Red Blood Cell Homeostasis: Pharmacological Interventions to Explore Biochemical, Morphological and Mechanical Properties.

Duringtheirpassagethroughthecirculation,redbloodcells(RBCs)encounterseverephysiologicalconditionsconsistingofmechanicalstress,oxidativedamageandfastchangesinionicandosmoticconditions.Inordertosurvivefor120days,RBCsadapttotheirsurroundingsbysubtleregulationofmembraneorganizationandmetabolism.RBChomeostasisdependsoninteractionsbetweentheintegralmembraneproteinband3withothermembraneandcytoskeletalproteins,andwithkeyenzymesofvariousmetabolicpathways.Theseinteractionsareregulatedbythebindingofdeoxyhemoglobintoband3,andbyasignalingnetworkrevolvingaroundLynkinaseandSrcfamilykinase-mediatedphosphorylationofband3.Hereweshowthatmanipulationoftheinteractionbetweenthelipidbilayerandthecytoskeleton,usingvariouspharmacologicalagentsthatinterferewithprotein-proteininteractionsandmembranelipidorganization,hasvariouseffectson:(1)morphology,asshownbyhighresolutionmicroscopyandquantitativeimageanalysis;(2)organizationofmembraneproteins,asindicatedbyimmunofluorescenceconfocalmicroscopyandquantitativeaswellasqualitativeanalysisofvesiclegeneration;(3)membranelipidorganization,asindicatedbyflowcytometricanalysisofphosphatidylserineexposure;(4)deformability,asassessedincapillary-mimickingcircumstancesusingamicrofluidicssystem;(5)deformabilityasdeterminedusingaspleen-mimickingdevice;(6)metabolicactivityasindicatedbymetabolomics.Ourdatashowthatthereisacomplexrelationshipbetweenredcellmorphology,membraneorganizationanddeformability.Also,ourdatashowthatredbloodcellshavearelativelyhighresistancetodisturbanceofmembraneorganizationinvitro,whichmayreflecttheircapacitytowithstandmechanical,oxidativeandosmoticstressinvivo

Development of a psychiatric disorder linked to cerebellar lesions

Cerebellar dysfunction plays a critical role in neurodevelopmental disorders with long-term behavioral and neuropsychiatric symptoms. A 43-year-old woman with a cerebellum arteriovenous malformation and history of behavioral dysregulation since childhood is described. After the rupture of the cerebellar malformation in adulthood, her behavior morphed into specific psychiatric symptoms and cognitive deficits occurred. The neuropsychological assessment evidenced impaired performance in attention, visuospatial, memory, and language domains. Moreover, psychiatric assessment indicated a borderline personality disorder. Brain MRI examination detected macroscopic abnormalities in the cerebellar posterior lobules VI, VIIa (Crus I), and IX, and in the posterior area of the vermis, regions usually involved in cognitive and emotional processing. The described patient suffered from cognitive and behavioral symptoms that are part of the cerebellar cognitive affective syndrome. This case supports the hypothesis of a cerebellar role in personality disorders emphasizing the importance of also examining the cerebellum in the presence of behavioral disturbances in children and adults

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

International audienceRecently, several genome wide association studies (GWAS) have led to the discovery of 9 new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches.. We performed a genome wide haplotype association (GWHA) study in the EADI1 study (n=2,025 AD cases and 5,328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2,820 AD cases and 6,356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5,093 AD cases and 4,061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analysed (OR=1.68, 95% CI 1.43- 1.96; p=1.1x10-10). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non demented populations (n=2,579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, p=5.4x10-7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease

Preliminary Evidence for Cell Membrane Amelioration in Children with Cystic Fibrosis by 5-MTHF and Vitamin B12 Supplementation: A Single Arm Trial

