Acetylcholinesterase (AChE) is an important link in the apoptotic pathway induced by hyperglycemia in Y79 retinoblastoma cell line

Acetylcholinesterase (AChE) expression was found to be induced in the mammalian CNS, including the retina, by different types of stress leading to cellular apoptosis. Here, we tested possible involvement of AChE in hyperglycemia-induced apoptosis in a retinal cell line. Y79 retinoblastoma cells were incubated in starvation media (1% FBS and 1 mg/ml glucose) for 16–24 h, and then exposed to hyperglycemic environment by raising extracellular glucose concentrations to a final level of 3.5 mg/ml or 6 mg/ml. Similar levels of mannitol were used as control for hyperosmolarity. Cells were harvested at different time intervals for analysis of apoptosis and AChE protein expression. Apoptosis was detected by the cleavage of Poly ADP-ribose polymerase (PARP) using western blot, and by Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling (TUNEL) assay. AChE protein expression and activity was detected by western blot and by the Karnovsky and Roots method, respectively. MissionTM shRNA for AChE was used to inhibit AChE protein expression. Treating Y79 cells with 3.5 mg/ml of glucose, but not with 3.5 mg/ml mannitol, induced apoptosis which was confirmed by TUNEL assay and by cleavage of PARP. A part of the signaling pathway accompanying the apoptotic process involved up-regulation of the AChE-R variant and an N-extended AChE variant as verified at the mRNA and protein level. Inhibition of AChE protein expression by shRNA protected Y79 cell from entering the apoptotic pathway. Our data suggest that expression of an N-extended AChE variant, most probably an R isoform, is involved in the apoptotic pathway caused by hyperglycemia in Y79 cells

Visitor Management System Design and Implementation during the Covid-19 Pandemic

In todays computer technology environment, the effect of IT plays a significant part in all real-time systems. Various management systems are in place to help the company organization achieve profit, standards, and future commercial growth. The VMS is important for monitoring how many visitors are there, what the objective of the facility visit will be, and who will be put in the block listed record due to rule violation. This technology also protects the buildings overall security. The goal of this system is to synchronize the organizations business and visitors in order to achieve a wonderful connection among organizations globally. The background was compiled from many papers that discussed similar subjects and were connected to the system. In addition, the limitations and analyses of the present system have been addressed in order to demonstrate the organizations demands for a new system. In part three, we will go through the project planning, covering the feasibility study, Gantt chart, and software methodology in specific stages. Stepping on functional and non- functional requirements of the system, it is covered in the same chapter, as well as the system steps in the implementation part of section four, and finally with clear and direct conclusion and recommendations in section five with future work of the visitor management system, which will be added after the system is implanted in the organization and other related organizations

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers

A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology

Aims ATI-2042 (budiodarone) is a chemical analogue of amiodarone with a half life of 7 h. It is electrophysiologically similar to amiodarone, but may not have metabolic and interaction side effects. The sophisticated electrocardiograph logs of advanced DDDRP pacemakers were used to monitor the efficacy of ATI-2042. The aim of this study was to determine the preliminary efficacy and safety of ATI-2042 in patients with paroxsymal atrial fibrillation (PAF) and pacemakers. Methods and results Six women with AF burden (AFB) between 1 and 50% underwent six sequential 2-week study periods. Patients received 200 mg bid of ATI-2042 during Period 2 (p2), 400 mg bid during p3, 600 mg bid during p4, 800 mg bid during p5, and no drug during baseline and washout (p1 and p6). Pacemaker data for the primary outcome measure AFB were downloaded during each period. Mean AFB decreased between baseline and all doses: AFB at baseline (SD) was 20.3 ± 14.6% and mean AFB at 200 mg bid was 5.2 ± 4.2%, at 400 mg bid 5.2 ± 5.2%, at 600 mg bid 2.8 ± 3.4%, and at 800 mg bid 1.5 ± 0.5%. The mean reductions in AFB at all doses of ATI-2042 were statistically significant (P < 0.005). Atrial fibrillation burden increased in washout. Atrial fibrillation episodes tended to increase with ATI-2042, but this was offset by substantial decreases in episode duration. ATI-2042 was generally well tolerated. Conclusion ATI-2042 effectively reduced AFB over all doses studied by reducing mean episode duration. A large-scale study will be required to confirm this effect

