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In this trial, 443 patients with pulmonary arterial hypertension were assigned to placebo or to the soluble guanylate cyclase stimulator riociguat. At 12 weeks, riociguat significantly improved the 6-minute walk distance and pulmonary vascular resistance. Pulmonary arterial hypertension is a life-threatening disease that is characterized by increased pulmonary vascular resistance owing to progressive vascular remodeling, which can ultimately lead to right heart failure and death. 1 , 2 Current treatments include phosphodiesterase type 5 inhibitors, prostanoids, and endothelin-receptor antagonists. 1 However, mortality remains high despite treatment, 3 and there is a considerable unmet medical need in the management of this disorder. As noted elsewhere in this issue of the Journal, 4 riociguat is a member of a novel therapeutic class known as soluble guanylate cyclase stimulators. Riociguat has a dual mode of action, acting in synergy with endogenous nitric oxide . . .

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila , we identified 4 genes, not previously linked to human obesity, that regulate adiposity ( itpr , dachsous , calpA , and sdk ). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

Securing a diagnosis of ovarian cancer and establishing means to predict outcomes to therapeutics remain formidable clinical challenges. Early diagnosis is particularly important since survival rates are markedly improved if tumour is detected early. Comprehensive miRNA profiles were generated on presurgical plasma samples from 42 women with confirmed serous epithelial ovarian cancer, 36 women diagnosed with a benign neoplasm, and 23 comparably age-matched women with no known pelvic mass. Twenty-two miRNAs were differentially expressed between healthy controls and the ovarian cancer group (P<0.05), while a six miRNA profile subset distinguished presurgical plasma from benign and ovarian cancer patients. There were also significant differences in miRNA profiles in presurgical plasma from women diagnosed with ovarian cancer who had short overall survival when compared to women with long overall survival (P<0.05). Our preliminary data support the utility of circulating plasma miRNAs to distinguish women with ovarian cancer from those with a benign mass and identify women likely to benefit from currently available treatment for serous epithelial ovarian cancer from those who may not.

On whole-exome sequencing, a child with clinical hypothyroidism but borderline-abnormal thyroid hormone levels was found to have a heterozygous nonsense mutation in THRα, encoding a mutant protein inhibiting wild-type receptor action in a dominant negative manner. Thyroid hormones have diverse actions, which include regulation of skeletal growth, maturation of the central nervous system, cardiac and gastrointestinal function, and energy homeostasis. In addition, thyroid hormones control their own production by feedback inhibition of hypothalamic thyrotropin-releasing hormone and pituitary thyroid-stimulating hormone, which direct their synthesis or release. These physiological effects are principally mediated by hormone action through nuclear receptor proteins that act as ligand-inducible transcription factors and either positively or negatively regulate the expression of target genes in different tissues in a hormone-dependent manner. The receptors are encoded by two genes ( THRA and THRB ), each of . . .

Abstract Context While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with leptin can provide unique insights into the role that leptin plays in metabolic and endocrine function. Objective The aim of this study was to characterize changes in peripheral metabolism in people with congenital leptin deficiency undergoing leptin replacement therapy, and to investigate the extent to which these changes are explained by reduced caloric intake. Design Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) was used to measure 661 metabolites in 6 severely obese people with congenital leptin deficiency before, and within 1 month after, treatment with recombinant leptin. Data were analyzed using unsupervised and hypothesis-driven computational approaches and compared with data from a study of acute caloric restriction in healthy volunteers. Results Leptin replacement was associated with class-wide increased levels of fatty acids and acylcarnitines and decreased phospholipids, consistent with enhanced lipolysis and fatty acid oxidation. Primary and secondary bile acids increased after leptin treatment. Comparable changes were observed after acute caloric restriction. Branched-chain amino acids and steroid metabolites decreased after leptin, but not after acute caloric restriction. Individuals with severe obesity due to leptin deficiency and other genetic obesity syndromes shared a metabolomic signature associated with increased BMI. Conclusion Leptin replacement was associated with changes in lipolysis and substrate utilization that were consistent with negative energy balance. However, leptin’s effects on branched-chain amino acids and steroid metabolites were independent of reduced caloric intake and require further exploration.

Disruption of brain-expressed G protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identify multiple rare variants in GPR10 in people with severe obesity and in normal weight controls. These variants impair ligand binding and G protein-dependent signalling in cells. Transgenic mice harbouring a loss of function GPR10 variant found in an individual with obesity, gain excessive weight due to decreased energy expenditure rather than increased food intake. This evidence supports a role for GPR10 in human energy homeostasis. Therapeutic targeting of GPR10 may represent an effective weight-loss strategy. The brain-expressed receptor GPR10 is involved in energy homeostasis in mice. Here the authors identify rare loss of function variants in GPR10 in people with severe obesity and showed that one of these variants causes obesity when modelled in mice, suggesting that future studies could explore GPR10 as a potential target for weight-loss therapy.

