Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Genome rearrangements of Streptomyces albus J1074 lead to the carotenoid gene cluster activation

Myronovskyi M, Tokovenko B, Brötz E, Rückert C, Kalinowski J, Luzhetskyy A. Genome rearrangements of Streptomyces albus J1074 lead to the carotenoid gene cluster activation. Applied microbiology and biotechnology. 2014;98(2):795-806.Streptomyces albus J1074 is a derivative of the S. albus G1 strain defective in SalG1 restriction-modification system. Genome sequencing of S. albus J1074 revealed that the size of its chromosome is 6.8 Mb with unusually short terminal arms of only 0.3 and 0.4 Mb. Here we present our attempts to evaluate the dispensability of subtelomeric regions of the S. albus J1074 chromosome. A number of large site-directed genomic deletions led to circularization of the S. albus J1074 chromosome and to the overall genome reduction by 307 kb. Two spontaneous mutants with an activated carotenoid cluster were obtained. Genome sequencing and transcriptome analysis indicated that phenotypes of these mutants resulted from the right terminal 0.42 Mb chromosomal region deletion, followed by the carotenoid cluster amplification. Our results indicate that the right terminal 0.42 Mb fragment is dispensable under laboratory conditions. In contrast, the left terminal arm of the S. albus J1074 chromosome contains essential genes and only 42 kb terminal region is proved to be dispensable. We identified overexpressed carotenoid compounds and determined fitness costs of the large genomic rearrangements

Marine Population Genomics: Challenges and Opportunities

Population genomics is revolutionizing biology and stimulating new research questions and directions. While human health has driven many of the genomics tools and approaches, all other biological fields have benefitted. This is certainly true in the world’s oceans, which encompass a large diversity of species and ecosystems. In the world’s oceans, population genomics approaches are giving us an unprecedented ability to gain a better understanding of the organisms inhabiting these ecosystems. While population genomics approaches are improving our understanding of genetic diversity and population genetic parameters in marine organisms, they also are providing unexpected insights into marine invasions, population connectivity, and how marine organisms are responding to different stimuli and environments. Some examples include identification of connectivity among populations that is not predicted by geography as well as identification of genes and genetic variants under natural selection in response to environment and climate conditions as indicators of genes and pathways responsible for adaption. This knowledge is important because so much of the world’s oceans is understudied. This knowledge also is critical for understanding how marine organisms will respond to environmental change and thus how we can better protect marine biodiversity and marine resources. That is, we can better predict the effects of enhanced migration on mitigating anthropogenic stressors affecting marine populations and whether outcrossing will enhance population survival or result in outbreeding depression. Simply put, population genomics provides the genetic resolution to make better predictions about how environmental change is affecting populations and thus provides insights into how we might address environmental change’s deleterious effects on important marine resources. In this chapter, we provide an overview of the challenges and opportunities for marine population genomics, addressing how population genomics can be used to understand marine biodiversity, population demographics and connectivity, and response to environmental changes as well as assist sustainable management, protection, and conservation of marine biodiversity