The One-State as a Demand of International Law: Jus Cogens

This article provides the initial contours of an argument that uses International Law to challenge the validity of Israeli apartheid. It challenges the conventional discourse of legal debates on Israel’s actions and bordersand seeks to link the illegalities of these actions to the validity of an inbuilt Israeli apartheid. The argument also connects the deontological doctrine of peremptory norms of International Law (jus cogens), the right of self-determination and the International Crime of Apartheid to the doctrine of state recognition. It applies these to the State of Israel and the vision of a single democratic state in historic Palestine

Improving mental health and psychosocial wellbeing in humanitarian settings: Reflections on research funded through R2HC

From Springer Nature via Jisc Publications RouterMajor knowledge gaps remain concerning the most effective ways to address mental health and psychosocial needs of populations affected by humanitarian crises. The Research for Health in Humanitarian Crisis (R2HC) program aims to strengthen humanitarian health practice and policy through research. As a significant portion of R2HC’s research has focused on mental health and psychosocial support interventions, the program has been interested in strengthening a community of practice in this field. Following a meeting between grantees, we set out to provide an overview of the R2HC portfolio, and draw lessons learned. In this paper, we discuss the mental health and psychosocial support-focused research projects funded by R2HC; review the implications of initial findings from this research portfolio; and highlight four remaining knowledge gaps in this field. Between 2014 and 2019, R2HC funded 18 academic-practitioner partnerships focused on mental health and psychosocial support, comprising 38% of the overall portfolio (18 of 48 projects) at a value of approximately 7.2 million GBP. All projects have focused on evaluating the impact of interventions. In line with consensus-based recommendations to consider a wide range of mental health and psychosocial needs in humanitarian settings, research projects have evaluated diverse interventions. Findings so far have both challenged and confirmed widely-held assumptions about the effectiveness of mental health and psychosocial interventions in humanitarian settings. They point to the importance of building effective, sustained, and diverse partnerships between scholars, humanitarian practitioners, and funders, to ensure long-term program improvements and appropriate evidence-informed decision making. Further research needs to fill knowledge gaps regarding how to: scale-up interventions that have been found to be effective (e.g., questions related to integration across sectors, adaptation of interventions across different contexts, and optimal care systems); address neglected mental health conditions and populations (e.g., elderly, people with disabilities, sexual minorities, people with severe, pre-existing mental disorders); build on available local resources and supports (e.g., how to build on traditional, religious healing and community-wide social support practices); and ensure equity, quality, fidelity, and sustainability for interventions in real-world contexts (e.g., answering questions about how interventions from controlled studies can be transferred to more representative humanitarian contexts).All studies described here were funded by Elrha’s Research for Health in Humanitarian Crises (R2HC) Programme, which aims to improve health outcomes by strengthening the evidence base for public health interventions in humanitarian crises.14pubpu

α/β–T Cell Receptor (TCR)+CD4−CD8− (NKT) Thymocytes Prevent Insulin-dependent Diabetes Mellitus in Nonobese Diabetic (NOD)/Lt Mice by the Influence of Interleukin (IL)-4 and/or IL-10

We have previously shown that nonobese diabetic (NOD) mice are selectively deficient in α/β-T cell receptor (TCR)+CD4−CD8− NKT cells, a defect that may contribute to their susceptibility to the spontaneous development of insulin-dependent diabetes mellitus (IDDM). The role of NKT cells in protection from IDDM in NOD mice was studied by the infusion of thymocyte subsets into young female NOD mice. A single intravenous injection of 106 CD4−/lowCD8− or CD4−CD8− thymocytes from female (BALB/c × NOD)F1 donors protected intact NOD mice from the spontaneous onset of clinical IDDM. Insulitis was still present in some recipient mice, although the cell infiltrates were principally periductal and periislet, rather than the intraislet pattern characteristic of insulitis in unmanipulated NOD mice. Protection was not associated with the induction of “allogenic tolerance” or systemic autoimmunity. Accelerated IDDM occurs after injection of splenocytes from NOD donors into irradiated adult NOD recipients. When α/β-TCR+ and α/β-TCR− subsets of CD4−CD8− thymocytes were transferred with diabetogenic splenocytes and compared for their ability to prevent the development of IDDM in irradiated adult recipients, only the α/β-TCR+ population was protective, confirming that NKT cells were responsible for this activity. The protective effect in the induced model of IDDM was neutralized by anti–IL-4 and anti–IL-10 monoclonal antibodies in vivo, indicating a role for at least one of these cytokines in NKT cell-mediated protection. These results have significant implications for the pathogenesis and potential prevention of IDDM in humans