Knockdown of the Drosophila Fused in Sarcoma (FUS) Homologue Causes Deficient Locomotive Behavior and Shortening of Motoneuron Terminal Branches

Mutations in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS, FUS) have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein that is normally localized in the nucleus, but is mislocalized to the cytoplasm in ALS, and comprises cytoplasmic inclusions in ALS-affected areas. However, it is still unknown whether the neurodegeneration that occurs in ALS is caused by the loss of FUS nuclear function, or by the gain of toxic function due to cytoplasmic FUS aggregation. Cabeza (Caz) is a Drosophila orthologue of human FUS. Here, we generated Drosophila models with Caz knockdown, and investigated their phenotypes. In wild-type Drosophila, Caz was strongly expressed in the central nervous system of larvae and adults. Caz did not colocalize with a presynaptic marker, suggesting that Caz physiologically functions in neuronal cell bodies and/or their axons. Fly models with neuron-specific Caz knockdown exhibited reduced climbing ability in adulthood and anatomical defects in presynaptic terminals of motoneurons in third instar larvae. Our results demonstrated that decreased expression of Drosophila Caz is sufficient to cause degeneration of motoneurons and locomotive disability in the absence of abnormal cytoplasmic Caz aggregates, suggesting that the pathogenic mechanism underlying FUS-related ALS should be ascribed more to the loss of physiological FUS functions in the nucleus than to the toxicity of cytoplasmic FUS aggregates. Since the Caz-knockdown Drosophila model we presented recapitulates key features of human ALS, it would be a suitable animal model for the screening of genes and chemicals that might modify the pathogenic processes that lead to the degeneration of motoneurons in ALS

Integration of Electric Vehicles into the Electric Power System Based on Results of Road Traffic Census

We propose a model for the integration of electric vehicles (EVs) into the grid power system in Japan. The potential of the switchover from conventional vehicles to EVs and the incurred charging loads for the EV fleet were evaluated based on the results of a Japanese road traffic census. Furthermore, an EV battery operation model was incorporated into the production cost analysis model, which is capable of determining the optimal electricity supply and demand, considering the existing interconnector power flows. The potential economic and environmental contributions of EV charge and discharge controls, with the ultimate goal of realizing the introduction of a massive renewable energy source in the future, were also evaluated. We found that EVs can greatly contribute to expanding the use of renewable energy and reducing system cost by charging and discharging not only at the owner’s home but also at his/her workplace

Genome-Wide Association Study Adjusted for Occupational and Environmental Factors for Bladder Cancer Susceptibility

This study examined the effects of single-nucleotide polymorphisms (SNPs) on the development of bladder cancer, adding longest-held occupational and industrial history as regulators. The genome purified from blood was genotyped, followed by SNP imputation. In the genome-wide association study (GWAS), several patterns of industrial/occupational classifications were added to logistic regression models. The association test between bladder cancer development and the calculated genetic score for each gene region was evaluated (gene-wise analysis). In the GWAS and gene-wise analysis, the gliomedin gene satisfied both suggestive association levels of 10−5 in the GWAS and 10−4 in the gene-wise analysis for male bladder cancer. The expression of the gliomedin protein in the nucleus of bladder cancer cells decreased in cancers with a tendency to infiltrate and those with strong cell atypia. It is hypothesized that gliomedin is involved in the development of bladder cancer

Novel Drosophila model for parkinsonism by targeting phosphoglycerate kinase

Patients with Parkinson’s disease (PD) show a common progressive neurodegenerative movement disordercharacterized by rigidity, tremors, postural instability, and bradykinesia due to the loss of dopaminergic neuronsin the substantia nigra, and is often accompanied by several non-motor symptoms, called parkinsonism. Severallines of recent evidence support the hypothesis that mutations in the gene encoding phosphoglycerate kinase(PGK) play an important role in the PD mechanism. PGK is a key enzyme in the glycolytic pathway that catalyzesthe reaction from 1,3-diphosphoglycerate to 3-phosphoglycerate. We herein established a parkinsonism modeltargeting Drosophila Pgk. Dopaminergic (DA) neuron-specific Pgk knockdown lead to locomotive defects in bothyoung and aged adult flies and was accompanied by progressive DA neuron loss with aging. Pgk knockdown inDA neurons decreased dopamine levels in the central nervous system (CNS) of both young and aged adult flies.These phenotypes are similar to the defects observed in human PD patients, suggesting that the Pgk knockdownflies established herein are a promising model for parkinsonism. Furthermore, pan-neuron-specific Pgk knockdowninduced low ATP levels and the accumulation of reactive oxygen species (ROS) in the CNS of third instarlarvae. Collectively, these results indicate that a failure in the energy production system of Pgk knockdown fliescauses locomotive defects accompanied by neuronal dysfunction and degeneration in DA neurons

Clinical Impact of a Pharmacist-Driven Prospective Audit with Intervention and Feedback on the Treatment of Patients with Bloodstream Infection

Evidence for the utility of pharmacist-driven antimicrobial stewardship programs remains limited. This study aimed to evaluate the usefulness of our institutional pharmacist-driven prospective audit with intervention and feedback (PAF) on the treatment of patients with bloodstream infections (BSIs). The effect of pharmacist-driven PAF was estimated using an interrupted time series analysis with a quasi-experimental design. The proportion of de-escalation during BSI treatment increased by 44% after the implementation of pharmacist-driven PAF (95% CI: 30–58, p p = 0.012) and by 15 per 100 patient days for tazobactam/piperacillin (95% CI: −26 to −4.9, p Staphylococcus aureus significantly increased (p < 0.01). In conclusion, our pharmacist-driven PAF increased the proportion of de-escalation and decreased the use of broad-spectrum antibiotics, as well as the proportion of inappropriate treatment in patients with BSI. This indicates that pharmacist-driven PAF is useful in improving the quality of antimicrobial treatment and reducing broad-spectrum antimicrobial use in the management of patients with BSI

TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors

Abstract Notch signaling is an evolutionarily conserved mechanism required for numerous types of cell fate decisions in metazoans. It mediates short-range communication between cells with receptors and ligands, both of which are expressed on the cell surfaces. In response to the ligand-receptor interaction, the ligand and the extracellular domain of the Notch receptor (NECD) in the complex are internalized into ligand-expressing cells by endocytosis, a prerequisite process for the conformational change of the membrane proximal region of Notch to induce critical proteolytic cleavages for its activation. Here we report that overexpression of transmembrane 2 (TM2) domain containing 3 (TM2D3), a mammalian homologue of Drosophila melanogaster Almondex (Amx), activates Notch1. This activation requires the ligand-binding domain in Notch1 and the C-terminal region containing TM2 domain in TM2D3. TM2D3 physically associates with Notch1 at the region distinct from the ligand-binding domain and enhances expression of Notch1 on the cell surface. Furthermore, cell surface expression of Notch1 and Notch2 is reduced in Tm2d3-deficient cells. Finally, amx-deficient Drosophila early embryos exhibit impaired endocytosis of NECD and Delta ligand, for which surface presentation of Notch is required. These results indicate that TM2D3 is an element involved in Notch signaling through the surface presentation