The melanocortin receptors and their accessory proteins.

The five melanocortin receptors (MCRs) named MC1R-MC5R have diverse physiological roles encompassing pigmentation, steroidogenesis, energy homeostasis and feeding behavior as well as exocrine function. Since their identification almost 20 years ago much has been learnt about these receptors. As well as interacting with their endogenous ligands the melanocortin peptides, there is now a growing list of important peptides that can modulate the way these receptors signal, acting as agonists, antagonists, and inverse agonists. The discovery of melanocortin 2 receptor accessory proteins as a novel accessory factor to the MCRs provides further insight into the regulation of these important G protein-coupled receptor

Influence of rotation and sources of nutrients on soil properties and productivity of finger millet (Eleusinecoracana L. Gaertn.)

A field experiment was conducted at the All India Co-ordinated Research Project for Dryland Agriculture, UAS, GKVK, Bengaluru during kharif 2013-14. The experiment was laid out with 20 treatment combinations with three factors using factorial RBD with two replications comprised of on a permanent manurial trial with 35th crop cycle. Application of FYM at 10 t ha-1 has recorded significantly higher grain yield (1.76 t ha-1), maximum water holding capacity (MWHC) of 43.85 % and dehydrogenase activity (DHA) of 357.60?g TPF g-1 24 h-1 obtained after harvest of the crop as compared to application of maize residues at 5 t ha-1 (1.37 t ha-1, 42.27 % and 193.0?g TPF g-1 24 h-1 respectively) due to improved growth and yield parameters of finger millet. However, finger millet-groundnut rotation has given significantly higher grain yield (1.78 t ha-1), MWHC (43.66 %) and DHA (298.48?g TPF g-1 24 h-1) after harvest of the crop over mono cropping of finger millet (1.34 t ha-1, 42.46% and 252.12?g TPFg-1 24 h-1respectively ). Among different nutrient sources, application of organic matter with 100 % RDF have given significantly higher grain yield (2.74 t ha-1), MWHC (45.86 %) and DHA (431.13?g TPF g-1 24 h-1) after harvest of the crop compared to absolute control (0.28 t ha-1, 41.76 % and 133.67?g TPFg-1 24 h-1 respectively). The 100 % recommended dose of fertilizer + organic matter significantly increased yield attributes because of improved soil physical and chemical properties and increased microbial activity of the soil with continued application of organic matter

Potassium release characteristics, potassium balance, and fingermillet (Eleusine coracana G.) yield sustainability in a 27- year long experiment on an Alfisol in the semi-arid tropical India

Aim In Alfisols, potassium (K) deficiency limits productivity, as these soils are poor in K-bearing minerals such as mica. As nutrient management practices greatly influence K nutrition of crops especially in the longer term, we evaluated the effects of 27 (1978–2004) years of cropping fingermillet (Eleusine coracana G.) under different manure and mineral fertilizer treatments on K release, balance and yield sustainability on K deficient Alfisols in the semi-arid tropical region of southern India. Methods Fingermillet (variety: PR-202) was grown each year under rainfed conditions with 5 different nutrient management treatments: control (no amendment), 10 Mg ha−1 farm yard manure (FYM), 10 Mg ha−1 FYM +50 % NPK, 10 Mg ha−1 FYM +100 % NPK and 100 % NPK. Potassium release characteristics in the soil profile were determined using 1 N boiling HNO3 (strong extracting solution), 0.01 M HCl (medium extracting solution) and 0.01 M CaCl2 (mild extracting solution). Results Continuous cropping of Alfisols for 27 years resulted in a decrease in K supplying capacity due to soil K depletion through crop K uptake. In soils without K addition, inherent soil supply could not meet the K requirement of fingermillet; thus, a negative K balance following 27 years of cropping affected K nutrition of the crop in all the treatments. As a result, the highest sustainable yield index (SYI) was observed using an integrated nutrient supply (combined application of nutrients from organic and inorganic sources), and the lowest index was obtained without K additions. Conclusion For balanced nutrient management in cereal production systems, K nutrition needs urgent attention in the K deficient Alfisol region of southern India. Addition of any amount of organic manures available at field level offers an alternative strategy for maintaining soil K fertility to improve and sustain crop productivity

Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling

Protocol for a randomised controlled trial of treatment of asymptomatic candidiasis for the prevention of preterm birth [ACTRN12610000607077]

