Exploring the Conformational Landscape of Bioactive Small Molecules

By using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug-like molecules present bound to proteins in the Protein Data Bank (PDB) can access easily the bioactive conformation and in fact for 73% of the studied molecules the bioactiveconformation is within 3kBT from the most-stable conformation in solution as determined by DFT/SCRF calculations. Cases with large differences between the most-stable and the bioactive conformations appear in ligands recognized by ionic contacts, or very large structures establishing many favorable interactions with the protein. There are also a few cases where we observed a non-negligible uncertainty related to the experimental structure deposited in PDB. Remarkably, the rough automatic force field used here provides reasonable estimates of the conformational ensemble of drugs in solution. The outlined protocol can be used to better estimate the cost of adopting the bioactive conformation

Diels-Alder-based thermo-reversibly crosslinked polymers:Interplay of crosslinking density, network mobility, kinetics and stereoisomerism

Polymers crosslinked through thermo-reversible furan/maleimide Diels-Alder chemistry have been widely explored, since they stand as an ingenious design for reprocessable and self-healing thermosets and elastomers. For these polymeric products, crosslinking density plays a key role on the polymer thermo-reversibility. However, how this degree of network interconnectivity influences the kinetics of thermal reversibility has not yet been addressed. In order to tackle this problem, furan-grafted polyketones crosslinked by a bi-functional maleimide were prepared with different ratios between maleimide and furan groups. The thermo-reversible dynamics of the prepared polymers were then studied by rheology and differential scanning calorimetry. Here we show that, the thermo-reversible process occurs faster and at lower temperatures in polymers with lower crosslinking densities. Network mobility is responsible for this effect. It allows the formulations to rearrange their polymer network differently through the heating-cooling cycles. The results also indicate that the crosslinking density rather than the stereoisomerism of the Diels-Alder adducts plays a larger role in the reversible behavior of the system. Additionally, the thermo-reversible features of the polymer were shown to be dependent on its thermal history. This work impacts the development of reprocessable and self-healing crosslinked polymers, and the design of the corresponding reprocessing and healing procedures

Evidence of Strong Quantum Turbulence in Bose Einstein Condensates

By combining experiments and numerical simulations which model precisely the dynamics of shaken atomic Bose-Einstein condensates, we reveal the surprising nature of quantum turbulence in these systems. Unlike the tangles of vortex lines described in the superfluid helium literature, we find that a turbulent atomic condensate contains a mixture of strong fragmented density fluctuations and small random vortex loops which are not homogeneously distributed. This unusual form of quantum turbulence, with its own properties and scaling behaviour, is significantly different from the turbulence which is observed in either classical or other quantum systems, thus posing a new challenge in turbulence research.Comment: 8 pages, 5 figure

Aplicación de la descomposición del 2-propanol como técnica de caracterización ácido-base de catalizadores CoMo para hidrotratamiento

RESUMENCon el propósito de implementar una técnica sencilla para medir propiedades ácido-base de sólidos se analizaron las propiedades ácido-base de catalizadores CoMo soportados sobre alúmino-silicatos amorfos (ASA) con diferentes relaciones atómicas Si/(Si+Al) y sobre alúmina modificada con B. Estas propiedades fueron determinadas usando la reacción de descomposición del 2-propanol. Los resultados obtenidos se compararon y validaron con pruebas de descomposición de isopropilamina y medidas con Infrarrojo de piridina adsorbida. Se observó buena reproducibilidad y alta sensibilidad de la reacción de deshidratación del 2-propanol ante los cambios y/o modificaciones de la superficie del catalizador. Se encontró que para los catalizadores CoMo soportados en ASA, la densidad, fuerza y número de sitios ácidos totales se incrementa cuando se aumenta la relación Si/(Si+Al); este incremento se atribuye al aumento en el número de sitios ácidos de Brönsted. Por otro lado, para los catalizadores CoMo modificados con B se observó aumento en la densidad y fuerza de sitios ácidos con el aumento en la cantidad de B. Los resultados de este trabajo permiten concluir que la selectividad de la reacción de descomposición de 2-propanol es sensible a las características ácido-base de catalizadores, y los resultados obtenidos con esta técnica son reproducibles y acordes con métodos más sofisticados y costosos como infrarrojo de piridina adsorbida.Palabras clave: catalizadores CoMo, características ácido-base, descomposición de isopropilamina, adsorción de piridina. ABSTRACTThe acid-base properties of CoMo catalysts supported on amorphous alumino-silicates (ASA) with different Si/(Si+Al) atomic ratios and on alumina modified with B were determined using the 2-propanol decomposition reaction. Results were compared and validated with isopropylamine decomposition tests and with FT-IR measurements of adsorbed pyridine. A good reproducibility and high sensitivity of the 2-propanol dehydration reaction to changes and/or modifications of the catalyst surface were observed. In the case of the CoMo catalysts supported on ASA, density, strength and total active sites number increases when the Si/(Si+Al) ratio increases. This fact is attributed to an increase in the Brönsted acid sites. On the other hand, an increase in density and strength of acid sites with the increase in the B amount was observed in the case of CoMo catalysts modified with B. The results of this study support the conclusion that the selectivity in the decomposition of 2-propanol reaction is sensitive to changes in the acid-base properties showing reproducible results and comparable with the ones obtained from more expensive and sophisticated methods.Keywords: CoMo catalysts, acid-base characteristics, isopropylamine decomposition, pyridine adsorption

