FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish

Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish.     

Long-term follow-up of cognitive dysfunction in patients with aluminum hydroxide-induced macrophagic myofasciitis (MMF)

Macrophagic myofasciitis (MMF) is characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and cognitive dysfunction. Representative features of MMF-associated cognitive dysfunction (MACD) include (i) dysexecutive syndrome; (i) visual memory; (iii) left ear extinction at dichotic listening test. In present study we retrospectively evaluated the progression of MACD in 30 MMF patients. Most patients fulfilled criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits seemed unusually severe. MACD remained stable over time, although dysexecutive syndrome tended to worsen. Long-term follow-up of a subset of patients with 3 or 4 consecutive neuropsychological evaluations confirmed the stability of MACD with time, despite marked fluctuations.     

Effectiveness of a protected areas network in the conservation of Tamarindus indica (Leguminosea–Caesalpinioideae) in Benin

In the absence of effective conservation of its wild relatives, exploitation of a species could lead to genetic depletion. Research on how well do protected areas contribute to the conservation of plant species subject to human exploitation is still limited. The potential niche of Tamarindus indica (tamarind) was evaluated and the contribution of the protected areas network (PAN) of Benin to its conservation was assessed. The maximum entropy approach was used to model the ecological niche of the species, and forest inventories were used to address its population structure. To test its effectiveness, the PAN map was overlapped with the habitat suitability map of the species, and its population structures in protected versus unprotected areas were compared. Tamarindus natural populations were confined to the Sudanian and Sudano‐Guinean regions. The species populations in the Sudanian region appeared well represented in protected areas in contrast to those in the Sudano‐Guinean region. Results showed a positive effect of protected areas on juvenile density but a weak effect on adult density and current size‐class distribution. Protection seemed to be unlikely to ensure the long‐term persistence of the species. Cryopreservation, assisted recruitment and artificial enrichment of tamarind stands are recommended to ensure the long‐term persistence of the species.     

Ecological adaptation of the shea butter tree (Vitellaria paradoxa C.F. Gaertn.) along climatic gradient in Bénin,West Africa

The ecological adaptation of shea butter trees was assessed based on their dendrometric and production traits in four shea butter tree parks occurring in different climatic zones of Bénin. A total of 99 rectangular plots of 50 × 30 m were established within the four parks according to a random sampling scheme. In each plot, all trees with a diameter at breast height (dbh) >10 cm were inventoried and measured for stem and crown diameters, and total height. The production of 120 productive shea butter trees was quantified. Collected data were used to compute structural parameters for each park. Moreover, stem diameter and height structures of the trees were established. Principal component analysis was performed on the dendrometric variables, and the first three components were correlated with the climatic parameters. Results revealed significant differences between parks in most of the dendrometric and production parameters of shea butter trees. For all the four parks, stem diameter and height structures present a Gaussian shape with left dissymmetry. In the Guinean zone, shea butter trees develop large crowns but produce little quantities of fruits, whereas in the Sudanian regions, the opposite trend was observed.     

Macrophage podosomes go 3D

Macrophage tissue infiltration is a critical step in the immune response against microorganisms and is also associated with disease progression in chronic inflammation and cancer. Macrophages are constitutively equipped with specialized structures called podosomes dedicated to extracellular matrix (ECM) degradation. We recently reported that these structures play a critical role in trans-matrix mesenchymal migration mode, a protease-dependent mechanism. Podosome molecular components and their ECM-degrading activity have been extensively studied in two dimensions (2D), but yet very little is known about their fate in three-dimensional (3D) environments. Therefore, localization of podosome markers and proteolytic activity were carefully examined in human macrophages performing mesenchymal migration. Using our gelled collagen I 3D matrix model to obligate human macrophages to perform mesenchymal migration, classical podosome markers including talin, paxillin, vinculin, gelsolin, cortactin were found to accumulate at the tip of F-actin-rich cell protrusions together with β1 integrin and CD44 but not β2 integrin. Macrophage proteolytic activity was observed at podosome-like protrusion sites using confocal fluorescence microscopy and electron microscopy. The formation of migration tunnels by macrophages inside the matrix was accomplished by degradation, engulfment and mechanic compaction of the matrix. In addition, videomicroscopy revealed that 3D F-actin-rich protrusions of migrating macrophages were as dynamic as their 2D counterparts. Overall, the specifications of 3D podosomes resembled those of 2D podosome rosettes rather than those of individual podosomes. This observation was further supported by the aspect of 3D podosomes in fibroblasts expressing Hck, a master regulator of podosome rosettes in macrophages. In conclusion, human macrophage podosomes go 3D and take the shape of spherical podosome rosettes when the cells perform mesenchymal migration. This work sets the scene for future studies of molecular and cellular processes regulating macrophage trans-migration.     

