SUMOylated SNF2PH promotes variant surface glycoprotein expression in bloodstream trypanosomes

SUMOylation is a post¿translational modification that positively regulates monoallelic expression of the trypanosome variant surface glycoprotein (VSG). The presence of a highly SUMOylated focus associated with the nuclear body, where the VSG gene is transcribed, further suggests an important role of SUMOylation in regulating VSG expression. Here, we show that SNF2PH, a SUMOylated plant homeodomain (PH)¿transcription factor, is upregulated in the bloodstream form of the parasite and enriched at the active VSG telomere. SUMOylation promotes the recruitment of SNF2PH to the VSG promoter, where it is required to maintain RNA polymerase I and thus to regulate VSG transcript levels. Further, ectopic overexpression of SNF2PH in insect forms, but not of a mutant lacking the PH domain, induces the expression of bloodstream stage¿specific surface proteins. These data suggest that SNF2PH SUMOylation positively regulates VSG monoallelic transcription, while the PH domain is required for the expression of bloodstream¿specific surface proteins. Thus, SNF2PH functions as a positive activator, linking expression of infective form surface proteins and VSG regulation, thereby acting as a major regulator of pathogenicity.The authors thank Dr. Alicia Barroso Del Jesus for excellent assistance and input with NSG methodology at the Genomic Unit and Dr. Laura Montosa at the Microscopy Unit (IPBLN-CSIC). This work was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (RTI2018-098834-B-I00) and the Wellcome Trust (WTI 204697/Z/16/Z to MCF) and thegrant from the Argentinian National Agency for Promotion of Scientific and Technological Research to VEA (PICT/2016/0465)

Oral contraceptives do not modify the risk of a second attack and disability accrual in a prospective cohort of women with a clinically isolated syndrome and early multiple sclerosis

Cohort study; Oral contraceptives; Second relapseEstudio de cohorte; Anticonceptivos orales; Segunda recaídaEstudi de cohorts; Anticonceptius orals; Segona recaigudaObjective: To evaluate whether oral contraceptive (OC) use is associated with the risk of a second attack and disability accrual in women with a clinically isolated syndrome (CIS) and early multiple sclerosis (MS). Methods: Reproductive information from women included in the Barcelona CIS prospective cohort was collected through a self-reported cross-sectional survey. We examined the relationship of OC exposure with the risk of a second attack and confirmed Expanded Disability Status Scale of 3.0 using multivariate Cox regression models, adjusted by age, topography of CIS, oligoclonal bands, baseline brain T2 lesions, body size at menarche, smoking, and disease-modifying treatment (DMT). OC and DMT exposures were considered as time-varying variables. Findings were confirmed with sensitivity analyses using propensity score models. Results: A total of 495 women were included, 389 (78.6%) referred to ever use OC and 341 (68.9%) started OC before the CIS. Exposure to OC was not associated with a second attack (adjusted hazard ratio (aHR) = 0.73, 95% confidence interval (CI) = 0.33–1.61) or disability accrual (aHR = 0.81, 95% CI = 0.17–3.76). Sensitivity analyses confirmed these results. Conclusion: OC use does not modify the risk of second attack or disability accrual in patients with CIS and early MS, once considered as a time-dependent exposure and adjusted by other potential confounders.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by FIS PI15/0070 from Ministry of Economy and Competitiveness of Spain

Recent Changes in Breast Cancer Incidence in Spain, 1980–2004

BACKGROUND: Since the 1980s, Spain experienced two decades of sharply increasing breast cancer incidence. Declines in breast cancer incidence have recently been reported in many developed countries. We examined whether a similar downturn might have taken place in Spain in recent years. METHODS: Cases of invasive female breast cancer were drawn from all population-based Spanish cancer registries that had at least 10 years of uninterrupted registration over the period 1980-2004. Overall and age-specific changes in incidence rates were evaluated using change-point Poisson models, which allow for accurate detection and estimation of trend changes. All statistical tests were two-sided. RESULTS: A total of 80,453 incident cases of invasive breast cancer were identified. Overall age- and registry-adjusted incidence rates rose by 2.9% (95% confidence interval [CI] = 2.7% to 3.1%) annually during the 1980s and 1990s; there was a statistically significant change in this trend in 2001 (95% CI = 1998 to 2004; P value for the existence of a change point <.001), after which incidence declined annually by 3.0% (95% CI = 1.8% to 4.1%). This trend differed by age group: There was a steady increase in incidence for women younger than 45 years, an abrupt downturn in 2001 for women aged 45-64 years, and a gradual leveling off in 1995 for women aged 65 years or older. Separate analyses for registries that had at least 15 years of uninterrupted registration detected a statistically significant interruption of the previous upward trend in breast cancer incidence in provinces that had aggressive breast cancer screening programs and high screening participation rates, including Navarra (change point = 1991, P < .001), Granada (change point = 2002, P = .003), Bizkaia (change point = 1998, P < .001), Gipuzkoa (change point = 1998, P = .001), and Araba (change point = 1997, P = .002). CONCLUSIONS: The recent downturn in breast cancer incidence among Spanish women older than 45 years is best explained by a period effect linked to screening saturation.Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP) (AC07-005 to M.P., PM07-004 to R.P-B.) and Carlos III Institute of Health (ISCIII-CIBERESP collaborative agreement “Acción Transversal del Cancer”).S

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Estudio experimental comparativo del comportamiento a flexión de un hormigón ligero estructural frente a un hormigón convencional

