The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination.

Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2.

Innovativeness and the effects of urbanization on risk-taking behaviors in wild Barbados birds.

The effects of urbanization on avian cognition remain poorly understood. Risk-taking behaviors like boldness, neophobia and flight distance are thought to affect opportunism and innovativeness, and should also vary with urbanization. Here, we investigate variation in risk-taking behaviors in the field in an avian assemblage of nine species that forage together in Barbados and for which innovation rate is known from previous work. We predicted that birds from highly urbanized areas would show more risk-taking behavior than conspecifics from less urbanized parts of the island and that the differences would be strongest in the most innovative of the species. Overall, we found that urban birds are bolder, less neophobic and have shorter flight distances than their less urbanized conspecifics. Additionally, we detected between-species differences in the effect of urbanization on flight distance, more innovative species showing smaller differences in flight distance between areas. Our results suggest that, within successful urban colonizers, species differences in innovativeness may affect the way species change their risk-taking behaviors in response to the urban environment.

Variability in screening prevention activities in primary care in Spain: a multilevel analysis.

BACKGROUND: Despite evidence of the benefits of prevention activities, studies have reported only partial integration and great variability of screening in daily clinical practice. The study objectives were: 1) To describe Primary Health Care (PHC) screening for arterial hypertension, dyslipidaemia, obesity, tobacco use, and excessive alcohol consumption in 2008 in 2 regions of Spain, based on electronic health records, and 2) To assess and quantify variability in screening, and identify factors (of patient, general practitioners and PHC team) associated with being screened, that are common throughout the PHC population. METHODS: Multicentre, cross-sectional study of individuals aged ≥ 16 years (N = 468,940) who visited the 426 general practitioners (GPs) in 44 PHC teams in Catalonia and Navarre in 2008. OUTCOMES: screening for hypertension, dyslipidaemia, obesity, tobacco use, and excessive alcohol consumption. Other variables were considered at the individual (sociodemographics, visits, health problems), GP and PHC team (region among others). Individual and contextual factors associated with the odds of being screened and the variance attributable to each level were identified using the SAS PROC GLIMMIX macro. RESULTS: The most prevalent screenings were for dyslipidaemia (64.4%) and hypertension (50.8%); the least prevalent was tobacco use (36.6%). Overall, the odds of being screened were higher for women, older patients, those with more comorbidities, more cardiovascular risk factors, and more frequent office visits, and those assigned to a female GP, a GP with a lower patient load, or a PHC team with a lower percentage of patients older than 65 years. On average, individuals in Navarre were less likely to be screened than those in Catalonia. Hypertension and dyslipidaemia screenings had the least unexplained variability between PHC teams and GPs, respectively, after adjusting for individual and contextual factors. CONCLUSIONS: Of the studied screenings, those for obesity, tobacco, and alcohol use were the least prevalent. Attention to screening, especially for tobacco and alcohol, can be greatly improved in the PHC setting.

Neurodevelopmental disorders associated variants in ADAT3 disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.

The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 7 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the expression and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.

Construction and validation of a scoring system for the selection of high-quality data in a Spanish population primary care database (SIDIAP).

BACKGROUND: Computerised databases of primary care clinical records are widely used for epidemiological research. In Catalonia, the Information System for the Development of Research in Primary Care (SIDIAP) aims to promote the development of research based on high-quality validated data from primary care electronic medical records. OBJECTIVE: The purpose of this study is to create and validate a scoring system (Registry Quality Score, RQS) that will enable all primary care practices (PCPs) to be selected as providers of researchusable data based on the completeness of their registers. METHODS: Diseases that were likely to be representative of common diagnoses seen in primary care were selected for RQS calculations. The observed/expected cases ratio was calculated for each disease. Once we had obtained an estimated value for this ratio for each of the selected conditions we added up the ratios calculated for each condition to obtain a final RQS. Rate comparisons between observed and published prevalences of diseases not included in the RQS calculations (atrial fibrillation, diabetes, obesity, schizophrenia, stroke, urinary incontinence and Crohn's disease) were used to set the RQS cutoff which will enable researchers to select PCPs with research-usable data. RESULTS: Apart from Crohn's disease, all prevalences were the same as those published from the RQS fourth quintile (60th percentile) onwards. This RQS cut-off provided a total population of 1 936 443 (39.6% of the total SIDIAP population). CONCLUSIONS: SIDIAP is highly representative of the population of Catalonia in terms of geographical, age and sex distributions. We report the usefulness of rate comparison as a valid method to establish research-usable data within primary care electronic medical records.

Computational methods for diffusion-influenced biochemical reactions.

