Septin/anillin filaments scaffold central nervous system myelin to accelerate nerve conduction

Myelination of axons facilitates rapid impulse propagation in the nervous system. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular cause of many pathological features, including the frequently observed myelin outfoldings, remained unknown. Using label-free quantitative proteomics, we find that the presence of myelin outfoldings correlates with a loss of cytoskeletal septins in myelin. Regulated by phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2)-levels, myelin septins (SEPT2/SEPT4/SEPT7/SEPT8) and the PI(4,5)P2-adaptor anillin form previously unrecognized filaments that extend longitudinally along myelinated axons. By confocal microscopy and immunogold-electron microscopy, these filaments are localized to the non-compacted adaxonal myelin compartment. Genetic disruption of these filaments in Sept8-mutant mice causes myelin outfoldings as a very specific neuropathology. Septin filaments thus serve an important function in scaffolding the axon/myelin-unit, evidently a late stage of myelin maturation. We propose that pathological or aging-associated diminishment of the septin/anillin-scaffold causes myelin outfoldings that impair the normal nerve conduction velocity

Comprehensive Techno-Economic Analysis of a Multi-Feedstock Biorefinery Plant in Oil-Rich Country: A Case Study of Iran

This is the final version. Available on open access from MDPI via the DOI in this recordThe high energy consumption in Iran, particularly in the transportation sector, has contaminated large cities and jeopardized the society health. Therefore, in this study technical and economic features of the production of biodiesel plant in Iran from various wastes are investigated. Based on the Analytic Hierarchy Process (AHP) method’s findings, the southern area of Iran is selected for establishing the biodiesel plant in Iran. The biorefinery, which includes three units of sewage sludge, edible waste oil and microalgae. The results of the economic evaluation show that the lowest costs of investment and production of biodiesel are related to microalgae units ($0.375/kg) and edible waste oil ($0.53/kg), respectively. Also, among all units, the lowest break even prices are related to biodiesel production ($1.17/kg) and the highest ATROR rate (29.16%) belongs to the microalgae unit. This indicates that this unit is more profitable than other units and the invested cost is returned to the investor in a shorter period of time (3.43 years). On the other hand, the results of sensitivity analysis show that the highest sensitivity of changes in the selling price of biodiesel and the cost of raw materials to ATROR to the microalgae and sludge unit. Therefore, the construction of a biorefinery in Iran has an economic justification

Dietary cholesterol promotes repair of demyelinated lesions in the adult brain

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes

Performance enhancement of specific adsorbents for hardness reduction of drinking water and groundwater

This is the final version. Available from MDPI via the DOI in this record. One of the most advantageous methods for lowering water hardness is the use of low-cost adsorbents. In this research, the effectiveness of natural zeolite (clinoptilolite type), activated carbon, and activated alumina was evaluated. These adsorbents were sequentially modified by NaCl, HCl, and NaCl-HCL to improve their ability to adsorb. The contact time and the amount of adsorbent used in the adsorption process were investigated experimentally to determine their effects. The results indicated that the best contact time for hardness reduction was 90 min, and the best concentrations of adsorbents in drinking water for zeolite, activated carbon, and activated alumina were 40, 60, and 60 g/L, respectively. In addition, for groundwater, these figures were 60, 40, and 40 g/L, respectively. The greatest possible decreases in total hardness under the best conditions by natural zeolite, activated carbon, and activated alumina adsorbents were 93.07%, 30.76%, and 56.92%, respectively, for drinking water and 59.23%, 15.67 %, and 39.72% for groundwater. According to the results obtained from experiments, NaCl-modified zeolite, natural zeolite, and NaCl-HCl-modified activated carbon performed better in terms of parameter reduction. The equilibrium data were well fitted by the Langmuir isotherm model, whereas the kinetic data for the adsorption process were consistent with the pseudo-second-order model. The equilibrium study of the adsorption process by the Morris–Weber model revealed that both chemical and physical adsorption are involved.Bushehr Water & WasteWater Company (Iran

Patient-Specific three-dimensional printing models for planning the human shoulder orthopaedic surgeries

Poster presentationThe human shoulder is a stable, complex and multi-functional anatomical joint within the human body. Its remarkable range of motion for abduction/adduction, rotation, and movements within the sagittal plane makes this important joint susceptive to several types of dislocations. While diagnosis usually starts with scanning techniques such as MRI/CT, three-dimensional printing could provide more detailed information about the patient for personalised treatment. In this study, after the MRI data was captured, the Bio-CAD image-based modelling technique [1] was used, using ScanIP software, and the anatomical structures were manufactured for pre-surgery planning using Fused Deposition Modelling (FDM) and Stereolithography (SLA). Besides this, the finite element model was developed to assess stability in different conditions. The use of three-dimensional (3D) printed models can aid in effective pre-operative planning, for example for analysing the shoulder dislocations, rotator cuff tears [2], or for any other pre-planned treatments. This helps to design detailed surgeries, improve the diagnosis, therapeutic strategies, and increase the awareness of the patients

Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial

Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). Patients and methods: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. Results: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. Conclusions: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients

In Vivo Imaging Reveals Distinct Inflammatory Activity of CNS Microglia versus PNS Macrophages in a Mouse Model for ALS

Mutations in the enzyme superoxide dismutase-1 (SOD1) cause hereditary variants of the fatal motor neuronal disease Amyotrophic lateral sclerosis (ALS). Pathophysiology of the disease is non-cell-autonomous: neurotoxicity is derived not only from mutant motor neurons but also from mutant neighbouring non-neuronal cells. In vivo imaging by two-photon laser-scanning microscopy was used to compare the role of microglia/macrophage-related neuroinflammation in the CNS and PNS using ALS-linked transgenic SOD1G93A mice. These mice contained labeled projection neurons and labeled microglia/macrophages. In the affected lateral spinal cord (in contrast to non-affected dorsal columns), different phases of microglia-mediated inflammation were observed: highly reactive microglial cells in preclinical stages (in 60-day-old mice the reaction to axonal transection was ∼180% of control) and morphologically transformed microglia that have lost their function of tissue surveillance and injury-directed response in clinical stages (reaction to axonal transection was lower than 50% of control). Furthermore, unlike CNS microglia, macrophages of the PNS lack any substantial morphological reaction while preclinical degeneration of peripheral motor axons and neuromuscular junctions was observed. We present in vivo evidence for a different inflammatory activity of microglia and macrophages: an aberrant neuroinflammatory response of microglia in the CNS and an apparently mainly neurodegenerative process in the PNS