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This study aims to examine the impact of the characteristics of the board of directors (BOD), namely board independence, board size, frequency of board meetings, and board gender diversity, on firm performance. This quantitative study uses data from all firms listed in the Bahrain Bourse for 2019 and 2020. Data on BODs were taken from the companies’ governance reports, while data on firm performance, namely return on assets (ROA), return on equity (ROE), and earnings per share (EPS), were taken from annual reports. Based on the ordinary least squares (OLS) approach, the results show insignificant relationships between BOD characteristics and firm performance. Board independence, size, frequency of meetings, and gender diversity insignificantly enhance Bahraini firms’ performance. The results indicate that firms may need to effectively implement BOD mechanisms. Moreover, other factors may moderate the impact of BOD mechanisms on firm performance. Hence, the study suggests a need for more regulations and policies to increase the effectiveness of board members. This study alerts policymakers, firms’ shareholders and stakeholders, and researchers to the need to increase directors’ roles in boosting company performance, especially in developing countries, where it is complicated to force business to follow best governance practices.

The current study intends to characterize the respiratory tract infections that have an association with gram positive bacterial pathogens, emm typing, the pattern of antibacterial resistance in isolated pathogens, phenotyping of virulence factor and molecular detection of Macrolide resistance gene. Various samples from patients with respiratory tract infections were collected and identification and antimicrobial susceptibility of clinical isolates was performed as per standard laboratory procedure. Macrolides (Eruthromycin, Clindamycin)-resistant isolates were again subjected to MIC method. Macrolide-inducible resistance to clindamycin (D test) was conducted upon Erythromycin and Clindamycin discs. Multiplex PCR was used to detect the resistance genes in all the three types of macrolide resistance strains. Serum Opacity Factor (SOF) was detected for all the isolates of GAS. Every isolate was checked to produce biofilm through micro titre plate method. Bacterial growth got registered in 156 (36.28%) samples. The most common isolate from URI samples was GAS i.e., 64 (14.9%), only to be followed by GGS 38(8.8%), GCS 29 (6.7%) and Staphylococcus aureus 18 (4.2%). Among GAS, only one isolate was recorded from blood, whereas 8.50% from sputum and the rest. All 71 GAS isolates were found to exhibit sensitivity towards Penicillin and Ceftriazone. GAS exhibited 55% Mtype of resistance whereas 40% were resistant to cMLS and 5% to iMLS. GCS showcased an equal number of cMLS and M type too. GGS portrayed 54.54% resistance to cMLS followed by 36.36% to Mtype and 9.09% to iMLS. The current study found iMLS type with least resistance. The current study identified that Streptococcus pyogenes is the most common bacteria that cause and recur the infection. The prevalence of resistance tends to change geographically and periodically. For this purpose and to achieve a sound public health outcome, periodical screening of antibiotic-resistance pattern becomes inevitable.

Language users are impacted by sociolinguistic factors like semantics and pragmatics in every circumstance. Even in a proficiency test, those two contexts are present because they serve as the test's framework. In order to identify the semantic and pragmatic settings in the TOEFL test simulation for the Listening component, research was done. In this study, the researcher used a qualitative descriptive strategy, using document analysis as the instrument. The study's focus was the FORUM TENTOR INDONESIA publication TOP NO. 1TOEFL SIMULATION. The outcome demonstrates that different kinds of semantic and pragmatic context were present in the test simulation. In 8 of the 30 questions that were analyzed, there were semantic contexts. Semantic contexts of three different types—meaning, semantic feature, and semantic roles—were discovered. Semantic Roles (4 Questions), Semantic Feature (2 Questions), and Meaning are the other predominant semantic types (2 Questions). The Pragmatic context quantities, however, are more prevalent than the Semantic context. Because one test item can contain multiple types of pragmatic language, 40 questions from the 30 studied items were found to have pragmatic contexts. Additionally, the majority of the pragmatic inquiries were of the Reference type since the narrator of the listening section used referring to formulate the question. Context, Politeness, Reference, and Speech Act are the different types of pragmatic context that can be encountered. Reference-type pragmatic contexts are the most common (25 questions).

