CO-releasing Metal Carbonyl Compounds as Antimicrobial Agents in the Post-antibiotic Era

The possibility of a “post-antibiotic era” in the 21st century, in which common infections may kill, has prompted research into radically new antimicrobials. CO-releasing molecules (CORMs), mostly metal carbonyl compounds, originally developed for therapeutic CO delivery in animals, are potent antimicrobial agents. Certain CORMs inhibit growth and respiration, reduce viability, and release CO to intracellular hemes, as predicted, but their actions are more complex, as revealed by transcriptomic datasets and modeling. Progress is hindered by difficulties in detecting CO release intracellularly, limited understanding of the biological chemistry of CO reactions with non-heme targets, and the cytotoxicity of some CORMs to mammalian cells

Do nitric oxide, carbon monoxide and hydrogen sulfide really qualify as 'gasotransmitters' in bacteria?

A gasotransmitter is defined as a small, generally reactive, gaseous molecule that, in solution, is generated endogenously in an organism and exerts important signalling roles. It is noteworthy that these molecules are also toxic and antimicrobial. We ask: is this definition of a gasotransmitter appropriate in the cases of nitric oxide, carbon monoxide and hydrogen sulfide (H2S) in microbes? Recent advances show that, not only do bacteria synthesise each of these gases, but the molecules also have important signalling or messenger roles in addition to their toxic effects. However, strict application of the criteria proposed for a gasotransmitter leads us to conclude that the term 'small molecule signalling agent', as proposed by Fukuto and others, is preferable terminology

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries

Role of carbon monoxide in host–gut microbiome communication

Nature is full of examples of symbiotic relationships. The critical symbiotic relation between host and mutualistic bacteria is attracting increasing attention to the degree that the gut microbiome is proposed by some as a new organ system. The microbiome exerts its systemic effect through a diverse range of metabolites, which include gaseous molecules such as H2, CO2, NH3, CH4, NO, H2S, and CO. In turn, the human host can influence the microbiome through these gaseous molecules as well in a reciprocal manner. Among these gaseous molecules, NO, H2S, and CO occupy a special place because of their widely known physiological functions in the host and their overlap and similarity in both targets and functions. The roles that NO and H2S play have been extensively examined by others. Herein, the roles of CO in host–gut microbiome communication are examined through a discussion of (1) host production and function of CO, (2) available CO donors as research tools, (3) CO production from diet and bacterial sources, (4) effect of CO on bacteria including CO sensing, and (5) gut microbiome production of CO. There is a large amount of literature suggesting the “messenger” role of CO in host–gut microbiome communication. However, much more work is needed to begin achieving a systematic understanding of this issue

Psychosocial Functioning Problems over Time among High Risk Youths: A Latent Class Transition Analysis

The authors report the results of latent class analyses and latent class transition analyses of antisocial behavior risk factors among 137 youths participating in a juvenile diversion program. The study examined the youths’ latent classifications using baseline and 1-year follow-up measures of family, peer, education, and mental health risk factors. Latent class transition analyses were conducted to determine the stability and change of latent class membership across two time points. For both baseline and follow-up measures, latent class analyses suggested that two latent classes were most appropriate for characterizing the youths using the four domains of risk factors. One class reflected youths reporting few problems in any risk area; the second class reflected youths reporting problems in many of the risk domains. The latent class transition analyses indicated that about two thirds of the youths experienced similar problems over time. The results emphasize the heterogeneity of this study’s sample. Policy implications and intervention service needs are discussed

Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits.

Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r2 > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post–oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.Liana K. Billings, Yi-Hsiang Hsu, Rachel J. Ackerman, Josée Dupuis, Benjamin F. Voight, Laura J. Rasmussen-Torvik, Serge Hercberg, Mark Lathrop, Daniel Barnes, Claudia Langenberg, Jennie Hui, Mao Fu, Nabila Bouatia-Naji, Cecile Lecoeur, Ping An, Patrik K. Magnusson, Ida Surakka, Samuli Ripatti, Lene Christiansen, Christine Dalgård, Lasse Folkersen, Elin Grundberg, the MAGIC Investigators, the DIAGRAM, Consortium, the MuTHER Consortium, the ASCOT Investigators, the GEFOS Consortium, Per Eriksson, Jaakko Kaprio, Kirsten Ohm Kyvik, Nancy L. Pedersen, Ingrid B. Borecki, Michael A. Province, Beverley Balkau, Philippe Froguel, Alan R. Shuldiner, Lyle J. Palmer, Nick Wareham, Pierre Meneton, Toby Johnson, James S. Pankow, David Karasik, James B. Meigs, Douglas P. Kiel, and Jose C. Flore

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity. © 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR &lt; 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity. © 2015 Reppe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P &lt; 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits