Design, synthesis and anticancer evaluation of novel arylhydrazones of active methylene compounds

Nerve growth factor (NGF) and its receptor, tropomyosin kinase receptor kinase type A (TrkA) is emerging as an important target for Glioblastoma (GBM) treatment. TrkA is the cancer biomarker majorly involved in tumor invasion and migration into nearby normal tissue. However, currently, available Trk inhibitors exhibit many adverse effects in cancer patients, thus demanding a novel class of ligands to regulate Trk signaling. Here, we exploited the role of TrkA (NTRK1) expression from the 651 datasets of brain tumors. RNA sequence analysis identified overexpression of NTRK1 in GBM, recurrent GBM as well in Oligoastrocytoma patients. Also, TrkA expression tends to increase over the higher grades of GBM. TrkA protein targeting hydrazone derivatives, R48, R142, and R234, were designed and their mode of interaction was studied using molecular docking and dynamic simulation studies. Ligands' stability and binding assessment reveals R48, 2 2-(2-(2-hydroxy-4-nitrophenyl) hydrazineylidene)-1-phenylbutane-1,3-dione, as a potent ligand that interacts well with TrkA's hydrophobic residues, Ile, Phe, Leu, Ala, and Val. R48- TrkA exhibits stable binding potentials with an average RMSD value <0.8 nm. R48 obeyed Lipinski's rule of five and possessed the best oral bioavailability, suggesting R48 as a potential compound with drug-likeness properties. In-vitro analysis also revealed that R48 exhibited a higher cytotoxicity effect for U87 GBM cells than TMZ with the IC50 value of 68.99 μM. It showed the lowest percentage of cytotoxicity to the non-cancerous TrkA expressing MEF cells. However, further SiRNA analysis validates the non-specific binding of R48, necessitating structural alteration for the development of R48-based TrkA inhibitor for GBM therapeutics.Peer reviewe

Nonlinear Dynamics of Ion Concentration Polarization in Porous Media: The Leaky Membrane Model

The conductivity of highly charged membranes is nearly constant, due to counter-ions screening pore surfaces. Weakly charged porous media, or "leaky membranes", also contain a significant concentration of co-ions, whose depletion at high current leads to ion concentration polarization and conductivity shock waves. To describe these nonlinear phenomena the absence of electro-osmotic flow, a simple Leaky Membrane Model is formulated, based on macroscopic electroneutrality and Nernst-Planck ionic fluxes. The model is solved in cases of unsupported binary electrolytes: steady conduction from a reservoir to a cation-selective surface, transient response to a current step, steady conduction to a flow-through porous electrode, and steady conduction between cation-selective surfaces in cross flow. The last problem is motivated by separations in leaky membranes, such as shock electrodialysis. The article begins with a tribute to Neal Amundson, whose pioneering work on shock waves in chromatography involved similar mathematics

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Analysis of The Effect of Taxes on The Relationship between Financial Markets and Economical Growth

The relationship between financial markets and the economic growth is a subject that has obviously been observed by many economists since the lifetime of Joseph Schumpeter. There have been various analyses and opinions on the development of financial markets and their effects on economic growth, and various conclusions have been achieved through experimental studies.  Some theoreticians view religious and cultural condition of countries as the factors of satisfactory effects on economical growth. Others believe bureaucracy and political establishment to be the main causes of such growth, while another group believes that the economic policy and strategies of each country play roles. The present article emphasizes the effect of taxes on the relationship between financial markets and economic growth in a model of endogenous growth. This effectiveness will be analyzed for period of (1992-2008). In this analysis, the study of panel data of more than 65 countries in the world signifies that taxes have negative effects and the development of commercial interactions has positive effects on the relationship between financial markets and economic growth. of Course, empirical findings of the study do not indicate significant relationship between taxes, financial markets and economic growth in the middle east countries

مقایسه بار مالی و میزان خدمات ارائه شده در بخش اورژانس قبل و بعد از اجرای طرح تحول نظام سلامت: مطالعه مقطعی چند مرکزی