MOTIVATION: We compare stochastic computational methods accounting for space and discrete nature of reactants in biochemical systems. Implementations based on Brownian dynamics (BD) and the reaction-diffusion master equation are applied to a simplified gene expression model and to a signal transduction pathway in Escherichia coli. RESULTS: In the regime where the number of molecules is small and reactions are diffusion-limited predicted fluctuations in the product number vary between the methods, while the average is the same. Computational approaches at the level of the reaction-diffusion master equation compute the same fluctuations as the reference result obtained from the particle-based method if the size of the sub-volumes is comparable to the diameter of reactants. Using numerical simulations of reversible binding of a pair of molecules we argue that the disagreement in predicted fluctuations is due to different modeling of inter-arrival times between reaction events. Simulations for a more complex biological study show that the different approaches lead to different results due to modeling issues. Finally, we present the physical assumptions behind the mesoscopic models for the reaction-diffusion systems. AVAILABILITY: Input files for the simulations and the source code of GMP can be found under the following address: http://www.cwi.nl/projects/sic/bioinformatics2007/

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R.

Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit. We performed an RNAi-based genetic screen in a human TNBC cell line to identify kinases whose knockdown synergizes with the PI3K inhibitor GDC-0941 (pictilisib). We discovered that knockdown of insulin-like growth factor-1 receptor (IGF1R) expression potently increased sensitivity of these cells to GDC-0941. Pharmacologic inhibition of IGF1R using OSI-906 (linsitinib) showed a strong synergy with PI3K inhibition. Furthermore, we found that the combination of GDC-0941 and OSI-906 is synergistic in 8 lines from a panel of 18 TNBC cell lines. In these cell lines, inhibition of IGF1R further decreases the activity of downstream PI3K pathway components when PI3K is inhibited. Expression analysis of the panel of TNBC cell lines indicates that the expression levels of IGF2BP3 can be used as a potential predictor for sensitivity to the PI3K/IGF1R inhibitor combination. Our data show that combination therapy consisting of PI3K and IGF1R inhibitors could be beneficial in a subset of TNBCs. Mol Cancer Ther; 15(7); 1545-56. ©2016 AACR.

Study of the factors influencing the preparation of advance directives.

The aim of the study is to analyze the factors influencing the decision to prepare advance directives (AD) related to socio-demographic situation, health status, degree of dependence, healthcare characteristics and psychosocial aspects. This is a case-control study conducted using a personal interview. We compared 123 subjects who had completed AD with 123 subjects who had not and who belonged to two health centers in the Albacete Health District. Study variables included self-perceived health, functional status, morbidity, socio-demographic characteristics, use of health services, attitudes toward AD and psychosocial aspects. We found a predominance of women (64.2%) among those who prepared AD, with a mean age of 53.3 years. Preparing AD was associated with secondary or higher education (OR=2.5), a lifestyle other than living with a partner and with children (OR=2.5), chronic medication use (OR=3.2), higher than average number of specialist visits (OR=4.0), a longer-term relationship with the family physician (OR=3.5), a family history of having AD (OR=17.3) and with lower levels of social interaction (OR=3.0). The results suggest that several factors, resulting from both the socio-demographic situation and health or functional status, can affect the decision to formalize AD.

[Treatment of uterine fibroids using high-intensity ultrasound]. / Tratamiento de los miomas uterinos mediante ultrasonidos de alta intensidad.

High-intensity ultrasound surgery is being actively introduced as an alternative treatment to conventional surgery for uterine fibroids. Numerous studies have shown that high-intensity ultrasound surgery is a safe and effective treatment, with fewer side effects than fibroidectomy and hysterectomy, and is cost-effective. It is now possible to offer this alternative therapy to patients with symptomatic uterine fibroids. We describe the technical basis of ultrasound surgery, the pretherapy selection of patients, the limiting factors and the risks of high-intensity ultrasound therapy. We describe our unit's clinical experience with 319 patients treated in an outpatient regimen, which resulted in a high rate of success (81%) and an acceptable rate of mild complications, as well as a virtually immediate return to daily activities. We comment on the follow-up of pregnancies that occurred after treatment with high-intensity focused ultrasound (HIFU) with no side effects attributable to the therapy.

Fabrication and electrical characterization of circuits based on individual tin oxide nanowires.

Two- and four-probe electrical measurements on individual tin oxide (SnO(2)) nanowires were performed to evaluate their conductivity and contact resistance. Electrical contacts between the nanowires and the microelectrodes were achieved with the help of an electron- and ion-beam-assisted direct-write nanolithography process. High contact resistance values and the nonlinear current-bias (I-V) characteristics of some of these devices observed in two-probe measurements can be explained by the existence of back-to-back Schottky barriers arising from the platinum-nanowire contacts. The nanoscale devices described herein were characterized using impedance spectroscopy, enabling the development of an equivalent circuit. The proposed methodology of nanocontacting and measurements can be easily applied to other nanowires and nanometre-sized materials.

Hiperglicemia reactiva / Reactive hyperglycemia

La presente es una revisión bibliográfica de hiperglicemia inducida por drogas, a propósito de un caso clínico en el cual un preescolar de 3 años de edad, previamente asintomático, presentó cifras elevadas de glicemia posterior a la ingesta accidental de un medicamento (cinarizina). El paciente desarrolló durante el transcurso de este episodio una cetoacidosis diabética que requirió tratamiento con insulina. En la literatura consultada no se encontró el reporte de esta complicación con la ingesta de tal medicamento. Se revisan las diversas drogas que producen hiperglicemia tanto en dosis indicadas como en sobredosis