66 research outputs found
Two-photon laser-scanning microscopy for single and repetitive imaging of dorsal and lateral spinal white matter in vivo
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
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
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 (0.53/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
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
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
Application of Photo-Fenton, Electro-Fenton, and Photo-Electro-Fenton processes for the treatment of DMSO and DMAC wastewaters
This is the final version. Available from Elsevier via the DOI in this record. Biological treatment, due to the formation of hazardous chemicals to remove organic compounds such as dimethyl sulfoxide (DMSO) and N, N-dimethylacetamide (DMAC), has limited potential. Advanced oxidation processes (AOPs) are regarded as a viable alternative for treating molecules containing carbon-hydrogen bonds that cannot be broken down by traditional physico-chemical methods. In this investigation, various AOPs such as Photo-Fenton, Electro-Fenton, and Photo-Electro-Fenton processes were studied to treat wastewaters containing DMSO and DMAC. The effects of the operating parameters, including various initial concentrations of DMSO and DMAC, initial pH, reaction time, different concentrations of Fenton's reagent, power of UV lamp, different concentrations of electrolytes, the distance between electrodes and current intensity, were investigated. The findings of the experiments revealed that a pH of 3 and a reaction time of 120 min were optimal. At 2000 mg L−1 of DMSO, maximum degradation and the final concentration of TOC were 98.64 % and 256.8 mg L−1, respectively, by the Electro-Fenton process under the optimal conditions. The Electro-Fenton process was successful in determining the maximum degradation of DMAC (96.31 %) and the final TOC concentration (10.03 mg L−1) at 250 mg L−1 of DMAC under optimal conditions. Finally, it can be concluded that the Electro-Fenton process was the best process for the efficient removal of DMSO and DMAC. The second step of the kinetic model follows a pseudo-first-order reaction for 250 and 500 mg L−1 of pollutants and obeyed a pseudo-second-order kinetic model for concentrations of 1000, 2000 mg L−1.Bushehr province water company, Ira
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
A comparison of in vitro properties of resting SOD1 transgenic microglia reveals evidence of reduced neuroprotective function
<p>Abstract</p> <p>Background</p> <p>Overexpression of mutant copper/zinc superoxide dismutase (<it>SOD1</it>) in rodents has provided useful models for studying the pathogenesis of amyotrophic lateral sclerosis (ALS). Microglia have been shown to contribute to ALS disease progression in these models, although the mechanism of this contribution remains to be elucidated. Here, we present the first evidence of the effects of overexpression of mutant (TG G93A) and wild type (TG WT) human <it>SOD1 </it>transgenes on a set of functional properties of microglia relevant to ALS progression, including expression of integrin β-1, spreading and migration, phagocytosis of apoptotic neuronal cell debris, and intracellular calcium changes in response to an inflammatory stimulus.</p> <p>Results</p> <p>TG SOD1 G93A but not TG SOD1 WT microglia had lower expression levels of the cell adhesion molecule subunit integrin β-1 than their NTG control cells [NTG (G93A) and NTG (WT), respectively, 92.8 ± 2.8% on TG G93A, 92.0 ± 6.6% on TG WT, 100.0 ± 1.6% on NTG (G93A), and 100.0 ± 2.7% on NTG (WT) cells], resulting in decreased spreading ability, with no effect on ability to migrate. Both TG G93A and TG WT microglia had reduced capacity to phagocytose apoptotic neuronal cell debris (13.0 ± 1.3% for TG G93A, 16.5 ± 1.9% for TG WT, 28.6 ± 1.8% for NTG (G93A), and 26.9 ± 2.8% for NTG (WT) cells). Extracellular stimulation of microglia with ATP resulted in smaller increase in intracellular free calcium in TG G93A and TG WT microglia relative to NTG controls (0.28 ± 0.02 μM for TG G93A, 0.24 ± 0.03 μM for TG WT, 0.39 ± 0.03 μM for NTG (G93A), and 0.37 ± 0.05 μM for NTG (WT) microglia).</p> <p>Conclusions</p> <p>These findings indicate that, under resting conditions, microglia from mutant <it>SOD1 </it>transgenic mice have a reduced capacity to elicit physiological responses following tissue disturbances and that higher levels of stimulatory signals, and/or prolonged stimulation may be necessary to initiate these responses. Overall, resting mutant <it>SOD1</it>-overexpressing microglia may have reduced capacity to function as sensors of disturbed tissue/cellular homeostasis in the CNS and thus have reduced neuroprotective function.</p
- …