Aplicación de la descomposición del 2-propanol como técnica de caracterización ácido-base de catalizadores CoMo para hidrotratamiento

RESUMENCon el propósito de implementar una técnica sencilla para medir propiedades ácido-base de sólidos se analizaron las propiedades ácido-base de catalizadores CoMo soportados sobre alúmino-silicatos amorfos (ASA) con diferentes relaciones atómicas Si/(Si+Al) y sobre alúmina modificada con B. Estas propiedades fueron determinadas usando la reacción de descomposición del 2-propanol. Los resultados obtenidos se compararon y validaron con pruebas de descomposición de isopropilamina y medidas con Infrarrojo de piridina adsorbida. Se observó buena reproducibilidad y alta sensibilidad de la reacción de deshidratación del 2-propanol ante los cambios y/o modificaciones de la superficie del catalizador. Se encontró que para los catalizadores CoMo soportados en ASA, la densidad, fuerza y número de sitios ácidos totales se incrementa cuando se aumenta la relación Si/(Si+Al); este incremento se atribuye al aumento en el número de sitios ácidos de Brönsted. Por otro lado, para los catalizadores CoMo modificados con B se observó aumento en la densidad y fuerza de sitios ácidos con el aumento en la cantidad de B. Los resultados de este trabajo permiten concluir que la selectividad de la reacción de descomposición de 2-propanol es sensible a las características ácido-base de catalizadores, y los resultados obtenidos con esta técnica son reproducibles y acordes con métodos más sofisticados y costosos como infrarrojo de piridina adsorbida.Palabras clave: catalizadores CoMo, características ácido-base, descomposición de isopropilamina, adsorción de piridina. ABSTRACTThe acid-base properties of CoMo catalysts supported on amorphous alumino-silicates (ASA) with different Si/(Si+Al) atomic ratios and on alumina modified with B were determined using the 2-propanol decomposition reaction. Results were compared and validated with isopropylamine decomposition tests and with FT-IR measurements of adsorbed pyridine. A good reproducibility and high sensitivity of the 2-propanol dehydration reaction to changes and/or modifications of the catalyst surface were observed. In the case of the CoMo catalysts supported on ASA, density, strength and total active sites number increases when the Si/(Si+Al) ratio increases. This fact is attributed to an increase in the Brönsted acid sites. On the other hand, an increase in density and strength of acid sites with the increase in the B amount was observed in the case of CoMo catalysts modified with B. The results of this study support the conclusion that the selectivity in the decomposition of 2-propanol reaction is sensitive to changes in the acid-base properties showing reproducible results and comparable with the ones obtained from more expensive and sophisticated methods.Keywords: CoMo catalysts, acid-base characteristics, isopropylamine decomposition, pyridine adsorption

Dietary, Cultural, and Pathogens-Related Selective Pressures Shaped Differential Adaptive Evolution among Native Mexican Populations

