Robust Analysis of Metabolic Pathways

Flux Balance Analysis (FBA) is a widely used computational model for studying the metabolic pathways of cells and the role individual metabolites and reactions play in maintaining cell function. However, the successes of FBA have been limited by faulty biological assumptions and computational imperfections. We introduce Robust Analysis of Metabolic Pathways (RAMP) to provide a more theoretically sound and computationally accurate model of cellular metabolism. RAMP overcomes the faulty assumptions of traditional FBA by allowing deviation from steady-state and accounting for variability across a cellular culture. Computationally, RAMP more successfully predicts the lethality of gene knockouts and reduces degeneracy in optimal ux values. Analytical results establish the stability of RAMP under perturbations in modeling parameters. The inclusion of new modeling parameters in RAMP opens the possibility of modeling different cellular cultures in a wider range of conditions, including non- optimized cultures. We conclude that RAMP is an improvement over traditional FBA and deserves further study

Episodic population fragmentation and gene flow reveal a trade-off between heterozygosity and allelic richness

In episodic environments like deserts, populations of some animal species exhibit irregular fluctuations such that populations are alternately large and connected or small and isolated. Such dynamics are typically driven by periodic resource pulses due, for example, to large but infrequent rainfall events. The repeated population bottlenecks resulting from fragmentation should lower genetic diversity over time, yet species undergoing these fluctuations appear to maintain high levels of genetic diversity. To resolve this apparent paradox, we simulated a metapopulation of constant size undergoing repeat episodes of fragmentation and change in gene flow to mimic outcomes experienced by mammals in an Australian desert. We show that episodic fragmentation and gene flow have contrasting effects on two measures of genetic diversity: heterozygosity and allelic richness. Specifically, fragmentation into many, small subpopulations, coupled with periods of infrequent gene flow, preserves allelic richness at the expense of heterozygosity. In contrast, fragmentation into a few, large subpopulations maintains heterozygosity at the expense of allelic richness. The strength of the trade-off between heterozygosity and allelic richness depends on the amount of gene flow and the frequency of gene flow events. Our results imply that the type of genetic diversity maintained among species living in strongly fluctuating environments will depend on the way populations fragment, with our results highlighting different mechanisms for maintaining allelic richness and heterozygosity in small, fragmented populations

The Fermi GBM Gamma-Ray Burst Spectral Catalog: Four Years Of Data

In this catalog we present the updated set of spectral analyses of GRBs detected by the Fermi Gamma-Ray Burst Monitor (GBM) during its first four years of operation. It contains two types of spectra, time-integrated spectral fits and spectral fits at the brightest time bin, from 943 triggered GRBs. Four different spectral models were fitted to the data, resulting in a compendium of more than 7500 spectra. The analysis was performed similarly, but not identically to Goldstein et al. 2012. All 487 GRBs from the first two years have been re-fitted using the same methodology as that of the 456 GRBs in years three and four. We describe, in detail, our procedure and criteria for the analysis, and present the results in the form of parameter distributions both for the observer-frame and rest-frame quantities. The data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center (HEASARC).Comment: Accepted for publication in ApJ

States of epistemic curiosity interfere with memory for incidental scholastic facts

Curiosity can be a powerful motivator to learn and retain new information. Evidence shows that high states of curiosity elicited by a specific source (i.e., a trivia question) can promote memory for incidental stimuli (non-target) presented close in time. The spreading effect of curiosity states on memory for other information has potential for educational applications. Specifically, it could provide techniques to improve learning for information that did not spark a sense of curiosity on its own. Here, we investigated how high states of curiosity induced through trivia questions affect memory performance for unrelated scholastic facts (e.g., scientific, English, or historical facts) presented in close temporal proximity to the trivia question. Across three task versions, participants viewed trivia questions closely followed in time by a scholastic fact unrelated to the trivia question, either just prior to or immediately following the answer to the trivia question. Participants then completed a surprise multiple-choice memory test (akin to a pop quiz) for the scholastic material. In all three task versions, memory performance was poorer for scholastic facts presented after trivia questions that had elicited high versus low levels of curiosity. These results contradict previous findings showing curiosity-enhanced memory for incidentally presented visual stimuli and suggest that target information that generates a high-curiosity state interferes with encoding complex and unrelated scholastic facts presented close in time

Projeto de Extensão riscos da automedicação: relato de experiências em educação em saúde

