Detailed Action Research Articles

Structural basis for TRIM72 oligomerization during membrane damage repair

Tripartite Motif Protein 72 (TRIM72, also named MG53) mediates membrane damage repair through membrane fusion and exocytosis. During injury, TRIM72 molecules form intermolecular disulfide bonds in response to the oxidative environment and TRIM72 oligomers are proposed to connect vesicles to the plasma membrane and promote membrane fusion in conjunction with other partners like dysferlin and caveolin. However, the detailed mechanism of TRIM72 oligomerization and action remains unclear. Here we present the crystal structure of TRIM72 B-box-coiled-coil-SPRY domains (BCC-SPRY), revealing the molecular basis of TRIM72 oligomerization, which is closely linked to disulfide bond formation. Through structure-guided mutagenesis, we have identified and characterized key residues that are important for the membrane repair function of TRIM72. Our results also demonstrate that TRIM72 interacts with several kinds of negatively charged lipids in addition to phosphatidylserine. Our work provides a structural foundation for further mechanistic studies as well as the clinical application of TRIM72.

Host Cell Rap1b mediates cAMP-dependent invasion by Trypanosoma cruzi.

Trypanosoma cruzi cAMP-mediated invasion has long been described, however, the detailed mechanism of action of the pathway activated by this cyclic nucleotide still remains unknown. We have recently demonstrated a crucial role for Epac in the cAMP-mediated invasion of the host cell. In this work, we gathered evidence indicating that the cAMP/Epac pathway is activated in different cells lines. In accordance, data collected from pull-down experiments designed to identify only the active form of Rap1b (Rap1b-GTP), and infection assays using cells transfected with a constitutively active mutant of Rap1b (Rap1b-G12V), strongly suggest the participation of Rap1b as mediator of the pathway. In addition to the activation of this small GTPase, fluorescence microscopy allowed us to demonstrate the relocalization of Rap1b to the entry site of the parasite. Moreover, phospho-mimetic and non-phosphorylable mutants of Rap1b were used to demonstrate a PKA-dependent antagonistic effect on the pathway, by phosphorylation of Rap1b, and potentially of Epac. Finally, Western Blot analysis was used to determine the involvement of the MEK/ERK signalling downstream of cAMP/Epac/Rap1b-mediated invasion.

What are the concerns with New European Bauhaus initiative? Vernacular knowledge as the primary driver toward a sustainable future

The revolutionary aspect and core values of the New European Bauhaus (NEB) are highly praised, but the initiative's success can only be judged by its approach to defining those values. The local climate plays an inextricable role in informing vernacular architecture, as do other physical, social, economic, and cultural determinants. On the NEB initiative website, it states that the NEB "calls on all of us to imagine and build together a sustainable and inclusive future," with inclusive defined as "encouraging a dialogue across cultures, disciplines, genders, and ages." Such a high-level vision is positive and encouraging, but the detailed action plans outlined in the NEB concept paper presented in June 2021 to the President of the European Commission, Ursula von der Leyen, fell short of real evolutionary thinking about how to integrate vernacular knowledge. The NEB concept paper stated, "Both frontier technologies and vernacular techniques must be equally embraced. Advanced and emerging technologies must be balanced by other locally accessible tools, techniques, and strategies." The fundamental problem with such a statement is that it positions "vernacular techniques" at the other end of "frontier technologies," indicating that vernacular techniques are not "advanced and emerging." On the contrary, we believe that vernacular (or indigenous understanding) is the more advanced scientific knowledge in understanding the symbiotic relationship between the built environment and the natural environment.Hence, it should play a leading role in all climate change adaptation and mitigation efforts.

