Late Holocene linkages between decade–century scale climate variability and productivity at Lake Tanganyika, Africa

Microlaminated sediment cores from the Kalya slope region of Lake Tanganyika provide a near-annually resolved paleoclimate record between ~~2,840 and 1,420 cal. yr B.P. demonstrating strong linkages between climate variability and lacustrine productivity. Laminae couplets comprise dark, terrigenous-dominated half couplets, interpreted as low density underflows deposited from riverine sources during the rainy season, alternating with light, planktonic diatomaceous ooze, with little terrigenous component, interpreted as windy/dry season deposits. Laminated portions of the studied cores consist of conspicuous dark and light colored bundles of laminae couplets. Light and dark bundles alternate at decadal time scales. Within dark bundles, both light and dark half couplets are significantly thinner than within light bundles, implying slower sediment accumulation rates during both seasons over those intervals. Time series analyses of laminae thickness patterns demonstrate significant periodicities at interannual¿centennial time scales. Longer time scale periodicities (multidecadal to centennial scale) of light and dark half couplet thicknesses are coherent and in some cases are similar to solar cycle periods on these time scales. Although laminae thickness cycles do not strongly covary with the actual ¿14C record for this same time period, two large ¿14C anomalies are associated with substantial decreases in both light and dark laminae thickness. In contrast to the multidecadal¿ centennial time scale, significant annual to decadal periodicities, which are broadly consistent with ENSO/PDO forcing and their impact on East African climate, are not coherent between light and dark half couplets. The coherency of light¿dark couplets at decadal¿centennial time scales, but not at shorter time scales, is consistent with a model of a long-term relationship between precipitation (recorded in wet season dark laminae thickness) and productivity (light laminae thickness), which is not manifest at shorter time scales. We hypothesize that this coupling results from long-term recharging of internal nutrient loading during wet periods (higher erosion of soil P) and reduced loading during drought intervals. The relationship is not expressed on short time scales during which the dominant control on productivity is wind-driven, dry season upwelling, which is uncorrelated with wet-season precipitation. Our record greatly extends the temporal record of this quasi-periodic behavior throughout the late Holocene and provides the first evidence linking decade- to century-scale episodes of enhanced productivity to enhanced precipitation levels and nutrient recharge in a productive tropical lake

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Divalent Metal Ions Tune the Self-Splicing Reaction of the Yeast Mitochondrial Group II Intron Sc.ai5γ

Group II introns are large ribozymes, consisting of six functionally distinct domains that assemble in the presence of Mg2+ to the active structure catalyzing a variety of reactions. The first step of intron splicing is well characterized by a Michaelis–Menten-type cleavage reaction using a two-piece group II intron: the substrate RNA, the 5′-exon covalently linked to domains 1, 2, and 3, is cleaved upon addition of domain 5 acting as a catalyst. Here we investigate the effect of Ca2+, Mn2+, Ni2+, Zn2+, Cd2+, Pb2+, and [Co(NH3)6]3+ on the first step of splicing of the Saccharomyces cerevisiae mitochondrial group II intron Sc.ai5γ. We find that this group II intron is very sensitive to the presence of divalent metal ions other than Mg2+. For example, the presence of only 5% Ca2+ relative to Mg2+ results in a decrease in the maximal turnover rate k cat by 50%. Ca2+ thereby has a twofold effect: this metal ion interferes initially with folding, but then also competes directly with Mg2+ in the folded state, the latter being indicative of at least one specific Ca2+ binding pocket interfering directly with catalysis. Similar results are obtained with Mn2+, Cd2+, and [Co(NH3)6]3+. Ni2+ is a much more powerful inhibitor and the presence of either Zn2+ or Pb2+ leads to rapid degradation of the RNA. These results show a surprising sensitivity of such a large multidomain RNA on trace amounts of cations other than Mg2+ and raises the question of biological relevance at least in the case of Ca2+

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferator-activated receptor γ coactivators 1 (PGC-1s) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that, in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-κB) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications