Autocrine Transforming Growth Factor β Signaling Regulates Extracellular Signal-regulated Kinase 1/2 Phosphorylation via Modulation of Protein Phosphatase 2A Expression in Scleroderma Fibroblasts

BACKGROUND. During scleroderma (SSc) pathogenesis, fibroblasts acquire an activated phenotype characterized by enhanced production of extracellular matrix (ECM) and constitutive activation of several major signaling pathways including extracellular signal-related kinase (ERK1/2). Several studies have addressed the role of ERK1/2 in SSc fibrosis however the mechanism of its prolonged activation in SSc fibroblasts is still unknown. Protein phosphatase 2A (PP2A) is a key serine threonine phosphatase responsible for dephosphorylation of a wide array of signaling molecules. Recently published microarray data from cultured SSc fibroblasts suggests that the catalytic subunit (C-subunit) of PP2A is downregulated in SSc. In this study we examined the role and regulation of PP2A in SSc fibroblasts in the context of ERK1/2 phosphorylation and matrix production. RESULTS. We show for the first time that PP2A mRNA and protein expression are significantly reduced in SSc fibroblasts and correlate with an increase in ERK1/2 phosphorylation and collagen expression. Furthermore, transforming growth factor β (TGFβ), a major profibrotic cytokine implicated in SSc fibrosis, downregulates PP2A expression in healthy fibroblasts. PP2A-specific small interfering RNA (siRNA) was utilized to confirm the role of PP2A in ERK1/2 dephosphorylation in dermal fibroblasts. Accordingly, blockade of autocrine TGFβ signaling in SSc fibroblasts using soluble recombinant TGFβ receptor II (SRII) restored PP2A levels and decreased ERK1/2 phosphorylation and collagen expression. In addition, we observed that inhibition of ERK1/2 in SSc fibroblasts increased PP2A expression suggesting that ERK1/2 phosphorylation also contributes to maintaining low levels of PP2A, leading to an even further amplification of ERK1/2 phosphorylation. CONCLUSIONS. Taken together, these studies suggest that decreased PP2A levels in SSc is a result of constitutively activated autocrine TGFβ signaling and could contribute to enhanced phosphorylation of ERK1/2 and matrix production in SSc fibroblasts.National Institutes of Health (AR-44883

Roots, tubers and bananas: Planning and research for climate resilience

The CGIAR Research Program (CRP) on Roots, Tubers and Bananas (RTB) includes vegetatively propagated staple crops linked by common breeding, seed, and postharvest issues, and by the frequency with which women are involved in their production and use. RTB crops are the backbone of food security across the humid tropics in sub-Saharan Africa (SSA) and in more localized areas of Asia and Latin America. Around 300 million poor people in developing countries currently depend on RTB value chains for food security, nutrition and income. Climate change poses challenges which could undo progress in poverty reduction and markedly increase food insecurity. This article examines planning and research for climate resilience across RTB crops, with a particular focus on the contrasting potato and sweet potato cases in SSA. A six-step framework for climatesmart breeding is proposed: (1) downscaling climate change models and crop modeling; (2) identifying and understanding key climate change responsive traits; (3) breeding and varietal selection; (4) phenotyping and genomic research to accelerate gains; (5) developing management options for climate-smart varieties; and (6) deployment (seed systems). In summary, climate-smart breeding means we need to do what we already do but faster, better, and smarter. (Résumé d'auteur

MERS-CoV (Middle East Respiratory Syndrome Coronavirus) outside the Arabian Peninsula an One Health approach: Understanding the role of wildlife, livestock and human in the virus dynamic

One of the big paradoxes of the MERS-CoV epidemiology is the apparent lack of human cases in large parts Africa where the virus and an animal host, the dromedary camel, are present. Understanding the differences between Africa and the Arabian Peninsula (where MERS-CoV is now endemic) would provide crucial understanding on how to reduce zoonotic infection. We set up field protocols for estimating (i) the prevalence of MERS-CoV infection in camel populations and other sensitive species outside Arabian Peninsula, (ii) the 'at risk' farming practices that facilitate transmission between camels, (iii) infection variation pattern in both camels and humans. The first project phase consisted in a descriptive serological and virological mapping of MERS-CoV in Africa and central Asia in camel populations (i.e. dromedary and Bactrian).The second project phase consists in a longitudinal epidemiological monitoring (monthly time step) in camel populations from Morocco and Ethiopia (blood, swabs, urine, milk); complemented by a questionnaire based survey of camel owners' practices. Finally, in parallel a cross-sectional sero-prevalence survey in human, particularly camel owners and animal workers in abattoirs is conducted by the Institut Pasteur in Morocco. A cross-sectional sero-prevalence survey is e also conducted on bats in houses and 'oasis' close to farms in Ethiopia. Addressing these questions is crucial for developing recommendations for animal and human health institutions and countries