Melanocortin 4 receptor (MC4R) deficiency is the most common form of monogenic obesity. To examine the clinical spectrum and mode of inheritance, the investigators determined the MC4R nucleotide sequence in 500 probands with severe childhood obesity. Twenty-nine had mutations in MC4R — 23 were heterozygous and 6 were homozygous. Homozygotes were more severely affected than heterozygotes. This is about the most common form of monogenic obesity. Although changes in diet and exercise underlie the current global increase in the prevalence of obesity, there is considerable evidence of a substantial genetic contribution to the regulation of body weight. 1 Causative mutations underlying several recognizable pleiotropic obesity syndromes (e.g., Bardet–Biedl syndrome) have recently been identified, but in no case has a clear mechanistic link between the product of the mutant gene and disordered energy balance been clarified. 2 Study of strains of genetically obese mice has resulted in the discovery of several genes, mutations of which have subsequently been found to lead to severe human obesity. Deficiency of the adipocyte-derived . . .

This study shows that the prevalence of hypertension in subjects carrying a loss-of-function mutation in MC4R is less than that in overweight or obese control subjects. Metabolic measurements and results of a clinical trial testing an MC4R agonist suggest that melanocortinergic signaling influences blood pressure through an insulin-independent mechanism. This study shows that the prevalence of hypertension in subjects carrying a loss-of-function mutation in MC4R is less than that in overweight or obese control subjects. Metabolic measurements and results of a clinical trial testing an MC4R agonist suggest that melanocortinergic signaling influences blood pressure through an insulin-independent mechanism. Epidemiologic and physiological studies have consistently demonstrated that obesity is a major cause of hypertension. 1 , 2 Studies of rodents with diet-induced obesity suggest that increased activation of the sympathetic nervous system is an important mediator of obesity-induced hypertension: alpha- and beta-adrenergic receptor antagonists and renal denervation significantly blunt the rise in arterial pressure associated with weight gain. 3 – 5 However, the physiological mechanisms linking the development of obesity and hypertension are unclear. The hypothalamic leptin–melanocortin pathway is critically involved in the control of energy balance, and genetic disruption of molecules in this pathway leads to severe obesity in rodents and humans. . . .

The fine-tuning of gene expression is critical for all cellular processes; aberrations in this activity can lead to pathology, and conversely, resilience. As their role in coordinating organismal responses to both internal and external factors have increasingly come into focus, small non-coding RNAs have emerged as an essential component to disease etiology. Using Systemic RNA interference Defective (SID) mutants of the nematode Caenorhabditis elegans , deficient in gene silencing, we examined the potential consequences of dysfunctional epigenomic regulation in the context of Parkinson’s disease (PD). Specifically, the loss of either the sid-1 or sid-3 genes, which encode a dsRNA transporter and an endocytic regulatory non-receptor tyrosine kinase, respectively, conferred neuroprotection to dopaminergic (DA) neurons in an established transgenic C . elegans strain wherein overexpression of human α-synuclein (α-syn) from a chromosomally integrated multicopy transgene causes neurodegeneration. We further show that knockout of a specific microRNA, mir-2 , attenuates α-syn neurotoxicity; suggesting that the native targets of mir-2 -dependent gene silencing represent putative neuroprotective modulators. In support of this, we demonstrated that RNAi knockdown of multiple mir-2 targets enhanced α-syn-induced DA neurodegeneration. Moreover, we demonstrate that mir-2 overexpression originating in the intestine can induce neurodegeneration of DA neurons, an effect that was reversed by pharmacological inhibition of SID-3 activity. Interestingly, sid-1 mutants retained mir-2 -induced enhancement of neurodegeneration. Transcriptomic analysis of α-syn animals with and without a sid-1 mutation revealed 27 differentially expressed genes with human orthologs related to a variety of diseases, including PD. Among these was pgp-8 , encoding a P-glycoprotein-related ABC transporter. Notably, sid-1 ; pgp-8 double mutants abolished the neurodegeneration resulting from intestinal mir-2 overexpression. This research positions known regulators of small RNA-dependent gene silencing within a framework that facilitates mechanistic evaluation of epigenetic responses to exogenous and endogenous factors influencing DA neurodegeneration, revealing a path toward new targets for therapeutic intervention of PD.

Objective: To ascertain antepartum predictors of newborn encephalopathy in term infants. Design: Population based, unmatched case-control study. Setting: Metropolitan area of Western Australia, June 1993 to September 1995. Subjects: All 164 term infants with moderate or severe newborn encephalopathy; 400 randomly selected controls. Main outcome measures: Adjusted odds ratio estimates. Results: The birth prevalence of moderate or severe newborn encephalopathy was 3.8/1000 term live births. The neonatal fatality was 9.1%. The risk of newborn encephalopathy increased with increasing maternal age and decreased with increasing parity. There was an increased risk associated with having a mother who was unemployed (odds ratio 3.60), an unskilled manual worker (3.84), or a housewife (2.48). Other risk factors from before conception were not having private health insurance (3.46), a family history of seizures (2.55), a family history of neurological disease (2.73), and infertility treatment (4.43). Risk factors during pregnancy were maternal thyroid disease (9.7), severe pre-eclampsia (6.30), moderate or severe bleeding (3.57), a clinically diagnosed viral illness (2.97), not having drunk alcohol (2.91); and placenta described at delivery as abnormal (2.07). Factors related to the baby were birth weight adjusted for gestational age between the third and ninth centile (4.37) or below the third centile (38.23). The risk relation with gestational age was J shaped with 38 and 39 weeks having the lowest risk. Conclusions: The causes of newborn encephalopathy are heterogeneous and many of the causal pathways start before birth.