Cyclin-dependent kinase 6 (EC 2.7.11.22) play significant roles in numerous biological processes and triggers cell cycle events. CDK6 controlled the transcriptional regulation. A dysregulated function of CDK6 is linked with the development of progression of multiple tumor types. Thus, it is considered as an effective drug target for cancer therapy. Based on the direct roles of CDK4/6 in tumor development, numerous inhibitors developed as promising anti-cancer agents. CDK4/6 inhibitors regulate the G1 to S transition by preventing Rb phosphorylation and E2F liberation, showing potent anti-cancer activity in several tumors, including HR+/HER2- breast cancer. CDK4/6 inhibitors such as abemaciclib, palbociclib, and ribociclib, control cell cycle, provoke cell senescence, and induces tumor cell disturbance in pre-clinical studies. Here, we discuss the roles of CDK6 in cancer along with the present status of CDK4/6 inhibitors in cancer therapy. We further discussed, how structural features of CDK4/6 could be implicated in the design and development of potential anti-cancer agents. In addition, the therapeutic potential and limitations of available CDK4/6 inhibitors are described in detail. Recent pre-clinical and clinical information for CDK4/6 inhibitors are highlighted. In addition, combination of CDK4/6 inhibitors with other drugs for the therapeutic management of cancer are discussed.

The goal is to look at how language helps people from different cultures get along. Language is an important part of how people interact with each other because it is the most basic way to share ideas and information. Language is a reflection of culture, so when people from more than one culture live together, how they use language is more important and complicated. The is also going to be one of the goals that is reviewed How the use of different languages creates barriers in cross-cultural communities and how these barriers affect the bonds that are made in cross-cultural communities. In the field of development, the question of what role language plays in communities with many different cultures is becoming more and more important. The world-wide study of both literature and social studies. As Cross-cultural communication brings together the seemingly unrelated fields of cultural anthropology and communication. Its goal is to bridge the gap between these two fields. Cross-cultural communication is based on being able to understand the different ways that people from different cultures interact with each other. In addition, it is supposed to come up with some recommendations that can help people from different cultures communicate better with each other. As a society's cultural practices and linguistic patterns shape the way people think, act, and communicate with the outside world, they also shape the way people think, act, and communicate with each other.

The world is divided into various countries. These countries have their own policy for economic development. There are various methods for determining economic development out of that one method or one measure is Gross Domestic Product (GDP). Every country has their own GDP which measure the performance of economy. For this study gross domestic product per capita in United States dollar has been analyzed with selected Asian countries based on respective nation's population as on 2021. The study period is considered from 2015 to 2021. For identify difference among per capita GDP of selected nations one way ANOVA tool has been used as statistical parameter. The major finding of the study indicated as China saw increasing trend of per capital GDP for selected time period. India indicated fluctuating trend of per capita GDP for the study period. Out of selected countries Pakistan indicated lowest per capital GDP from selected countries. On an average performance of Indonesia, Philippines and Vietnam in concern with per capita GDP was same during the study period. Japan indicated highest per capital GDP out of selected countries.

This paper presents and analyses some Mean Field Games (MFGs) models that depict interactions between two groups where the number of participants tends to +infinity.Solutions to differential game problems, systems of partial differential equations. MFGtheory equations have been developed to approximate the static and evolutionary versions of such models. We present numerical methods and simulations. To solve the problem in the resulting system of equations, we propose nonstandard finite difference schemes for the optimal planning problem, which has an optimal control formulation. We also conduct numerical tests. Mathematics Subject Classification: 65M06, 33F05.

The study aimed to identify the distinctive behavioral characteristics of outstanding students in light of the Triarchic theory of intelligence from the point of view of students and their teachers. The sample consisted of (51) students, 34% of whom were excelling in the sixth and eighth grades, as well as (76) teachers, and for this purpose, the distinctive behavioral characteristics of outstanding students scale was used, in addition to conducting a focus interview with teachers. The results of the study indicated that the level of behavioral characteristics from the point of view of students came significantly by 82.01%, where both the domains of creative ability and applied ability were ranked first, followed by the domain of analytical ability. As for the level of distinctive behavioral characteristics of outstanding students from the point of view of teachers, it came significantly by 77.29% and in this order; analytical ability, then applied ability, and finally creative ability, and these results corresponded to the corresponding data collected from teachers, but the ranking of these domains differed, where analytical characteristics were ranked first, then applied, and finally creative.

