Dynamic regulation of canonical TGF beta signalling by endothelial transcription factor ERG protects from liver fibrogenesis

The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (ErgcEC-Het) and inducible homozygous deficient mice (ErgiEC-KO), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease

Plant Trait Diversity Buffers Variability in Denitrification Potential over Changes in Season and Soil Conditions

BACKGROUND: Denitrification is an important ecosystem service that removes nitrogen (N) from N-polluted watersheds, buffering soil, stream, and river water quality from excess N by returning N to the atmosphere before it reaches lakes or oceans and leads to eutrophication. The denitrification enzyme activity (DEA) assay is widely used for measuring denitrification potential. Because DEA is a function of enzyme levels in soils, most ecologists studying denitrification have assumed that DEA is less sensitive to ambient levels of nitrate (NO(3)(-)) and soil carbon and thus, less variable over time than field measurements. In addition, plant diversity has been shown to have strong effects on microbial communities and belowground processes and could potentially alter the functional capacity of denitrifiers. Here, we examined three questions: (1) Does DEA vary through the growing season? (2) If so, can we predict DEA variability with environmental variables? (3) Does plant functional diversity affect DEA variability? METHODOLOGY/PRINCIPAL FINDINGS: The study site is a restored wetland in North Carolina, US with native wetland herbs planted in monocultures or mixes of four or eight species. We found that denitrification potentials for soils collected in July 2006 were significantly greater than for soils collected in May and late August 2006 (p<0.0001). Similarly, microbial biomass standardized DEA rates were significantly greater in July than May and August (p<0.0001). Of the soil variables measured--soil moisture, organic matter, total inorganic nitrogen, and microbial biomass--none consistently explained the pattern observed in DEA through time. There was no significant relationship between DEA and plant species richness or functional diversity. However, the seasonal variance in microbial biomass standardized DEA rates was significantly inversely related to plant species functional diversity (p<0.01). CONCLUSIONS/SIGNIFICANCE: These findings suggest that higher plant functional diversity may support a more constant level of DEA through time, buffering the ecosystem from changes in season and soil conditions

A framework for the development of a global standardised marine taxon reference image database (SMarTaR-ID) to support image-based analyses

Video and image data are regularly used in the field of benthic ecology to document biodiversity. However, their use is subject to a number of challenges, principally the identification of taxa within the images without associated physical specimens. The challenge of applying traditional taxonomic keys to the identification of fauna from images has led to the development of personal, group, or institution level reference image catalogues of operational taxonomic units (OTUs) or morphospecies. Lack of standardisation among these reference catalogues has led to problems with observer bias and the inability to combine datasets across studies. In addition, lack of a common reference standard is stifling efforts in the application of artificial intelligence to taxon identification. Using the North Atlantic deep sea as a case study, we propose a database structure to facilitate standardisation of morphospecies image catalogues between research groups and support future use in multiple front-end applications. We also propose a framework for coordination of international efforts to develop reference guides for the identification of marine species from images. The proposed structure maps to the Darwin Core standard to allow integration with existing databases. We suggest a management framework where high-level taxonomic groups are curated by a regional team, consisting of both end users and taxonomic experts. We identify a mechanism by which overall quality of data within a common reference guide could be raised over the next decade. Finally, we discuss the role of a common reference standard in advancing marine ecology and supporting sustainable use of this ecosystem

Current challenges facing the assessment of the allergenic capacity of food allergens in animal models

Food allergy is a major health problem of increasing concern. The insufficiency of protein sources for human nutrition in a world with a growing population is also a significant problem. The introduction of new protein sources into the diet, such as newly developed innovative foods or foods produced using new technologies and production processes, insects, algae, duckweed, or agricultural products from third countries, creates the opportunity for development of new food allergies, and this in turn has driven the need to develop test methods capable of characterizing the allergenic potential of novel food proteins. There is no doubt that robust and reliable animal models for the identification and characterization of food allergens would be valuable tools for safety assessment. However, although various animal models have been proposed for this purpose, to date, none have been formally validated as predictive and none are currently suitable to test the allergenic potential of new foods. Here, the design of various animal models are reviewed, including among others considerations of species and strain, diet, route of administration, dose and formulation of the test protein, relevant controls and endpoints measured

Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

BACKGROUND: Progressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP. OBJECTIVES: To determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS. METHODS: Multicenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity. RESULTS: The earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity. CONCLUSION: The PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials

Multidimensional pain assessment of preterm newborns at the 1st, 3rd and 7th days of life

CONTEXT AND OBJECTIVE: It is challenge to assess and treat pain in premature infants. The objective of this study was to compare the multidimensional pain assessment of preterm neonates subjected to an acute pain stimulus at 24 hours, 72 hours and seven days of life. DESIGN AND SETTING: Prospective cohort study, at Universidade Federal de São Paulo (UNIFESP). METHODS: Eleven neonates with gestational age less than 37 weeks that needed venepuncture for blood collection were studied. The exclusion criteria were Apgar score < 7 at five minutes, presence of any central nervous system abnormality, and discharge or death before seven days of life. Venepuncture was performed in the dorsum of the hand, and the heart rate, oxygen saturation and pain scales [Neonatal Facial Coding System (NFCS), Neonatal Infant Pain Scale (NIPS), and Premature Infant Pain Profile (PIPP)] were assessed at 24 hours, 72 hours and 7 days of life. NFCS and NIPS were evaluated prior to procedure (Tpre), during venepuncture (T0), and two (T2) and five (T5) minutes after needle withdrawal. Heart rate, O2 saturation and PIPP were measured at Tpre and T0. Mean values were compared by repeated-measurement analysis of variance. RESULTS: The pain parameters did not differ at 24 hours, 72 hours and 7 days of life: heart rate (p = 0.22), oxygen saturation (p = 0.69), NFCS (p = 0.40), NIPS (p = 0.32) and PIPP (p = 0.56). CONCLUSION: Homogeneous pain scores were observed following venepuncture in premature infants during their first week of life.CONTEXTO E OBJETIVO: É um desafio avaliar e tratar a dor do bebê prematuro. O objetivo deste estudo foi comparar, diante de um mesmo estímulo doloroso agudo, as respostas multidimensionais à dor obtidas ao longo da primeira semana de vida de prematuros. TIPO DE ESTUDO E LOCAL: Coorte prospectiva, na Universidade Federal de São Paulo (UNIFESP). MÉTODOS: Estudo de 11 neonatos com idade gestacional inferior a 37 semanas e necessidade de punção venosa para coleta de sangue, sendo excluídos aqueles com Apgar < 7 aos cinco minutos, alterações do sistema nervoso central e os que faleceram ou tiveram alta até sete dias de vida. A punção venosa foi feita no dorso da mão e avaliou-se a freqüência cardíaca, a saturação de oxigênio e as seguintes escalas de dor: NFCS (Neonatal Facial Coding System), NIPS (Neonatal Infant Pain Scale) e PIPP (Premature Infant Pain Profile) com 24, 72 horas e no sétimo dia de vida. A NFCS e a NIPS foram pontuadas antes da punção venosa (Tpré), durante (T0), dois (T2) e cinco (T5) minutos após. A freqüência cardíaca, a saturação de oxigênio e a PIPP foram analisadas em Tpré e T0. Compararam-se os valores médios das variáveis nos três momentos por análise de variância com medidas repetidas. RESULTADOS: Não houve diferenças no primeiro, terceiro e sétimo dias para freqüência cardíaca (p = 0,22), saturação de oxigênio (p = 0,69), NFCS (p = 0,40), NIPS (p = 0,32) e PIPP (p = 0,56). CONCLUSÃO: Houve homogeneidade da avaliação da dor causada por punção venosa em prematuros, ao longo da primeira semana de vida.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Department of PediatricsUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Department of Preventive MedicineUNIFESP, EPM, Department of PediatricsUNIFESP, EPM, Department of Preventive MedicineCAPES: 1068-02SciEL