Structural and functional implications of positive selection at the primate angiogenin gene

BACKGROUND: Angiogenesis, the formation of new blood vessels, is a primordial process in development and its dysregulation has a central role in the pathogenesis of many diseases. Angiogenin (ANG), a peculiar member of the RNase A superfamily, is a potent inducer of angiogenesis involved in many different types of cancer, amyotrophic lateral sclerosis and also with a possible role in the innate immune defense. The evolutionary path of this family has been a highly dynamic one, where positive selection has played a strong role. In this work we used a combined gene and protein level approach to determine the main sites under diversifying selection on the primate ANG gene and analyze its structural and functional implications. RESULTS: We obtained evidence for positive selection in the primate ANG gene. Site specific analysis pointed out 15 sites under positive selection, most of which also exhibited drastic changes in amino acid properties. The mapping of these sites in the ANG 3D-structure described five clusters, four of which were located in functional regions: two in the active site region, one in the nucleolar location signal and one in the cell-binding site. Eight of the 15 sites under selection in the primate ANG gene were highly or moderately conserved in the RNase A family, suggesting a directed event and not a simple consequence of local structural or functional permissiveness. Moreover, 11 sites were exposed to the surface of the protein indicating that they may influence the interactions performed by ANG. CONCLUSION: Using a maximum likelihood gene level analysis we identified 15 sites under positive selection in the primate ANG genes, that were further corroborated through a protein level analysis of radical changes in amino acid properties. These sites mapped onto the main functional regions of the ANG protein. The fact that evidence for positive selection is present in all ANG regions required for angiogenesis may be a good indication that angiogenesis is the process under selection. However, other possibilities to be considered arise from the possible involvement of ANG in innate immunity and the potential influence or co-evolution with its interacting proteins and ligands

Sobre la modularidad de la mente y su vigencia

Aunque la idea de organización modular de la mente se remonta a la propuesta de facultades mentales innatas ya presente en la filosofia de la escuela escocesa y en la de Kant, y probablemente podemos encontrar antecedentes en épocas anteriores, la concepción moderna de la modularidad se desarrolla de forma independiente a esta tradición filosófica y también a la idea de organización modular del cerebro central en la frenologia de Gall. La concepción moderna sobre la modularidad se inicia en 10s años cincuenta con la aparición de 10s primeros ordenadores y 10s primeros trabajos en el kea de la inteligencia artificial (IA) y la psicologia cognitiva. En esta forma de entender la modularidad el concepto de módulo va ligado claramente a la concepción computacional de la inteligencia y posee un estatus científic0 que no poseia la concepción modular de tradición filosófica o frenológica

Short-range charge-order in RRNiO3_{3} perovskites (RR=Pr,Nd,Eu) probed by X-ray absorption spectroscopy

The short-range organization around Ni atoms in orthorhombic $R$NiO$_{3}$ ($R$=Pr,Nd,Eu) perovskites has been studied over a wide temperature range by Ni K-edge x-ray absorption spectroscopy. Our results demonstrate that two different Ni sites, with different average Ni-O bond lengths, coexist in those orthorhombic compounds and that important modifications in the Ni nearest neighbors environment take place across the metal-insulator transition. We report evidences for the existence of short-range charge-order in the insulating state, as found in the monoclinic compounds. Moreover, our results suggest that the two different Ni sites coexists even in the metallic state. The coexistence of two different Ni sites, independently on the $R$ ion, provides a common ground to describe these compounds and shed new light in the understanding of the phonon-assisted conduction mechanism and unusual antiferromagnetism present in all $R$NiO$_{3}$ compounds.Comment: 4 pages, 3 figures, accepted PRB - Brief Report Dec.200

A data-driven approach to decode metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), defined by the presence of liver steatosis together with at least one out of five cardiometabolic factors, is the most common cause of chronic liver disease worldwide, affecting around one in three people. Yet the clinical presentation of MASLD and the risk of progression to cirrhosis and adverse clinical outcomes is highly variable. It therefore represents both a global public health threat and a precision medicine challenge. The use of artificial intelligence (AI) is being investigated in MASLD to develop reproducible, quantitative, and automated methods to enhance patient stratification and to discover new biomarkers and therapeutic targets in MASLD. This review details the different applications of AI and machine learning algorithms in MASLD, particularly in the context of analyzing electronic health record, digital pathology, and imaging data. Additionally, it also describes how specific MASLD consortia are leveraging multimodal data sources to spark research breakthroughs in the field. Using a new national level ‘data commons’ (SteatoSITE) as an exemplar, the opportunities as well as the technical challenges of large-scale databases in MASLD research are highlighted