Solar photovoltaic (PV) microgrids have gained popularity in recent years as a way to improve the stability of intermittent renewable energy generation in systems, both off-grid and on-grid, and to meet the needs of emergency settings during natural catastrophes. Over the last several decades, researchers have been interested in improving the efficiency of photovoltaic (PV) systems. Solar-battery charge controllers based on various algorithms are continuously and intensively employed to improve energy transfer efficiency and reduce charging time. This paper presents state-of-the-art solar photovoltaic (PV) integrated battery energy storage systems (BESS). An overview of and motivations for PV-battery systems is initially introduced, followed by the survey methodology and its contributions. In addition, this study classifies residential solar PV systems and battery charge controllers with their corresponding references in the review structure, which also provides details on battery charger topologies. Subsequently, an analytical review of the PV-Battery charge controller and the failure probability of such systems is discussed to determine the system components that mostly fail and their importance in the system. Finally, recommendation amendments to the existing charge controller that potentially contribute to increasing the system efficiency, reducing the failure probabilities, and reducing the cost are presented as future design concepts for the entire system.

We presented in this paper a new concept of sets that we launched it neutrosophic axial sets . These sets are considered as generalization of neutrosophic sets . The union relationships , intersection, union , belonging and other concepts were built on these sets , then we created two different concepts of points . Also we studied many important properties and basic theories about axial sets theory.

The purpose of this master's research thesis is to categorize the cutting-edge AI-based cyber security network to reduce cybercrimes globally and provide a resilient cyberattack-free environment for consumers. One of the most often used real applications in areas like cost control, traffic scene analysis, and thought attack identification is attacks restriction. Contextual information, which in our study is described as the relationship between the cyber security and the Rivest-Shamir-Adleman, is important to get total comprehension along with the information on the owner vehicle. The research study suggested a KNN classifier for continuously limiting the position of organizations and digital protection in the area. The modified districts are passed to the Rivest-Shamir-Adleman after being preprocessed to reduce commotion (RSA). The preprocessing of the RSA separates associated components, divides them into lines of attack, and channels them by size. The well-known technique used in the research is RSA. The user is advised to acquire a new attack of that portion of the assault if the RSA reported a low confidence score for at least one attack region. The new attack is then compared to the existing attack, and the attack processing steps are once more carried out. If all locations have a sufficiently high score or enough retries have been used up, the security cycle ends. The outcome includes the type of assault that was discovered, a list of the districts that were subject to the removed assault, and the accuracy of the RSA calculation through KNN, which was calculated across 300 preparation and testing iterations. The proposed framework was created using 75% of the available data, 20% of which was used for testing, and 5% for validation. We used a Cyber Data Dataset made up of multiple classes that addressed a portion of all current forms of digital protection to illustrate the meaning of the proposed component vector. Multiple machine learning toolboxes were utilized for the research effort, which was implemented and carried out in the MATLAB programming language. Our strategy has three practical head networks, so a potential preparation risk is prompted by the start to finish and synchronous preparation. It is incredibly challenging to determine which head configuration is producing a problem on the off chance that the model doesn't come together. As a result, in our plan cycle, we gradually added each helpful head to make sure the single head plan idea was functioning correctly before extending the model with the remaining useful heads.

