Heavy ion ranges from first-principles electron dynamics

The effects of incident energetic particles, and the modification of materials under irradiation, are governed by the mechanisms of energy losses of ions in matter. The complex processes affecting projectiles spanning many orders of magnitude in energy depend on both ion and electron interactions. Developing multi-scale modeling methods that correctly capture the relevant processes is crucial for predicting radiation effects in diverse conditions. In this work, we obtain channeling ion ranges for tungsten, a prototypical heavy ion, by explicitly simulating ion trajectories with a method that takes into account both the nuclear and the electronic stopping power. The electronic stopping power of self-ion irradiated tungsten is obtained from first-principles time-dependent density functional theory (TDDFT). Although the TDDFT calculations predict a lower stopping power than SRIM by a factor of three, our result shows very good agreement in a direct comparison with ion range experiments. These results demonstrate the validity of the TDDFT method for determining electronic energy losses of heavy projectiles, and in turn its viability for the study of radiation damage.Peer reviewe

Identification and functional analysis of novel phosphorylation sites in the RNA surveillance protein Upf1.

One third of inherited genetic diseases are caused by mRNAs harboring premature termination codons as a result of nonsense mutations. These aberrant mRNAs are degraded by the Nonsense-Mediated mRNA Decay (NMD) pathway. A central component of the NMD pathway is Upf1, an RNA-dependent ATPase and helicase. Upf1 is a known phosphorylated protein, but only portions of this large protein have been examined for phosphorylation sites and the functional relevance of its phosphorylation has not been elucidated in Saccharomyces cerevisiae. Using tandem mass spectrometry analyses, we report the identification of 11 putative phosphorylated sites in S. cerevisiae Upf1. Five of these phosphorylated residues are located within the ATPase and helicase domains and are conserved in higher eukaryotes, suggesting a biological significance for their phosphorylation. Indeed, functional analysis demonstrated that a small carboxy-terminal motif harboring at least three phosphorylated amino acids is important for three Upf1 functions: ATPase activity, NMD activity and the ability to promote translation termination efficiency. We provide evidence that two tyrosines within this phospho-motif (Y-738 and Y-742) act redundantly to promote ATP hydrolysis, NMD efficiency and translation termination fidelity

Tabaquismo: un problema que afecta a los jóvenes universitarios a nivel nacional e internacional: Tobacco: A problem that affects young universities at the national and international levels

The World Health Organization defines smoking as a chronic addictive disease widespread worldwide. It represents one of the greatest threats to public health, affecting children, youth and adults. It is estimated, that there are 1.300 million smokers in the world and about 80% of these live in countries where there is a high rate of morbidity and mortality associated with tobacco mainly in adult consumers. In particular, the consumption of tobacco among young university students is evident and worrisome. Different authors in the world have raised factors for tobacco use among adolescents and young adults. Such studies argue that the habit of smoking usually begins during adolescence and consolidates in the university stage. Smoking in parents, relatives, and friends is a factor, perhaps the most remarkable, which is associated with the acquisition of smoking as a habit.La Organización Mundial de la Salud define al tabaquismo como una enfermedad adictiva crónica muy extendida a nivel mundial. Representa una de las mayores amenazas para la salud púbica, afectando a niños, jóvenes y adultos. Se calcula que existen 1.300 millones de fumadores en el mundo y alrededor del 80% de estos viven en países en los que existe una alta tasa de morbilidad y mortalidad asociada al tabaco principalmente en consumidores adultos. De manera particular, el consumo de tabaco ente jóvenes universitarios es evidente y preocupante. Diferentes autores en el mundo han planteado factores para el consumo de tabaco entre adolescentes y adultos jóvenes. Tales estudios sostienen que el hábito de fumar inicia, por lo general, durante la adolescencia y se consolida en la etapa universitaria. Además, el tabaquismo en progenitores, familiares y amigos es un factor, quizás el más destacable, que se asocia a la adquisición del hábito tabáquico

Factores asociados al consumo de tabaco en estudiantes universitarios de Lima metropolitana.: Factors associated with tobacco consumption in university students of Lima metropolitan