Conclave: Writing programs to understand programs

Software maintainers are often challenged with source code changes to improve software systems, or eliminate defects, in unfamiliar programs. To undertake these tasks a sufficient understanding of the system, or at least a small part of it, is required. One of the most time consuming tasks of this process is locating which parts of the code are responsible for some key functionality or feature. This paper introduces Conclave, an environment for software analysis, that enhances program comprehension activities. Programmers use natural languages to describe and discuss the problem domain, programming languages to write source code, and markup languages to have programs talking with other programs, and so this system has to cope with this heterogeneity of dialects, and provide tools in all these areas to effectively contribute to the understanding process. The source code, the problem domain, and the side effects of running the program are represented in the system using ontologies. A combination of tools (specialized in different kinds of languages) create mappings between the different domains. Conclave provides facilities for feature location, code search, and views of the software that ease the process of understanding the code, devising changes. The underlying feature location technique explores natural language terms used in programs (e.g. function and variable names); using textual analysis and a collection of Natural Language Processing techniques, computes synonymous sets of terms. These sets are used to score relatedness between program elements, and search queries or problem domain concepts, producing sorted ranks of program elements that address the search criteria, or concepts respectively. © Nuno Ramos Carvalho, José João Almeida, Maria João Varanda Pereira, and Pedro Rangel Henriques.(undefined)info:eu-repo/semantics/publishedVersio

Comparative evolutionary genomics of the HADH2 gene encoding Aβ-binding alcohol dehydrogenase/17β-hydroxysteroid dehydrogenase type 10 (ABAD/HSD10)

BACKGROUND: The Aβ-binding alcohol dehydrogenase/17β-hydroxysteroid dehydrogenase type 10 (ABAD/HSD10) is an enzyme involved in pivotal metabolic processes and in the mitochondrial dysfunction seen in the Alzheimer's disease. Here we use comparative genomic analyses to study the evolution of the HADH2 gene encoding ABAD/HSD10 across several eukaryotic species. RESULTS: Both vertebrate and nematode HADH2 genes showed a six-exon/five-intron organization while those of the insects had a reduced and varied number of exons (two to three). Eutherian mammal HADH2 genes revealed some highly conserved noncoding regions, which may indicate the presence of functional elements, namely in the upstream region about 1 kb of the transcription start site and in the first part of intron 1. These regions were also conserved between Tetraodon and Fugu fishes. We identified a conserved alternative splicing event between human and dog, which have a nine amino acid deletion, causing the removal of the strand β(F). This strand is one of the seven strands that compose the core β-sheet of the Rossman fold dinucleotide-binding motif characteristic of the short chain dehydrogenase/reductase (SDR) family members. However, the fact that the substrate binding cleft residues are retained and the existence of a shared variant between human and dog suggest that it might be functional. Molecular adaptation analyses across eutherian mammal orthologues revealed the existence of sites under positive selection, some of which being localized in the substrate-binding cleft and in the insertion 1 region on loop D (an important region for the Aβ-binding to the enzyme). Interestingly, a higher than expected number of nonsynonymous substitutions were observed between human/chimpanzee and orangutan, with six out of the seven amino acid replacements being under molecular adaptation (including three in loop D and one in the substrate binding loop). CONCLUSION: Our study revealed that HADH2 genes maintained a reasonable conserved organization across a large evolutionary distance. The conserved noncoding regions identified among mammals and between pufferfishes, the evidence of an alternative splicing variant conserved between human and dog, and the detection of positive selection across eutherian mammals, may be of importance for further research on ABAD/HSD10 function and its implication in the Alzheimer's disease

A toxicokinetic study reflecting the absorption, distribution, metabolism and excretion of deoxynivalenol in broiler chickens

To identify the specific biomarkers of exposure of DON in chickens, a toxicokinetic study was performed via oral or intravenous application of deoxynivalenol (DON). Doses of 0.75 and 2.25 mg DON/kg of body weight (BW) were administrated intravenously or orally to the chickens. Next, blood samples were collected at several time points and plasma was obtained. Liquid chromatography–tandem massspectrometry (LC–MS/MS) was used to quantify plasma levels of DON and its metabolite DON-3- sulphate (DON-3S). A non-compartmental analysis was performed to study the main toxicokinetic parameters after intravenous or oral application of the toxin. Regarding oral administration, DON plasma level was below the limit of detection (LOD) of the method (1.5 ng/mL) and DON-3S could not be identified. After intravenous administration of DON at 0.75 and 2.25 mg DON/kg BW, the elimination half-life was 57.1 and 47.7 min, respectively, indicating the rapid elimination of DON. The metabolite DON-3S was found in plasma of broilers exposed to DON intravenously. The absence of DON in chicken plasma after oral bolus application suggests the low absorption of this mycotoxin. The presence of DON-3S in plasma indicates that this metabolite could be the appropriate biomarker of DON exposure in chickens