«Зеленые» рабочие места в России

Introduction. The paper examines the trends in the development of the “green” economy associated with the creation of “green” jobs that contribute to the preservation, restoration and improvement of the quality of the environment. In Russia, there are prerequisites for the spread of “green” principles: the regulatory framework of the “green” economy is being formed; there are successful projects to save resources at individual enterprises. Purpose. The issues of employment are considered in the context of the development of a “green” economy, which makes it possible to coordinate the solution of the tasks of greening the labor market with its modernization and reduction of unemployment, with an increase in the environmental and energy efficiency of the economy. Methods. The methodological framework for the study is the methods of scientific cognition, among which the main ones are the methods of consistency, analysis and comparative law. Results. One of the main measures of the formation of a “green” economy in Russia should be the creation of “green” jobs to form an environmentally oriented labor market. For the development of “green” employment in Russia, it is necessary to develop and implement a detailed action plan at the state level, to underline priority economic activities to create “green” jobs. Conclusions. The main problems hindering the creation of “green” jobs in Russia and the training of qualified personnel for the “green” economy are considered. The factors contributing to the growth of “green” employment are identified. A list of “green” professions of the future is proposed. The key types of economic activity for the creation of “green” jobs in Russia are pointed out.

Natural Alkaloids as Multi-Target Compounds towards Factors Implicated in Alzheimer’s Disease

Alzheimer's disease (AD) is the most common cause of dementia in elderly people; currently, there is no efficient treatment. Considering the increase in life expectancy worldwide AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. A great amount of experimental and clinical evidence indicated that AD is a complex disorder characterized by widespread neurodegeneration of the CNS, with major involvement of the cholinergic system, causing progressive cognitive decline and dementia. The current treatment, based on the cholinergic hypothesis, is only symptomatic and mainly involves the restoration of acetylcholine (ACh) levels through the inhibition of acetylcholinesterase (AChE). Since the introduction of the Amaryllidaceae alkaloid galanthamine as an antidementia drug in 2001, alkaloids have been one of the most attractive groups for searching for new AD drugs. The present review aims to comprehensively summarize alkaloids of various origins as multi-target compounds for AD. From this point of view, the most promising compounds seem to be the β-carboline alkaloid harmine and several isoquinoline alkaloids since they can simultaneously inhibit several key enzymes of AD's pathophysiology. However, this topic remains open for further research on detailed mechanisms of action and the synthesis of potentially better semi-synthetic analogues.

(Bio)dissolution of arsenopyrite coupled with multiple proportions of pyrite: Emphasis on the mobilization and existential state of arsenic

The formation of arsenic-bearing acid mine drainage (AMD) via the oxidation of arsenopyrite refuse ore has attracted significant attention. Pyrite, as main a concomitant mineral, is a crucial factor that affects the (bio)dissolution of arsenopyrite, but there are still some points on the detailed action mechanism under normal environmental conditions that need further study. In this study, the effect mechanism of pyrite with a systematic pyrite content (0, 10, 25, 50, 75, 90, and 100 wt %) on arsenopyrite oxidation and arsenic release in the presence of Acidithiobacillus ferrooxidans was investigated. The X-ray diffraction (XRD), scanning election microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and electrochemical analyses were also carried out. Results showed that the existence of pyrite and Acidithiobacillus ferrooxidans significantly accelerated the dissolution of arsenopyrite and the oxidation of As (Ⅲ) to As (Ⅴ), resulting from the galvanic effect, an increase in the Fe3+/Fe2+ ratio and the oxidation–reduction potential (Eh) value, and a decrease in pH level. As the detected main intermediate products, element sulphur was considered as the dominating obstructive factor during arsenopyrite oxidation, while the added pyrite could accelerate its oxidation. Moreover, a close relationship between different mineral proportions and the galvanic effect was also observed and discussed. Finally, suggestions on AMD governance and source control are proposed.

YB-1 Protein Prevents Age Decline in Plasma Estradiol in 5xFAD Transgenic Aging Female Mice