The multidrug resistance developed in many organisms due to the prolonged use of antibiotics has been an increasing global health crisis. Klebsiella pneumoniae is a causal organism for various infections, including respiratory, urinary tract and biliary diseases. Initially, immunocompromised individuals are primarily affected by K. pneumoniae. Due to the emergence of hypervirulent strains recently, both healthy and immunocompetent individuals are equally susceptible to K. pneumoniae infections. The infections caused by multidrug-resistant and hypervirulent K. pneumoniae strains are complicated to treat, illustrating an urgent need to develop novel and more practical approaches to combat the pathogen. We focused on the previously performed high-throughput analyses by other groups to discover several novel enzymes that may be considered attractive drug targets of K. pneumoniae. These targets qualify most of the selection criteria for drug targeting, including an absence of its homolog’s gene in the host. The capsule, lipopolysaccharide, fimbriae, siderophores and essential virulence factors facilitate the pathogen entry, infection and survival inside the host. This review discusses K. pneumoniae pathophysiology, including its virulence determinants and further the potential drug targets that might facilitate the discovery of novel drugs and effective treatment regimens shortly.

TANK-binding kinase 1 (TBK1) regulates various biological processes including, NF-κB signaling, immune response, autophagy, cell division, Ras-mediated oncogenesis, and AKT pro-survival signaling. Enhanced TBK1 activity is associated with autoimmune diseases and cancer, suggesting its role in therapeutic targeting of interferonopathies. In addition, dysregulation of TBK1 activity promotes several inflammatory disorders and oncogenesis. Structural and biochemical study reports provide the molecular process of TBK1 activation and recap the substrate selection about TBK1. This review summarizes recent findings on the molecular mechanisms by which TBK1 is involved in cancer signaling. The IKK-e and TBK1 are together associated with inflammatory diseases by inducing type I IFNs. Furthermore, TBK1 signaling regulates radiation-induced epithelial-mesenchymal transition by controlling phosphorylation of GSK-3β and expression of Zinc finger E-box-binding homeobox 1, suggesting, TBK1 could be targeted for radiotherapy-induced metastasis therapy. Despite a considerable increase in the list of TBK1 inhibitors, only a few has potential to control cancer. Among them, a compound BX795 is considered a potent and selective inhibitor of TBK1. We discussed the therapeutic potential of small-molecule inhibitors of TBK1, particularly those with high selectivity, which will enable further exploration in the therapeutic management of cancer and inflammatory diseases.

The incentive for international agencies to promote 'local' peacebuilding is commonly premised on the hope that micro-level interventions can nourish grassroots activism and participatory citizenship. Tracing reconciliation processes across Iraq following the defeat of ISIL provides a window through which to view the transactional relationships between 'national' and 'local' forms of politics, conflict and peace in post-Ba'athist Iraq. This paper focuses on the example of Yathrib, Salah al-Din province, where over ninety per cent of residents were displaced in 2014, and an estimated eighty-five per cent subsequently returned following peace negotiations. The paper uses qualitative interview findings to demonstrate on the one hand that seemingly 'local' tribal solutions are built into national-level 'peace strategies', while on the other, state capture and power politics is infused into the management of apparently parochial disputes. While these observations are not an indictment of international efforts to intervene at the subnational level, they serve to thoroughly 'de-romanticise' the local.

The human genome encodes more than 500 protein kinases that work by transferring the γ-phosphate group from ATP to serine, threonine, or tyrosine (Ser/Thr/Tyr) residues. Various kinases are associated with the onset of cancer and its further progression. The recent advancements in developing small-molecule kinase inhibitors to treat different cancer types have shown noticeable results in clinical therapies. Microtubule-affinity regulating kinase 4 (MARK-4) is a Ser/Thr protein kinase that relates structurally to AMPK/Snf1 subfamily of the CaMK kinases. The protein kinase modulates major signalling pathways such as NF-κB, mTOR and the Hippo-signalling pathway. MARK4 is associated with various cancer types due to its important role in regulating microtubule dynamics and subsequent cell division. Aberrant expression of MARK4 is linked with several pathologies such as cancer, Alzheimer's disease, obesity, etc. This review provides detailed information on structural aspects of MARK4 and its role in various signalling pathways related to cancer. Several therapeutic molecules were designed to inhibit the MARK4 activity from controlling associated diseases. The review further highlights kinase-targeted drug discovery and development in oncology and cancer therapies. Finally, we summarize the latest findings regarding the role of MARK4 in cancer, diabetes, and neurodegenerative disease path to provide a solid rationale for future investigation and therapeutic intervention.

