First evidence of population genetic structure of the deep-water blackmouth catshark Galeus melastomus Rafinesque, 1810

Genetic connectivity at large spatial scales. Given the lack of species-specific nuclear markers, a total of 129 microsatellite loci (Simple Sequence Repeats, SSRs) were cross-amplified on blackmouth catshark specimens collected in eight geographically distant areas in the Mediterranean Sea and North-eastern Atlantic Ocean. A total of 13 SSRs were finally selected for genotyping, based on which the species exhibited signs of weak, but tangible genetic structure. The clearcut evidence of genetic differentiation of G. melastomus from Scottish waters from the rest of the population samples was defined, indicating that the species is genetically structured in the Mediterranean Sea and adjacent Southern North-eastern Atlantic. Both individual and frequency-based analyses identified a genetic unit formed by the individuals collected in the Tyrrhenian Sea and the Strait of Sicily, distinguished from the rest of the Mediterranean and Portuguese samples. In addition, Bayesian analyses resolved a certain degree of separation of the easternmost Aegean sample and the admixed nature of the other Mediterranean and the Portuguese samples. Here, our results supported the hypothesis that the interaction between the ecology and biology of the species and abiotic drivers such as water circulations, temperature and bathymetry may affect the dispersion of G. melastomus, adding new information to the current knowledge of the connectivity of this deep-water species and providing powerful tools for estimating its response to anthropogenic impacts

Targeting colorectal cancer stem cells with inducible caspase-9

Colorectal cancer stem cells (CSCs) drive tumor growth and are suggested to initiate distant metastases. Moreover, colon CSCs are reportedly more resistant to conventional chemotherapy, which is in part due to upregulation of anti-apoptotic Bcl-2 family members. To determine whether we could circumvent this apoptotic blockade, we made use of an inducible active caspase-9 (iCasp9) construct to target CSCs. Dimerization of iCasp9 with AP20187 in HCT116 colorectal cancer cells resulted in massive and rapid induction of apoptosis. In contrast to fluorouracil (5-FU)-induced apoptosis, iCasp9-induced apoptosis was independent of the mitochondrial pathway as evidenced by Bax/Bak double deficient HCT116 cells. Dimerizer treatment of colon CSCs transduced with iCasp9 (CSC-iCasp9) also rapidly induced high levels of apoptosis, while these cells were unresponsive to 5-FU in vitro. More importantly, injection of the dimerizer into mice that developed a colon CSC-iCasp9-induced tumor resulted in a strong decrease in tumor size, an increase in tumor cell apoptosis and a clear loss of CD133+ CSCs. Taken together, our data indicate that dimerization of iCasp9 circumvents the apoptosis block in CSCs, which results in effective tumor regression in vivo

Search for supersymmetric particles in scenarios with a gravitino LSP and stau NLSP

Sleptons, neutralinos and charginos were searched for in the context of scenarios where the lightest supersymmetric particle is the gravitino. It was assumed that the stau is the next-to-lightest supersymmetric particle. Data collected with the DELPHI detector at a centre-of-mass energy near 189 GeV were analysed combining the methods developed in previous searches at lower energies. No evidence for the production of these supersymmetric particles was found. Hence, limits were derived at 95% confidence level.Comment: 31 pages, 14 figure

Study of B0_s anti-B0_s oscillations and B0_s lifetimes using hadronic decays of B0_s mesons

Oscillations of B0s mesons have been studied in samples selected from about 3.5 million hadronic Z decays detected by DELPHI between 1992 and 1995. One analysis uses events in the exclusive decay channels: B0s -> Ds- pi+ or Ds- a1+ and B0s -> anti-D0 K- pi+ or anti-D0 K- a1+, where the D decays are completely reconstructed. In addition, B0s anti-B0s oscillations have been studied in events with an exclusively reconstructed Ds accompanied in the same hemisphere by a high momentum hadron of opposite charge. Combining the two analyses, a limit on the mass difference between the physical B0s states has been obtained: Delta(m_B0s) > 4.0 ps^{-1} at the 95% C.L. with a sensitivity of Delta(m_B0s) = 3.2 ps^{-1}. Using the latter sample of events, the B0s lifetime has been measured and an upper limit on the decay width difference between the two physical B0s states has been obtained: tau(B0s) = 1.53^{+0.16}_{-0.15}(stat.) +/- {0.07}(syst.) ps \Delta\Gamma(B0s)/\Gamma(B0s) < 0.69 at the 95% C.L. The combination of these results with those obtained using Ds+- lepton-+ sample gives: Delta(m_B0s) > 4.9 ps^{-1} at the 95% C.L. with a sensitivity of Delta(m_B0s) = 8.7 ps^{-1}. tau(B0s) = 1.46 +/- 0.11 ps and \Delta\Gamma(B0s)/\Gamma(B0s) < 0.45 at the 95% C.L.Comment: 42 pages, 13 figure

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