Thermal diffusion of dextran in aqueous solutions in the absence and the presence of urea

The Ludwig-Soret effect was studied for aqueous solutions of dextran in the temperature range 15 < T < 55 degrees C taking into account the effect of the addition of urea. In the absence of urea, the Soret coefficient S(T) changes sign; it is positive for T > 45.0 degrees C but negative for T < 45.0 degrees C. The positive sign of S(T) means that the dextran molecules migrate toward the cold side of the fluid; this behavior is typical for polymer solutions, whereas a negative sign indicates the macromolecules move toward the hot side. The addition of urea to the aqueous solution of dextran rises S(T) and reduces the inversion temperature. For 2 M urea the change in the sign of S(T) is observed at T = 29.7 degrees C and beyond that value S(T) is always positive in the studied temperature range. To rationalize these observations, it is assumed that the addition of urea leads to an opening of hydrogen bonds similar to that induced by an increase in temperature.     

Phagosomes induced by cytokines function as anti-Listeria vaccines: novel role for functional compartmentalization of STAT-1 protein and cathepsin-D

Phagosomes are critical compartments for innate immunity. However, their role in the protection against murine listeriosis has not been examined. We describe here that listericidal phago-receptosomes are induced by the function of IFN-γ or IL-6 as centralized compartments for innate and adaptive immunity because they are able to confer protection against murine listeriosis. These phago-receptosomes elicited LLO(91-99)/CD8(+)- and LLO(189-201)/CD4(+)-specific immune responses and recruited mature dendritic cells to the vaccination sites controlled by T cells. Moreover, they present exceptional features as efficient vaccine vectors. First, they compartmentalize a novel listericidal STAT-1-mediated signaling pathway that confines multiple innate immune components to the same environment. Second, they show features of MHC class II antigen-loading competent compartments for cathepsin-D-mediated LLO processing. Third, murine cathepsin-D deficiencies fail to develop protective immunity after vaccination with listericidal phago-receptosomes induced by IFN-γ or IL-6. Therefore, it appears that the connection of STAT-1 and cathepsin-D in a single compartment is relevant for protection against listeriosis.     

A constant and similar assembly defect of mitochondrial respiratory chain complex I allows rapid identification of NDUFS4 mutations in patients with Leigh syndrome

Isolated complex I deficiency is a frequent cause of respiratory chain defects in childhood. In this study, we report our systematic approach with blue native PAGE (BN-PAGE) to study mitochondrial respiratory chain assembly in skin fibroblasts from patients with Leigh syndrome and CI deficiency. We describe five new NDUFS4 patients with a similar and constant abnormal BN-PAGE profile and present a meta-analysis of the literature. All NDUFS4 mutations that have been tested with BN-PAGE result in a constant and similar abnormal assembly profile with a complete loss of the fully assembled complex I usually due to a truncated protein and the loss of its canonical cAMP dependent protein kinase phosphorylation consensus site. We also report the association of abnormal brain MRI images with this characteristic BN-PAGE profile as the hallmarks of NDUFS4 mutations and the first founder NDUFS4 mutations in the North-African population.     

Photobiocatalyzed asymmetric reduction of ketones using Chlorella sp. MK201

Aromatic ketones were reduced using suspension culture of Chlorella sp. MK201 under fluorescent light illumination producing the corresponding chiral alcohols in high yields with excellent enantiomeric excess (ee). For example, 2′,3′,4′,5′,6′-pentafluoroacetophenone at 0.25?mg/ml was converted to the corresponding (S)-alcohol in 80?% yield with?>99?% ee by 1?mg dry wt of Chlorella/ml in 12?h illumination (2,000 lux).     

Identification of a series of 1,3,4-oxadiazol-2-amines as potent alpha-7 agonists with efficacy in the novel object recognition model of cognition

A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement.     

In vivo evidence that TRAF4 is required for central nervous system myelin homeostasis

