Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models

GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD. We treated fibroblast cells from PD patients with heterozygous GBA mutations and Drosophila expressing human wild-type, N370S and L444P GBA with the molecular chaperones ambroxol and isofagomine. Both chaperones increased GCase levels and activity, but also GBA mRNA, in control and mutant GBA fibroblasts. Expression of mutated GBA in Drosophila resulted in dopaminergic neuronal loss, a progressive locomotor defect, abnormal aggregates in the ER and increased levels of the ER stress reporter Xbp1-EGFP. Treatment with both chaperones lowered ER stress and prevented the loss of motor function, providing proof of principle that small molecule chaperones can reverse mutant GBA-mediated ER stress in vivo and might prove effective for treating PD

Heterogeneity but individual constancy of epitopes, isotypes and avidity of factor H autoantibodies in atypical hemolytic uremic syndrome

Factor H (FH) autoantibodies are present in 6-10% of atypical hemolytic uremic syndrome (aHUS) patients, most of whom have homozygous deficiency of the FH-related protein FHR-1. Although the pathogenic role of the autoantibodies is established, little is known about their molecular characteristics and changes over time. Here, we describe the specificity and other immunological features of anti-FH autoantibodies in the Spanish and Hungarian aHUS cohorts. A total of 19 patients were included and serial samples of 14 of them were available. FH autoantibodies from FHR-1 deficient patients (n=13) mainly recognized FH, its SCR19-20 fragment and FHR-1, but autoantibody specificity in patients who are homo- or heterozygous for the CFHR1 gene (n=6) was heterogeneous. No significant changes apart from total antibody titer were observed during follow-up in each patient. Fine epitope mapping with recombinant FH SCR19-20 containing single amino acid mutations showed significantly reduced binding in 6 out of 14 patients. In most cases, autoantibody binding to residues 1183-1189 and 1210-1215 was impaired, revealing a major common autoantibody epitope. Avidities showed variations between patients, but in most cases the avidity index did not change upon time. Most autoantibodies were IgG3, and all but three presented only with kappa or with lambda light chains. Although the pathogenic role of anti-FH autoantibodies in aHUS is well established, this study shows autoantibody heterogeneity among patients, but no significant variation in their characteristics over time in each patient. The presence of a single light chain in 16 out of 19 patients and the limited number of recognized epitopes suggest a restricted autoantibody response in most patients

Increased Risk of Musculoskeletal Disorders and Mental Health Problems in Retired Professional Jockeys: A Cross-Sectional Study

To examine the prevalence of chronic disease and mental health problems in retired professional, male jockeys compared to an age-matched reference population. A cross-sectional study comparing data from a cohort of retired professional jockeys with an age-matched general population sample. Male participants (age range: 50–89 years old) were used to compare health outcomes of self-reported physician-diagnosed conditions: heart disease, stroke, diabetes, hypertension, osteoporosis, osteoarthritis, depression and anxiety between study populations. Conditional logistic regression models were used to estimate associations between study groups and health outcome. In total, 810 participants (135 retired professional male jockeys and 675 participants from the reference population) were included, with an average age of 64.7±9.9 years old. Increased odds of having osteoporosis (OR=6.5, 95%CI 2.1–20.5), osteoarthritis (OR=7.5, 95%CI 4.6–12.2), anxiety (OR=2.8, 95%CI 1.3–5.9) and depression (OR=2.6, 95%CI 1.3–5.7) were seen in the retired professional jockeys. No differences were found for the remaining health outcomes. Retired professional jockeys had increased odds of musculoskeletal disease and mental health problems compared to the general population. Understanding the prevalence of chronic disease and mental health problems in retired professional jockeys will help inform screening and intervention strategies for jockeys

Defect-Free Self-Catalyzed GaAs/GaAsP Nanowire Quantum Dots Grown on Silicon Substrate

The III-V nanowire quantum dots (NWQDs) monolithically grown on silicon substrates, combining the advantages of both one- and zero-dimensional materials, represent one of the most promising technologies for integrating advanced III-V photonic technologies on a silicon microelectronics platform. However, there are great challenges in the fabrication of high-quality III-V NWQDs by a bottom-up approach, that is, growth by the vapor-liquid-solid method, because of the potential contamination caused by external metal catalysts and the various types of interfacial defects introduced by self-catalyzed growth. Here, we report the defect-free self-catalyzed III-V NWQDs, GaAs quantum dots in GaAsP nanowires, on a silicon substrate with pure zinc blende structure for the first time. Well-resolved excitonic emission is observed with a narrow line width. These results pave the way toward on-chip III-V quantum information and photonic devices on silicon platform