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is the main cause of dementia in the elderly. When looking for new treatments for AD, attention was drawn to the multifunctional Y-box-binding protein 1 (YB-1). Previously, we revealed a positive effect of intranasal administration of YB-1 on learning and spatial memory, along with a decrease in the content of cerebral β-amyloid and the intensity of plaque initiation, with an improvement in the survival of neurons in the cortex and hippocampus of male AD mice. However, AD affects women twice as often as men, so it is of great interest to study the effects of YB-1 on aging females. Estrogens and androgens are necessary for the maintenance of cognitive function during aging and, apparently, may prevent the development of AD. In this work, peripheral levels of estradiol (E2) and cytokines were studied after intranasal administration of YB-1 to aging female 5xFAD transgenic mice and control non-transgenic animals. In intact aging animals of both groups, a violation of the estrous cycle and a decrease in the level of E2 in blood plasma were revealed. Mice treated with YB-1 did not show a characteristic age-related decrease in plasma E2 levels. The introduction of YB-1 did not affect the peripheral level of cytokines. Thus, a novel, previously undescribed effect of YB-1 on plasma E2 levels in aging female mice is shown. These data indicate that YB-1 may be a promising compound in the prevention and treatment of neurodegenerative diseases. However, further experiments are needed to gain insight into the detailed mechanisms of YB-1 action.

Emergency solutions in the field of social security caused by the COVID-19 pandemic in selected countries that are parties of the European Code of Social Security

Objective: The aim of the study is to present extraordinary solutions in the field of social security, adopted by states - parties to the European Code of Social Security (EKZS) in the event of the COVID-19 pandemic, as well as their verification in relation to the represented model of social policy and ETUC standards Materials and methods: To achieve the aim of the work, research methods based on inductive reasoning were used, related to the research of the literature on the subject, reports of countries on the implementation of the European Code of Social Security for the period from July 1, 2019 to June 30, 2020, as well as searching internet resources. Based on the information contained in the analyzed sources, secondary research was carried out, including an in-depth analysis of activities undertaken in Sweden, Great Britain and Belgium. Spain and Estonia in relation to four main areas of support, i.e., health care system, job protection and financial relief for employers, support for small and medium-sized enterprises and social transfers.Results: The generally accepted policies and strategies of countries in the fight against the COVID-19 pandemic were consistent with the represented model of social policy. However, in many cases, specific, detailed actions by states deviated from this model. In terms of sickness, unemployment and old age benefits, the states introduced higher standards than those set by the Code. On the other hand, the regulations were not properly applied to medical care, as delays in planned procedures and operations for patients with other diseases were noted due to the treatment of people infected with COVID-19.

Computational Approaches to Enzyme Inhibition by Marine Natural Products in the Search for New Drugs.

The exploration of biologically relevant chemical space for the discovery of small bioactive molecules present in marine organisms has led not only to important advances in certain therapeutic areas, but also to a better understanding of many life processes. The still largely untapped reservoir of countless metabolites that play biological roles in marine invertebrates and microorganisms opens new avenues and poses new challenges for research. Computational technologies provide the means to (i) organize chemical and biological information in easily searchable and hyperlinked databases and knowledgebases; (ii) carry out cheminformatic analyses on natural products; (iii) mine microbial genomes for known and cryptic biosynthetic pathways; (iv) explore global networks that connect active compounds to their targets (often including enzymes); (v) solve structures of ligands, targets, and their respective complexes using X-ray crystallography and NMR techniques, thus enabling virtual screening and structure-based drug design; and (vi) build molecular models to simulate ligand binding and understand mechanisms of action in atomic detail. Marine natural products are viewed today not only as potential drugs, but also as an invaluable source of chemical inspiration for the development of novel chemotypes to be used in chemical biology and medicinal chemistry research.

Matcha Tea Powder's Antidepressant-like Effect through the Activation of the Dopaminergic System in Mice Is Dependent on Social Isolation Stress.

Matcha tea powder is believed to have various physiological benefits; however, its detailed mechanism of action has been poorly understood. Here, we investigated whether the mental state of mice, due to social isolation stress, affects the antidepressant-like effect of Matcha tea powder by using the tail suspension test. Oral administration of Matcha tea powder reduced the duration of immobility in the stress-susceptible C57BL/6J strain, but not in BALB/c strain. In C57BL/6J mice, SCH23390, a dopamine D1 receptor blocker, prevented Matcha tea powder from exerting its antidepressant-like effect. Matcha tea powder also increased the number of c-Fos-positive cells in the prefrontal cortex (PFC) region and the nucleus accumbens (NAc) region in C57BL/6J mice, but not in BALB/c mice. In contrast, Matcha tea powder did not change the number of c-Fos-positive cells in the ventral tegmental area (VTA) region. Notably, C57BL/6J mice with a shorter immobility time had a higher number of c-Fos-positive cells in the PFC, NAc, and VTA regions. However, no such correlation was observed in the stress-tolerant BALB/c mice. These results suggest that Matcha tea powder exerts an antidepressant-like effect through the activation of the dopaminergic system including the PFC-NAc-VTA circuit and that mental states are important factors affecting the physiological benefits of Matcha tea powder.

