A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia

Mendelian randomization (MR) is increasingly employed as a technique to assess the causation of a risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure is commonly used to examine the causation using genetic variants as the instrument variables. The validity of 2SLS relies on a representative sample randomly selected from a study cohort or a population for genome-wide association study (GWAS), which is not always true in practice. For example, the extreme phenotype sequencing (EPS) design is widely used to investigate genetic determinants of an outcome in GWAS as it bears many advantages such as efficiency, low sequencing or genotyping cost, and large power in detecting the involvement of rare genetic variants in disease etiology. In this paper, we develop a novel, versatile, and efficient approach, namely MR analysis under Extreme or random Phenotype Sampling (MREPS), for one-sample MR analysis based on samples drawn through either the random sampling design or the nonrandom EPS design. In simulations, MREPS provides unbiased estimates for causal effects, correct type I errors for causal effect testing. Furthermore, it is robust under different study designs and has high power. These results demonstrate the superiority of MREPS over the widely used standard 2SLS approach. We applied MREPS to assess and highlight the causal effect of total fetal hemoglobin on anemia risk in patients with sickle cell anemia using two independent cohort studies. A user-friendly Shiny app web interface was implemented for professionals to easily explore the MREPS

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Systems-level conservation of the proximal TCR signaling network of mice and humans

International audienceWe exploited traceable gene tagging in primary human T cells to establish the composition and dynamics of seven canonical TCR-induced protein signaling complexes (signalosomes) using affinity purification coupled with mass spectrometry (AP-MS). It unveiled how the LAT adaptor assembles higher-order molecular condensates and revealed that the proximal TCR-signaling network has a high degree of qualitative and quantitative conservation between human CD4 + and CD8 + T cells. Such systemslevel conservation also extended across human and mouse T cells and unexpectedly encompassed protein-protein interaction stoichiometry. Independently of evolutionary considerations, our study suggests that a drug targeting the proximal TCR signaling network should behave similarly when applied to human and mouse T cells. However, considering that signaling differences likely exist between the distal TCR-signaling pathway of human and mouse, our fast-track AP-MS approach should be favored to determine the mechanism of action of drugs targeting human T cell activation. An opportunity is illustrated here using an inhibitor of the LCK protein tyrosine kinase as a proof-of-concept

A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia

Mendelian randomization (MR) is increasingly employed as a technique to assess the causation of a risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure is commonly used to examine the causation using genetic variants as the instrument variables. The validity of 2SLS relies on a representative sample randomly selected from a study cohort or a population for genome-wide association study (GWAS), which is not always true in practice. For example, the extreme phenotype sequencing (EPS) design is widely used to investigate genetic determinants of an outcome in GWAS as it bears many advantages such as efficiency, low sequencing or genotyping cost, and large power in detecting the involvement of rare genetic variants in disease etiology. In this paper, we develop a novel, versatile, and efficient approach, namely MR analysis under Extreme or random Phenotype Sampling (MREPS), for one-sample MR analysis based on samples drawn through either the random sampling design or the nonrandom EPS design. In simulations, MREPS provides unbiased estimates for causal effects, correct type I errors for causal effect testing. Furthermore, it is robust under different study designs and has high power. These results demonstrate the superiority of MREPS over the widely used standard 2SLS approach. We applied MREPS to assess and highlight the causal effect of total fetal hemoglobin on anemia risk in patients with sickle cell anemia using two independent cohort studies. A user-friendly Shiny app web interface was implemented for professionals to easily explore the MREPS

Assessment of the ecotoxicity of the pharmaceuticals bisoprolol, sotalol, and ranitidine using standard and behavioral endpoints

The pharmaceuticals bisoprolol (BIS), sotalol (SOT), and ranitidine (RAN) are among the most consumed pharmaceuticals worldwide and are frequently detected in different aquatic ecosystems. However, very few ecotoxicity data are available in the literature for them. To help fill these data gaps, toxicity tests with the algae Raphidocelis subcapitata, the macrophyte Lemna minor, the cnidarian Hydra attenuata, the crustacean Daphnia similis, and the fish Danio rerio were performed for assessing the ecotoxicity of these pharmaceuticals. Standard, as well as non-standard endpoint, was evaluated, including the locomotor behavior of D. rerio larvae. Results obtained for SOT and RAN showed that acute adverse effects are not expected to occur on aquatic organisms at the concentrations at which these pharmaceuticals are usually found in fresh surface waters. On the other hand, BIS was classified as hazardous to the environment in the acute III category. Locomotor behavior of D. rerio larvae was not affected by BIS and RAN. A disturbance on the total swimming distance at the dark cycle was observed only for larvae exposed to the highest test concentration of 500 mg L−1 of SOT. D. similis reproduction was affected by BIS with an EC10 of 3.6 (0.1–34.0) mg L−1. A risk quotient (RQ) of 0.04 was calculated for BIS in fresh surface water, considering a worst-case scenario. To the best of our knowledge, this study presents the first chronic toxicity data with BIS on non-target organisms2754695481COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES88881.132858/2016-0

Earning and learning: Role congruence, state/trait factors and adjustment to university life

Background. Undertaking term-time employment is increasingly commonplace for university students. Much research suggests that combining 'earning and learning' may be detrimental to university life, generating role conflicts, increasing stress and reducing academic success, participation and overall adjustment to university. Potential positive effects of term-time employment on well-being are often neglected. Aims. This study adopted a balanced perspective, investigating the relationship between role congruence in academic, social and career domains and adjustment, with state and trait psychological factors as mediators/moderators. Methods. A questionnaire measuring perceived role congruence, adjustment to university life and psychological state and trait characteristics was mailed to all undergraduates at a Scottish university during term-time. Sample. Results for a subsample of 625 university students currently in term-time employment were included in this paper. Results. Findings suggested that students generally perceived employment and university roles to be in balance, and there was no difference in adjustment for students whether currently in term-time employment or not. However, psychological factors, particularly positive affectivity and stress were important mediators of the relationship between role congruence and adjustment. Conclusions. Since promoting role congruence may enhance students' adjustment and well-being, the study has implications for universities, student welfare organizations and employers offering term-time employment

Probabilistic reference and grounding with PRAGR for dialogues with robots

In this paper, we present a system for effective referential human-robot communication in the face of perceptual deviation using the Probabilistic Reference And GRounding mechanism PRAGR and vague feature models based on prototypes. PRAGR can handle descriptions of arbitrary complexity including spatial relations and uses flexible concept assignment in generation and resolution of referring expressions for bridging conceptual gaps in referential robot-robot or human-robot interaction. We evaluate the benefit of using vague as compared to crisp properties regarding referential success and robustness towards perspective alignment error in referential robot-robot and human-robot communication