Single-step production of a recyclable nanobiocatalyst for organophosphate pesticides biodegradation using functionalized bacterial magnetosomes

Enzymes are versatile catalysts in laboratories and on an industrial scale; improving their immobilization would be beneficial to broadening their applicability and ensuring their (re)use. Lipid-coated nano-magnets produced by magnetotactic bacteria are suitable for a universally applicable single-step method of enzyme immobilization. By genetically functionalizing the membrane surrounding these magnetite particles with a phosphohydrolase, we engineered an easy-to-purify, robust and recyclable biocatalyst to degrade ethyl-paraoxon, a commonly used pesticide. For this, we genetically fused the opd gene from Flavobacterium sp. ATCC 27551 encoding a paraoxonase to mamC, an abundant protein of the magnetosome membrane in Magnetospirillum magneticum AMB-1. The MamC protein acts as an anchor for the paraoxonase to the magnetosome surface, thus producing magnetic nanoparticles displaying phosphohydrolase activity. Magnetosomes functionalized with Opd were easily recovered from genetically modified AMB-1 cells: after cellular disruption with a French press, the magnetic nanoparticles are purified using a commercially available magnetic separation system. The catalytic properties of the immobilized Opd were measured on ethyl-paraoxon hydrolysis: they are comparable with the purified enzyme, with K(m) (and k(cat)) values of 58 μM (and 178 s(-1)) and 43 μM (and 314 s(-1)) for the immobilized and purified enzyme respectively. The Opd, a metalloenzyme requiring a zinc cofactor, is thus properly matured in AMB-1. The recycling of the functionalized magnetosomes was investigated and their catalytic activity proved to be stable over repeated use for pesticide degradation. In this study, we demonstrate the easy production of functionalized magnetic nanoparticles with suitably genetically modified magnetotactic bacteria that are efficient as a reusable nanobiocatalyst for pesticides bioremediation in contaminated effluents.     

Management of metformin-associated lactic acidosis by continuous renal replacement therapy

Background

Metformin-associated lactic acidosis (MALA) is a severe metabolic failure with high related mortality. Although its use is controversial, intermittent hemodialysis is reported to be the most frequently used treatment in conjunction with nonspecific supportive measures. Our aim was to report the evolution and outcome of cases managed by continuous renal replacement therapy (CRRT).

Methodology and Principal Findings

Over a 3-year period, we retrospectively identified patients admitted to the intensive care unit for severe lactic acidosis caused by metformin. We included patients in our study who were treated with CRRT because of shock. We describe their clinical and biological features at admission and during renal support, as well as their evolution. We enrolled six patients with severe lactic acidosis; the mean pH and mean lactate was 6.92±0.20 and 14.4±5.1 mmol/l, respectively. Patients had high illness severity scores, including the Simplified Acute Physiology Score II (SAPS II) (average score 63±12 points). Early CRRT comprised either venovenous hemofiltration (n = 3) or hemodiafiltration (n = 3) with a mean effluent flow rate of 34±6 ml/kg/h. Metabolic acidosis control and metformin elimination was rapid and there was no rebound. Outcome was favorable in all cases.

Conclusions and Significance

Standard use of CRRT efficiently treated MALA in association with symptomatic organ supportive therapies.     

Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib

Portal hypertension, the most important complication with cirrhosis of the liver, is a serious disease. Sorafenib, a tyrosine kinase inhibitor is validated in advanced hepatocellular carcinoma. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of our study was to determine the effect of sorafenib on portal venous flow and portosystemic collateral circulation in patients receiving sorafenib therapy for advanced hepatocellular carcinoma. Porto-collateral circulations were evaluated using a magnetic resonance technique prior sorafenib therapy, and at day 30. All patients under sorafenib therapy had a decrease in portal venous flow of at least 36%. In contrast, no specific change was observed in the azygos vein or the abdominal aorta. No portal venous flow modification was observed in the control group. Sorafenib is the first anti-angiogenic therapy to demonstrate a beneficial and reversible decrease of portal venous flow among cirrhotic patients.     

Subinhibitory arsenite concentrations lead to population dispersal in Thiomonas sp

Biofilms represent the most common microbial lifestyle, allowing the survival of microbial populations exposed to harsh environmental conditions. Here, we show that the biofilm development of a bacterial species belonging to the Thiomonas genus, frequently found in arsenic polluted sites and playing a key role in arsenic natural remediation, is markedly modified when exposed to subinhibitory doses of this toxic element. Indeed, arsenite [As(III)] exposure led to a considerable impact on biofilm maturation by strongly increasing the extracellular matrix synthesis and by promoting significant cell death and lysis within microcolonies. These events were followed by the development of complex 3D-biofilm structures and subsequently by the dispersal of remobilized cells observed inside the previously formed hollow voids. Our results demonstrate that this biofilm community responds to arsenite stress in a multimodal way, enhancing both survival and dispersal. Addressing this complex bacterial response to As(III) stress, which might be used by other microorganisms under various adverse conditions, may be essential to understand how Thiomonas strains persist in extreme environments.