A Customizable No-Code Realistic Motion Editor for VRM-Based Avatars

Avatar actions can be captured using certain gesture sensors or can be predefined by game designers through desktop applications. In other words, developing an online avatar editor could be necessary to specify the detailed actions for use by people who are not game creators. Our research team proposed a web-based toolset, myKLA, to construct and design avatar actions with editor and player features. The goal of myKLA is to help users define the required behaviors of avatars within a set time frame without codes. We used cyber–physical system theory in a software reconstruction initiative. Additionally, an exchangeable JSON file format for predefining the avatar actions was opened and shared here. Furthermore, the cyclomatic complexity of the main code blocks in our toolset was measured and changed using the McCabe approach to fine-tune the performance. An algorithm was proposed for quickly calculating an integrated activity diagram from several sub-activity diagrams. Our research showed that it is easy to create an avatar head and embed it in other web-based applications for additional interaction utilization. Therefore, our findings will be useful in creating and designing new educational tools.

Cyclic AMP-Mediated Inhibition of Cholesterol Catabolism in Mycobacterium tuberculosis by the Novel Drug Candidate GSK2556286.

Despite the deployment of combination tuberculosis (TB) chemotherapy, efforts to identify shorter, nonrelapsing treatments have resulted in limited success. Recent evidence indicates that GSK2556286 (GSK286), which acts via Rv1625c, a membrane-bound adenylyl cyclase in Mycobacterium tuberculosis, shortens treatment in rodents relative to standard of care drugs. Moreover, GSK286 can replace linezolid in the three-drug, Nix-TB regimen. Given its therapeutic potential, we sought to better understand the mechanism of action of GSK286. The compound blocked growth of M. tuberculosis in cholesterol media and increased intracellular cAMP levels ~50-fold. GSK286 did not inhibit growth of an rv1625c transposon mutant in cholesterol media and did not induce cyclic AMP (cAMP) production in this mutant, suggesting that the compound acts on this adenylyl cyclase. GSK286 also induced cAMP production in Rhodococcus jostii RHA1, a cholesterol-catabolizing actinobacterium, when Rv1625c was heterologously expressed. However, these elevated levels of cAMP did not inhibit growth of R. jostii RHA1 in cholesterol medium. Mutations in rv1625c conferred cross-resistance to GSK286 and the known Rv1625c agonist, mCLB073. Metabolic profiling of M. tuberculosis cells revealed that elevated cAMP levels, induced using either an agonist or a genetic tool, did not significantly affect pools of steroid metabolites in cholesterol-incubated cells. Finally, the inhibitory effect of agonists was not dependent on the N-acetyltransferase MtPat. Together, these data establish that GSK286 is an Rv1625c agonist and sheds light on how cAMP signaling can be manipulated as a novel antibiotic strategy to shorten TB treatments. Nevertheless, the detailed mechanism of action of these compounds remains to be elucidated.

Therapeutic Effect of Tinospora cordifolia (Willd) Extracts on Letrozole-Induced Polycystic Ovarian Syndrome and its Complications in Murine Model.