Created in 2006, the Extension Project “Self-Medication Risks” aims to reduce the risks associated with self-medication by promoting the rational use of medicines. This paper is an experience report conducted during the last five years. During the period mentioned, 7,267 people from diverse audiences and age groups were served by this project by means of lectures, distribution and application of educational materials, workshops and activities connected to the central and/or peripheral themes perceived as necessary. In all these actions, there were only positive remarks about them and terms like “good”, “great” and “excellent” were widely used, revealing high levels of satisfaction with the project and its consequential effectiveness in health education. For results stratification and specific objectives implementation, the project was divided into 4 strands: Research, Events, Educational Materials and Social Media. Such division was conducted to set objectives which were prone to be supplied when not fully achieved taking into account their high impact on the community. This extension project aligned students’ academic formation with their own life reality and it was also able to have its benefits spread out over the university limits to the community.Criado em 2006, o Projeto de Extensão “Riscos da Automedicação”, visa a reduzir os riscos associados à automedicação na população por meio da promoção do uso racional de medicamentos. Este trabalho é um relato de experiências dos últimos 5 anos, período em que o projeto atendeu 7.267 pessoas de diversos públicos e faixas etárias, por intermédio de palestras, distribuição e aplicação de materiais educativos, oficinas e atividades conectadas ao tema central e/ou temas periféricos percebidos como necessários. Em todas essas ações, houve apenas avaliações positivas, com termos “bom”, “ótimo” e “excelente”, revelando altos índices de satisfação e efetivação da educação em saúde. Para estratificação dos resultados e efetivação dos objetivos específicos, o projeto foi dividido em 4 vertentes: Pesquisa, Eventos, Materiais Educativos e Mídias Sociais. Essa divisão foi implementada a fim de permitir a elaboração de metas que, quando não totalmente atingidas, foram supridas, levando-se em consideração seu alto impacto na comunidade. Este projeto de extensão tem possibilitado formação alinhada à realidade aos acadêmicos e traz benefícios de ações da universidade para a comunidade

Physicochemical analysis of rotavirus segment 11 supports a 'modified panhandle' structure and not the predicted alternative tRNA-like structure (TRLS)

.Rotaviruses are a major cause of acute gastroenteritis, which is often fatal in infants. The viral genome consists of 11 double-stranded RNA segments, but little is known about their cis-acting sequences and structural elements. Covariation studies and phylogenetic analysis exploring the potential structure of RNA11 of rotaviruses suggested that, besides the previously predicted "modified panhandle" structure, the 5' and 3' termini of one of the isoforms of the bovine rotavirus UKtc strain may interact to form a tRNA-like structure (TRLS). Such TRLSs have been identified in RNAs of plant viruses, where they are important for enhancing replication and packaging. However, using tRNA mimicry assays (in vitro aminoacylation and 3'- adenylation), we found no biochemical evidence for tRNA-like functions of RNA11. Capping, synthetic 3' adenylation and manipulation of divalent cation concentrations did not change this finding. NMR studies on a 5'- and 3'-deletion construct of RNA11 containing the putative intra-strand complementary sequences supported a predominant panhandle structure and did not conform to a cloverleaf fold despite the strong evidence for a predicted structure in this conserved region of the viral RNA. Additional viral or cellular factors may be needed to stabilise it into a form with tRNA-like properties

Barriers and facilitators to screen for and address social needs in primary care practices in Maryland: a qualitative study

BackgroundSocial needs screening can help modify care delivery to meet patient needs and address non-medical barriers to optimal health. However, there is a need to understand how factors that exist at multiple levels of the healthcare ecosystem influence the collection of these data in primary care settings.MethodsWe conducted 20 semi-structured interviews involving healthcare providers and primary care clinic staff who represented 16 primary care practices. Interviews focused on barriers and facilitators to awareness of and assistance for patients' social needs in primary care settings in Maryland. The interviews were coded to abstract themes highlighting barriers and facilitators to conducting social needs screening. The themes were organized through an inductive approach using the socio-ecological model delineating individual-, clinic-, and system-level barriers and facilitators to identifying and addressing patients' social needs.ResultsWe identified several individual barriers to awareness, including patient stigma about verbalizing social needs, provider frustration at eliciting needs they were unable to address, and provider unfamiliarity with community-based resources to address social needs. Clinic-level barriers to awareness included limited appointment times and connecting patients to appropriate community-based organizations. System-level barriers to awareness included navigating documentation challenges on the electronic health record.ConclusionsOvercoming barriers to effective screening for social needs in primary care requires not only practice- and provider-level process change but also an alignment of community resources and advocacy of policies to redistribute community assets to address social needs

Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension

Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing’s syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites – 18 in PPGL, 15 in CS, and 23 in PA – were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL’s metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.</p