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

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

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

Rapid biotic homogenization of marine fish assemblages

The role human activities play in reshaping biodiversity is increasingly apparent in terrestrial ecosystems. However, the responses of entire marine assemblages are not well-understood, in part, because few monitoring programs incorporate both spatial and temporal replication. Here, we analyse an exceptionally comprehensive 29-year time series of North Atlantic groundfish assemblages monitored over 5° latitude to the west of Scotland. These fish assemblages show no systematic change in species richness through time, but steady change in species composition, leading to an increase in spatial homogenization: the species identity of colder northern localities increasingly resembles that of warmer southern localities. This biotic homogenization mirrors the spatial pattern of unevenly rising ocean temperatures over the same time period suggesting that climate change is primarily responsible for the spatial homogenization we observe. In this and other ecosystems, apparent constancy in species richness may mask major changes in species composition driven by anthropogenic change

Isonatraemic haemodialysis in the management of salt and water overload: a crossover trial at an academic hospital in Dakar, Senegal

Introduction: The aims of this study were to assess the impact of isonatraemic haemodialysis on reduction of interdialytic weight gain (IDWG) and blood pressure (BP) as well as its tolerability in our study population. Methods: This crossover trial, at the Aristide Le Dantec University Hospital in Senegal, was conducted on 32 patients with kidney failure who were stable on treatment with chronic haemodialysis. In the initial “control phase”, patients had nine haemodialysis sessions with a dialysate sodium (Na+) concentration (Na+ dialysate) of 138 mmol/L. The serum Na+ set point (SP) for each patient was calculated from three predialytic mid-week values. In the second phase, the “individualized phase”, patients had nine haemodialysis sessions with Na+ dialysate equal to their SP. Results: The mean age of the patients was 55.5 ± 12.1 years, with a male/female ratio of 1.3 and the most common cause of kidney disease was hypertension (47%). Mean predialytic serum Na+ concentration was 135.8 ± 1.9 mmol/L, with a mean intra-individual coefficient of variation of 2%. Mean interdialytic weight gain (IDWG) was 1.9 kg and 1.8 kg in the control and individualized phases, respectively (P = 0.75). A reduction in postdialytic systolic blood pressure (BP) was observed during the individualized phase (P = 0.04). A similar trend was noted in pre- and intradialytic BP but this was not statistically significant. Apart from headaches, which were more common in the individualized phase (P = 0.04), isonatraemic haemodialysis was well tolerated. Conclusions: IDWG as well as pre- and intradialytic BP were unaffected by isonatraemic haemodialysis. Postdialytic BP was significantly reduced. Introduction: Les objectifs de cette étude étaient d’évaluer l’impact de l’hémodialyse isonatrémique sur la réduction de la prise de poids inter-dialytique (PPID) et de la pression artérielle (PA) ainsi que sa tolérance dans notre population d’étude. Méthodes: Cet essai croisé a été mené au centre hospitalier universitaire Aristide Le Dantec de Dakar (Sénégal) chez des patients hémodialysés chroniques. Durant la première phase dite « phase contrôle », les patients ont eu neuf séances d’hémodialyse avec une concentration de sodium dans le dialysat (Na+ dialysat) de 138 mmol/L. Le set-point (SP) de la natrémie a été calculé pour chaque patient et correspondait à la moyenne de 3 natrémies pré-dialytiques en milieu de semaine. Durant la deuxième phase dite « phase individualisée », les patients ont eu neuf séances d’hémodialyse avec du Na+ dialysat égal à leur SP. Résultats: Trente-deux patients ont été inclus. L’âge moyen était de 55,5 ± 12,1 ans avec un ratio homme/femme de 1,3 et la néphropathie initiale la plus fréquente était l’hypertensive (47%). La natrémie pré-dialytique moyenne était de 135,8 ± 1,9 mmol/L, avec un coefficient de variation intra-individuel moyen de 2 %. La PPID moyenne était de 1,9 kg et 1,8 kg dans les phases de contrôle et individualisé, respectivement (P = 0,75). Une diminution de la PA systolique post-dialytique a été observée au cours de la phase individualisée (P = 0,04). Une tendance similaire sans significativité statistique a été notée sur les PA pré- et intra-dialytiques. Hormis les céphalées, plus fréquentes pendant la phase individualisée (P = 0,04), l’hémodialyse isonatrémique a été bien tolérée. Conclusions: La PPID, les PA pré- et intra-dialytiques n’ont pas été affectées par l’hémodialyse isonatrémique. La PA post-dialytique était significativement réduite

Scleroderma renal crisis in tropical region: two senegalese cases

Scleroderma renal crisis (SRC) is defined as the new onset of accelerated arterial hypertension and /or rapidly progressive oliguric renal failure during the course of systemic sclerosis. It is a rare but life-threatening complication. This formerly serious complication has got a considerable brighter outlook since the introduction of angiotensin converting enzyme inhibitors (ACE) however the mortality is still remaining high. We report two cases of SRC which to our knowledge are the firsts described in Dakar. They were two women aged 45 and 32 years, one of them was previously following for systemic sclerosis. Both of them had malignant hypertension associated with rapidly progressive renal failure, the other was put under corticosteroid therapy four months before SRC occurrence. The histological and laboratory finding showed thrombotic microangiopathy. The height blood pressure returned to normal value after treatment with ACE inhibitors. The final outcome was undesirable with the death of one after two months due to the hemodialysis discontinuation and persistence of renal failure in the other.Keywords: Scleroderma renal crisis, corticosteroids, thrombotic microangiopathy, Daka