Phenomenology of Light Sneutrino Dark Matter in cMSSM/mSUGRA with Inverse Seesaw

We study the possibility of a light Dark Matter (DM) within a constrained Minimal Supersymmetric Standard Model (cMSSM) framework augmented by a SM singlet-pair sector to account for the non-zero neutrino masses by inverse seesaw mechanism. Working within a 'hybrid' scenario with the MSSM sector fixed at high scale and the singlet neutrino sector at low scale, we find that, contrary to the case of the usual cMSSM where the neutralino DM cannot be very light, we can have a light sneutrino DM with mass below 100 GeV satisfying all the current experimental constraints from cosmology, collider as well as low-energy experiments. We also note that the supersymmetric inverse seesaw mechanism with sneutrino as the lightest supersymmetric partner can have enhanced same-sign dilepton final states with large missing transverse energy (mET) coming from the gluino- and squark-pair as well as the squark-gluino associated productions and their cascade decay through charginos. We present a collider study for the same-sign dilepton+jets+mET signal in this scenario and propose some distinctions with the usual cMSSM. We also comment on the implications of such a light DM scenario on the invisible decay width of an 125 GeV Higgs boson.Comment: 24 pages, 4 figures, 7 tables; matches published versio

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In Argentina, colorectal cancer (CRC) is the second most common cancer in terms of incidence and mortality (12.2% of the total). Early diagnosis (pre-neoplastic lesions and stage 0) allows a 90% survival rate. To encourage early detection of CRC in Cordoba, a pilot experience (PE) population-based screening using a fecal immunochemical test (iFOBT) among adults aged 50 to 75 years, was designed by the Ministry of Health of the Province; taking place in the Department of Pocho (2018–2019). Objectives: to describe the sociodemographic characteristics and lifestyle habits of PE participants and to identify risk profiles associated with the iFOBT result and risk group: average (AR) or elevated (ER). The results of the iFOBT and interviews conducted during the implementation of the project were analyzed. Simple descriptive statistics, χ² test, multiple correspondence analysis (MCA), and logistic regressions were calculated. A total of 265 individuals participated (49.8% women), 19.6% ER and 80.4% AR; positivity rate of the test=19.3%. According to the MCA, the ER group was characterized by obesity, elevated glucose, blood pressure and cholesterol, and no physical activity; while the AR group was characterized by physical activity, eutrophic Body Mass Index and low educational level (EL). Regarding ER, consuming grilled meat was a protective factor (PF) (OR=0.30 - IC95% 0.10-0.86), and being obese was a risk factor (RF) (OR=3.82 - IC95% 1.03-14.08). The iFOBT+ group was characterized by being formed by males, ≤60 years old, with low EL and without health coverage (HC); the iFOBTi- group by being formed by females, ≥60 years old, overweight, HC, and complete secondary school. Regarding the iFOBT outcome, the female sex was a PF (OR=0.13 -IC95% 0.04-0.54) and low EL a RF (OR=8.02-IC95% 1.71-37.56).  This PE allowed us to characterize a population of adults in an area with low accessibility to the health system, to identify a high burden of morbidity potentially associated with CRC, and to install a screening program with high acceptance, laying the groundwork for future actions.En Argentina el Cáncer Colorrectal (CCR) es el segundo en incidencia y mortalidad (12,2% del total). El diagnóstico temprano (lesiones pre-neoplásicas y estadío 0), permite una sobrevida del 90%. A fin de promover la detección temprana del CCR en Córdoba, el Ministerio de Salud provincial diseñó una experiencia piloto (EP) de tamizaje poblacional mediante Test Inmunoquímico de Sangre Oculta en Materia Fecal (TSOMFi), entre adultos de 50 a 75 años del Departamento de Pocho (2018-2019). Objetivos: describir las características sociodemográficas y hábitos de vida de las/os participantes en la EP e identificar perfiles de riesgo asociados al resultado del TSOMFi y al grupo de riesgo, promedio (RP) o elevado (RE). Se analizaron los resultados del TSOMFi y entrevistas realizadas durante su implementación. Se calcularon estadísticas descriptivas simples, test χ², análisis factorial de correspondencias múltiples (AFCM) y regresiones logísticas. Participaron 265 personas, (49,8% mujeres), 19,6% RE y 80,4% RP, tasa de positividad del test=19,3%. Según el AFCM, el grupo de RE se caracterizó por presentar obesidad, glucemia, tensión arterial y colesterol elevados y no realizar actividad física; y el de RP por realizar actividad física, presentar Índice de Masa Corporal eutrófico y bajo nivel de instrucción (NI). Con respecto al RE, consumir carne asada fue un factor de protección (FP); (OR=0,30 -IC95% 0,10-0,86) y ser obesas/os, un factor de riesgo (FR) (OR=3,82 IC95% 1,03-14,08). El grupo con TSOMFi+ se caracterizó por estar integrado por varones, ≤60 años, con bajo NI y sin cobertura de salud (CS); el grupo con TSOMFi- por estar integrado por mujeres, ≥60 años, con sobrepeso, CS y secundario completo. Respecto al resultado del TSOMFi, el sexo femenino fue un FP (OR=0,13 -IC95% 0,04-0,54) y el bajo NI un FR (OR=8,02-IC95% 1,71-37,56). Este EP permitió caracterizar una población de adultos de una zona de baja accesibilidad al sistema de salud, identificar una alta carga de morbilidad potencialmente asociada al CCR e instalar un programa de tamizaje con alta aceptación, sentando bases para acciones futuras.  