Introduction: The consumption of tobacco is very harmful to people’s health. According to WHO, smoking is the cause of death of 8 million people a year. Objetive: The purpose of the research was to determine the factors associated with the consumption of tobacco in university students in Metropolitan Lima. Methods: The sample consisted of 447 students from Lima universities, the survey was applied: Fagerstrom test. Subsequently the data was analyzed using tables of: distribution, frequency, contingency.  Results: It was evidenced through the X2 statistical test that there is a significant association between the variables sex and smoking habit, OR = 1.93, IC 95%[1.29-6,519]. It was also observed that having smoking parents is significantly associated with the habit of smoking by the children, with a value p =0,000 of X2 and the OR 3.31, IC 95%[2,145 - 5,116]. Conclusion: The variables sex and parental background have a significant association with tobacco consumption, emphasizing that our family environment deserves to be safe, healthy and free of tobacco smokeIntroducción: El consumo de tabaco es muy perjudicial para la salud de las personas, según la OMS el tabaquismo es la causa de muerte de 8 millones de personas al año. Objetivo: El propósito de la investigación fue determinar los factores asociados al consumo de tabaco en estudiantes universitarios de Lima Metropolitana. Métodos: La muestra estuvo conformada por 447 estudiantes de universidades de Lima, se aplicó la encuesta: Test de Fagerstrom. Los datos fueron analizados utilizando tablas de distribución, frecuencia, y contingencia. Resultados: Se evidenció a través de la prueba estadística X2 que existe asociación significativa entre las variables sexo y el hábito de fumar, OR = 1.93, IC 95% [1.29 – 6,519].  También se pudo observar que tener padres fumadores está asociado significativamente al hábito de fumar por parte de los hijos, con un valor de p=0,000 del X2 y el OR 3,31, IC 95% [2,145 – 5,116].  Conclusión: Las variables sexo masculino y antecedentes parentales tienen asociación significativa con el consumo de tabaco enfatizando que nuestro entorno familiar merece ser seguro, saludable y libre del humo de tabaco

Primer registro de Litomosoides pardinasi (Nematoda: Onchocercidae) en roedores nativos y exóticos de Chile

Litomosoides pardinasi es registrada por primera vez en roedores nativos y exóticos de Chile. La especie Litomosoides pardinasi, parásita de Phyllotis xanthopygus y Oligoryzomys longicaudatus en la Patagonia Argentina, fue encontrada en Chile parasitando la cavidad torácica y abdominal de O. longicaudatus (prevalencia (P)= 18.9%, intensidad media (MI)= 57.3) y de Phyllotis darwini (P= 4.2%, MI= 10), y la cavidad abdominal del roedor exótico Rattus rattus (P= 1.24%; MI= 22.5). La P total en roedores nativos de Chile fue significativamente menor que la P de Argentina, en tanto la MI total fue significativamente mayor. La P y MI de L. pardinasi en O. longicaudatus de Chile y Argentina no mostraron diferencias significativas; la P en P. darwini de Chile fue significativamente menor que la de P. xanthopygus de Argentina y que la de O. longicaudatus de Chile. Considerando la distribución de las especies de Litomosoides entre los sigmodontinos, estos resultados apoyan la hipótesis que L. pardinasi está bien establecida en O. longicaudatus y que posiblemente haya sido recientemente adquirida por P. darwini y R. rattus. Así, L. pardinasi colonizó primero a la Tribu Oryzomyini y posteriormente por un fenómeno de cambio de hospedero a la Tribu Phyllotini y a R. rattus.We report the first record of Litomosoides pardinasi in native and exotic rodents from Chile. Litomosoides pardinasi, described in the Argentine Patagonia parasitizing Phyllotis xanthopygus and Oligoryzomys longicaudatus, was found in Chile parasitizing the peritoneal and thoracic cavities of O. longicaudatus (prevalence (P)= 18.9%, mean intensity (MI)= 57.3) and Phyllotis darwini (P= 4.2%, MI= 10), and in the peritoneal cavity of Rattus rattus (P= 1.24%; MI= 22.5). Total P in native rodents from Chile was significantly lower than in Argentina, while the total MI was higher. Prevalence and MI of L. pardinasi in O. longicaudatus from Chile and Argentina showed non-significant differences; prevalence in P. darwini from Chile was significantly lower than in P. xanthopygus from Argentina and than in Chilean O. longicaudatus. Our results, together with those from Argentina, support the hypothesis that L. pardinasi is well established in O. longicaudatus, but seems to be recently acquired by P. darwini and the exotic R. rattus. Considering the known host distribution of Litomosoides species among the sigmodontines, our results also support the hypothesis that L. pardinasi first colonized the Oryzomyini tribe and later, by different phenomena of host-switching, colonized the Phyllotini tribe and the exotic R. rattus.Fil: Landaeta Aqueveque, Carlos. Universidad de Concepción; ChileFil: Notarnicola, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Estudios Parasitológicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios Parasitológicos y de Vectores; ArgentinaFil: Correa, Juana P.. Universidad de Chile; ChileFil: Yánez Mesa, Andrea. Universidad de Chile; ChileFil: Henriquez, AnaLía. Universidad Santo Tomás; ChileFil: Cattan, Pedro E.. Universidad de Chile; ChileFil: Botto Mahan, Carezza. Universidad de Chile; ChileFil: Torres Pérez, Fernando. Pontificia Universidad Catolica de Valparaiso; Chil