Ensuring genetic integrity is essential during the cell cycle to avoid aneuploidy, one of the underlying causes of malignancies. Aurora kinases are serine/threonine kinase that play a vital role in maintaining the genomic integrity of the cells. There are three forms of aurora kinases in the mammalian cells, which are highly conserved and act together with several other proteins to control chromosome alignment and its equal distribution to daughter cells in mitosis and meiosis. We provide here a detailed analysis of Aurora B kinase (ABK) in terms of its expression, structure, function, disease association and potential therapeutic implications. ABK plays an instrumental in mitotic entry, chromosome condensation, spindle assembly, cytokinesis, and abscission. Small-molecule inhibitors of ABK are designed and synthesized to control cancer progression. A detailed understanding of ABK pathophysiology in different cancers is of great significance in designing and developing effective therapeutic strategies. In this review, we have discussed the physiological significance of ABK followed by its role in cancer progression. We further highlighted available small-molecule inhibitors to control the tumor proliferation and their mechanistic insights.

Neurodegeneration is a prevalent and one of the emerging reasons for morbidity, mortality, and cognitive impairment in aging. Dementia is one of such conditions of neurodegeneration, partially manageable, irreversible, and worsens over time. This review is focused on biological and psychosocial risk factors associated with Alzheimer's and Parkinson's diseases, highlighting the value of cognitive decline. We further emphasized on current therapeutic strategies from pharmacological and non-pharmacological perspectives focusing on their effects on cognitive impairment, protein aggregation, tau pathology, and improving the quality of life. Deeper mechanistic insights into the multifactorial neurodegeneration could offer the design and development of promising diagnostic and therapeutic strategies.

Chitin, a polysaccharide that occurs abundantly in nature after cellulose, has attracted the interest of the scientific community due to its plenty of availability and low cost. Mostly, it is derived from the exoskeleton of insects and marine crustaceans. Often, it is insoluble in common solvents that limit its applications but its deacetylated product, named chitosan is found to be soluble in protonated aqueous medium and used widely in various biomedical fields. Indeed, the existence of the primary amino group on the backbone of chitosan provides it an important feature to modify it chemically into other derivatives easily. In the present review, we present the structural properties of chitin, and its derivatives and highlighted their biomedical implications including, tissue engineering, drug delivery, diagnosis, molecular imaging, antimicrobial activity, and wound healing. We further discussed the limitations and prospects of this versatile natural polysaccharide.

The carcinogenic dog nematode, Spirocerca lupi, is a canine causative agent of the oesophagal nodular granuloma. Worldwide availability of the biological host (beetle) and the presence of some environmental factors help in the comprehensive epidemiology of this nodular forming nematode. Coprologically, it depends on the presence and characteristics of the rhabdiform larvae in most nematodes due to the similarity in egg shape. In contrast, in the case of the presence of carcinogenic nematodes, the morphological appearance of the eggs is definitive for diagnosis, which can be detected by flotation and sedimentation techniques in the faecal examination to detect the gastrointestinal parasites. The morphological identification of the parasite's eggs in the dog's faecal samples requires more confirmation by molecular and specific gene amplification. They should be aware of the possibility of a spirurid worm infection, which needs to be diagnosed and treated.

In the first quarter of the 21st century, we are already facing the third emergence of a coronavirus outbreak, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the coronavirus disease 2019 (COVID-19) pandemic. Comparative genomics can inform a deeper understanding of the pathogenesis of COVID-19. Previous strains of coronavirus, SARS-CoV, and Middle-East respiratory syndrome-coronavirus (MERS-CoV), have been known to cause acute lung injuries in humans. SARS-CoV-2 shares genetic similarity with SARS-CoV with some modification in the S protein leading to their enhanced binding affinity toward the angiotensin-converting enzyme 2 (ACE2) receptors of human lung cells. This expert review examines the features of all three coronaviruses through a conceptual lens of comparative genomics. In particular, the life cycle of SARS-CoV-2 that enables its survival within the host is highlighted. Susceptibility of humans to coronavirus outbreaks in the 21st century calls for comparisons of the transmission history, hosts, reservoirs, and fatality rates of these viruses so that evidence-based and effective planetary health interventions can be devised to prevent future zoonotic outbreaks. Comparative genomics offers new insights on putative and novel viral targets with an eye to both therapeutic innovation and prevention. We conclude the expert review by (1) articulating the lessons learned so far, whereas the research is still being actively sought after in the field, and (2) the challenges and prospects in deciphering the linkages among multiomics biological variability and COVID-19 pathogenesis.