Cystic fibrosis (CF) is one of the most common fatal autosomal recessive disorders in the Caucasian population caused by mutations of gene for the cystic fibrosis transmembrane conductance regulator (CFTR). New experimental therapeutic strategies for CF propose a diet supplementation to affect the plasma membrane fluidity and to modulate amplified inflammatory response. The objective of this study was to evaluate the efficacy of 5-methyltetrahydrofolate (5-MTHF) and vitamin B12 supplementation for ameliorating cell plasma membrane features in pediatric patients with cystic fibrosis.A single arm trial was conducted from April 2004 to March 2006 in an Italian CF care centre. 31 children with CF aged from 3 to 8 years old were enrolled. Exclusion criteria were diabetes, chronic infections of the airways and regular antibiotics intake. Children with CF were supplemented for 24 weeks with 5-methyltetrahydrofolate (5-MTHF, 7.5 mg /day) and vitamin B12 (0.5 mg/day). Red blood cells (RBCs) were used to investigate plasma membrane, since RBCs share lipid, protein composition and organization with other cell types. We evaluated RBCs membrane lipid composition, membrane protein oxidative damage, cation content, cation transport pathways, plasma and RBCs folate levels and plasma homocysteine levels at baseline and after 24 weeks of 5-MTHF and vitamin B12 supplementation. In CF children, 5-MTHF and vitamin B12 supplementation (i) increased plasma and RBC folate levels; (ii) decreased plasma homocysteine levels; (iii) modified RBC membrane phospholipid fatty acid composition; (iv) increased RBC K(+) content; (v) reduced RBC membrane oxidative damage and HSP70 membrane association.5-MTHF and vitamin B12 supplementation might ameliorate RBC membrane features of children with CF.ClinicalTrials.gov NCT00730509

Monitoring of microbial hydrocarbon remediation in the soil

Bioremediation of hydrocarbon pollutants is advantageous owing to the cost-effectiveness of the technology and the ubiquity of hydrocarbon-degrading microorganisms in the soil. Soil microbial diversity is affected by hydrocarbon perturbation, thus selective enrichment of hydrocarbon utilizers occurs. Hydrocarbons interact with the soil matrix and soil microorganisms determining the fate of the contaminants relative to their chemical nature and microbial degradative capabilities, respectively. Provided the polluted soil has requisite values for environmental factors that influence microbial activities and there are no inhibitors of microbial metabolism, there is a good chance that there will be a viable and active population of hydrocarbon-utilizing microorganisms in the soil. Microbial methods for monitoring bioremediation of hydrocarbons include chemical, biochemical and microbiological molecular indices that measure rates of microbial activities to show that in the end the target goal of pollutant reduction to a safe and permissible level has been achieved. Enumeration and characterization of hydrocarbon degraders, use of micro titer plate-based most probable number technique, community level physiological profiling, phospholipid fatty acid analysis, 16S rRNA- and other nucleic acid-based molecular fingerprinting techniques, metagenomics, microarray analysis, respirometry and gas chromatography are some of the methods employed in bio-monitoring of hydrocarbon remediation as presented in this review

Comparative genomics reveals diversity among xanthomonads infecting tomato and pepper

<p>Abstract</p> <p>Background</p> <p>Bacterial spot of tomato and pepper is caused by four <it>Xanthomonas </it>species and is a major plant disease in warm humid climates. The four species are distinct from each other based on physiological and molecular characteristics. The genome sequence of strain 85-10, a member of one of the species, <it>Xanthomonas euvesicatoria </it>(<it>Xcv</it>) has been previously reported. To determine the relationship of the four species at the genome level and to investigate the molecular basis of their virulence and differing host ranges, draft genomic sequences of members of the other three species were determined and compared to strain 85-10.</p> <p>Results</p> <p>We sequenced the genomes of <it>X. vesicatoria </it>(<it>Xv</it>) strain 1111 (ATCC 35937), <it>X. perforans </it>(<it>Xp</it>) strain 91-118 and <it>X. gardneri </it>(<it>Xg</it>) strain 101 (ATCC 19865). The genomes were compared with each other and with the previously sequenced <it>Xcv </it>strain 85-10. In addition, the molecular features were predicted that may be required for pathogenicity including the type III secretion apparatus, type III effectors, other secretion systems, quorum sensing systems, adhesins, extracellular polysaccharide, and lipopolysaccharide determinants. Several novel type III effectors from <it>Xg </it>strain 101 and <it>Xv </it>strain 1111 genomes were computationally identified and their translocation was validated using a reporter gene assay. A homolog to Ax21, the elicitor of XA21-mediated resistance in rice, and a functional Ax21 sulfation system were identified in <it>Xcv</it>. Genes encoding proteins with functions mediated by type II and type IV secretion systems have also been compared, including enzymes involved in cell wall deconstruction, as contributors to pathogenicity.</p> <p>Conclusions</p> <p>Comparative genomic analyses revealed considerable diversity among bacterial spot pathogens, providing new insights into differences and similarities that may explain the diverse nature of these strains. Genes specific to pepper pathogens, such as the O-antigen of the lipopolysaccharide cluster, and genes unique to individual strains, such as novel type III effectors and bacteriocin genes, have been identified providing new clues for our understanding of pathogen virulence, aggressiveness, and host preference. These analyses will aid in efforts towards breeding for broad and durable resistance in economically important tomato and pepper cultivars.</p

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10)