Density-Dependent Prevalence of Francisella tularensis in Fluctuating Vole Populations, Northwestern Spain

Self Archiving; https://wwwnc.cdc.gov/eid/page/copyright-and-disclaimers J.J.L.L., F.M., and R.R.P. held official licenses for trapping wildlife in Spain. Capture permits were provided by the Dirección General del Medio Natural, Junta de Castilla y León. This study was supported by projects ECOVOLE (grant CGL2012-35348), ECOTULA (grant CGL2015-66962-C2-1-R), and RESERTULA (grant CLG2015-66962-C2-2-R), which were funded by the Ministerio de Economía y Competitividad MINECO/FEDER, Spain. R.R.P. was supported by a PhD studentship from the University of Valladolid (co-funded by Banco Santander).Peer reviewedPublisher PD

On the determinants of local government debt: Does one size fit all?

This paper analyzes the factors that directly influence levels of debt in Spanish local governments. Specifically, the main objective is to find out the extent to which indebtedness is originated by controllable factors that public managers can influence, or whether it hinges on other variables beyond managers’ control. The importance of this issue has intensified since the start of the crisis in 2007, due to the abrupt decline of revenues and, simultaneously, to the stagnation (or even increase) in the levels of costs facing these institutions face. Results can be explored from multiple perspectives, given that the set of explanatory factors is also multiple. However, the most interesting result relates to the varying effect of each covariate depending on each municipality’s specific debt level, which suggests that economic policy recommendations should not be homogeneous across local governments

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer

The Extracellular Vesicles of the Helminth Pathogen, Fasciola hepatica: Biogenesis Pathways and Cargo Molecules Involved in Parasite Pathogenesis

Extracellular vesicles (EVs) released by parasites have important roles in establishing and maintaining infection. Analysis of the soluble and vesicular secretions of adult Fasciola hepatica has established a definitive characterization of the total secretome of this zoonotic parasite. Fasciola secretes at least two subpopulations of EVs that differ according to size, cargo molecules and site of release from the parasite. The larger EVs are released from the specialized cells that line the parasite gastrodermus and contain the zymogen of the 37 kDa cathepsin L peptidase that performs a digestive function. The smaller exosome-like vesicle population originate from multivesicular bodies within the tegumental syncytium and carry many previously described immunomodulatory molecules that could be delivered into host cells. By integrating our proteomics data with recently available transcriptomic data sets we have detailed the pathways involved with EV biogenesis in F. hepatica and propose that the small exosome biogenesis occurs via ESCRT-dependent MVB formation in the tegumental syncytium before being shed from the apical plasma membrane. Furthermore, we found that the molecular "machinery" required for EV biogenesis is constitutively expressed across the intramammalian development stages of the parasite. By contrast, the cargo molecules packaged within the EVs are developmentally regulated, most likely to facilitate the parasites migration through host tissue and to counteract host immune attack

Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia

Background and aims: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3?,7?,12?-trihydroxy-5?-cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods and results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high-performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAX? expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusions: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.Funding information: This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI-100, PID2020-115055RB-I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A-2015-9456; FPU-14/00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the article

Advanced EFL learners' beliefs about language learning and teaching: a comparison between grammar, pronunciation, and vocabulary

This paper reports on the results of a study exploring learners’ beliefs on the learning and teaching of English grammar, pronunciation and vocabulary at tertiary level. While the importance of learners’ beliefs on the acquisition process is generally recognized, few studies have focussed on and compared learners’ views on different components of the language system. A questionnaire containing semantic scale and Likert scale items probing learners’ views on grammar, pronunciation and vocabulary was designed and completed by 117 native speakers of Dutch in Flanders, who were studying English at university. The analysis of the responses revealed that (i) vocabulary was considered to be different from grammar and pronunciation, both in the extent to which an incorrect use could lead to communication breakdown and with respect to the learners’ language learning strategies, (ii) learners believed in the feasibility of achieving a native-like proficiency in all three components, and (iii) in-class grammar, pronunciation and vocabulary exercises were considered to be useful, even at tertiary level. The results are discussed in light of pedagogical approaches to language teaching