Tinosopora cordifolia (Willd) (TC) is commonly used in Ayurvedic medicine since long time for number of ailments and its preparations are also considered by food safety and standards authority of India as nutritional supplement. However the scientific evidence on its possible safety and efficacy in polycystic ovarian syndrome and associated complications was not studied in detail. The purpose of this investigation is to examine whether or not TC can have therapeutic effects on letrozole induced PCOS and related complications such as body weight, dyslipidaemia, glucose tolerance, hormonal regulation, insulin resistance and sensitivity, severity of PCOS and histopathological changes in ovary using mice animal model. Present study is a preclinical study involving laboratory animals. After verifying the absence of PCOS, the animals began receiving Letrozole, which lasted for 21 days. Fasting blood glucose (FBG), the oral glucose tolerance test (OGTT), triglycerides, cholesterol, and weight were recorded. The levels of hormones like oestrogen, progesterone, insulin, testosterone, luteinising hormone (LH) and follicle stimulating hormone (FSH), histopathology was carried out. The Institutional Animal Ethics Committee at DITU gave its clearance to the animal experimentation on July 10, 2021 (DITU/IAEC/21-22/07-06). The majority of cornified epithelial cells were seen in groups treated with TC extract during the estrous phase of the cycle. Mice exposed to TC retained normal body weight. FBG, 1- and 2-hour OGTT, triglyceride and cholesterol levels were all significantly improved by extracts. Estradiol, progesterone, testosterone, insulin, LH and FSH concentration were all corrected in TC-treated animals. The HOMA-IR, HOMA-Beta and QUICKI values were also corrected with TC extracts. The morphological and microscopic features of the ovary were also greatly enhanced. Based on these findings, we conclude that treating PCOS mice with TC extracts significantly ameliorates the disease and severity down to nil-to-moderate levels by reducing hyperinsulinemia, hyperandrogenism, dyslipidaemia, enhancing insulin sensitivity, correcting oestrogen, progesterone, LH and FSH levels via enhanced ovarian function. Further molecular and cellular level of study is recommended for further elaboration of mechanism of action. • Tinospora cordifolia satva, oil and hydroalcoholic extract were studied in letrozole-induced PCOS in mice model• Anti PCOS efficacy of 3 preparations studied with respect to their mechanism of action in detail• For the first time proposing method of calculating severity of PCOS in animal model• Tinospora cordifolia oil preparation completely reversed PCOS effect of letrozole and made them normal• Histopathological and morphological studies support the biochemical claims.

Metal-organic frameworks (MOFs) as apt luminescent probes for the detection of biochemical analytes.

The detection of active substances in the body is very important for good human health as it gives important insights into the smooth functioning of the body. Most of the conventional materials that can be used as suitable probes require complicated fabrication methodologies, have poor stability and are susceptible to environmental effects. In contrast, metal-organic frameworks (MOFs) offer unique advantages as probes for testing analytes due to their tunable porosity, good specific surface area and ease of modification. Unlike previously reported perspectives/reviews, this perspective focuses on the latest applications of MOFs as detection materials for hydrogen peroxide, various metal ions, hydrogen sulfide, organic small molecules, glutathione, and organic macromolecules such as nucleic acids, and focuses on providing a more detailed mechanism of action. Also, the basic principles of action utilized by this class of materials are discussed.

Recent developments in membrane targeting antifungal agents to mitigate antifungal resistance.

Fungal infections cause severe and life-threatening complications especially in immunocompromised individuals. Antifungals targeting cellular machinery and cell membranes including azoles are used in clinical practice to manage topical to systemic fungal infections. However, continuous exposure to clinically used antifungal agents in managing the fungal infections results in the development of multi-drug resistance via adapting different kinds of intrinsic and extrinsic mechanisms. The unique chemical composition of fungal membranes presents attractive targets for antifungal drug discovery as it is difficult for fungal cells to modify the membrane targets for emergence of drug resistance. Here, we discussed available antifungal drugs with their detailed mechanism of action and described different antifungal resistance mechanisms. We further emphasized structure-activity relationship studies of membrane-targeting antifungal agents, and classified membrane-targeting antifungal agents on the basis of their core scaffold with detailed pharmacological properties. This review aims to pique the interest of potential researchers who could explore this interesting and intricate fungal realm.

