HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.     

The role of the Notch pathway in healthy and osteoarthritic articular cartilage: from experimental models to <Emphasis Type="Italic">ex vivo</Emphasis> studies

Osteoarthritis is the most prevalent form of arthritis in the world. With the progressive ageing of the population, it is becoming a major public health problem. The involvement of certain signaling pathways, such as the Notch pathway, during cartilage pathology has been reported. In this review, we report on studies that investigated the expression pattern of the Notch family members in articular cartilage and the eventual involvement of this pathway in the modulation of the physiology and pathology of chondrocytes. Temporal and/or spatial modulation of this signaling pathway may help these cells to synthesize a new functional extracellular matrix and restore the functional properties of the articular cartilage.     

Environmental and economic issues arising from the pooling of SMEs’ supply chains: case study of the food industry in western France

Supply chains pooling is an emergent strategy for improving logistical performance. The pooling concept consists in transferring the effort of coordination for consolidating independent operators’ flows towards an ad hoc pooled system. This organisation results from a design of a pooled logistics network by merging different supply chains to share transport and logistics resources in order to improve logistics performance. In this case study, the pooling concept is applied to a collection of small and medium-sized western France food suppliers serving the same retail chain. In order to demonstrate the efficiency of the pooling, the existing transport organisation was compared to various pooling scenarios. The methodology consisted in accessing a current situation through a survey of the flow of goods at one of the main distribution centre of the studied supply network, then comparing this situation with three other pooling scenarios. Using supply network optimisation models, these scenarios were assessed considering cost and CO₂ emission levels. This study demonstrates the interest of transport pooling in the case independent shipping networks of Small and Medium Enterprises compared to the partially know existing strategies adopted by logistics service providers for less than truckload shipments. Moreover, it suggests that there is no dominant supply organisation and that transport pooling is a new stimulus for network design. These results also bring new research perspectives for generalisation of pooling and gain sharing within large coalitions.     

Early Triassic Archosaur-Dominated Footprint Assemblage from the Argana Basin (Western High Atlas,Morocco)

An assemblage of abundant and well-preserved tetrapod footprints has been discovered in the Tanamert Member (T3) of the Triassic Timezgadiouine Formation (Argana basin, western High Atlas, Morocco). It is the first fossil record from T3. Surfaces from different localities show a uniform tetrapod ichnofauna that consists of chirotherian and small lacertoid forms. The chirotherians are assigned to the plexus Protochirotherium—Synaptichnium, their trackmakers interpreted as basal archosaurs. The lacertoid imprints show close affinities with Rhynchosauroides and may reflect archosauromorphs or lepidosauromorphs. Protochirotherium—Synaptichnium assemblages are characteristic of the Early Triassic and were known previously only from units of this age in central Europe. Biostratigraphically, the European record implies a wide-spread pre-Anisian Protochirotherium—Synaptichnium dominated assemblage preceding the first appearance of Chirotherium barthii near the Olenekian-Anisian boundary. The stratigraphic position of T3 between Late Permian (uppermost T2) and Middle Triassic (T4) and the European correlatives suggest an Early Triassic age of this unit. It is the first record of Early Triassic continental deposits in Morocco. The surfaces from T3 open up perspectives for further contributions to ecology, biogeography and locomotion of early archosaurs. Furthermore, excellent outcrops and quality of footprint preservation in the Argana basin offer a potential for clarification of ichnotaxonomic and biostratigraphic issues.     

减轻二滩水库泥沙淤积的生态系统服务价值评估

基于ArcGIS 9.2,构建了生态系统减轻水库泥沙淤积的评估模型,并结合泥沙输移比（SDR）和通用水土流失方程（USLE）,模拟了二滩水库集水区的产沙量和保沙量及其空间分布特征以及水库使用年限内其生态系统服务价值.结果表明：2000年,二滩水库集水区土壤保持量12.1×10⁸ t·a^-1,土壤保持量高值区主要分布于雅砻江干流和支流水网附近;泥沙输移比的高值主要分布在河道附近和水库周边,水库周边是最主要的产沙区和保沙区;研究区实际产沙量为629.3×10⁴ t·a^-1,占实际土壤侵蚀量的12.7%;农田是研究区最主要的产沙源,其产沙量占集水区总产沙量的62.9%;林地平均单位面积的保沙价值最高.在二滩水库使用年限内（100 a）,集水区对于减轻二滩水库泥沙淤积的总价值为27.53亿元.     

