Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

Chromosomal instability (CIN) lies at the core of cancer development leading to aneuploidy, chromosomal copy-number heterogeneity (chr-CNH) and ultimately, unfavorable clinical outcomes. Despite its ubiquity in cancer, the presence of CIN in childhood B-cell acute lymphoblastic leukemia (cB-ALL), the most frequent pediatric cancer showing high frequencies of aneuploidy, remains unknown. Here, we elucidate the presence of CIN in aneuploid cB-ALL subtypes using single-cell whole-genome sequencing of primary cB-ALL samples and by generating and functionally characterizing patient-derived xenograft models (cB-ALL-PDX). We report higher rates of CIN across aneuploid than in euploid cB-ALL that strongly correlate with intraclonal chr-CNH and overall survival in mice. This association was further supported by in silico mathematical modeling. Moreover, mass-spectrometry analyses of cB-ALL-PDX revealed a "CIN signature" enriched in mitotic-spindle regulatory pathways, which was confirmed by RNA-sequencing of a large cohort of cB-ALL samples. The link between the presence of CIN in aneuploid cB-ALL and disease progression opens new possibilities for patient stratification and offers a promising new avenue as a therapeutic target in cB-ALL treatment.</p

Explaining telecoms and electricity internationalization in the European Union: a political economy perspective

One consequence of the liberalization of certain services in the European Union was that a number of formerly inward-looking incumbents in telecommunications and electricity rapidly transformed themselves into some of the world’s leading Multinationals. However, the precise relationship between liberalization and incumbent internationalization is contested. This article tests three persuasive arguments derived from the political economy literature on this relationship. The first claims that those incumbents most exposed to domestic liberalization would internationalise most. The second asserts the opposite: incumbents operating where liberalization was restricted could exploit monopolistic rents to finance their aggressive internationalisation. The third argument claims that a diversity of paths will be adopted by countries and incumbents vis-à-vis liberalization and internationalization. Using correlation and cluster analysis of the sample of all major EU telecoms and electricity incumbent Multinationals evidence is found in favour of the third hypothesis. Internationalization as a response to liberalization took diverse forms in terms of timing and extent and this is best explained using a country, sector and firm logic

After the epidemic: Zika virus projections for Latin America and the Caribbean

Background: Zika is one of the most challenging emergent vector-borne diseases, yet its future public health impact remains unclear. Zika was of little public health concern until recent reports of its association with congenital syndromes. By 3 August 2017 ~217,000 Zika cases and ~3,400 cases of associated congenital syndrome were reported in Latin America and the Caribbean. Some modelling exercises suggest that Zika virus infection could become endemic in agreement with recent declarations from the The World Health Organisation. Methodology/Principal findings: We produced high-resolution spatially-explicit projections of Zika cases, associated congenital syndromes and monetary costs for Latin America and the Caribbean now that the epidemic phase of the disease appears to be over. In contrast to previous studies which have adopted a modelling approach to map Zika potential, we project case numbers using a statistical approach based upon reported dengue case data as a Zika surrogate. Our results indicate that ~12.3 (0.7–162.3) million Zika cases could be expected across Latin America and the Caribbean every year, leading to ~64.4 (0.2–5159.3) thousand cases of Guillain-Barré syndrome and ~4.7 (0.0–116.3) thousand cases of microcephaly. The economic burden of these neurological sequelae are estimated to be USD ~2.3 (USD 0–159.3) billion per annum. Conclusions/Significance: Zika is likely to have significant public health consequences across Latin America and the Caribbean in years to come. Our projections inform regional and federal health authorities, offering an opportunity to adapt to this public health challenge

The Smallest Known Genomes of Multicellular and Toxic Cyanobacteria: Comparison, Minimal Gene Sets for Linked Traits and the Evolutionary Implications

Cyanobacterial morphology is diverse, ranging from unicellular spheres or rods to multicellular structures such as colonies and filaments. Multicellular species represent an evolutionary strategy to differentiate and compartmentalize certain metabolic functions for reproduction and nitrogen (N2) fixation into specialized cell types (e.g. akinetes, heterocysts and diazocytes). Only a few filamentous, differentiated cyanobacterial species, with genome sizes over 5 Mb, have been sequenced. We sequenced the genomes of two strains of closely related filamentous cyanobacterial species to yield further insights into the molecular basis of the traits of N2 fixation, filament formation and cell differentiation. Cylindrospermopsis raciborskii CS-505 is a cylindrospermopsin-producing strain from Australia, whereas Raphidiopsis brookii D9 from Brazil synthesizes neurotoxins associated with paralytic shellfish poisoning (PSP). Despite their different morphology, toxin composition and disjunct geographical distribution, these strains form a monophyletic group. With genome sizes of approximately 3.9 (CS-505) and 3.2 (D9) Mb, these are the smallest genomes described for free-living filamentous cyanobacteria. We observed remarkable gene order conservation (synteny) between these genomes despite the difference in repetitive element content, which accounts for most of the genome size difference between them. We show here that the strains share a specific set of 2539 genes with >90% average nucleotide identity. The fact that the CS-505 and D9 genomes are small and streamlined compared to those of other filamentous cyanobacterial species and the lack of the ability for heterocyst formation in strain D9 allowed us to define a core set of genes responsible for each trait in filamentous species. We presume that in strain D9 the ability to form proper heterocysts was secondarily lost together with N2 fixation capacity. Further comparisons to all available cyanobacterial genomes covering almost the entire evolutionary branch revealed a common minimal gene set for each of these cyanobacterial traits

