Preconditioned extracellular vesicles from hypoxic microglia reduce poststroke AQP4 depolarization, disturbed cerebrospinal fluid flow, astrogliosis, and neuroinflammation

Background: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia

Dynamic temporary blood facility location-allocation during and post-disaster periods

The key objective of this study is to develop a tool (hybridization or integration of different techniques) for locating the temporary blood banks during and post-disaster conditions that could serve the hospitals with minimum response time. We have used temporary blood centers, which must be located in such a way that it is able to serve the demand of hospitals in nearby region within a shorter duration. We are locating the temporary blood centres for which we are minimizing the maximum distance with hospitals. We have used Tabu search heuristic method to calculate the optimal number of temporary blood centres considering cost components. In addition, we employ Bayesian belief network to prioritize the factors for locating the temporary blood facilities. Workability of our model and methodology is illustrated using a case study including blood centres and hospitals surrounding Jamshedpur city. Our results shows that at-least 6 temporary blood facilities are required to satisfy the demand of blood during and post-disaster periods in Jamshedpur. The results also show that that past disaster conditions, response time and convenience for access are the most important factors for locating the temporary blood facilities during and post-disaster periods

Effect of autoclave sterilisation and heat activated sodium hypochlorite irrigation on the performance of nickel-titanium rotary files against cyclic fatigue

The present study aims to assess the impact of heat-activated sodium hypochlorite (NaOCl) and/or autoclave sterilisation on the cyclic fatigue resistance (CFR) of heat-treated nickel-titanium rotary files used in root canal treatment. The CFR of One Curve (OC) files was evaluated under the following conditions: as received (Group 1; control), immersion in NaOCl at 23 ± 1ºC (Group 2), immersion in NaOCl at 60 ± 1ºC (Group 3), autoclave sterilisation at 135 1ºC (Group 4), combined treatment of autoclave sterilisation and immersion in NaOCl at 23 ± 1ºC (Group 5), and combined treatment of autoclave sterilisation and immersion in NaOCl at 60 ± 1ºC (Group 6). A simulated root canal in a zirconia block was utilised to test the performance of the files. All the types of treatments resulted in significant reductions in fracture resistance of the OC files. Immersion of the files in NaOCl at 23ºC revealed the smallest reduction, while combined treatment of autoclaving and immersion in NaOCl at 60ºC caused the greatest reduction. Autoclave sterilisation or exposure of OC files to 2.5% NaOCl adversely affect the cyclic fatigue life and increasing solution temperature or combined treatment caused additionally significant reduction in CFR

Supply chain optimization and distribution network application with ahp in a yarn company

In today's global market, entire management of supply chain becomes a key factor for successful business processes. Worldwide organizations realize they're inadequate for success in non-integrated manufacturing/distribution processes & weak realitionships with suppliers/customers. Supply chain management becomes main solution for getting high profits and low costs. A fundamental characteristic of logistics is holistic structure with integrated view of all activities. Logistics is distribution of important components like procurement, warehouse management, inventory management, transportation management. It also deals with integration and other activities to provide time and value to the system or corporation.The problems have been determined by SWOT Analysis in a company.In this study, model of Analytical Hierarchy Process is designed for solution of supplier selection problem; Distribution network problem is modelled with linear programming and solved by using WinQSB software. In this paper, the optimized distribution network from yarn company to warehouse and customers is tried to achieve by developing optimized supply chain model