MERS-CoV at the animal–human interface: inputs on exposure pathways from an expert-opinion elicitation

Nearly 4 years after the first report of the emergence of Middle-East respiratory syndrome Coronavirus (MERS-CoV) and nearly 1800 human cases later, the ecology of MERS-CoV, its epidemiology, and more than risk factors of MERS-CoV transmission between camels are poorly understood. Knowledge about the pathways and mechanisms of transmission from animals to humans is limited; as of yet, transmission risks have not been quantified. Moreover the divergent sanitary situations and exposures to animals among populations in the Arabian Peninsula, where human primary cases appear to dominate, vs. other regions in the Middle East and Africa, with no reported human clinical cases and where the virus has been detected only in dromedaries, represents huge scientific and health challenges. Here, we have used expert-opinion elicitation in order to obtain ideas on relative importance of MERS-CoV risk factors and estimates of transmission risks from various types of contact between humans and dromedaries. Fourteen experts with diverse and extensive experience in MERS-CoV relevant fields were enrolled and completed an online questionnaire that examined pathways based on several scenarios, e.g., camels-camels, camels-human, bats/other species to camels/humans, and the role of diverse biological substances (milk, urine, etc.) and potential fomites. Experts believed that dromedary camels play the largest role in MERS-CoV infection of other dromedaries; however, they also indicated a significant influence of the season (i.e. calving or weaning periods) on transmission risk. All experts thought that MERS-CoV-infected dromedaries and asymptomatic humans play the most important role in infection of humans, with bats and other species presenting a possible, but yet undefined, risk. Direct and indirect contact of humans with dromedary camels were identified as the most risky types of contact, when compared to consumption of various camel products, with estimated 'most likely' incidence risks of at least 22 and 13% for direct and indirect contact, respectively. The results of our study are consistent with available, yet very limited, published data regarding the potential pathways of transmission of MERS-CoV at the animal-human interface. These results identify key knowledge gaps and highlight the need for more comprehensive, yet focused research to be conducted to better understand transmission between dromedaries and humans.published_or_final_versio

Metagenomic sequencing, molecular characterization, and Bayesian phylogenetics of imported type 2 vaccine-derived poliovirus, Spain, 2021

Introduction: In 2021, a type 2 vaccine-derived poliovirus (VDPV2) was isolated from the stool of a patient with acute flaccid paralysis (AFP) admitted to Spain from Senegal. A virological investigation was conducted to characterize and trace the origin of VDPV2. Methods: We used an unbiased metagenomic approach for the whole-genome sequencing of VDPV2 from the stool (pre-treated with chloroform) and from the poliovirus-positive supernatant. Phylogenetic analyses and molecular epidemiological analyses relying on the Bayesian Markov Chain Monte Carlo methodology were used to determine the geographical origin and estimate the date of the initiating dose of the oral poliovirus vaccine for the imported VDPV2. Results: We obtained a high percentage of viral reads per total reads mapped to the poliovirus genome (69.5% for pre-treated stool and 75.8% for isolate) with a great depth of sequencing coverage (5,931 and 11,581, respectively) and complete genome coverage (100%). The two key attenuating mutations in the Sabin 2 strain had reverted (A481G in the 5'UTR and Ile143Thr in VP1). In addition, the genome had a recombinant structure between type-2 poliovirus and an unidentified non-polio enterovirus-C (NPEV-C) strain with a crossover point in the protease-2A genomic region. VP1 phylogenetic analysis revealed that this strain is closely related to VDPV2 strains circulating in Senegal in 2021. According to Bayesian phylogenetics, the most recent common ancestor of the imported VDPV2 could date back 2.6 years (95% HPD: 1.7-3.7) in Senegal. We suggest that all VDPV2s circulating in 2020-21 in Senegal, Guinea, Gambia, and Mauritania have an ancestral origin in Senegal estimated around 2015. All 50 stool samples from healthy case contacts collected in Spain (n = 25) and Senegal (n = 25) and four wastewater samples collected in Spain were poliovirus negative. Discussion: By using a whole-genome sequencing protocol with unbiased metagenomics from the clinical sample and viral isolate with high sequence coverage, efficiency, and throughput, we confirmed the classification of VDPV as a circulating type. The close genomic linkage with strains from Senegal was consistent with their classification as imported. Given the scarce number of complete genome sequences for NPEV-C in public databases, this protocol could help expand poliovirus and NPEV-C sequencing capacity worldwide.This study was partially supported by two grants from the Instituto de Salud Carlos III [grant numbers PI18CIII/00017 and PI20CIII/00005].S