Dynamical downscaling of historical climate over CORDEX Central America domain with a regionally coupled atmosphere–ocean model

The climate in Mexico and Central America is influenced by the Pacific and the Atlantic oceanic basins and atmospheric conditions over continental North and South America. These factors and important ocean–atmosphere coupled processes make the region’s climate a great challenge for global and regional climate modeling. We explore the benefits that coupled regional climate models may introduce in the representation of the regional climate with a set of coupled and uncoupled simulations forced by reanalysis and global model data. Uncoupled simulations tend to stay close to the large-scale patterns of the driving fields, particularly over the ocean, while over land they are modified by the regional atmospheric model physics and the improved orography representation. The regional coupled model adds to the reanalysis forcing the air–sea interaction, which is also better resolved than in the global model. Simulated fields are modified over the ocean, improving the representation of the key regional structures such as the Intertropical Convergence Zone and the Caribbean Low Level Jet. Higher resolution leads to improvements over land and in regions of intense air–sea interaction, e.g., off the coast of California. The coupled downscaling improves the representation of the Mid Summer Drought and the meridional rainfall distribution in southernmost Central America. Over the regions of humid climate, the coupling corrects the wet bias of the uncoupled runs and alleviates the dry bias of the driving model, yielding a rainfall seasonal cycle similar to that in the reanalysis-driven experiments.Universidad de Costa Rca/[805-B7-507]/UCR/Costa RicaCRYOPERU/[144-2015]//PerúUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigaciones Geofísicas (CIGEFI

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Registro ACESUR: atención de pacientes adultos con crisis epilépticas en servicios de urgencias: diferencias entre primer episodio y recurrencia

Objetivo. Describir las características y la atención recibida de pacientes adultos que consultan por crisis epiléptica (CE) en los servicios de urgencias hospitalarios (SUH), diferenciando entre primera crisis y recurrencia en epiléptico conocido. Método. ACESUR es un registro observacional de cohortes multipropósito, prospectivo y multicéntrico con un muestreo sistemático, los días pares de febrero y julio alternando con los impares de abril y octubre de 2017. Se incluyeron pacientes 18 años con diagnóstico de CE en los SUH. Se recogieron variables clínico-asistenciales de la visita índice de pacientes, distinguiendo entre primera CE y recurrencia en epiléptico. Resultados. El registro ACESUR recogió a 664 pacientes procedentes de 18 SUH españoles, 229 (34, 5%) con primera CE y 435 (65, 5%) con CE recurrentes. Los pacientes con primera CE fueron de mayor edad (p < 0, 001), presentaron motivos de consulta distintos (p < 0, 001) y requirieron más traslados en ambulancia (p < 0, 001). La atención recibida en el SUH fue diferente, en pacientes con primera CE se solicitó con mayor probabilidad una prueba complementaria específica (OR ajustada = 13, 94; IC95%:7, 29-26, 7; p < 0, 001) y se necesitó mayor hospitalización o estancia prolongada en el SUH (OR ajustada = 1, 69; IC95%:1, 11-2, 58; p = 0, 015). No hubo diferencias en cuanto al tratamiento farmacológico en fase aguda ni preventivo (OR ajustada = 1, 40; IC95%:0, 94-2, 09; p = 0, 096). Se inició tratamiento con fármacos antiepiépticos (FAE) en 100 pacientes (43, 7%) tras primera CE y se reinició o modificó añadiendo nuevo FAE en 142 pacientes (32, 6%) con CE recurrentes. Conclusiones. Las características clínicas y la atención recibida de pacientes adultos con primera CE en SUH en España difieren de las recurrencias en epiléptico conocido. Objective. To describe the characteristics of care received by patients who come to the emergency department with a first epileptic seizure versus a recurrent seizure in a patient with diagnosed epilepsy. Methods. ACESUR (Acute Epileptic Seizures in the Emergency Department) is a prospective multicenter, multipurpose registry of cases obtained by systematic sampling on even days in February and July 2017 and on odd days in April and October 2017. Patients were aged 18 years or older and had an emergency department diagnosis of epileptic seizure. We recorded clinical variables and details related to care given during each patient''s visit, including whether the event was a first or recurrent seizure. Results. A total of 664 patients attended by 18 Spanish emergency departments were entered into the ACESUR registry. Two hundred twenty-nine (34.5%) were first seizures and 435 (65.5%) were recurrences. Patients who were attended for first seizures were older, consulted for a wider variety of reasons, and were transported in ambulances (P<.001, all comparisons). Care received differed between patients with first seizures versus recurrent seizures. Specific complementary testing was more likely in patients with first seizures (adjusted odds ratio [aOR], 13.94; 95% CI, 29-26.7; P<.001), and they were more often hospitalized or stayed longer in the emergency department, (aOR, 1.69; 95% CI, 1.11-2.58; P=.015). Pharmacologic treatment did not differ between the groups, either in the acute phase or for prevention (aOR, 1.40; 95% CI, 0.94-2.09; P=.096). Antiepileptic drugs were given to 100 patients (43.7%) after a first seizure and were restarted or changed in 142 patients with recurrent seizure (32.6%). Conclusions. The clinical characteristics of adults attended for a first epileptic seizure differ from those of patients with diagnosed epilepsy who were attended for recurrent seizures in Spain. The care received also differs

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| &lt; 0.03 at 95% confidence level. [Figure not available: see fulltext.