ІННОВАЦІЙНІ ПІДХОДИ ДО УПРАВЛІННЯ КОНКУРЕНТОСПРОМОЖНІСТЮ ТОРГОВЕЛЬНИХ ПІДПРИЄМСТВ У СФЕРІ E-COMMERCE

This article improves the academic understanding of the innovative approaches to the manage-ment of enterprise competitiveness in the sphere of electronic commerce. E-commerce competitiveness is an integral indicator that characterizes the effectiveness of the enterprise’s activities, the stage and possibility of its development, and changes aimed to increase the resilience of the enterprise to disrup-tions within the industry and socio-economic system. The authors proposed to identify the competitive-ness of the e-commerce enterprise as a complex characteristic that reflects the ability of the enterprise to resist competition in the short-term and long-term perspectives due to the set of competitive ad-vantages formed with the help of internal and external resources. The research helped to identify the direct link between competitiveness and innovativeness of e-commerce enterprises. Among the internal factors that influence the enterprise’s competitiveness, thereare resources available to the enterprise; marketing potential; financial opportunities; supply system; strategy and tactics; characteristics of goods and services; and innovativeness of the enterprise. At the same time, external factors that influ-ence the enterprise’s competitiveness include the influence of external agents (consumers, suppliers, etc.), competition level, and dissemination of innovative solutions within the industry. The authors formed stages of the process of managing the competitivenessof e-commerce enterprises. The authors propose to use process, systems, situations, and innovative approaches to managing the competitiveness of e-commerce enterprises and also examine their features and mechanisms of action in detail. It needs to be noted that innovations that an enterprise adopts should align with the general enterprise’s strategy and align with its resource potential. There is also the perspective of combining tangible and intangible resources to create a unique value proposition

Analysis of Potential Mechanism of Herbal Formula Taohong Siwu Decoction against Vascular Dementia Based on Network Pharmacology and Molecular Docking.

Vascular dementia (VaD) is the second most prevalent dementia, which is attributable to neurovascular dysfunction. Currently, no approved pharmaceuticals are available. Taohong Siwu decoction (TSD) is a traditional Chinese medicine prescription with powerful antiapoptosis and anti-inflammatory properties. In this study, a network pharmacology approach together with molecular docking validation was used to explore the probable mechanism of action of TSD against VaD. A total of 44 active components, 202 potential targets of components, and 3,613 VaD-related targets including 161 intersecting were obtained. The potential chemical components including kaempferol, baicalein, beta-carotene, luteolin, quercetin, and beta-sitosterol involved in the inflammatory response, oxidative stress, and apoptosis might have potential therapeutic effects on the treatment of VaD. The potential core targets including AKT1, CASP3, IL1β, JUN, and TP53 associated with cell apoptosis and inflammatory might account for the essential therapeutic effects of TSD in VaD. The results indicated that TSD protected against VaD through multicomponent and multitarget modes. Though the detailed mechanism of action of various active ingredients needs to be further illustrated, TSD still showed a promising therapeutic agent for VaD due to its biological activity.

PS-B02-14: DISCOVERY OF A NEW DRUG FOR PRIMARY ALDOSTERONISM TARGETING THE CYP11B2 AND KCNJ5 MUTANTS

Primary aldosteronism (PA) is a common cause of secondary hypertension. PA induces damage to cardiovascular and renal blood vessels. Therefore, PA is regarded as a problem because it increases the risk of stroke, cardiomyopathy, kidney disease, etc. Aldosterone-producing adenomas (APA) are one of the major causes of PA, and gene mutations are often identified in tumor cells. KCNJ5 mutation is well known as a gene mutation that causes the loss of ion selectivity in APA. KCNJ5 is an inwardly rectifying potassium channel. KCNJ5 induces sodium ion influx due to mutations in APA. The sodium ion influx induces depolarization, and which overexpresses CYP11B2. CYP11B2 is the rate-determining enzyme for aldosterone synthesis, overexpression of CYP11B2 induces aldosterone overproduction. Examples of therapeutic drugs for PA and APA include calcium channel blockers, aldosterone antagonist and β;-blockers. However, therapeutic drugs for PA and APA targeting cell membrane depolarization have not been developed yet. We aim to find compounds that suppress CYP11B2 expression by membrane depolarization to develop novel therapeutic drugs for PA and APA. By developing a therapeutic drug that targets depolarization, we hope to establish an effective therapeutic method for APA caused by gene mutations such as KCNJ5 mutation. We performed high-throughput screening (HTS) using Tohoku University Compound Library (6080 compounds). First, we generated H295R-CYP11B2 N-Luc cells in which the luciferase gene is inserted downstream of the CYP11B2 locus. The cells H295R-CYP11B2 N-Luc were stimulated with KCl to cause depolarization, after which candidate compounds were added and HTS was performed by Luc assay. As a result, 101 compounds were selected. Furthermore, 25 of 101 compounds were selected by examining the cytotoxicity and dose response. Also, 11 of the 25 compounds suppressed CYP11B2 mRNA expression in KCl stimulated H295R cells. Secondary, we generated KCNJ5 mutant cells that expressed the KCNJ5 mutant (L168R) in a Doxycycline-inducible manner. 3 of 11 compounds that suppressed the expression of CYP11B2 mRNA were selected by examination using KCNJ5 mutant cells. After that, 2 of 3 compounds decreased the aldosterone production. These compounds have a different structure from existing therapeutic drugs such as calcium channel blockers. Since these can be novel therapeutic drugs for PA and APA caused by depolarization such as KCNJ5, we are examing the detailed mechanism of action of the compounds. In addition, we would like to further experiment the effects of the compounds in vivo using hypertensive model mice, Task1 /Task3 double KO mice.

