The appendage role of insect disco genes and possible implications on the evolution of the maggot larval form

AbstractThough initially identified as necessary for neural migration, Disconnected and its partially redundant paralog, Disco-related, are required for proper head segment identity during Drosophila embryogenesis. Here, we present evidence that these genes are also required for proper ventral appendage development during development of the adult fly, where they specify medial to distal appendage development. Cells lacking the disco genes cannot contribute to the medial and distal portions of ventral appendages. Further, ectopic disco transforms dorsal appendages toward ventral fates; in wing discs, the medial and distal leg development pathways are activated. Interestingly, this appendage role is conserved in the red flour beetle, Tribolium (where legs develop during embryogenesis), yet in the beetle we found no evidence for a head segmentation role. The lack of an embryonic head specification role in Tribolium could be interpreted as a loss of the head segmentation function in Tribolium or gain of this function during evolution of flies. However, we suggest an alternative explanation. We propose that the disco genes always function as appendage factors, but their appendage nature is masked during Drosophila embryogenesis due to the reduction of limb fields in the maggot style Drosophila larva

Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes: results from the CANVAS Program

Patients with type 2 diabetes mellitus are at high risk of developing heart failure (HF).1 Sodium glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated, in large scale trials, to reduce the risk of HF events in patients with type 2 diabetes deemed to be at high risk based on established cardiovascular disease or multiple risk factors.2-4 However, it is unclear whether benefits are experienced across the broad spectrum of HF patients that includes those with preserved (HFpEF) as well as reduced ejection fraction (HFrEF)

Canagliflozin and heart failure in Type 2 diabetes mellitus: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)

BACKGROUND : Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure and cardiovascular death overall, in those with and without a baseline history of heart failure, and in other participant subgroups. METHODS : The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized heart failure. RESULTS : Participants with a history of heart failure at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of heart failure (P=0.03). CONCLUSIONS : In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized heart failure across a broad range of different patient subgroups. Benefits may be greater in those with a history of heart failure at baseline. CLINICAL TRIAL REGISTRATION : URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754

Association of chronic obstructive pulmonary disease with morbidity and mortality in patients with peripheral artery disease: insights from the EUCLID trial

Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of developing lower extremity peripheral artery disease (PAD) and suffering PAD-related morbidity and mortality. However, the effect and burden of COPD on patients with PAD is less well defined. This post hoc analysis from EUCLID aimed to analyze the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with PAD and concomitant COPD compared with those without COPD, and to describe the adverse events specific to patients with COPD. Methods: EUCLID randomized 13,885 patients with symptomatic PAD to monotherapy with either ticagrelor or clopidogrel for the prevention of MACE. In this analysis, MACE, MALE, mortality, and adverse events were compared between groups with and without COPD using unadjusted and adjusted Cox proportional hazards model. Results: Of the 13,883 patients with COPD status available at baseline, 11% (n=1538) had COPD. Patients with COPD had a higher risk of MACE (6.02 vs 4.29 events/100 patient-years; p< 0.001) due to a significantly higher risk of myocardial infarction (MI) (3.55 vs 1.85 events/100 patient-years; p< 0.001) when compared with patients without COPD. These risks persisted after adjustment (MACE: adjusted hazard ratio (aHR) 1.30, 95% confidence interval [CI] 1.11– 1.52; p< 0.001; MI: aHR 1.45, 95% CI 1.18– 1.77; p< 0.001). However, patients with COPD did not have an increased risk of MALE or major bleeding. Patients with COPD were more frequently hospitalized for dyspnea and pneumonia (2.66 vs 0.9 events/100 patient-years; aHR 2.77, 95% CI 2.12– 3.63; p< 0.001) and more frequently discontinued study drug prematurely (19.36 vs 12.54 events/100 patient-years; p< 0.001; aHR 1.34, 95% CI 1.22– 1.47; p< 0.001). Conclusion: In patients with comorbid PAD and COPD, the risks of MACE, respiratory-related adverse events, and premature study drug discontinuation were higher when compared with patients without COPD. Registration: ClinicalTrials.gov: NCT01732822

An Arctic strait of two halves: The changing dynamics of nutrient uptake and limitation across the Fram Strait

The hydrography of the Arctic Seas is being altered by ongoing climate change, with knock-on effects to nutrient dynamics and primary production. As the major pathway of exchange between the Arctic and the Atlantic, the Fram Strait hosts two distinct water masses in the upper water column, northward flowing warm and saline Atlantic Waters in the east, and southward flowing cold and fresh Polar Surface Water in the west. Here, we assess how physical processes control nutrient dynamics in the Fram Strait using nitrogen isotope data collected during 2016 and 2018. In Atlantic Waters, a weakly stratified water column and a shallow nitracline reduce nitrogen limitation. To the west, in Polar Surface Water, nitrogen limitation is greater because stronger stratification inhibits nutrient resupply from deeper water and lateral nitrate supply from central Arctic waters is low. A historical hindcast simulation of ocean biogeochemistry from 1970 to 2019 corroborates these findings and highlights a strong link between nitrate supply to Atlantic Waters and the depth of winter mixing, which shoaled during the simulation in response to a local reduction in sea-ice formation. Overall, we find that while the eastern Fram Strait currently experiences seasonal nutrient replenishment and high primary production, the loss of winter sea ice and continued atmospheric warming has the potential to inhibit deep winter mixing and limit primary production in the future

Association between TNF Receptors and KIM-1 with Kidney Outcomes in Early-Stage Diabetic Kidney Disease

Background and objectives: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. Tumor Necrosis Factor Receptor (TNFR)-1, TNFR-2 and Kidney Injury Marker (KIM)-1 are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNFR-1, TNFR-2 and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria. Design, setting, participants and measurements: TNFR-1, TNFR-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the CANVAS trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome and stratified the population by the 4th quartile of each biomarker distribution and assessed the number of events and event rates. Results: In patients with normoalbuminuria (N=2,553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (IQR 5.8 to 6.4) years (event rate 3.5 [95%CI 2.6-4.6] per 1,000-patient-years). Each doubling of baseline TNFR-1 (HR 4.16; 95%CI 1.80-9.61) and TNFR-2 (HR 2.35; 95%CI 1.51-3.63) was associated with a higher risk for the kidney outcome. Baseline KIM-1, UACR and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of the TNFR-1 (≥2,992 ng/ml) or TNFR-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000-patient-years compared to 2.4 and 2.8 in the lower three quartiles. Conclusion: TNFR-1 and TNFR-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria

Investigation of the Chaotic Dynamics of an Electron Beam with a Virtual Cathode in an External Magnetic Field

The effect of the strength of the focusing magnetic field on chaotic dynamic processes occurring inan electron beam with a virtual cathode, as well as on the processes whereby the structures form in the beamand interact with each other, is studied by means of two-dimensional numerical simulations based on solving a self-consistent set of Vlasov-Maxwell equations. It is shown that, as the focusing magnetic field is decreased,the dynamics of an electron beam with a virtual cathode becomes more complicated due to the formation andinteraction of spatio-temporal longitudinal and transverse structures in the interaction region of a vircator. The optimum efficiency of the interaction of an electron beam with the electromagnetic field of the vircator isachieved at a comparatively weak external magnetic field and is determined by the fundamentally two-dimensional nature of the motion of the beam electrons near the virtual cathode.Comment: 12 pages, 8 figure