT FROM AUTHOR]

Objectives: Aberrations in placental vascular development compromising fetal supply of oxygen and essential nutrients can be a significant contributor to intrauterine growth restriction (IUGR). The development of placental vascular tree is under the influence of two families of growth factors, namely the vascular endothelial growth factor (VEGF) family and angiopoietin/TEK family. In this study, we have examined the expression of angiogenesis-related growth factors, mainly VEGF family and angiopoietin-TEK (endothelial-specific receptor tyrosine kinase) family genes in placentae from IUGR pregnancies uncomplicated by preeclampsia (PE) compared to normal pregnancies. Methods: Placentae from normotensive IUGR (n = 42) and appropriate for gestational age (AGA) pregnancies (n = 47) were collected and examined histologically. Clinical parameters were obtained from the medical records. Real-time quantitative PCR was performed to assess placental transcript abundance of VEGF, PGF, FLT1, ANGPT1, ANGPT2, and TEK normalized to a panel of reference genes. Associations of placental transcript abundance of the genes with maternal, placental, and neonatal parameters were tested. Results: Placental transcript abundance for VEGF (relative expression 10.81 versus 12.98, p <.001), PGF (12.14 versus 13.8, p <.001) and ANGPT2 (3.67 versus 9.55, p =.002) were significantly lower in IUGR placentae compared to AGA. The transcript level of VEGF showed significant negative correlation with birth weight (r = −0.419, p =.006), placental weight (r = −0.318, p =.040), placental length (r = −0.389, p =.011) and breadth (r = −0.308, p =.047) only in the IUGR group. Presence of histopathological features of hypoxia correlated with significantly higher transcript levels of PGF in IUGR placentae (12.6 versus 10.9, p =.046). Conclusion: The low levels of VEGF transcripts may be responsible for the impaired angiogenesis in IUGR placentae. The significance of higher relative expression of PGF in the presence of chronic hypoxia needs to be explored. [ABSTRACT FROM AUTHOR]

Background. Medical professionals in India need to understand the concepts of molecular genetics to stay up-todate with clinical care as well as to strengthen basic research in the biomedical sciences. Methods. We introduced a modular course on 'Fundamentals in molecular and cellular biology' for first-year medical undergraduate students in the second semester of the first MBBS year in 2015, as part of 'Innovations in teaching physiology' at St John's Medical College. This was a voluntary, add-on course with didactic lectures, hands-on practical classes and a research paper presentation. Evaluation of students' performance in the course took into account their performance in the research paper presentation-based group activity and their attendance for the hands-on practical sessions. Feedback on the content, delivery, evaluation and future improvements of the course was sought from the students. Results. About 65% of students regularly attended the 10-hour long course. Of the students evaluated for the course, 43% achieved the highest, and 11% achieved the lowest grade assigned. Nearly 72% of the students provided feedback on the course. Conclusion. This first outing of the modular course on 'Fundamentals in molecular and cellular biology' generated excitement among the students and achieved some learning for them. It also brought to light hidden challenges in conducting such a voluntary course for medical students in India. Our experience with the course will help in designing a betterintegrated course for exposure of first-year medical students to advances in molecular biology and its applied aspects as they progress through the MBBS course. [ABSTRACT FROM AUTHOR]

The prevalence of the double burden of malnutrition in society is well known with the coexistence of undernutrition with an increase in overweight/obesity; this has been increasing globally with nutritional imbalances and infectious diseases being the major etiological factors. However, there is also the coexistence of inappropriate adiposity or metabolic dysfunction in an individual who appears currently undernourished by anthropometric standards (stunted or underweight); this is the intraindividual double burden of malnutrition. It could also occur in temporal sequence, as anthropometric overweight in an individual who has previously endured childhood under-nutrition. IIDBM has increased the risk for diet-related non-communicable diseases over the past few decades, as it tracks into adulthood, warranting an urgent need for intervention and prevention. While gut dysbiosis has been associated with various forms of malnutrition, the early life gut microbiome composition and its related metabolites and regulatory factors, are possibly linked to the development of inflammatory and metabolic conditions in IIDBM. The possible underlying physiological mechanisms are reviewed here, working through host dietary influences, gut microbial metabolites, host inflammation and metabolic dysregulation. When validated experimentally and tested through appropriately designed randomised, controlled trials, these mechanistic insights will likely lead to development of preventive strategies. [ABSTRACT FROM AUTHOR]

Introduction: Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India's distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants., Research Design and Methods: We mined 1029 Indian whole genomes for PGx variants, drug-drug interaction (DDI) and drug-drug-gene interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies were estimated and compared using Fisher's exact test., Results: Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to type 2 diabetes therapy among Indians. We report remarkable interethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared with other global populations. Network analysis of shared PGx genes predicts high DDI risk during coadministration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when coadministered with proton-pump inhibitors (PPIs)., Conclusions: Indians and South Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of poor treatment response-associated alleles for various NIAD classes. This suggests the possibility of a population-specific reduced drug response in atleast some NIADs. In addition, our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and South Asians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: We describe the rationale and broad study design of the Indian Diabetes and Metabolic Health (InDiMeT) study, a new prospective, observational study incorporating extensive epigenetic (DNA methylation) and lipidomic signatures to examine their association with the dysregulation of adipose de novo lipogenesis (DNL) in South Asian Indians. The InDiMeT study aims to use a case-control design to identify genetic and modifiable-environmental-lifestyle associated determinants of (1) epigenomic (DNA methylome) dysregulation of adipose DNL in type 2 diabetes mellitus (T2DM) adipose tissue, (2) identify correlates of epigenomic (DNA methylome) dysregulation of adipose DNL in peripheral blood mononuclear cells (PBMCs) from T2DM subjects and (3) elucidate plasma lipidomic correlates of adipose DNL in T2DM that can be used as biomarkers of adipose tissue dysfunction., Methods and Analysis: The InDiMeT study will involve recruitment of 176 normoglycaemic and T2DM individuals who will be undergoing laparoscopic surgery for clinical conditions. Extensive phenotyping of the subjects will be conducted and DNA methylome and lipidomic measurements will be made. The adipose DNL pathway genes are likely to be hypermethylated in patients with T2DM with corresponding reduction of gene expression. Correlates of epigenomic (DNA methylome) dysregulation of adipose DNL pathway in PBMCs and their adipose and plasma lipidomic signatures in T2DM subjects could act as early markers of development of T2DM., Ethics and Dissemination: For the InDiMeT study, ethical approval for addressing the specific aims has been obtained from the Institutional Ethics Committee, St John's Medical College and Hospital, St John's National Academy of Health Sciences, Bangalore. Findings from this study will be disseminated through scientific publications in peer-reviewed journals, research conferences and via presentations to stakeholders, patients, clinicians, public and policymakers through appropriate channels., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Purpose of Review: The present review presents a current view of vascular development, with a focus on the factors contributing to the establishment of arterial-venous identity and the potential of chemical biology for providing new insights into this field., Recent Findings: Genetics and gene expression studies have begun to define the complex network of molecular pathways that govern the formation of the embryonic vasculature, but these approaches have limited ability to spatially and temporally manipulate gene expression and function. Recently, the power of chemical biology, combined with model systems like zebrafish, has enabled discovery of additional contributors to vascular development and has provided a means of manipulating gene function with enhanced spatial and temporal control., Summary: The molecular pathways directing arterial-venous specification during embryogenesis are relevant for understanding the causes of human arteriovenous malformations, tumor angiogenesis, and diabetic retinopathy. Through the complementary strengths of genetics and chemical biology, it is hoped that novel therapeutic approaches for these conditions will emerge.

We have identified a novel gene expressed in murine embryonic stem (ES) cells and in a restricted, tissue-specific pattern during mouse development. The gene is also expressed in blood vessels; hence, we have named it asrij (Sanskrit; asRîj= blood). The gene encodes a novel conserved, predicted transmembrane protein of 247 amino acids, which is localized to lysosomes and endosomes. During ES cell-derived blood vessel formation in vitro, Asrij expression precedes and partially overlaps with the vascular markers Flk-1 and PECAM. During development, Asrij is expressed predominantly in mouse embryonic blood vessels. The asrij transcript is alternatively spliced, and its expression is regulated in a tissue-specific manner. An asrij splice variant that is enriched in the adult mouse brain encodes a protein of 196 amino acids. Asrij can serve as an early stem cell marker that is down-regulated in nonvascular tissues. Our data indicate that Asrij belongs to a novel class of conserved proteins with a complex developmental profile and suggests multiple functions for the gene., (Copyright 2003 Wiley-Liss, Inc.)