The cost of inbreeding in a socially polymorphic ant population

Trabalho de projecto de mestrado em Medicina (Gastroenterologia), apresentado á Faculdade de Medicina da Universidade de CoimbraA encefalopatia hepática é uma das principais complicações da doença hepática crónica e pode estar presente em 50 a 70% de todos os pacientes cirróticos, incluindo aqueles com alterações demonstráveis apenas por testes psicométricos, sendo uma complicação de grande relevância clínica. Na insuficiência hepática aguda, os doentes podem sucumbir a uma morte neurológica, com edema cerebral e hipertensão intracraniana. A sobrevida em pacientes com doença hepática crónica depende da avaliação dos critérios da classificação de Child-Pugh que reconhece a importância prognóstica da encefalopatia hepática. Esta complicação da doença hepática, aguda ou crónica, resulta da diminuição da actividade hepática com incapacidade marcada de eliminação de determinadas toxinas do organismo. Hoje sabe-se que os astrócitos, nomeadamente as células de Alzheimer tipo II, tem um papel importante na fisiopatologia da encefalopatia hepática. A epidemiologia e a fisiopatologia da encefalopatia hepática permanecem ainda apenas parcialmente esclarecidas, tornando este tema fonte importante de estudos constantes. O trabalho proposto tem como objectivo uma actualizada revisão bibliográfica, centrando-se nos últimos avanços científicos sobre esta alteração neuropsiquiátrica. Com este trabalho, propõe-se estudar os diferentes métodos de diagnóstico, indicações das diferentes opções terapêuticas, comparando-as entre si, identificar o impacto económico e social da encefalopatia hepática, assim como perceber os mecanismos fisiopatológicos que contribuem para esta grave alteraçãoHepatic encephalopathy is one of the main complications of chronic liver disease and can occur in 50 to 70% of all cirrhotic patients, including those with alterations demonstrated only through psychometric tests, being a complication of great clinical relevance. In severe liver failure, patients can perish due to neurological death, with brain swelling and intracranial hypertension. Chronic liver disease patients’ survival time depends on the evaluation of Child- Pugh classification criteria that recognizes the prognostic importance of hepatic encephalopathy. This liver disease complication, chronic or severe, is a result of the reduction of liver activity with marked incapacity to eliminate certain toxins from the organism. Today it is known that astrocytes, namely Alzheimer type II cells, have an important role in hepatic encephalopathy physiopathology. The epidemiology and physiopathology of hepatic encephalopathy still remain partially clarified, becoming this subject an important source of constant studies. The main goal of this study is to make an actualized bibliographical revision, grounded on the last scientific advances on this neuropsychiatric abnormality. Through this work, one considers studying the different diagnostic methods, the different therapeutic option indications, by comparing them, identifying the economic and social impact of hepatic encephalopathy, as well as understanding the physiopathological mechanisms that contribute for this serious abnormalit

Toxin inhibition in <i>C. crescentus</i> VapBC1 is mediated by a flexible pseudo-palindromic protein motif and modulated by DNA binding

Expression of bacterial type II toxin-antitoxin (TA) systems is regulated at the transcriptional level through direct binding of the antitoxin to pseudo-palindromic sequences on operator DNA. In this context, the toxin functions as a co-repressor by stimulating DNA binding through direct interaction with the antitoxin. Here, we determine crystal structures of the complete 90 kDa heterooctameric VapBC1 complex from Caulobacter crescentus CB15 both in isolation and bound to its cognate DNA operator sequence at 1.6 and 2.7 Å resolution, respectively. DNA binding is associated with a dramatic architectural rearrangement of conserved TA interactions in which C-terminal extended structures of the antitoxin VapB1 swap positions to interlock the complex in the DNA-bound state. We further show that a pseudo-palindromic protein sequence in the antitoxin is responsible for this interaction and required for binding and inactivation of the VapC1 toxin dimer. Sequence analysis of 4127 orthologous VapB sequences reveals that such palindromic protein sequences are widespread and unique to bacterial and archaeal VapB antitoxins suggesting a general principle governing regulation of VapBC TA systems. Finally, a structure of C-terminally truncated VapB1 bound to VapC1 reveals discrete states of the TA interaction that suggest a structural basis for toxin activation in vivo

