Sensibilidad de la microestructura en un sistema multi-escala

Este trabajo analiza la sensibilidad de los parámetros de optimización de una microestructura periódica isotrópica en la optimización topológica de una viga MBB. La función objetivo para optimización de la microestructura es el módulo volumétrico, y los parámetros analizados son: fracción volumétrica, radio de filtro y factor de penalización. En la macroestructura la función objetivo es la minimización de la flexibilidad, sujeta a un volumen predefinido de 0.5. Se desarrolló un algoritmo, con base en el método SIMP, capaz de transferir las informaciones de la microestructura para la macroestructura. Se realizaron análisis numéricos, variando los parámetros y observando el comportamiento de las soluciones. Los resultados demuestran que la fracción volumétrica de la microestructura tiene gran influencia en la maximización de la rigidez, sin embargo el radio de filtro y el factor de penalización presentaron poca influencia, así como sobre el perfil de la macroestructura.Publicado en: Mecánica Computacional vol. XXXV, no. 23Facultad de Ingenierí

Sensibilidad de la microestructura en un sistema multi-escala

Este trabajo analiza la sensibilidad de los parámetros de optimización de una microestructura periódica isotrópica en la optimización topológica de una viga MBB. La función objetivo para optimización de la microestructura es el módulo volumétrico, y los parámetros analizados son: fracción volumétrica, radio de filtro y factor de penalización. En la macroestructura la función objetivo es la minimización de la flexibilidad, sujeta a un volumen predefinido de 0.5. Se desarrolló un algoritmo, con base en el método SIMP, capaz de transferir las informaciones de la microestructura para la macroestructura. Se realizaron análisis numéricos, variando los parámetros y observando el comportamiento de las soluciones. Los resultados demuestran que la fracción volumétrica de la microestructura tiene gran influencia en la maximización de la rigidez, sin embargo el radio de filtro y el factor de penalización presentaron poca influencia, así como sobre el perfil de la macroestructura.Publicado en: Mecánica Computacional vol. XXXV, no. 23Facultad de Ingenierí

Sensibilidad de la microestructura en un sistema multi-escala

Este trabajo analiza la sensibilidad de los parámetros de optimización de una microestructura periódica isotrópica en la optimización topológica de una viga MBB. La función objetivo para optimización de la microestructura es el módulo volumétrico, y los parámetros analizados son: fracción volumétrica, radio de filtro y factor de penalización. En la macroestructura la función objetivo es la minimización de la flexibilidad, sujeta a un volumen predefinido de 0.5. Se desarrolló un algoritmo, con base en el método SIMP, capaz de transferir las informaciones de la microestructura para la macroestructura. Se realizaron análisis numéricos, variando los parámetros y observando el comportamiento de las soluciones. Los resultados demuestran que la fracción volumétrica de la microestructura tiene gran influencia en la maximización de la rigidez, sin embargo el radio de filtro y el factor de penalización presentaron poca influencia, así como sobre el perfil de la macroestructura.Publicado en: Mecánica Computacional vol. XXXV, no. 23Facultad de Ingenierí

Ready ... Go: Amplitude of the fMRI Signal Encodes Expectation of Cue Arrival Time

What happens when the brain awaits a signal of uncertain arrival time, as when a sprinter waits for the starting pistol? And what happens just after the starting pistol fires? Using functional magnetic resonance imaging (fMRI), we have discovered a novel correlate of temporal expectations in several brain regions, most prominently in the supplementary motor area (SMA). Contrary to expectations, we found little fMRI activity during the waiting period; however, a large signal appears after the “go” signal, the amplitude of which reflects learned expectations about the distribution of possible waiting times. Specifically, the amplitude of the fMRI signal appears to encode a cumulative conditional probability, also known as the cumulative hazard function. The fMRI signal loses its dependence on waiting time in a “countdown” condition in which the arrival time of the go cue is known in advance, suggesting that the signal encodes temporal probabilities rather than simply elapsed time. The dependence of the signal on temporal expectation is present in “no-go” conditions, demonstrating that the effect is not a consequence of motor output. Finally, the encoding is not dependent on modality, operating in the same manner with auditory or visual signals. This finding extends our understanding of the relationship between temporal expectancy and measurable neural signals

Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures

Samples of human and rat skin in short-term organ culture exposed to ALA or a range of hydrophobic derivatives were examined for their effect on the accumulation of protoporphyrin IX (PpIX) measured using fluorescence spectroscopy. With the exception of carbobenzoyloxy-D-phenylalanyl-5-ALA-ethyl ester the data presented indicate that, in normal tissues, ALA derivatives generate protoporphyrin IX more slowly than ALA, suggesting that they are less rapidly taken up and/or converted to free ALA. However, the resultant depot effect may lead to the enhanced accumulation of porphyrin over long exposure periods, particularly in the case of ALA-methyl ester or ALA-hexyl ester, depending on the applied concentration and the exposed tissue. Addition of the iron chelator, CP94, greatly increased PpIX accumulation in human skin exposed to ALA, ALA-methyl ester and ALA-hexyl ester. The effect in rat skin was less marked.</p

The Evolution of Host Specialization in the Vertebrate Gut Symbiont Lactobacillus reuteri

Recent research has provided mechanistic insight into the important contributions of the gut microbiota to vertebrate biology, but questions remain about the evolutionary processes that have shaped this symbiosis. In the present study, we showed in experiments with gnotobiotic mice that the evolution of Lactobacillus reuteri with rodents resulted in the emergence of host specialization. To identify genomic events marking adaptations to the murine host, we compared the genome of the rodent isolate L. reuteri 100-23 with that of the human isolate L. reuteri F275, and we identified hundreds of genes that were specific to each strain. In order to differentiate true host-specific genome content from strain-level differences, comparative genome hybridizations were performed to query 57 L. reuteri strains originating from six different vertebrate hosts in combination with genome sequence comparisons of nine strains encompassing five phylogenetic lineages of the species. This approach revealed that rodent strains, although showing a high degree of genomic plasticity, possessed a specific genome inventory that was rare or absent in strains from other vertebrate hosts. The distinct genome content of L. reuteri lineages reflected the niche characteristics in the gastrointestinal tracts of their respective hosts, and inactivation of seven out of eight representative rodent-specific genes in L. reuteri 100-23 resulted in impaired ecological performance in the gut of mice. The comparative genomic analyses suggested fundamentally different trends of genome evolution in rodent and human L. reuteri populations, with the former possessing a large and adaptable pan-genome while the latter being subjected to a process of reductive evolution. In conclusion, this study provided experimental evidence and a molecular basis for the evolution of host specificity in a vertebrate gut symbiont, and it identified genomic events that have shaped this process

Dark Energy from Mass Varying Neutrinos

We show that mass varying neutrinos (MaVaNs) can behave as a negative pressure fluid which could be the origin of the cosmic acceleration. We derive a model independent relation between the neutrino mass and the equation of state parameter of the neutrino dark energy, which is applicable for general theories of mass varying particles. The neutrino mass depends on the local neutrino density and the observed neutrino mass can exceed the cosmological bound on a constant neutrino mass. We discuss microscopic realizations of the MaVaN acceleration scenario, which involve a sterile neutrino. We consider naturalness constraints for mass varying particles, and find that both ev cutoffs and ev mass particles are needed to avoid fine-tuning. These considerations give a (current) mass of order an eV for the sterile neutrino in microscopic realizations, which could be detectable at MiniBooNE. Because the sterile neutrino was much heavier at earlier times, constraints from big bang nucleosynthesis on additional states are not problematic. We consider regions of high neutrino density and find that the most likely place today to find neutrino masses which are significantly different from the neutrino masses in our solar system is in a supernova. The possibility of different neutrino mass in different regions of the galaxy and the local group could be significant for Z-burst models of ultra-high energy cosmic rays. We also consider the cosmology of and the constraints on the ``acceleron'', the scalar field which is responsible for the varying neutrino mass, and briefly discuss neutrino density dependent variations in other constants, such as the fine structure constant.Comment: 26 pages, 3 figures, refs added, typos corrected, comment added about possible matter effect

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)).This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field