Native American genetic ancestry has been remarkably implicated with increased risk of diverse health issues in several Mexican populations, especially in relation to the dramatic changes in environmental, dietary, and cultural settings they have recently undergone. In particular, the effects of these ecological transitions and Westernization of lifestyles have been investigated so far predominantly on Mestizo individuals. Nevertheless, indigenous groups, rather than admixed Mexicans, have plausibly retained the highest proportions of genetic components shaped by natural selection in response to the ancient milieu experienced by Mexican ancestors during their pre-Columbian evolutionary history. These formerly adaptive variants have the potential to represent the genetic determinants of some biological traits that are peculiar to Mexican people, as well as a reservoir of loci with possible biomedical relevance. To test such a hypothesis, we used genome-wide genotype data to infer the unique adaptive evolution of Native Mexican groups selected as reasonable descendants of the main pre-Columbian Mexican civilizations. A combination of haplotype-based and gene-network analyses enabled us to detect genomic signatures ascribable to polygenic adaptive traits plausibly evolved by the main genetic clusters of Mexican indigenous populations to cope with local environmental and/or cultural conditions. Some of these adaptations were found to play a role in modulating the susceptibility/resistance of these groups to certain pathological conditions, thus providing new evidence that diverse selective pressures have contributed to shape the current biological and disease-risk patterns of present-day Native and Mestizo Mexican populations

Adaptive Lévy processes and area-restricted search in human foraging

A considerable amount of research has claimed that animals’ foraging behaviors display movement lengths with power-law distributed tails, characteristic of Lévy flights and Lévy walks. Though these claims have recently come into question, the proposal that many animals forage using Lévy processes nonetheless remains. A Lévy process does not consider when or where resources are encountered, and samples movement lengths independently of past experience. However, Lévy processes too have come into question based on the observation that in patchy resource environments resource-sensitive foraging strategies, like area-restricted search, perform better than Lévy flights yet can still generate heavy-tailed distributions of movement lengths. To investigate these questions further, we tracked humans as they searched for hidden resources in an open-field virtual environment, with either patchy or dispersed resource distributions. Supporting previous research, for both conditions logarithmic binning methods were consistent with Lévy flights and rank-frequency methods–comparing alternative distributions using maximum likelihood methods–showed the strongest support for bounded power-law distributions (truncated Lévy flights). However, goodness-of-fit tests found that even bounded power-law distributions only accurately characterized movement behavior for 4 (out of 32) participants. Moreover, paths in the patchy environment (but not the dispersed environment) showed a transition to intensive search following resource encounters, characteristic of area-restricted search. Transferring paths between environments revealed that paths generated in the patchy environment were adapted to that environment. Our results suggest that though power-law distributions do not accurately reflect human search, Lévy processes may still describe movement in dispersed environments, but not in patchy environments–where search was area-restricted. Furthermore, our results indicate that search strategies cannot be inferred without knowing how organisms respond to resources–as both patched and dispersed conditions led to similar Lévy-like movement distributions

Gender Inequalities in Diagnostic Inertia around the Three Most Prevalent Cardiovascular Risk Studies: Protocol for a Population-Based Cohort Study

Evidence shows that objectives for detecting and controlling cardiovascular risk factors are not being effectively met, and moreover, outcomes differ between men and women. This study will assess the gender-related differences in diagnostic inertia around the three most prevalent cardiovascular risk factors: dyslipidemia, arterial hypertension, and diabetes mellitus, and to evaluate the consequences on cardiovascular disease incidence. This is an epidemiological and cohort study. Eligible patients will be adults who presented to public primary health care centers in a Spanish region from 2008 to 2011, with hypertension, dyslipidemia, or/and diabetes and without cardiovascular disease. Participants’ electronic health records will be used to collect the study variables in a window of six months from inclusion. Diagnostic inertia of hypertension, dyslipidemia, and/or diabetes is defined as the registry of abnormal diagnostic parameters—but no diagnosis—on the person’s health record. The cohort will be followed from the date of inclusion until the end of 2019. Outcomes will be cardiovascular events, defined as hospital admission due to ischemic cardiopathy, stroke, and death from any cause. The results of this study could inform actions to rectify the structure, organization and training of health care teams in order to correct the inequality