Mechanism and timing of Mcm2–7 ring closure during DNA replication origin licensing

The opening and closing of two ring-shaped Mcm2-7 DNA helicases is necessary to license eukaryotic origins of replication, although the mechanisms controlling these events are unclear. The origin-recognition complex (ORC), Cdc6 and Cdt1 facilitate this process by establishing a topological link between each Mcm2-7 hexamer and origin DNA. Using colocalization single-molecule spectroscopy and single-molecule Förster resonance energy transfer (FRET), we monitored ring opening and closing of Saccharomyces cerevisiae Mcm2-7 during origin licensing. The two Mcm2-7 rings were open during initial DNA association and closed sequentially, concomitant with the release of their associated Cdt1. We observed that ATP hydrolysis by Mcm2-7 was coupled to ring closure and Cdt1 release, and failure to load the first Mcm2-7 prevented recruitment of the second Mcm2-7. Our findings identify key mechanisms controlling the Mcm2-7 DNA-entry gate during origin licensing, and reveal that the two Mcm2-7 complexes are loaded via a coordinated series of events with implications for bidirectional replication initiation and quality control.National Institutes of Health (U.S.) (Grant R01 GM52339)National Institutes of Health (U.S.) (Pre-Doctoral Training Grant GM007287)National Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051

Mediterranean-climate streams and rivers: geographically separated but ecologically comparable freshwater systems

Streams and rivers in mediterranean-climate regions (med-rivers in med-regions) are ecologically unique, with flow regimes reflecting precipitation patterns. Although timing of drying and flooding is predictable, seasonal and annual intensity of these events is not. Sequential flooding and drying, coupled with anthropogenic influences make these med-rivers among the most stressed riverine habitat worldwide. Med-rivers are hotspots for biodiversity in all med-regions. Species in med-rivers require different, often opposing adaptive mechanisms to survive drought and flood conditions or recover from them. Thus, metacommunities undergo seasonal differences, reflecting cycles of river fragmentation and connectivity, which also affect ecosystem functioning. River conservation and management is challenging, and trade-offs between environmental and human uses are complex, especially under future climate change scenarios. This overview of a Special Issue on med-rivers synthesizes information presented in 21 articles covering the five med-regions worldwide: Mediterranean Basin, coastal California, central Chile, Cape region of South Africa, and southwest and southern Australia. Research programs to increase basic knowledge in less-developed med-regions should be prioritized to achieve increased abilities to better manage med-rivers

Purification and preliminary crystallographic analysis of a new Lys49-PLA2 from B-jararacussu

BjVIII is a new myotoxic Lys49-PLA2 isolated from Bothrops jararacussu venom that exhibits atypical effects on human platelet aggregation. To better understand the mode of action of BjVIII, crystallographic studies were initiated. Two crystal forms were obtained, both containing two molecules in the asymmetric unit (ASU). Synchrotron radiation diffraction data were collected to 2.0 angstrom resolution and 1.9 angstrom resolution for crystals belonging to the space group P2(1)2(1)2(1) (a = 48.4 angstrom, b = 65.3 angstrom, c = 84.3 angstrom) and space group P3(1)21 (a = b = 55.7 angstrom, c = 127.9 angstrom), respectively. Refinement is currently in progress and the refined structures are expected to shed light on the unusual platelet aggregation activity observed for BjVIII.9573675

Expression of glycolytic enzymes in ovarian cancers and evaluation of the glycolytic pathway as a strategy for ovarian cancer treatment

Table S2. Spearman correlation of the expression of four glycolytic enzymes in a cohort of 380 ovarian cancers. Spearman rho correlation values (top value) along with the respective adjusted P value (bottom value) of statistically significant correlations thresholded at FDR P < 0.01 are summarised. (DOCX 21 kb

Prenylation Inhibition-Induced Cell Death in Melanoma: Reduced Sensitivity in BRAF Mutant/PTEN Wild-Type Melanoma Cells.

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.