Due to its nature the stock markets can be affected by many factors. The factors are different from each other and every single one of them has its own effects. Moreover, they are different from one situation to another, but generally they are considered to be natural reasons, political issues or economical reasons. Inflation as one of the macroeconomic variables is one of the factors that many researchers and policymakers have studied and determined its impacts on stock markets. Because it can directly impact the stock market indices and the investors in the market. Many investors may lose their rationality in decision making when inflation happens. Furthermore, it causes uncertainty in the market. In that context, this paper aims to investigate the impacts of inflation rate on stock market indices in Turkey. For that purpose, we throwed light on the BIST-100 index as a representative for stock indices traded in ISE and CPI index is representing inflation rate in the same country. The study is depending on monthly published data by central bank of Turkey from which starts from January 2009 and ends with March 2020. The VAR model and Granger Causality test is applied to analyze the collected data. According to the results, it is found that there is only a one-way causality relationship between inflation and BIST-100. On the other hand, the results of impulse responses provided no meaning for relationship between the variables. Furthermore, according to variance decomposition both of the variables were contained dynamics with themselves.

The sphingosine kinase-1/sphingosine-1-phosphate pathway is linked with the cancer progression and survival of the chemotherapy-challenged cells. Sphingosine kinase-1 (SphK1) has emerged as an attractive drug target, but their inhibitors from natural sources are limited. In this study, we have chosen harmaline, one of the β-carboline alkaloids, and report its mechanism of binding to SphK1 and subsequent inhibition. Molecular docking combined with fluorescence binding studies revealed that harmaline binds to the substrate-binding pocket of SphK1 with an appreciable binding affinity and significantly inhibits the kinase activity of SphK1 with an IC50 value in the micromolar range. The cytotoxic effect of harmaline on non-small-cell lung cancer cells by MTT assay was found to be higher for H1299 compared to A549. Harmaline induces apoptosis in non-small-cell lung carcinoma cells (H1299 and A549), possibly via the intrinsic pathway. Our findings suggest that harmaline could be implicated as a scaffold for designing potent anticancer molecules with SphK1 inhibitory potential.

Persons working in the mortuaries face numerous hazards and if proper precautions are not observed such persons can fall sick by the infectious agents. A review has been carried out to find out the various agents responsible for causing infection in the mortuaries. Practices in the mortuaries that can cause harm to the workers have also been reviewed. The various methods that can reduce or eliminate the chances of such infections and precautions to reduce the hazards in postmortem examination have also been reviewed.

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

Sphingosine kinase 1 (SphK1) is an oncogenic lipid kinase that catalyzes the formation of sphingosine-1-phosphate via phosphorylation of sphingosine and known to play a crucial role in angiogenesis, lymphocyte trafficking, signal transduction pathways, and response to apoptotic stimuli. SphK1 has received attention because of its involvement in varying types of cancer and inflammatory diseases such as rheumatoid arthritis, diabetes, renal fibrosis, pulmonary fibrosis, asthma, and neurodegenerative disorders. In the malignancies of breast, lung, uterus, ovary, kidney, and leukemia, overexpression of SphK1 has been reported and thus considered as a potential drug target. In this study, we have performed virtual high-throughput screening of ∼90,000 natural products from the ZINC database to find potential SphK1-inhibitors. Initially, the hits were selected by applying absorption, distribution, metabolism, excretion, and toxicity properties, Lipinski's rule, and PAINS filters. Further, docking analysis was performed to estimate the binding affinities and specificity to find safe and effective preclinical leads against SphK1. Two compounds, ZINC05434006 and ZINC04260971, bearing appreciable binding affinity and SphK1 selectivity were selected for 100 ns molecular dynamics (MD) simulations under explicit water conditions. The all-atom MD simulation results suggested that the ZINC05434006 and ZINC04260971 binding induces a slight structural change and stabilizes the SphK1 structure. In conclusion, we propose natural compounds, ZINC05434006 and ZINC04260971, as potential inhibitors of SphK1, which may be further exploited as potential leads to develop effective therapeutics against SphK1-associated diseases including cancer after in vitro and in vivo validations.

