Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis

Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.This work-was supported by the Marie Curie activities of the European Commission (Oncotrain program; fellowship to P.W), the Spanish Ministry of Economy and Competitiveness (MINECO; fellowship to A.G.-L.), the CENIT AMIT Project "Advanced Molecular Imaging Technologies" (TEC2008-06715-C02-1, RD07/0014/2009 to F.M.), the Red de investigacion Cardiovascular (RIC), cofunded by FEDER (grant RD12/004240022 to J.M.R.; grant RD12/0042/0056 to L.J.J.-B), Fundacio La Marato TV3 (grant 20151331 to J.M.R.), the Castilla-Leon Autonomous Government (BIO/SA01/15, CS049U16 to X.R.B.), the Solorzano and Ramon Areces Foundations (to X.R.B.), MINECO (grants RD12/0036/0002 and SAF2015-64556-R to X.R.B.; SAF2015-63633-R to J.M.R.; and SAF2015-69920-R to M.M.), Consolider-Ingenio 2010 Programme (grant SAF2014-57791-REDC to M.M.), Red Tematica CellSYS (grant BFU2014-52125-REDT to M.M.), Comunidad de Madrid (OncoCycle Programme; grant S2010/BMD-2470 to M.M.), Worldwide Cancer Research (grants 14-1248 to X.R.B., and 15-0278 to M.M.) and the MitoSys project (European Union Seventh Framework Programme; grant HEALTH-F5-2010-241548 to M.M.). CNIC is supported by MINECO and the Pro-CNIC Foundation. CNIO and CNIC are Severo Ochoa Centers of Excellence (MINECO awards SEV-2015-0510 and SEV-2015-0505, respectively).S

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Survey and Molecular Characterization of Sarcocystidae protozoa in Wild Cricetid Rodents from Central and Southern Chile

In Chile, studies of parasites from the family Sarcocystidae (Apicomplexa) have mostly been related to domestic animals. We aimed to assess the presence of Sarcocystidae taxa in cricetid rodents from Central and Southern Chile. We studied 207 rodents, encompassing six species, from 13 localities. We isolated DNA from tissue samples, amplified the Sarcocystidae 18S rRNA gene with polymerase chain reaction, and performed phylogenetic analyses using maximum likelihood and Bayesian inferences. In addition, we examined blood smears and performed histological studies in organs from Sarcocystidae DNA-positive animals. Three specimens were DNA-positive and three genotypes were retrieved and named: Sarcocystis sp. P61, related to Sarcocystis strixi, was detected in two Abrothrix olivacea. Toxoplasmatinae gen. sp. P99 was retrieved from those same two specimens, and was related to Toxoplasma and other genera, although it branched independently. Besnoitia sp. R34 was detected in one Abrothrix hirta, and was clustered with congeneric species associated with rodents. No protozoa were found during microscopic studies; thus, it was not possible to confirm parasitic interactions rather than accidental encounters. However, the close relatedness of the retrieved genotypes to parasites of rodents supports the hypothesis of host–parasite associations. All three genotypes are suggested as potential new taxa, including a putative new genus.This research was funded by the ANID Programa Becas Doctorado Nacional under grant numbers 2019–21190078, 2020–21200182, and 2022-21220118; and Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) under grant number 11170294.Peer reviewe

Fostering English-taught higher education programs in a Spanish university: the "TechEnglish" innovative project

In recent years, coinciding with adjustments to the Bologna process, many European universities have attempted to improve their international profile by increasing course offerings in English. According to the Institute of International Education (IIE), Spain has notably increased its English-taught higher education programs, ranking fifth in the list of European countries by number of English-taught Master's programs in 2013. This article presents the goals and preliminary results of an on-going innovative education project (TechEnglish) that aims to promote course offerings in English at the Technical University of Madrid (Universidad Politécnica de Madrid, UPM). The UPM is the oldest and largest of all Technical Universities in Spain. It offers graduate and postgraduate programs that cover all the engineering disciplines as well as architecture. Currently, the UPM has no specific bilingual/multilingual program to promote teaching in English, although there is an Educational Model Whitepaper (with a focus on undergraduate degrees) that promotes the development of activities like an International Semester or a unique shared curriculum. The TechEnglish project is an attempt to foster courses taught in English at 7 UPM Technical Schools, including students and 80 faculty members. Four tasks were identified: (1) to design a university wide framework to increase course offerings, (2) to identify administrative difficulties, (3) to increase visibility of courses offered, and (4) to disseminate the results of the project. First, to design a program we analyzed existing programs at other Spanish universities, and other projects and efforts already under way at the UPM. A total of 13 plans were analyzed and classified according to their relation with students (learning), professors (teaching), administration, course offerings, other actors/institutions within the university (e.g., language departments), funds and projects, dissemination activities, mobility plans and quality control. Second, to begin to identify administrative and organizational difficulties in the implementation of teaching in English, we first estimated the current and potential course offerings at the undergraduate level at the UPM using a survey (student, teacher and administrative demand, level of English and willingness to work in English). Third, to make the course offerings more attractive for both Spanish and international students we examined the way the most prestigious universities in Spain and in Europe try to improve the visibility of their academic offerings in English. Finally, to disseminate the results of the project we created a web page and a workspace on the Moodle education platform and prepared conferences and workshops within the UPM. Preliminary results show that increasing course offerings in English is an important step to promote the internationalization of the University. The main difficulties identified at the UPM were related to how to acknowledge/certify the departments, teachers or students involved in English courses, how students should register for the courses, how departments should split and schedule the courses (Spanish and English), and the lack of qualified personnel. A concerted effort could be made to increase the visibility of English-taught programs offered on-line

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Evidence of spatial clustering of childhood acute lymphoblastic leukemia cases in Greater Mexico City: report from the Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia

BackgroundA heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC).MethodsA population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff’s spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained.ResultsA total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed.ConclusionsThe identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030