The Effect of Maternal Obesity on Breast Milk Fatty Acids and Its Association with Infant Growth and Cognition—The PREOBE Follow-Up

This study analyzed how maternal obesity affected fatty acids (FAs) in breast milk and their association with infant growth and cognition to raise awareness about the programming effect of maternal health and to promote a healthy prenatal weight. Mother–child pairs (n = 78) were grouped per maternal pre-pregnancy body mass index (BMI): normal-weight (BMI = 18.5–24.99), overweight (BMI = 25–29.99) and obese (BMI > 30). Colostrum and mature milk FAs were determined. Infant anthropometry at 6, 18 and 36 months of age and cognition at 18 were analyzed. Mature milk exhibited lower arachidonic acid (AA) and docosahexaenoic acid (DHA), among others, than colostrum. Breast milk of non-normal weight mothers presented increased saturated FAs and n6:n3 ratio and decreased a-linolenic acid (ALA), DHA and monounsaturated FAs. Infant BMI-for-age at 6 months of age was inversely associated with colostrum n6 (e.g., AA) and n3 (e.g., DHA) FAs and positively associated with n6:n3 ratio. Depending on the maternal weight, infant cognition was positively influenced by breast milk linoleic acid, n6 PUFAs, ALA, DHA and n3 LC-PUFAs, and negatively a ected by n6:n3 ratio. In conclusion, this study shows that maternal pre-pregnancy BMI can influence breast milk FAs and infant growth and cognition, endorsing the importance of a healthy weight in future generations.This research was funded by the European Commission (DynaHEALTH-HORIZON 2020GANo: 633595) and the Spanish Ministry of Economy and Competitiveness (BFU2012-40254-C03-02). Further support was obtained from, Spanish Ministry of Innovation and Science (Junta de Andalucía), Excellence Projects (P06-CTS-02341). ADLGP thanks the Mexican government and the National Council on Science and Technology (CONACYT) for her PhD grant. The funders had no role in the study design, data collection, data analysis, decision to publish, or preparation of the manuscript

Control oficial dels productes vitivinícoles: aplicació del SICA en establiments del sector del vi; criteris de flexibilitat