<p>Abstract</p> <p>Background</p> <p>Prevention of preterm birth remains one of the most important challenges in maternity care. We propose a randomised trial with: a simple <it>Candida </it>testing protocol that can be easily incorporated into usual antenatal care; a simple, well accepted, treatment intervention; and assessment of outcomes from validated, routinely-collected, computerised databases.</p> <p>Methods/Design</p> <p>Using a prospective, randomised, open-label, blinded-endpoint (PROBE) study design, we aim to evaluate whether treating women with asymptomatic vaginal candidiasis early in pregnancy is effective in preventing spontaneous preterm birth. Pregnant women presenting for antenatal care <20 weeks gestation with singleton pregnancies are eligible for inclusion. The intervention is a 6-day course of clotrimazole vaginal pessaries (100 mg) and the primary outcome is spontaneous preterm birth <37 weeks gestation.</p> <p>The study protocol draws on the usual antenatal care schedule, has been pilot-tested and the intervention involves only a minor modification of current practice. Women who agree to participate will self-collect a vaginal swab and those who are culture positive for Candida will be randomised (central, telephone) to open-label treatment or usual care (screening result is not revealed, no treatment, routine antenatal care). Outcomes will be obtained from population databases.</p> <p>A sample size of 3,208 women with <it>Candida </it>colonisation (1,604 per arm) is required to detect a 40% reduction in the spontaneous preterm birth rate among women with asymptomatic candidiasis from 5.0% in the control group to 3.0% in women treated with clotrimazole (significance 0.05, power 0.8). Analyses will be by intention to treat.</p> <p>Discussion</p> <p>For our hypothesis, a placebo-controlled trial had major disadvantages: a placebo arm would not represent current clinical practice; knowledge of vaginal colonisation with <it>Candida </it>may change participants' behaviour; and a placebo with an alcohol preservative may have an independent affect on vaginal flora. These disadvantages can be overcome by the PROBE study design.</p> <p>This trial will provide definitive evidence on whether screening for and treating asymptomatic candidiasis in pregnancy significantly reduces the rate of spontaneous preterm birth. If it can be demonstrated that treating asymptomatic candidiasis reduces preterm births this will change current practice and would directly impact the management of every pregnant woman.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ACTRN12610000607077.aspx">ACTRN12610000607077</a></p

Melanocortin receptor accessory proteins in adrenal disease and obesity.

Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity. Whole body deletion and targeted brain specific deletion of the Mrap2 gene result in severe obesity in mice. Interestingly, Mrap2 complete knockout (KO) mice have increased body weight without detectable changes to food intake or energy expenditure. Rare heterozygous variants of MRAP2 have been found in humans with severe, early-onset obesity. In vitro data have shown that Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affects receptor signaling. However, the mechanism by which Mrap2 regulates body weight in vivo is not fully understood and differences between the phenotypes of Mrap2 and Mc4r KO mice may point toward Mc4r independent mechanisms

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms “mental retardation”. To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus

Effects of the WHO Labour Care Guide on cesarean section in India: a pragmatic, stepped-wedge, cluster-randomized pilot trial

Cesarean section rates worldwide are rising, driven by medically unnecessary cesarean use. The new World Health Organization Labour Care Guide (LCG) aims to improve the quality of care for women during labor and childbirth. Using the LCG might reduce overuse of cesarean; however, its effects have not been evaluated in randomized trials. We conducted a stepped-wedge, cluster-randomized pilot trial in four hospitals in India to evaluate the implementation of an LCG strategy intervention, compared with routine care. We performed this trial to pilot the intervention and obtain preliminary effectiveness data, informing future research. Eligible clusters were four hospitals with >4,000 births annually and cesarean rates ≥30%. Eligible women were those giving birth at ≥20 weeks' gestation. One hospital transitioned to intervention every 2 months, according to a random sequence. The primary outcome was the cesarean rate among women in Robson Group 1 (that is, those who were nulliparous and gave birth to a singleton, term pregnancy in cephalic presentation and in spontaneous labor). A total of 26,331 participants gave birth. A 5.5% crude absolute reduction in the primary outcome was observed (45.2% versus 39.7%; relative risk 0.85, 95% confidence interval 0.54-1.33). Maternal process-of-care outcomes were not significantly different, though labor augmentation with oxytocin was 18.0% lower with the LCG strategy. No differences were observed for other health outcomes or women's birth experiences. These findings can guide future definitive effectiveness trials, particularly in settings where urgent reversal of rising cesarean section rates is needed. Clinical Trials Registry India number: CTRI/2021/01/03069