Comparative molecular analysis of evolutionarily distant glyceraldehyde-3-phosphate dehydrogenase from Sardina pilchardus and Octopus vulgaris

The NAD(+)-dependent cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12), which is recognized as a key to central carbon metabolism in glycolysis and gluconeogenesis and as an important allozymic polymorphic biomarker, was purified from muscles of two marine species: the skeletal muscle of Sardina pilchardus Walbaum (Teleost, Clupeida) and the incompressible arm muscle of Octopus vulgaris (Mollusca, Cephalopoda). Comparative biochemical studies have revealed that they differ in their subunit molecular masses and in pI values. Partial cDNA sequences corresponding to an internal region of the GapC genes from Sardina and Octopus were obtained by polymerase chain reaction using degenerate primers designed from highly conserved protein motifs. Alignments of the deduced amino acid sequences were used to establish the 3D structures of the active site of two enzymes as well as the phylogenetic relationships of the sardine and octopus enzymes. These two enzymes are the first two GAPDHs characterized so far from teleost fish and cephalopod, respectively. Interestingly, phylogenetic analyses indicated that the sardina GAPDH is in a cluster with the archetypical enzymes from other vertebrates, while the octopus GAPDH comes together with other molluscan sequences in a distant basal assembly closer to bacterial and fungal orthologs, thus suggesting their different evolutionary scenarios.     

Impact of some environmental factors on growth and production of ochratoxin A of/by <Emphasis Type="Italic">Aspergillus tubingensis,A. niger</Emphasis>, and <Emphasis Type="Italic">A. carbonarius</Emphasis> isolated from moroccan grapes

The effects of temperature, water activity (a_w), incubation time, and their combinations on radial growth and ochratoxin A (OTA) production of/by eight Aspergillus niger aggregate strains (six A. tubingensis and two A. niger) and four A. carbonarius isolated from Moroccan grapes were studied. Optimal conditions for the growth of most studied strains were shown to be at 25°C and 0.95 a_w. No growth was observed at 10°C regardless of the water activity and isolates. The optimal temperature for OTA production was in the range of 25°C∼30°C for A. carbonarius and 30°C∼37°C for A. niger aggregate. The optimal a_w for toxin production was 0.95∼0.99 for A. carbonarius and 0.90∼0.95 for A. niger aggregate. Mean OTA concentration produced by all the isolates of A. niger aggregate tested at all sampling times shows that maximum amount of OTA (0.24 μg/g) was produced at 37°C and 0.90 a_w. However, for A. carbonarius, mean maximum amounts of OTA (0.22 μg/g) were observed at 25°C and 0.99 a_w. Analysis of variance showed that the effects of all single factors (a_w, isolate, temperature and incubation time) and their interactions on growth and OTA production were highly significant.     

Wild-type and mutant ferroportins do not form oligomers in transfected cells

Ferroportin [FPN; Slc40a1 (solute carrier family 40, member 1)] is a transmembrane iron export protein expressed in macrophages and duodenal enterocytes. Heterozygous mutations in the FPN gene result in an autosomal dominant form of iron overload disorder, type-4 haemochromatosis. FPN mutants either have a normal iron export activity but have lost their ability to bind hepcidin, or are defective in their iron export function. The mutant protein has been suggested to act as a dominant negative over the wt (wild-type) protein by multimer formation. Using transiently transfected human epithelial cell lines expressing mouse FPN modified by the addition of a haemagglutinin or c-Myc epitope at the C-terminus, we show that the wtFPN is found at the plasma membrane and in Rab5-containing endosomes, as are the D157G and Q182H mutants. However, the delV162 mutant is mostly intracellular in HK2 cells (human kidney-2 cells) and partially addressed at the cell surface in HEK-293 cells (human embryonic kidney 293 cells). In both cell types, it is partially associated with the endoplasmic reticulum and with Rab5-positive vesicles. However, this mutant is complex-glycosylated like the wt protein. D157G and G323V mutants have a defective iron export capacity as judged by their inability to deplete the intracellular ferritin content, whereas Q182H and delV162 have normal iron export function and probably have lost their capacity to bind hepcidin. In co-transfection experiments, the delV162 mutant does not co-localize with the wtFPN, does not prevent its normal targeting to the plasma membrane and cannot be immunoprecipitated in the same complex, arguing against the formation of FPN hetero-oligomers.     

Characterization of two D-beta-hydroxybutyrate dehydrogenase populations in heavy and light mitochondria from jerboa (Jaculus orientalis) liver

Mitochondrial membrane-bound and phospholipid-dependent D-beta-hydroxybutyrate dehydrogenase (BDH) (EC 1.1.1.30), a ketone body converting enzyme in mitochondria, has been studied in two populations of mitochondria (heavy and light) of jerboa (Jaculus orientalis) liver. The results reveal significant differences between the BDH of the two mitochondrial populations in terms of protein expression, kinetic parameters and physico-chemical properties. These results suggest that the beta-hydroxybutyrate dehydrogenases from heavy and light mitochondria are isoform variants. These differences in BDH distribution could be the consequence of cell changes in the lipid composition of the inner mitochondrial membrane of heavy and light mitochondria. These changes could modify both BDH insertion and BDH lipid-dependent catalytic properties.