The major leucyl aminopeptidase of Trypanosoma cruzi (LAPTc) assembles into a homohexamer and belongs to the M17 family of metallopeptidases

<p>Abstract</p> <p>Background</p> <p>Pathogens depend on peptidase activities to accomplish many physiological processes, including interaction with their hosts, highlighting parasitic peptidases as potential drug targets. In this study, a major leucyl aminopeptidolytic activity was identified in <it>Trypanosoma cruzi</it>, the aetiological agent of Chagas disease.</p> <p>Results</p> <p>The enzyme was isolated from epimastigote forms of the parasite by a two-step chromatographic procedure and associated with a single 330-kDa homohexameric protein as determined by sedimentation velocity and light scattering experiments. Peptide mass fingerprinting identified the enzyme as the predicted <it>T. cruzi </it>aminopeptidase EAN97960. Molecular and enzymatic analysis indicated that this leucyl aminopeptidase of <it>T. cruzi </it>(LAPTc) belongs to the peptidase family M17 or leucyl aminopeptidase family. LAPTc has a strong dependence on neutral pH, is mesophilic and retains its oligomeric form up to 80°C. Conversely, its recombinant form is thermophilic and requires alkaline pH.</p> <p>Conclusions</p> <p>LAPTc is a 330-kDa homohexameric metalloaminopeptidase expressed by all <it>T. cruzi </it>forms and mediates the major parasite leucyl aminopeptidolytic activity. Since biosynthetic pathways for essential amino acids, including leucine, are lacking in <it>T. cruzi</it>, LAPTc could have a function in nutritional supply.</p

Making personalised nutrition the easy choice: creating policies to break down the barriers and reap the benefits

Personalised diets based on people\u27s existing food choices,and/or phenotypic, and/or genetic information hold potential to improve public dietary-related health. The aim of this analysis, therefore, has been to examine the degree to which factors which determine uptake of personalised nutrition vary between EU countries to better target of policies to encourage uptake, and optimise the health benefits of personalised nutrition technology. A questionnaire developed from previous qualitative research was used to survey nationally representative samples from 9 EU countries (N=9381). Perceived barriersto the uptake of personalised nutrition comprised three factors (data protection; the eating context; and societal acceptance). Trust insources of information comprised 4 factors (commerce and media;practitioners; government; family and friends). Benefits comprised single factor. Analysis of Variance (ANOVA) was employed to comparedifferences in responses between the United Kingdom; Ireland; Portugal;Poland; Norway; the Netherlands; Germany; and Spain. The resultsindicated that those in Greece, Poland, Ireland, Portugal and Spain,rated the benefits of personalised nutrition highest, suggesting aparticular readiness in these countries to adopt personalised nutritioninterventions. Greek participants were more likely to perceive the socialcontext of eating as a barrier to adoption of personalised nutrition,implying a need for support in negotiating social situations whilst on aprescribed diet. Those in Spain, Germany, Portugal and Poland scoredhighest on perceived barriers related to data protection. Government wasmore trusted than commerce to deliver and provide information onpersonalised nutrition overall. This was particularly the case inIreland, Portugal and Greece, indicating an imperative to build trust,particularly in the ability of commercial service providers to deliverpersonalised dietary regimes effectively in these countries. These findings, obtained from a nationally representative sample of EU citizensimply that a parallel, integrated, public-private delivery system would capture the needs of most potential consumer

Mortalidade infantil e acesso geográfico ao parto nos municípios brasileiros

OBJETIVO: Analisar o acesso geográfico ao parto hospitalar nos municípios brasileiros. MÉTODOS: Foram analisadas informações de óbitos e nascimentos quanto à sua adequação para o cálculo do coeficiente de mortalidade infantil no período de 2005 a 2007 para os 5.564 municípios brasileiros. O acesso geográfico foi expresso por indicadores de deslocamento, oferta e acesso aos serviços de saúde. A associação entre o acesso geográfico ao parto e o coeficiente de mortalidade infantil em municípios com adequação de suas informações vitais foi avaliada por meio de regressão múltipla. RESULTADOS: Dentre os municípios analisados, 56% apresentaram adequação das informações vitais, correspondendo a 72% da população brasileira. O deslocamento geográfico ao parto mostrou-se inversamente associado ao porte populacional, à renda per capita, e à mortalidade infantil, mesmo controlado por fatores demográficos e socioeconômicos. CONCLUSÕES: Embora tenham sido desenvolvidas estratégias importantes para a melhoria da qualidade do atendimento às gestantes no Brasil, as ações para garantir o acesso igualitário à assistência ao parto ainda são insuficientes. O maior deslocamento intermunicipal para o parto se mostrou como um fator de risco para a mortalidade infantil, aliado à desigualdade de oferta de serviços qualificados e à falta de integração com a atenção básica de saúde

Prevalence of Polypharmacy and Association to Pharmacotherapy Complexity in Older HIV-Positive Patients. The Sevihlla Study

Background: Increased life expectancy of older HIV-positive patients has been associated to a parallel increase in age-related comorbidities.Objectives: To ascertain the prevalence of polypharmacy and its association to pharmacotherapy complexity, as measured by the Medication Regimen Complexity Index, in older HIV-positive patients; to calculate the median value of pharmacotherapy complexity; to identify polypharmacy and multimorbidity patterns; and to address adherence to antiretroviral and concomitant drugs.Methods: A cross-sectional, observational study was conducted in patients over 50 years of age receiving active antiretroviral drugs during 2014 at outpatient pharmacy services of a tertiary hospital in Spain. Data collected from the electronic medical record included demographic, clinical and comorbidity related endpoints.The primary endpoint was the proportion of patients with polypharmacy and major polypharmacy. Polypharmacy was defined as treatment with six or more drugs (including antiretroviral). Major polypharmacy (more than 11 drugs) was also considered.Patients was categorized according to their polypharmacy pattern. Three patterns were applied based on age of participants: cardiovascular, depression-anxiety, and chronic obstructive pulmonary (COPD) disease patterns. A patient was classified into a pattern when at least three drugs of the treatment were in the same pattern.Antiretroviral treatment adherence was measured using the SMAQ questionnaire and hospital dispensing records. Adherence to concomitant medication was measured using the Morisky-Green questionnaire and electronic pharmacy dispensing records.Pharmacotherapy complexity index, as assessed by MRCI, was also considered. Patients were classified as low MRCI (less than 14 points) or high MRCI (more than 14 points).Results: The study sample consisted of 223 patients (86.5% men), with a median age of 53.0 years. More than 80.0% of the patients were viro-inmunological controlled. Prevalence of polypharmacy was 56.1%. The median value of pharmacotherapy complexity was 11.0. The main contribution to this value was from the concomitant medication.The polypharmacy pattern mainly calculated was cardiovascular (60.0%) and the multimorbidity pattern was cardiometabolic (73.8%).Presence of polypharmacy was associated to greater pharmacotherapy complexity (p&lt;0,001). Adequate adherence to the antiretroviral and to concomitant medication was found in 83.6% and 37.9% of patients respectively.Conclusions: More than a half of the older HIV-positive patients received six or more different drugs with a significant pharmacotherapy complexity showing adequate adherence to antiretroviral but not to concomitant drugs. Cardiovascular conditions were most common in terms of prescriptions and comorbidities

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases risk for Crohn’s disease and leprosy. We developed an unbiased liquid chromatography mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic paralogues additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.Includes ERC. Wellcome Trust and MRC