Modeling the Impact of Tuberculosis Control Strategies in Highly Endemic Overcrowded Prisons

International audienceBACKGROUND: Tuberculosis (TB) in prisons is a major health problem in countries of high and intermediate TB endemicity such as Brazil. For operational reasons, TB control strategies in prisons cannot be compared through population based intervention studies. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical model is proposed to simulate the TB dynamics in prison and evaluate the potential impact on active TB prevalence of several intervention strategies. The TB dynamics with the ongoing program was simulated over a 10 year period in a Rio de Janeiro prison (TB prevalence 4.6 %). Then, a simulation of the DOTS strategy reaching the objective of 70 % of bacteriologically-positive cases detected and 85 % of detected cases cured was performed; this strategy reduced only to 2.8% the average predicted TB prevalence after 5 years. Adding TB detection at entry point to DOTS strategy had no major effect on the predicted active TB prevalence. But, adding further a yearly X-ray mass screening of inmates reduced the predicted active TB prevalence below 1%. Furthermore, according to this model, after applying this strategy during 2 years (three annual screenings), the TB burden would be reduced and the active TB prevalence could be kept at a low level by associating X-ray screening at entry point and DOTS. CONCLUSIONS/SIGNIFICANCE: We have shown that X-ray mass screenings should be considered to control TB in highly endemic prison. Prisons with different levels of TB prevalence could be examined thanks to this model which provides a rational tool for public health deciders

Co-firing of biomass with coals Part 1. Thermogravimetric kinetic analysis of combustion of fir (abies bornmulleriana) wood

The chemical composition and reactivity of fir (Abies bornmulleriana) wood under non-isothermal thermogravimetric (TG) conditions were studied. Oxidation of the wood sample at temperatures near 600 A degrees C caused the loss of aliphatics from the structure of the wood and created a char heavily containing C-O functionalities and of highly aromatic character. On-line FTIR recordings of the combustion of wood indicated the oxidation of carbonaceous and hydrogen content of the wood and release of some hydrocarbons due to pyrolysis reactions that occurred during combustion of the wood. TG analysis was used to study combustion of fir wood. Non-isothermal TG data were used to evaluate the kinetics of the combustion of this carbonaceous material. The article reports application of Ozawa-Flynn-Wall model to deal with non-isothermal TG data for the evaluation of the activation energy corresponding to the combustion of the fir wood. The average activation energy related to fir wood combustion was 128.9 kJ/mol, and the average reaction order for the combustion of wood was calculated as 0.30

Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival

Proteomics as a quality control tool of pharmaceutical probiotic bacterial lysate products

Probiotic bacteria have a wide range of applications in veterinary and human therapeutics. Inactivated probiotics are complex samples and quality control (QC) should measure as many molecular features as possible. Capillary electrophoresis coupled to mass spectrometry (CE/MS) has been used as a multidimensional and high throughput method for the identification and validation of biomarkers of disease in complex biological samples such as biofluids. In this study we evaluate the suitability of CE/MS to measure the consistency of different lots of the probiotic formulation Pro-Symbioflor which is a bacterial lysate of heat-inactivated Escherichia coli and Enterococcus faecalis. Over 5000 peptides were detected by CE/MS in 5 different lots of the bacterial lysate and in a sample of culture medium. 71 to 75% of the total peptide content was identical in all lots. This percentage increased to 87–89% when allowing the absence of a peptide in one of the 5 samples. These results, based on over 2000 peptides, suggest high similarity of the 5 different lots. Sequence analysis identified peptides of both E. coli and E. faecalis and peptides originating from the culture medium, thus confirming the presence of the strains in the formulation. Ontology analysis suggested that the majority of the peptides identified for E. coli originated from the cell membrane or the fimbrium, while peptides identified for E. faecalis were enriched for peptides originating from the cytoplasm. The bacterial lysate peptides as a whole are recognised as highly conserved molecular patterns by the innate immune system as microbe associated molecular pattern (MAMP). Sequence analysis also identified the presence of soybean, yeast and casein protein fragments that are part of the formulation of the culture medium. In conclusion CE/MS seems an appropriate QC tool to analyze complex biological products such as inactivated probiotic formulations and allows determining the similarity between lots

Plastid evolution: gene transfer and the maintenance of 'stolen' organelles

Many heterotrophic organisms sequester plastids from prey algae and temporarily utilize their photosynthetic capacity. A recent article in BMC Genomics reveals that the dinoflagellate Dinophysis acuminata has acquired photosynthesis-related genes by horizontal gene transfer, which might explain its ability to retain 'stolen' plastids for extended periods of time