Introduction: Health systems today form one of the largest sectors of the world's economy. Increasing the rapidly growing costs of health care worldwide. Economic experts have challenged managers and doctors and nurses to find new ways to limit costs. The aim of this study was to compare the financial burden of services provided in the emergency department before and after implementation of the health system evolution plan in Imam Hossein، Loghman and Shohada hospitals. Methods: The present study was multicentric analytical، before-after study، and using data from 2013 to 2015، one year before (2013) and one years after (2015) the implementation of the Health system evolution plan will be done. The statistical population is the emergency department of Imam Hossein، Loghman and Shohada Hospitals affiliated to Shahid Beheshti University of Medical Sciences in Tehran. The sampling method is census. For analytical study used by SPSS software version 19. Results: The findings of this study showed that the health system evolution plan does not affect the average cost of services provided in hospitals (P&gt; 0.05)، but the mean of costs of services provided in emergency department of Imam Hossein (P = 0.009) and Loghman (P = 0.02) hospital have statistical significance definition. Also، the comparison of the average number of services provided in the emergency department of Imam Hossein hospital before and after the health system evolution plan، there was significant (P = 0.048). Conclusion: The health system evolution plan has been effective on the cost of services provided in the emergency department، but، on average of services provided in the emergency department has not been effective. &nbsp;خلاصه: مقدمه:افزایشسریع و روزافزونهزینه هایبخشسلامتدرسراسرجهان متخصصین اقتصادی، مدیرانوپزشکانرادرراستاییافتن شیوههایینوینبرای محدودسازیهزینههابهچالشکشیدهاست. دربيناجزايمختلفسيستمهايسلامت،خدماتبيمارستانيعمده ترین عاملرشدهزینهدربسيارياز کشورها است. این مطالعه با هدف مقایسه بار مالی و تعداد خدمات ارائه شده قبل و بعد از اجرای طرح تحول نظام سلامت در مراکز درمانی امام حسین، لقمان و شهدا انجام شده است. روش کار:مطالعه حاضر از نوع&nbsp;مقطعی آینده نگراست که با استفاده از داده هاي سال هاي 1392 و 1394 انجام شد. جامعه آماري پژوهش, بخش اورژانس بیمارستان های امام حسین، لقمان و شهدای تجریش شهر تهران بوده است. روش نمونه گیری مطالعه به روش سرشماری بوده و داده های پژوهش از طریق اطلاعات پرونده بیماران موجود در بخش حسابداری و مالی بیمارستان جمع آوری گردید. جهت آنالیز آماری از نرم افزار&nbsp;SPSSنسخه 19 استفاده گردید.&nbsp; &nbsp;یافته ها:یافته های این مطالعه نشان داد که طرح تحول نظام سلامت بر میانگین هزینه خدمات ارائه شده بين بخشي بيمارستان های مورد مطالعه تاثير ندارد(P &gt; 0.05) اما میانگین هزينه هاي اورژانس بيمارستان امام حسين (P = 0.009)و لقمان(P = 0.02) بعد از طرح تحول سلامت, افزایش یافته است.همچنین در مقایسه متوسط تعداد خدمات ارائه شده در بخش اورژانس قبل و بعد از طرح تحول، تنها در بخش اورژانس بيمارستان امام حسين (ع), افزایش مشاهده شد (P = 0.048). &nbsp;نتیجه گیری:&nbsp;طرح تحول نظام سلامت, هزینه کل خدمات ارائه شده در بخش اورژانس بیمارستان های مورد مطالعه را افزایش داده است, اما به طور کلی بر میانگین تعداد خدمات ارائه شده موثر نبوده است

RELIABILITY OPTIMIZATION OF A SERIES-PARALLEL K-OUT-OF-N SYSTEM WITH FAILURE RATE DEPENDS ON WORKING COMPONENTS OF SYSTEM

This paper presents a mathematical model for a redundancy allocation problem (RAP) with k-out-of-n subsystems and failure rate depends on working components of system. It means that failure rate of components increases when a component fails. The subsystems may use either active or cold-standby redundancy strategies which considered as a decision variable. Thus, the proposed model and solution methods are to select the best redundancy strategy among active or cold-standby, component type, and levels of redundancy for each subsystem. The objective function is to maximize the system reliability under cost and weight constraints. Since RAP belongs to Np-hard problems, four meta-heuristic algorithms named genetic algorithm, Memetic algorithm, simulated annealing and particle swarm optimization are proposed. The results shown that the MA is better than other algorithms. Finally, in order to determine whether there is any significant difference between the results of four algorithms or not, a statistical test is applied

Association of risky driving behavior with psychiatric disorders among Iranian drivers: A case-control study

Purpose: This study aimed to investigate the possible association between psychological disorders and risky driving behavior (RDB) in Iran. Methods: This case-control study conducted in Shiraz, Iran in 2021. The case group included drivers with psychological disorders and the control group included those without any disorders. The inclusion criteria for selecting patients were: active driving at the time of the study, being 18 – 65 years old, having a driving license, having a psychological disorder including depression, bipolar disorder, anxiety spectrum disorder, or psychotic disorder spectrum confirmed by a psychiatrist, and completing an informed consent form. The exclusion criterion was the existence of conditions that interfered with answering and understanding the questions. The inclusion criteria for selecting the healthy cases were: active driving at the time of the study, being 18 – 65 years old, having a driving license, lack of any past or present history of psychiatric problems, and completing an informed consent form. The data were gathered using a researcher-made checklist and Manchester driving behavior questionnaire. First, partition around medoids method was used to extract clusters of RDB. Then, backward logistic regression was applied to investigate the association between the independent variables and the clusters of RDB. Results: The sample comprised of 344 (153 with psychological disorder and 191 without confirmed psychological disorder) drivers. Backward elimination logistic regression on total data revealed that share of medical expenditure ≤ 10% of total household expenditure (OR = 3.27, 95% CI: 1.48 – 7.24), psychological disorder (OR = 3.08, 95% CI: 1.67 – 5.70), and substance abuse class (OR = 6.38, 95% CI: 3.55 – 11.48) were associated with high level of RDB. Conclusion: Substance abuse, psychological illnesses, and share of medical costs from total household expenditure were found to be main predictors of RDB. Further investigations are necessary to explain the impact of different psychological illnesses on driving behavior