Statistics in focus: Population and social conditions. Social protection in Europe. 2000.15

As the first step for approaching the uniqueness and blowup properties of the solutions of the stochastic wave equations with multiplicative noise, we analyze the conditions for the uniqueness and blowup properties of the solution (Xt,Yt) of the equations dXt=Ytdt, dYt=|Xt|αdBt, (X0,Y0)=(x0,y0). In particular, we prove that solutions are nonunique if 01 and (x0,y0)≠(0,0)

hMOB2 deficiency impairs homologous recombination-mediated DNA repair and sensitises cancer cells to PARP inhibitors

Monopolar spindle-one binder (MOBs) proteins are evolutionarily conserved and contribute to various cellular signalling pathways. Recently, we reported that hMOB2 functions in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest in untransformed cells. However, the question of how hMOB2 protects cells from endogenous DNA damage accumulation remained enigmatic. Here, we uncover hMOB2 as a regulator of double-strand break (DSB) repair by homologous recombination (HR). hMOB2 supports the phosphorylation and accumulation of the RAD51 recombinase on resected single-strand DNA (ssDNA) overhangs. Physiologically, hMOB2 expression supports cancer cell survival in response to DSB-inducing anti-cancer compounds. Specifically, loss of hMOB2 renders ovarian and other cancer cells more vulnerable to FDA-approved PARP inhibitors. Reduced MOB2 expression correlates with increased overall survival in patients suffering from ovarian carcinoma. Taken together, our findings suggest that hMOB2 expression may serve as a candidate stratification biomarker of patients for HR-deficiency targeted cancer therapies, such as PARP inhibitor treatments

Contrasting responses of native ant communities to invasion by an ant invader, Linepithema humile

Invasive alien species pose a serious threat to the integrity and function of natural ecosystems. Understanding how these invaders alter natural communities is therefore an important aspect in predicting the likely future outcomes of biological invasions. Many studies have documented the consequences of invasive alien species on native community structure, through the displacement and local extinction of native species. However, sampling methods and intensities are rarely standardised across such studies, meaning that it is not clear whether differences in response among native communities to the same invader species are due to biological differences between the invaded regions, or differences in the methodologies used. Here we use a matched sampling methodology to compare the effects of the Argentine ant (Linepithema humile Mayr) on native ant community assemblages in two distinct biogeographical regions that share similar ecologies: Girona (Spain) and Jonkershoek Nature Reserve (South Africa). We found a strong negative association between L. humile presence and native ant species richness within both geographic regions. However, the effects differed between the two study regions: in Girona, a single native ant species (Plagiolepis pygmaea) persisted in invaded sites; by contrast, substantially more native ant species persisted at invaded sites in Jonkershoek Nature Reserve. In addition, in Jonkershoek Nature Reserve, the abundance of certain native species appeared to increase in the presence of L. humile. This study therefore demonstrates the potential variable effects of an invasive species in contrasting locations within different biogeographical regions. Future work should explore the causes of this differential resistance among communities and expand standardised sampling approaches to more invaded zones to further explore how local biotic or abiotic conditions of a region determine the nature and extent of impact of L. humile invasion on native ant communities

Northern Hemisphere atmospheric pattern enhancing Eastern Mediterranean Transient-type events during the past 1000 years

High-resolution climate model simulations for the last millennium were used to elucidate the main winter Northern Hemisphere atmospheric pattern during enhanced Eastern Mediterranean Transient (EMT-type) events, a situation in which an additional overturning cell is detected in the Mediterranean at the Aegean Sea. The differential upward heat flux between the Aegean Basin and the Gulf of Lion was taken as a proxy of EMT-type events and correlated with winter mean geopotential height at 500 mbar in the Northern Hemisphere (20-90 degrees N and 100 degrees W-80 degrees E). Correlations revealed a pattern similar to the East Atlantic/Western Russian (EA/WR) mode as the main driver of EMT-type events, with the past 1000 years of EA/WR-like mode simulations being enhanced during insolation minima. Our model results are consistent with alkenone sea surface temperature (SST) reconstructions that documented an increase in the west-east basin gradients during EMT-type events

Tofacitinib in Patients With Psoriatic Arthritis and Metabolic Syndrome: A Post hoc Analysis of Phase 3 Studies

Objective: Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. Methods: Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease‐modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire‐Disability Index (HAQ‐DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C‐reactive protein, HAQ‐DI, Patient’s/Physician’s Global Assessment of Arthritis, and patient‐reported outcomes. Safety outcomes included treatment‐emergent all‐causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases. Results: Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib‐treated patients with MetS. Conclusion: Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS

Subhalo destruction in the Apostle and Auriga simulations

N-body simulations make unambiguous predictions for the abundance of substructures within dark matter halos. However, the inclusion of baryons in the simulations changes the picture because processes associated with the presence of a large galaxy in the halo can destroy subhalos and substantially alter the mass function and velocity distribution of subhalos. We compare the effect of galaxy formation on subhalo populations in two state-of-the-art sets of hydrodynamical ΛCDM simulations of Milky Way mass halos, APOSTLE and AURIGA. We introduce a new method for tracking the orbits of subhalos between simulation snapshots that gives accurate results down to a few kiloparsecs from the centre of the halo. Relative to a dark matter-only simulation, the abundance of subhalos in APOSTLE is reduced by 50% near the centre and by 10% within r200. In AURIGA the corresponding numbers are 80% and 40%. The velocity distributions of subhalos are also affected by the presence of the galaxy, much more so in AURIGA than in APOSTLE. The differences on subhalo properties in the two simulations can be traced back to the mass of the central galaxies, which in AURIGA are typically twice as massive as those in APOSTLE. We show that some of the results from previous studies are inaccurate due to systematic errors in the modelling of subhalo orbits near the centre of halos

MEK inhibition leads to BRCA2 downregulation and sensitization to DNA damaging agents in pancreas and ovarian cancer models

Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines. Apoptosis was assessed by Caspase 3/7 assay and protein expression was detected by immunoblotting. DNA damage response was monitored with γH2AX and RAD51 immunofluorescence staining. In vivo antitumor activity of pimasertib with evofosfamide were assessed in pancreatic cancer xenografts. We found that BRCA2 protein expression was downregulated following pimasertib treatment under hypoxic conditions. This translated into reduced homologous recombination repair demonstrated by levels of RAD51 foci. MEK inhibition was sufficient to induce formation of γH2AX foci, suggesting that inhibition of this pathway would impair DNA repair. When combined with olaparib or evofosfamide, pimasertib treatment enhanced DNA damage and increased apoptosis. The combination of pimasertib with evofosfamide demonstrated increased anti-tumor activity in BRCA wild-type Mia-PaCa-2 xenograft model, but not in the BRCA mutated BxPC3 model. Our data suggest that targeted MEK inhibition leads to impaired homologous recombination DNA damage repair and increased PARP inhibition sensitivity in BRCA- 2 proficient cancers

Kahler Moduli Inflation Revisited

We perform a detailed numerical analysis of inflationary solutions in Kahler moduli of type IIB flux compactifications. We show that there are inflationary solutions even when all the fields play an important role in the overall shape of the scalar potential. Moreover, there exists a direction of attraction for the inflationary trajectories that correspond to the constant volume direction. This basin of attraction enables the system to have an island of stability in the set of initial conditions. We provide explicit examples of these trajectories, compute the corresponding tilt of the density perturbations power spectrum and show that they provide a robust prediction of n_s approximately 0.96 for 60 e-folds of inflation.Comment: 27 pages, 9 figure

Leishmania isoenzyme polymorphisms in Ecuador: Relationships with geographic distribution and clinical presentation

Background: Determinants of the clinical presentation of the leishmaniases are poorly understood but Leishmania species and strain differences are important. To examine the relationship between clinical presentation, species and isoenzyme polymorphisms, 56 Leishmania isolates from distinct presentations of American tegumentary leishmaniasis (ATL) from Ecuador were analyzed. Methods: Isolates were characterized by multilocus enzyme electrophoresis for polymorphisms of 11 isoenzymes. Patients were infected in four different ecologic regions: highland and lowland jungle of the Pacific coast, Amazonian lowlands and Andean highlands. Results: Six Leishmania species constituting 21 zymodemes were identified: L. (Viannia) panamensis (21 isolates, 7 zymodemes), L. (V.) guyanensis (7 isolates, 4 zymodemes), L. (V.) braziliensis (5 isolates, 3 zymodemes), L. (Leishmania) mexicana (11 isolates, 4 zymodemes), L. (L.) amazonensis (10 isolates, 2 zymodemes) and L. (L.) major (2 isolates, 1 zymodeme). L. panamensis was the species most frequently identified in the Pacific region and was associated with several clinical variants of cutaneous disease (CL); eight cases of leishmaniasis recidiva cutis (LRC) found in the Pacific highlands were associated with 3 zymodemes of this species. Mucocutaneous leishmaniasis found only in the Amazonian focus was associated with 3 zymodemes of L. braziliensis. The papular variant of CL, Uta, found in the Andean highlands was related predominantly with a single zymodeme of L. mexicana. Conclusion: Our data show a high degree of phenotypic variation within species, and some evidence for associations between specific variants of ATL (i.e. Uta and LRC) and specific Leishmania zymodemes. This study further defines the geographic distribution of Leishmania species and clinical variants of ATL in Ecuador