MAP/Microtubule affinity regulating kinase 4 (MARK4) plays an important role in the regulation of microtubule dynamics by phosphorylation of tau protein. A higher expression of MARK4 is observed in the glioblastoma multiforme (GBM) cell lines. We identified eight synonymous and non-synonymous mutations in the MARK4 gene related to GBM in The Cancer Genome Atlas (TCGA) consortium. Out of these, three non-synonymous mutations were found in the catalytic domain of the protein (Lys231Asn, Tyr247His and Arg265Gln), were selected to see the possible deleterious effects on the structure and function using the cutting-edge in-silico tools. In addition, molecular dynamics simulation, principal component analysis, dynamic cross correlation matrix analysis and correlation network analysis were performed to gain insights into the conformation of the MARK4 and its mutants. We found that, Tyr247His shows a maximum deleterious impact, reflected from structural deviation in comparison to Lys231Asn and Arg265Gln. In conclusion, Tyr247His mutant of MARK4 has relatively higher chances of affecting the structure and function of the protein thus leading to abnormal MARK4 activity which is associated to GBM. Communicated by Ramaswamy H. Sarma

Thymoquinone (TQ), a natural phytochemical predominantly found in Nigella sativa, has been investigated for its numerous health benefits. TQ showed anti-cancer, anti-oxidant, and anti-inflammatory properties, validated in various disease models. The anti-cancer potential of TQ is goverened by anti-proliferation, cell cycle arrest, apoptosis induction, ROS production, anti-metastasis and anti-angiogenesis, inhibition of cell migration and invasion action. Additionally, TQ exhibited antitumor activity via the modulation of multiple pathways and molecular targets, including Akt, ERK1/2, STAT3, and NF-κB. The present review highlighted the anticancer potential of TQ . We summarize the anti-cancer, anti-oxidant, and anti-inflammatory properties of TQ, focusing on its molecular targets and its promising action in cancer therapy. We further described the molecular mechanisms by which TQ prevents signaling pathways that mediate cancer progression, invasion, and metastasis.

TANK-binding kinase 1 (TBK1) plays a fundamental role in regulating the cellular responses and controlling several signaling cascades. It regulates inflammatory, interferon, NF-κB, autophagy, and Akt pathways. Post-translational modifications (PTM) of TBK1 control its action and subsequent cellular signaling. The dysregulation of the TBK1 pathway is correlated to many pathophysiological conditions, including cancer, that implicates the promising therapeutic advantage for targeting TBK1. The present study summarizes current updates on the molecular mechanisms and cancer-inducing roles of TBK1. Designed inhibitors of TBK1 are considered a potential therapeutic agent for several diseases, including cancer. Data from pre-clinical tumor models recommend that the targeting of TBK1 could be an attractive strategy for anti-tumor therapy. This review further highlighted the therapeutic potential of potent and selective TBK1 inhibitors, including Amlexanox, Compound II, BX795, MRT67307, SR8185 AZ13102909, CYT387, GSK8612, BAY985, and Domainex. These inhibitors may be implicated to facilitate therapeutic management of cancer and TBK1-associated diseases in the future.