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Data-Driven Wildfire Propagation Modeling with FARSITE-EnKF

The goal of this study is to provide a framework for future researchers to understand and use the FARSITE wildfire-forecasting model with data assimilation. Current wildfire models lack the ability to provide accurate prediction of fire front position faster than real-time. When FARSITE is coupled with a recursive ensemble filter, the data assimilation forecast method improves. The scope includes an explanation of the standalone FARSITE application, technical details on FARSITE integration with a parallel program coupler called OpenPALM, and a model demonstration of the FARSITE-Ensemble Kalman Filter software using the FireFlux I experiment by Craig Clements. The results show that the fire front forecast is improved with the proposed data-driven methodology than with the standalone FARSITE model

Vascular access in Senegalese patients starting chronic haemodialysis

Introduction: It is recommended that patients should start chronic haemodialysis using an arteriovenous fistula (AVF). We aimed to determine the proportion of Senegalese patients who used an AVF at the start of  haemodialysis and examined the factors associated with its use. Methods: We conducted a cross-sectional study from 1 June 2021 to 2 October 2021 among patients on chronic haemodialysis in 10 centres in the Dakar and Thiès regions. Clinical and laboratory data were collected from medical records and also via patient interviews. Results: The patients (n = 543) had a median age of 50 years [interquartile range (IQR) 40–62 years] and 50.6% were male. The socio-economic level was low in two-thirds of cases. The median duration of haemodialysis was 40 (IQR 17–76) months. Hypertension was noted in 92% and diabetes in 13%. Hypertensive kidney disease was the cause of kidney failure in 33%. Only 47 patients (9%) had started dialysis using an arteriovenous fistula. Factors associated with its use at haemodialysis initiation were socio-economic level (OR 0.48; 95% confidence interval (CI) 0.25–0.94 for low socio-economic level) and duration of pre-dialysis follow-up by a nephrologist for >4 months (OR 7.82; 95% CI 3.05–26.50). In 65% of prevalent patients, the vascular access used was an AVF, a tunnelled central venous catheter in 28%, an arteriovenous graft in 2% and a temporary central venous catheter in 4.4%. Conclusions: The proportion of Senegalese patients with an AVF at the start of haemodialysis was low. AVF use was associated with socio-economic level and pre-dialysis follow-up by a nephrologist for >4 months

Evaluation des complications cardiaques chez les hémodialysés chroniques de Dakar

Introduction: L'évaluation cardiovasculaire est essentielle en hémodialyse périodique car les affections cardiovasculaires sont la première cause de mortalité chez les hémodialysés chroniques. Nous avons conduit cette étude afin de déterminer la prévalence et le type des différentes complications cardiovasculaires et d'identifier les principaux facteurs de risque cardiovasculaire. Méthodes: Il s'agissait d'une étude rétrospective de 4 ans portant sur les dossiers de patients traités au moins 6 mois en hémodialyse et ayant des explorations cardio-vasculaires comportant une radiographie du thorax de face, un électrocardiogramme et une échographie cardiaque. Les données épidémiologiques, cliniques, paracliniques, les aspects évolutifs des complications cardiaques ont été recueillies pour chaque patient retenu. Résultats: Trente huit dossiers de patients ont été inclus dans cette étude. L'âge moyen était de 52 ans ± 12,85 et le sex-ratio H/F de 1,53. Les complications cardiovasculaires étaient dominées par l'hypertrophie ventriculaire gauche (71,05 %), la maladie coronaire (34,21%), l'insuffisance cardiaque congestive (18,42%), Calcifications vasculaires (5,78 %), les troubles du rythme (7.89%), les fuites valvulaires mitrales (44,73%), tricuspidiennes (42,10%) et les accidents vasculaires cérébraux hémorragiques (5,26%). L'incidence moyenne de l'HVG était de 81% chez les patients hypertendus. Au cours de cette étude, 27 patients avaient poursuivi l'hémodialyse et 11 étaient décédés dont 6 de causes cardiovasculaires (54,55%). Conclusion: L'hémodialyse est une technique d'épuration qui expose les patients à de multiples complications cardiovasculaires.Pan African Medical Journal 2016; 23: 4