Una buena parte de los cálculos realizados en hormigón armado corresponden al estudio de elementos a flexión. El comportamiento del hormigón convencional (HC) ante este fenómeno está ampliamente estudiado. El hormigón ligero estructural (HLE) presenta ventajas evidentes por la reducción del peso frente al HC. Si bien se ha investigado al respecto, los estudios para este material están lejos de los realizados para el HC. Este trabajo pretende ampliar el conocimiento del comportamiento del HLE frente a la flexión para contribuir a su utilización en todas las situaciones en donde su empleo supone una clara ventaja frente al HC

Identification of elusive sequence-specific promoters of RNA polymerase II polycistronic transcription in African trypanosomes

Kinetoplastids have evolved in isolation for one billion years resulting in several divergent molecular and cellular processes. One example is protein-coding genes transcribed polycistronically by a typical RNA polymerase II (RNA pol II). Transcription most likely starts at divergent Strand Switch Regions (dSSRs), long sequences between divergently oriented polycistronic transcription units (PTUs). The lack of regulation in trypanosome transcription has become the paradigm in our field. Previous work suggests that changes in chromatin structure over broad SSR regions drives unregulated and dispersed transcription initiation. We investigate such an exceptional feature in trypanosomes by first identifying RNA pol II-enriched regions using ChIP-Seq, as potential promoter sequences. The high resolution of this technique allowed us to accurately determine peaks of RNA pol II accumulation in the dSSRs. To functionally investigate pol II-enriched sequences unbiasedly, the peaks on chromosome VII were assayed for their ability to direct transcription using transient transfection. This analysis suggests that two unidirectional short sequence specific promoters within each dSSR make up the general structure. Primer extension analysis of nascent RNA allowed us to identify precise transcription start sites (TSS) of promoters inserted in a chromosome. Detailed analysis of one of these promoters defined 75bp as sufficient to fully drive transcription and identified essential nucleotides for precise initiation around the TSS. In addition, mutations to internal and downstream boxes led to dramatic decreased activity. In summary, we show that sequence-specific unidirectional RNA pol II promoters with proper TSS transcription initiation are present in the T. brucei genome. Our results challenge the currently accepted hypothesis that trypanosomes lack true promoters with transcription initiation control

Trypanosomiasis and Leishmaniasis Symposium: Advances in Basic and Applied Research

About the British Society for Parasitology. About.Today many researchers and students are very passionate about the fascinating world of infectious diseases, parasites, their complex lifestyles and their associated impact on people and livelihoods.To draw attention to the unique importance of parasitology as a distinct discipline within biology, The British Society for Parasitology was formed in 1962 from the Parasitological Section of the Institute of Biology. Today the Society is the central networking and meeting point for many professional and amateur parasitologists throughout the UK and across the world.Did you know that the UK leads Europe – and Europe leads the world – in parasitology research? No European country publishes more parasitology research than the UK, and UK papers were cited more than those from any other country in the past 5 years (2011-2016, data from Elsevier SciVal, see News item for more details.)As the leading academic society for a country preeminent in parasitology, the remit of the BSP is broad. It promotes and supports the academic study of parasitology in all its many guises. This can be from experimental to theoretical approaches as applied to infection biology and disease research, or from ecological to medical and veterinary studies in global health and international aid. Each year students are given financial support to attend BSP meetings and scholarship schemes are in place to support fieldwork and training events.The membership of the BSP stands at around 1000 in number. Approximately a third of members are from overseas locations. Highlights of the annual BSP calendar include the annual residential meetings in spring and autumn which are focused upon general and specialist aspects of parasitology. The BSP has a close relationship with Cambridge University Press that prints a special issue on our autumn meeting.The BSP Society is a Charitable Incorporated Organisation and managed by the BSP Council. This comprises a President, Honorary Officers and ordinary Council Members, who together act as Company Trustees. Co-opted members of Council also include representation from the student, early career membership and other learned societies where clear synergies are apparent

Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis.

Multiple sclerosis (MS) is a complex and demyelinating disease of the central nervous system. One of the challenges of the post-genome-wide association studies (GWAS) era is to understand the molecular basis of statistical associations to reveal gene networks and potential therapeutic targets. The L3MBTL3 locus has been associated with MS risk by GWAS. To identify the causal variant of the locus, we performed fine mapping in a cohort of 3440 MS patients and 1688 healthy controls. The variant that best explained the association was rs6569648 (P = 4.13E-10, odds ratio = 0.71, 95% confidence interval (CI) = 0.64-0.79), which tagged rs7740107, located in intron 7 of L3MBTL3. The rs7740107 (A/T) variant has been reported to be the best expression and splice quantitative trait locus (eQTL and sQTL) of the region in up to 35 human genotype-tissue expression (GTEx) tissues. By sequencing RNA from blood of 17 MS patients and quantification by digital qPCR, we determined that this eQTL/sQTL originated from the expression of a novel short transcript starting in intron 7 near rs7740107. The short transcript was translated into three proteins starting at different translation initiation codons. These N-terminal truncated proteins lacked the region where L3MBTL3 interacts with the transcriptional regulator Recombination Signal Binding Protein for Immunoglobulin Kappa J Region which, in turn, regulates the Notch signalling pathway. Our data and other functional studies suggest that the genetic mechanism underlying the MS association of rs7740107 affects not only the expression of L3MBTL3 isoforms, but might also involve the Notch signalling pathway