Petits cellers; Requisits d’higiene; APPCC; Criteris flexibilitat; SICAPequeñas bodegas; Requisitos de higiene; APPCC; Criterios flexibilidad; SICASmall wineries; Hygiene requirements; HACCP; Criteria of flexibility; SICADurant el procés de treball de la comunitat de pràctica (CoP) s’ha establert un cronograma d’actuacions. Els objectius que s’han prioritzat són: a) Donar informació sobre la importància dels establiments relacionats amb el món del vi i el vi escumós a Catalunya i la distribució territorial que tenen. b) Donar informació sobre els perills que s’han detectat aquests darrers anys en vins i vins escumosos, que han estat motiu de notificacions d’alerta a la Unió Europea o d’alguna incidència a Catalunya. c) Posar a disposició dels inspectors un recull de la normativa que afecta el sector vitivinícola. d) Elaborar un protocol d’inspecció que proporcioni una eina eficaç i útil per efectuar el control oficial dels establiments que elaboren i/o envasen productes vitivinícoles. e) Elaborar material de suport per als inspectors que faciliti la interpretació de les preguntes del protocol que poden generar dubtes en relació amb les pràctiques enològiques i la informació alimentària. f) Realitzar consultes a Serveis Centrals en relació amb diversos punts de la normativa que presenten dubtes d’interpretació per obtenir criteris homogenis i poder incloure’ls en el material de suport per als inspectors. g) Elaborar documents que incloguin els requisits mínims que han de tenir els establiments que realitzen activitats relacionades amb productes vitivinícoles i els criteris de flexibilitat que es podrien aplicar en casos determinats. Aquest ha estat un treball que la CoP ha realitzat durant dos anys.Durante el proceso de trabajo de la comunidad de práctica (CoP) se ha establecido un cronograma de actuaciones. Los objetivos que se han priorizado son: a) Dar información sobre la importancia de los establecimientos relacionados con el mundo del vino y el vino espumoso en Cataluña y su distribución territorial. b) Dar información sobre los peligros que se han detectado estos últimos años en vinos y vinos espumosos, que han sido motivo de notificaciones de alerta en la Unión Europea o de alguna incidencia en Cataluña. c) Poner a disposición de los inspectores una recopilación de la normativa que afecta al sector vitivinícola. d) Elaborar un protocolo de inspección que proporcione una herramienta eficaz y útil para efectuar el control oficial de los establecimientos que elaboren y/o envasen productos vitivinícolas. e) Elaborar material de soporte para los inspectores que facilite la interpretación de las preguntas del protocolo que pueden generar dudas en relación con las prácticas enológicas y la información alimentaria. f) Realizar consultas a Servicios Centrales en relación con varios puntos de la normativa que presenten dudas de interpretación para obtener criterios homogéneos y poder incluirlos en el material de soporte para los inspectores. g) Elaborar documentos que incluyan los requisitos mínimos que deben tener los establecimientos que realizan actividades relacionadas con productos vitivinícolas y los criterios de flexibilidad que podrían aplicarse en casos determinados. Éste ha sido un trabajo que la CoP ha realizado durante dos años.During the work process of the community of practice (CoP) a schedule has been established of performances. The objectives that have been prioritized are: a) Give information about the importance of establishments related to the world of wine and wine sparkling wine in Catalonia and its territorial distribution. b) Provide information on the dangers that have been detected in recent years in wines and sparkling wines, which have been the reason for alert notifications in the European Union or an incident in Catalonia. c) Make a compilation of the regulations that affect the wine sector available to inspectors. d) Develop an inspection protocol that provides an effective and useful tool for carrying out official control of establishments that produce and/or package wine products. e) Prepare support material for inspectors that facilitates the interpretation of protocol questions that may raise doubts in relation to oenological practices and food information. f) Make inquiries to Central Services in relation to various points of the regulations that present doubts of interpretation in order to obtain homogeneous criteria and be able to include them in the support material for inspectors. g) Prepare documents that include the minimum requirements that must be met by establishments that carry out activities related to wine products and the flexibility criteria that could be applied in specific cases. This has been work that the CoP has done for two years

Soybean Date of Planting and Maturity in Northern Iowa

Inevitably, every year soybean planting gets delayed or needs to be replanted because of weather somewhere in Iowa. Even if soybean planting starts and progresses in a timely manner, there always is the question of what maturity group should be planted. This trial was setup to determine what maturities are well suited for a given geographic location, but also how maturity selection should be adjusted as planting dates get pushed into late spring

Beneficial Effect of Ursodeoxycholic Acid in Patients with ACOX2 Deficiency-Associated Hypertransaminasemia

Background: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly trihydroxycholestanoic acid (THCA). Aims: To investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods & results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals, and 13 of their relatives, 7 individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by HPLC-MS/MS. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in 2 patients and 3 family members. Two additional non-related patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In ADAH patients, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized transaminases levels. Incubation of HuH-7 liver cells with THCA, which was efficiently taken up, but not through BA transporters, increased ROS production (flow cytometry), ER stress biomarkers (GRP78, CHOP and XBP1-S/XBP1-U ratio), and BAX¿ expression (RT-qPCR and immunoblot), whereas cell viability was decreased (MTT). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusion: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a non-invasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI- 100, PID2020-115055RB- I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017- 1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A- 2015- 9456; FPU-14/ 00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the articl