In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as the central circadian pacemaker, orchestrating behavioral and physiological rhythms in alignment to the environmental light/dark cycle. The neurons that comprise the SCN are anatomically and functionally heterogeneous, but despite their physiological importance, little is known about the pathways that guide their specification and differentiation. Here, we report that the stem/progenitor cell transcription factor, Sex determining region Y-box 2 (Sox2), is required in the embryonic SCN to control the expression of SCN-enriched neuropeptides and transcription factors. Ablation of Sox2 in the developing SCN leads to downregulation of circadian neuropeptides as early as embryonic day (E) 15.5, followed by a decrease in the expression of two transcription factors involved in SCN development, Lhx1 and Six6, in neonates. Thymidine analog-retention assays revealed that Sox2 deficiency contributed to reduced survival of SCN neurons during the postnatal period of cell clearance, but did not affect progenitor cell proliferation or SCN specification. Our results identify SOX2 as an essential transcription factor for the proper differentiation and survival of neurons within the developing SCN.

Casein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski’s rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α.

The usage of reinforcement learning (RL) for many type of applications is increasing. The quick development of machine learning models in the recent years has motivated researchers to integrate Q-learning with deep learning which has opened the door for many vision based applications of RL. However, using RL with shallow types of neural network has not been tackled adequately in the literature despite its need for real time types of applications such as control systems or time constraint decision based system. In this article, we propose a novel online sequential extreme learning machine OSELM based RL using Q-learning named as OSELM-QL. In OSELM-QL, the role of the neural network NN is to learn the best criterion for selecting the action based on Q value for exploitation or select the action randomly for exploration. For validation, we compare the predicted Q values by NN to show its feasibility to operate as an assistant sub-block to classical Q-learning for balancing between exploration and exploitation. The convergence is proved in the simulation model. This emphasizes on the potential of using this approach as an assistant block in the standard Q-learning system for exploration and exploitation balancing.

Circadian clocks evolved to enable organisms to anticipate and prepare for periodic environmental changes driven by the day–night cycle. This internal timekeeping mechanism is built on autoregulatory transcription–translation feedback loops that control the rhythmic expression of core clock genes and their protein products. The levels of clock proteins rise and ebb throughout a 24-h period through their rhythmic synthesis and destruction. In the ubiquitin–proteasome system, the process of polyubiquitination, or the covalent attachment of a ubiquitin chain, marks a protein for degradation by the 26S proteasome. The process is regulated by E3 ubiquitin ligases, which recognize specific substrates for ubiquitination. In this review, we summarize the roles that known E3 ubiquitin ligases play in the circadian clocks of two popular model organisms: mice and fruit flies. We also discuss emerging evidence that implicates the N-degron pathway, an alternative proteolytic system, in the regulation of circadian rhythms. We conclude the review with our perspectives on the potential for the proteolytic and non-proteolytic functions of E3 ubiquitin ligases within the circadian clock system.

Communicated by Ramaswamy H. Sarma.

Background PIM kinases are well-studied drug targets for cancer, belonging to Serine/Threonine kinases family. They are the downstream target of various signaling pathways, and their up/down-regulation affects various physiological processes. PIM family comprises three isoforms, namely, PIM-1, PIM-2, and PIM-3, on alternative initiation of translation and they have different levels of expression in different types of cancers. Its structure shows a unique ATP-binding site in the hinge region which makes it unique among other kinases. Scope of review PIM kinases are widely reported in hematological malignancies along with prostate and breast cancers. Currently, many drugs are used as inhibitors of PIM kinases. In this review, we highlighted the physiological significance of PIM kinases in the context of disease progression and therapeutic targeting. We comprehensively reviewed the PIM kinases in terms of their expression and regulation of different physiological roles. We further predicted functional partners of PIM kinases to elucidate their role in the cellular physiology of different cancer and mapped their interaction network. Major conclusions A deeper mechanistic insight into the PIM signaling involved in regulating different cellular processes, including transcription, apoptosis, cell cycle regulation, cell proliferation, cell migration and senescence, is provided. Furthermore, structural features of PIM have been dissected to understand the mechanism of inhibition and subsequent implication of designed inhibitors towards therapeutic management of prostate, breast and other cancers. General significance Being a potential drug target for cancer therapy, available drugs and PIM inhibitors at different stages of clinical trials are discussed in detail.