CEP128 Localizes to the Subdistal Appendages of the Mother Centriole and Regulates TGF-β/BMP Signaling at the Primary Cilium

Summary: The centrosome is the main microtubule-organizing center in animal cells and comprises a mother and daughter centriole surrounded by pericentriolar material. During formation of primary cilia, the mother centriole transforms into a basal body that templates the ciliary axoneme. Ciliogenesis depends on mother centriole-specific distal appendages, whereas the role of subdistal appendages in ciliary function is unclear. Here, we identify CEP128 as a centriole subdistal appendage protein required for regulating ciliary signaling. Loss of CEP128 did not grossly affect centrosomal or ciliary structure but caused impaired transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) signaling in zebrafish and at the primary cilium in cultured mammalian cells. This phenotype is likely the result of defective vesicle trafficking at the cilium as ciliary localization of RAB11 was impaired upon loss of CEP128, and quantitative phosphoproteomics revealed that CEP128 loss affects TGF-β1-induced phosphorylation of multiple proteins that regulate cilium-associated vesicle trafficking. : Mönnich et al. show that CEP128 localizes to the subdistal appendages of the mother centriole and basal body of the primary cilium. CEP128 regulates vesicular trafficking and targeting of RAB11 to the primary cilium. CEP128 loss leads to impaired TGF-β/BMP signaling, which, in zebrafish, is associated with defective organ development. Keywords: primary cilium, basal body, centriole, subdistal appendage, centrosome, transforming growth factor β, TGF-β, bone morphogenetic protein, BMP, zebrafish, phosphoproteomics, CEP12

Deep phenotyping of the unselected COPSAC2010 birth cohort study

BACKGROUND: We hypothesize that perinatal exposures, in particular the human microbiome and maternal nutrition during pregnancy, interact with the genetic predisposition to cause an abnormal immune modulation in early life towards a trajectory to chronic inflammatory diseases such as asthma and others. OBJECTIVE: The aim of this study is to explore these interactions by conducting a longitudinal study in an unselected cohort of pregnant women and their offspring with emphasis on deep clinical phenotyping, exposure assessment, and biobanking. Exposure assessments focus on the human microbiome. Nutritional intervention during pregnancy in randomized controlled trials are included in the study to prevent disease and to be able to establish causal relationships. METHODS: Pregnant women from eastern Denmark were invited during 2008–2010 to a novel unselected ‘COPSAC(2010)’ cohort. The women visited the clinic during pregnancy weeks 24 and 36. Their children were followed at the clinic with deep phenotyping and collection of biological samples at nine regular visits until the age of 3 and at acute symptoms. Randomized controlled trials of high‐dose vitamin D and fish oil supplements were conducted during pregnancy, and a trial of azithromycin for acute lung symptoms was conducted in the children with recurrent wheeze. RESULTS: Seven hundred and thirty‐eight mothers were recruited from week 24 of gestation, and 700 of their children were included in the birth cohort. The cohort has an over‐representation of atopic parents. The participant satisfaction was high and the adherence equally high with 685 children (98%) attending the 1 year clinic visit and 667 children (95%) attending the 2 year clinic visit. CONCLUSIONS: The COPSAC(2010) birth cohort study provides longitudinal clinical follow‐up with highly specific end‐points, exposure assessments, and biobanking. The cohort has a high adherence rate promising strong data to elucidate the interaction between genomics and the exposome in perinatal life leading to lifestyle‐related chronic inflammatory disorders such as asthma

Habitual physical activity is associated with lower fasting and greater glucose-induced GLP-1 response in men.

RATIONALE: The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals. METHODS: Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis. RESULTS: In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: -33; -3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1-2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, P rAUC0-30 = 0.04) and 20% greater at full response (3; 40%, P rAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men. CONCLUSION: Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.S B was supported by the UK Medical Research Council (MC_UU_12015/3) and the NIHR Biomedical Research Centre Cambridge (IS-BRC-1215-20014)