Tumor Necrosis Factor Receptor-Associated Factors (TRAFs) are major signal transducers for the TNF and interleukin-1/Toll-like receptor superfamilies. However, TRAF4 does not fit the paradigm of TRAF function in immune and inflammatory responses. Its physiological and molecular functions remain poorly understood. Behavorial analyses show that TRAF4-deficient mice (TRAF4-KO) exhibit altered locomotion coordination typical of ataxia. TRAF4-KO central nervous system (CNS) ultrastructure shows strong myelin perturbation including disorganized layers and disturbances in paranode organization. TRAF4 was previously reported to be expressed by CNS neurons. Using primary cell culture, we now show that TRAF4 is also expressed by oligodendrocytes, at all stages of their differentiation. Moreover, histology and electron microscopy show degeneration of a high number of Purkinje cells in TRAF4-KO mice, that was confirmed by increased expression of the Bax pro-apoptotic marker (immunofluorescence), TUNEL analysis, and caspase-3 activation and PARP1 cleavage (western blotting). Consistent with this phenotype, MAG and NogoA, two myelin-induced neurite outgrowth inhibitors, and their neuron partners, NgR and p75NTR were overexpressed (Q-RT-PCR and western blotting). The strong increased phosphorylation of Rock2, a RhoA downstream target, indicated that the NgR/p75NTR/RhoA signaling pathway, known to induce actin cytoskeleton rearrangement that favors axon regeneration inhibition and neuron apoptosis, is activated in the absence of TRAF4 (western blotting). Altogether, these results provide conclusive evidence for the pivotal contribution of TRAF4 to myelination and to cerebellar homeostasis, and link the loss of TRAF4 function to demyelinating or neurodegenerative diseases.     

Resveratrol treatment reduces cardiac progenitor cell dysfunction and prevents morpho-functional ventricular remodeling in type-1 diabetic rats

Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n?=?128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n?=?54) or subjected to administration of trans-Resveratrol (i.p. injection: 2.5 mg/Kg/day; DR group; n?=?64). Twenty-five rats constituted the control group (C). After 1, 3 or 8 weeks of hyperglycemia, we evaluated cardiac hemodynamic performance, and cardiomyocyte contractile properties and intracellular calcium dynamics. Myocardial remodeling and tissue inflammation were also assessed by morphometry, immunohistochemistry and immunoblotting. Eventually, the impact of the diabetic "milieu" on CSPC turnover was analyzed in co-cultures of healthy CSPCs and cardiomyocytes isolated from D and DR diabetic hearts. In untreated animals, cardiac function was maintained during the first 3 weeks of hyperglycemia, although a definite ventricular remodeling was already present, mainly characterized by a marked loss of CSPCs and adult cardiac cells. Relevant signs of ventricular dysfunction appeared after 8 weeks of diabetes, and included: 1) a significant reduction in ±dP/dt in comparison with C group, 2) a prolongation of isovolumic contraction/relaxation times, 3) an impaired contraction of isolated cardiomyocytes associated with altered intracellular calcium dynamics. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention.     

Complete genome sequence of the thermophilic sulfate-reducing ocean bacterium Thermodesulfatator indicus type strain (CIR29812(T))

Thermodesulfatator indicus Moussard et al. 2004 is a member of the Thermodesulfobacteriaceae, a family in the phylum Thermodesulfobacteria that is currently poorly characterized at the genome level. Members of this phylum are of interest because they represent a distinct, deep-branching, Gram-negative lineage. T. indicus is an anaerobic, thermophilic, chemolithoautotrophic sulfate reducer isolated from a deep-sea hydrothermal vent. Here we describe the features of this organism, together with the complete genome sequence, and annotation. The 2,322,224 bp long chromosome with its 2,233 protein-coding and 58 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.     

Time of Progression to Osteopenia/Osteoporosis in Chronically HIV-Infected Patients: Screening DXA Scan

Background

Algorithms for bone mineral density (BMD) management in HIV-infected patients are lacking. Our objective was to assess how often a dual-energy x-ray absorptiometry (DXA) scan should be performed by assessing time of progression to osteopenia/osteoporosis.

Methods

All DXA scans performed between 2000 and 2009 from HIV-infected patients with at least two DXA were included. Time to an event (osteopenia and osteoporosis) was assessed using the Kaplan–Meier method. Strata (tertiles) were defined using baseline minimum T scores. Differences between strata in time to an event were compared with the log-rank test.

Results

Of 391 patients (1,639 DXAs), 49.6% had osteopenia and 21.7% osteoporosis at their first DXA scan. Of the 112 (28.6%) with normal BMD, 35.7% progressed to osteopenia; median progression time was 6.7 years. These patients were stratified: “low-risk" (baseline minimum T score >−0.2 SD), “middle-risk" (between −0.2 and −0.6 SD), and “high-risk" (from −0.6 to −1 SD); median progression time to osteopenia was 8.7, >7.2, and 1.7 years, respectively (p<0.0001). Of patients with osteopenia, 23.7% progressed to osteoporosis; median progression time was >8.5 years. Progression time was >8.2 years in “low-risk" tertile (T score between −1.1 and −1.6 SD), >8.5 years in “middle-risk" (between −1.6 and −2), and 3.2 years in “high-risk" (from −2 to −2.4) (p<0.0001).

Conclusions

Our results may help to define the BMD testing interval. The lowest T score tertiles would suggest recommending a subsequent DXA in 1–2 years; in the highest tertiles, ≥6 years. Early intervention in patients with bone demineralization could reduce fracture–related morbidity/mortality.