INCOME DISTRIBUTION AND ZAKAT CONTRIBUTION IN MALAYSIA

One of the fundamental obligations of every Muslim is to pay Zakat. The asnaf group may receive assistance from Zakat payments and income distribution to survive financial difficulties. This article aims to describe how Malaysian Zakat income and distribution function. The significance of Zakat donations to the community for its economic development is discussed in the first paragraph of this article. The history of the Zakat contribution controversy and Sharia-based theory are then covered. The study's conclusion indicates an imbalance in the distribution of Zakat by the state in Malaysia based on the country's poverty rate. In order to ensure that Zakat's contribution to the community is effective, the article underlines the necessity for a thorough action plan to ensure that no Muslim group is overlooked or marginalised. To fulfil their different obligations and more effectively and efficiently meet the responsibility to donate Zakat, every Muslim community member must honestly collaborate and adhere to the detailed action plan.

Immunotoxicity In Vitro Assays for Environmental Pollutants under Paradigm Shift in Toxicity Tests.

With the outbreak of COVID-19, increasingly more attention has been paid to the effects of environmental factors on the immune system of organisms, because environmental pollutants may act in synergy with viruses by affecting the immunity of organisms. The immune system is a developing defense system formed by all metazoans in the course of struggling with various internal and external factors, whose damage may lead to increased susceptibility to pathogens and diseases. Due to a greater vulnerability of the immune system, immunotoxicity has the potential to be the early event of other toxic effects, and should be incorporated into environmental risk assessment. However, compared with other toxicity endpoints, e.g., genotoxicity, endocrine toxicity, or developmental toxicity, there are many challenges for the immunotoxicity test of environmental pollutants; this is due to the lack of detailed mechanisms of action and reliable assay methods. In addition, with the strong appeal for animal-free experiments, there has been a significant shift in the toxicity test paradigm, from traditional animal experiments to high-throughput in vitro assays that rely on cell lines. Therefore, there is an urgent need to build high-though put immunotoxicity test methods to screen massive environmental pollutants. This paper reviews the common methods of immunotoxicity assays, including assays for direct immunotoxicity and skin sensitization. Direct immunotoxicity mainly refers to immunosuppression, for which the assays mostly use mixed immune cells or isolated single cells from animals with obvious problems, such as high cost, complex experimental operation, strong variability and so on. Meanwhile, there have been no stable and standard cell lines targeting immune functions developed for high-throughput tests. Compared with direct immunotoxicity, skin sensitizer screening has developed relatively mature in vitro assay methods based on an adverse outcome pathway (AOP), which points out the way forward for the paradigm shift in toxicity tests. According to the experience of skin sensitizer screening, this paper proposes that we also should seek appropriate nodes and establish more complete AOPs for immunosuppression and other immune-mediated diseases. Then, effective in vitro immunotoxicity assay methods can be developed targeting key events, simultaneously coordinating the studies of the chemical immunotoxicity mechanism, and further promoting the paradigm shift in the immunotoxicity test.