Primer registro de Litomosoides pardinasi (Nematoda: Onchocercidae) en roedores nativos y exóticos de Chile

We report the first record of Litomosoides pardinasi in native and exotic rodents from Chile. Litomosoides pardinasi, described in the Argentine Patagonia parasitizing Phyllotis xanthopygus and Oligoryzomys longicaudatus, was found in Chile parasitizing the peritoneal and thoracic cavities of O. longicaudatus (prevalence (P)= 18.9%, mean intensity (MI)= 57.3) and Phyllotis darwini (P= 4.2%, MI= 10), and in the peritoneal cavity of Rattus rattus (P= 1.24%; MI= 22.5). Total P in native rodents from Chile was significantly lower than in Argentina, while the total MI was higher. Prevalence and MI of L. pardinasi in O. longicaudatus from Chile and Argentina showed non-significant differences; prevalence in P. darwini from Chile was significantly lower than in P. xanthopygus from Argentina and than in Chilean O. longicaudatus. Our results, together with those from Argentina, support the hypothesis that L. pardinasi is well established in O. longicaudatus, but seems to be recently acquired by P. darwini and the exotic R. rattus. Considering the known host distribution of Litomosoides species among the sigmodontines, our results also support the hypothesis that L. pardinasi first colonized the Oryzomyini tribe and later, by different phenomena of host-switching, colonized the Phyllotini tribe and the exotic R. rattus.Litomosoides pardinasi es registrada por primera vez en roedores nativos y exóticos de Chile. La especie Litomosoides pardinasi, parásita de Phyllotis xanthopygus y Oligoryzomys longicaudatus en la Patagonia Argentina, fue encontrada en Chile parasitando la cavidad torácica y abdominal de O. longicaudatus (prevalencia (P)= 18.9%, intensidad media (MI)= 57.3) y de Phyllotis darwini (P= 4.2%, MI= 10), y la cavidad abdominal del roedor exótico Rattus rattus (P= 1.24%; MI= 22.5). La P total en roedores nativos de Chile fue significativamente menor que la P de Argentina, en tanto la MI total fue significativamente mayor. La P y MI de L. pardinasi en O. longicaudatus de Chile y Argentina no mostraron diferencias significativas; la P en P. darwini de Chile fue significativamente menor que la de P. xanthopygus de Argentina y que la de O. longicaudatus de Chile. Considerando la distribución de las especies de Litomosoides entre los sigmodontinos, estos resultados apoyan la hipótesis que L. pardinasi está bien establecida en O. longicaudatus y que posiblemente haya sido recientemente adquirida por P. darwini y R. rattus. Así, L. pardinasi colonizó primero a la Tribu Oryzomyini y posteriormente por un fenómeno de cambio de hospedero a la Tribu Phyllotini y a R. rattus.Facultad de Ciencias Naturales y Muse

Targeted protein degradation via intramolecular bivalent glues

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target 1–4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.</p

Targeted protein degradation via intramolecular bivalent glues

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target 1–4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target–ligase affinities that do not translate to BRD4 degradation in the absence of compound. Structural insights into the ternary BRD4–IBG1–DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, which works by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.</p

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth &gt;29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article