Rare variants in single-minded 1 (SIM1) are associated with severe obesity

Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.Shwetha Ramachandrappa, Anne Raimondo, Anna M.G. Cali, Julia M. Keough, Elana Henning, Sadia Saeed, Amanda Thompson, Sumedha Garg, Elena G. Bochukova, Soren Brage, Victoria Trowse, Eleanor Wheeler, Adrienne E. Sullivan, Mehul Dattani, Peter E. Clayton, Vippan Datta, John B. Bruning, Nick J. Wareham, Stephen O'Rahilly, Daniel J. Peet, Ines Barroso, Murray L. Whielaw and I. Sadaf Farooq

Dechlorinase activity and chlordane removal by Streptomyces strains as pure and mixed defined cultures

Chlordane (CLD) is a toxic fumigating agent widely used in the past, which is now found in air, soil and water resources. Technical chlordane consists in 147 components, and it has been included in the list of the 12 persistent organic pollutants of Stockholm Convention (2001) because of its persistence, toxicity and tendency to biomagnification. Bioremediation is an attractive cleaning technique of polluted environments. The use of actinobacteria for this purpose, results an effective biotechnological approach due to their metabolic versatility and furthermore their use in mixed cultures can increase the catabolic pathways available for biodegrading these contaminants. The aim of this work was to evaluate the chlordane removal capacity and dechlorinase activity by pure and mixed actinobacteria cultures, under controlled laboratory conditions, and to select one mixed culture for further morphological studies. Streptomyces spp. M7, A2, A5, A6, A13 previously isolated in the laboratory and Streptomyces coelicolor A3 (2) were cultivated individually in minimal medium (MM) with CLD for acclimation. These strains, as pure cultures and consortia from two to six microorganisms, were cultivated in MM with CLD (1.66 mg L-1). Microbial cells were used to obtain cell-free extracts for dechlorinase activity assays and the supernatants of these cultures were used to determine residual CLD by gas chromatography. The selected mixed culture according to their dechlorinase activity and capacity to remove CLD was grown in MM either with glucose or chlordane as carbon source and analyzed at 72 h in an optical microscope the probability of morphological changes. Dechlorinase activity ranged between 0.00 to 1291.28 mmolCl-/h/mg protein and CLD removal percentages was between 82.6 to 95.5%. The mixed culture consisting of Streptomyces sp. A2-A13-Streptomyces coelicolor A3(2) showed the best enzyme activity but not the minimal residual CLD concentration. Because no linear relationship between residual CLD and enzyme activity was obtained, the ratio between these two parameters was evaluated, and the mixed culture Streptomyces sp. A2-A5-A13 with the minimal obtained relationship was selected. In CLD presence, the microscopic analysis of this culture showed scarce vegetative cells and numerous spores, which results of the hyphal fragmentation. These Streptomyces strains were able to grow as mixed cultures, in CLD presence, and showed ability to dechlorinate and remove this toxic compound from the culture medium. Therefore the mixed culture of Streptomyces sp. A2-A5-A13 could be a promising tool for CLD biodegradation.Fil: Fuentes, María Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Colin, Veronica Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; ArgentinaFil: Raimondo, Enzo Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; ArgentinaFil: Benimeli, Claudia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; Argentina. Universidad del Norte Santo Tomás de Aquino; ArgentinaFil: Amoroso, Maria Julia del R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Planta Piloto de Procesos Industriales Microbiológicos; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; ArgentinaIX Congreso Argentino de Microbiología GeneralRosarioArgentinaSociedad Argentina de Microbiología Genera

Evaluation of Ki-67 expression in feline non-ocular melanocytic tumours

Fifty tumours located in skin (n = 33) and mucosae (n = 17) were included. Forty-eight percent and 95% of amelanotic tumours (n = 21) stained positive for Melan A and S100, respectively. Most achromic tumours were mucosal (P  5, Ki-67 > 20% and lack of treatment administration. On multivariable analysis, only tumour histotype and treatment retained prognostic significance. Conclusions Although the majority of feline NOMs behave aggressively, Ki-67 index, together with other parameters, may contribute to prognostic assessment. Prospective studies on homogeneous populations are warranted to identify reliable threshold values for this marker

Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs

Australian Drug Trends 2024: Key Findings from the National Illicit Drug Reporting System (IDRS) Interviews

The Illicit Drug Reporting System (IDRS) is a monitoring system identifying trends in illicit drug markets that has been conducted in all capital cities of Australia since 2000. The IDRS is an ongoing project that has been conducted on an annual basis in Sydney, New South Wales since 1996, and in all capital cities of Australia since 2000. Capital cities contain the major drug markets (e.g., the Melbourne suburb of North Richmond) wherein the majority of drug use occurs. As such, it is in these cities that new trends, that may diffuse to other areas, are likely to emerge. The IDRS monitors the price, perceived purity and perceived availability of heroin, methamphetamine, cocaine, cannabis and other drugs. It also examines trends in the use of these drugs, and associated behaviours and harms. The IDRS is designed to be sensitive to emerging trends, providing data in a timely manner, rather than describing issues in extensive detail. This report presents the findings from interviews conducted in 2024

Australian Drug Trends 2024: Key Findings From the National Ecstasy and Related Drugs Reporting System (EDRS) Interview

The Ecstasy and Related Drugs Reporting System (EDRS) is the most comprehensive and detailed study of ecstasy and related drug use, market features, and harms in Australia. The focus is on the capital city in each state/territory because trends in illicit drug markets are more likely to emerge in large cities rather than regional centres or rural areas. The exception to this is QLD, where data are collected in Brisbane and the Gold Coast. The EDRS interviews capture self-report information about drugs that are routinely used in the context of entertainment venues and other recreational locations including nightclubs, dance parties, pubs and music festivals. This includes ecstasy, methamphetamine, cocaine, LSD, ketamine, MDA, new psychoactive substances (NPS; e.g., mephedrone, synthetic cannabis) and GHB. The EDRS is designed to be sensitive to emerging trends, providing data in a timely manner, rather than describing issues in extensive detail. This report presents the findings from interviews conducted in 2024