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The applications of artificial intelligence (AI) in pharmaceutical sectors have advanced drug discovery and development methods. AI has been applied in virtual drug design, molecule synthesis, advanced research, various screening methods, and decision-making processes. In the fourth industrial revolution, when medical discoveries are happening swiftly, AI technology is essential to reduce the costs, effort, and time in the pharmaceutical industry. Further, it will aid "genome-based medicine" and "drug discovery." AI may prepare proactive databases according to diseases, disorders, and appropriate usage of drugs which will facilitate the required data for the process of drug development. The application of AI has improved clinical trials on patient selection in a population, stratification, and sample assessment such as biomarkers, effectiveness measures, dosage selection, and trial length. Various studies suggest AI could be perform better compared to conventional techniques in drug discovery. The present review focused on the positive impact of AI in drug discovery and development processes in the pharmaceutical industry and beneficial usage in health sectors as well., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Celastrol, a compound derived from traditional Chinese medicine, has therapeutic effects and has been used to treat inflammation-related diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. However, current reviews lack a comprehensive and systematic summary of the anti-tumor mechanisms and molecular targets of celastrol. For this reason, this paper reviews the anticancer properties of celastrol and the molecular mechanisms underlying its anticancer effects. This paper primarily focuses on the mechanism of action of celastrol in terms of inhibition of cell proliferation and regulation of the cell cycle, regulation of apoptosis and autophagy, inhibition of cell invasion and metastasis, anti-inflammation, regulation of immunotherapy, and angiogenesis. More importantly, the target proteins of celastrol identified by chemical proteomics or other methods are highlighted, providing detailed targets with novel therapeutic potential for anti-tumor treatment. In addition, we describe the side effects and strategies to improve the bioavailability of celastrol. In summary, this paper analyzes celastrol, a natural compound with therapeutic effects and clear targets, aiming to draw more attention from the scientific and pharmacological communities and accelerating its clinical application for the benefit of cancer patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

With the implementation of the European Green Deal, the circular bioeconomy model is gaining in relevance as well as the concept of circular bioeconomy, which promotes a renewed economic approach to conducting economic activity. The transition of a socio-economic system from one qualitative state to another, causes the need to measure dynamic changes and establish progressive factors towards the formation of a circular business environment. The objective of the study is to monitor the measurement system of the circular bioeconomy and to outline criterial limitations and relevant indicators based on the defined characteristics. The methodological basis of the study consists of the methods of empirical and theoretical level, particularly the historical, abstract-logical, descriptive, comparative methods, method of observation and formalisation, theoretical generalisation, etc. In the process of scientific research, it was possible to carry out comprehensive monitoring of scientific developments of foreign and Ukrainian scientists and to establish existing methodological approaches to assessing the circular bioeconomy. A review of the literature provided an opportunity to identify key structural components that are within the sectoral space and targets that have a complementary relationship with the three-dimensional sustainable development. Sectoral segmentation and target gradation by circular orientation and bioeconomic manifestation allowed to form a system of indicators for measuring the circular bioeconomy according to the established criteria. The practical value of the study consists in the scientific substantiation of the criterial characteristics of the measurement of the circular bioeconomy and the establishment of a system of indicators with relevant limitations

In July 2019, Eastbourne Borough Council declared a climate emergency and committed to making Eastbourne carbon neutral by 2030. In order to achieve this, citizens together with Council created a unique model of council-citizen collaborative climate governance, the Eastbourne Eco Action Network (EAN). EAN’s main strategy has been the setting up of targeted working groups, each bringing together Councillors, engaged citizens and providers, and each tackling a specific area of climate action through a combination of infrastructure, institutional and behavioural changes. As an environmental anthropologist living in Eastbourne, I was involved in this process right from the beginning, having had my own ‘ecophany’—the realisation that the climate emergency required urgent action—in February 2019. Two years and one pandemic later, in this paper I reflect on the overall experiences and challenges of EAN’s and Eastbourne Borough Council’s work towards town-wide carbon neutrality to date, discussing possible factors (structural and other) determining varying successes and failures. At the same time, this paper provides an auto-ethnographic account of what ‘engaged anthropology’ means in practice, mapping out the real contributions anthropologists can and should make in local climate action, but also reflecting on challenges encountered along the way.

In the context of the reorientation of the Russian economy towards an innovative development path, the issue of increasing labor productivity has become an important part of state policy.Currently, the country is implementing a large-scale national project «Labor productivity and employment support». The implementation of the project approach to managing labor productivity for the Russian economy is of strategic priority, since its application helps to increase the efficiency of resource use, realize the goals of modernizing production, and stimulate innovation and export activities of domestic enterprises.The aim of the study is to consider the regional aspect of the implementation of the priority national project «Labor productivity and employment support» on the example of the Perm region. The methodological basis of the study are comparative, statistical and expert methods.The paper analyzes the implementation of the national project «Labor productivity and employment support» in the Perm region; presents the actual results of the project; formulates problems in the implementation of project activities; identifies the prospects of the Perm region in the context of setting higher targets for the regional project «Labor productivity and employment support» in comparison with the figures for Russia as a whole.The materials outlined in this article can deepen knowledge about the specifics of the implementation of the priority national project «Labor productivity and employment support» at the regional level, as well as be used to adjust the course implementation of a regional project aimed at improving productivity in the Perm region.

MicroRNAs (miRNAs) are short noncoding RNAs (20–25 nucleotides) that regulate gene expression posttranscriptionally. However, identification and characterization of miRNAs remain limited for conifer species. In this study, we applied transcriptome-wide miRNAs sequencing to a conifer species Platycladus orientalis, which is highly adaptable to a wide range of environmental adversities, including drought, barren soil, and mild salinity. A total of 17,181,542 raw reads were obtained from the Illumina sequencing platform; 31 conserved and 91 novel miRNAs were identified, and their unique characteristics were further analyzed. Ten randomly selected miRNAs were validated by quantificational real-time polymerase chain reaction. Through miRNA target predictions based on psRNATarget, 2331 unique mRNAs were predicted to be targets of P. orientalis miRNAs that involved in 187 metabolic pathways in KEGG database. These targets included not only important transcription factors (e.g., class III homeodomain leucine zipper targeted by por-miR166d) but also indispensable nontranscriptional factor proteins (i.e., por-miR482a-3p regulated nucleotide-binding site leucine-rich repeat protein). Interestingly, six miRNAs (por-miR16, -miR44, -miR60-5p, -miR69–3p, -miR166b-5p, and -miR395c) were found in adaptation-related pathways (e.g., drought), indicating their possible involved in this species’ stress-tolerance characteristics. The present study provided essential information for understanding the regulatory role of miRNAs in P. orientalis and sheds light on their possible use in tree improvement for stress tolerance.

Abstract Due to the continuous rise in biofilm‐related infections, biofilms seriously threaten human health. The formation of biofilms makes conventional antibiotics ineffective and dampens immune clearance. Therefore, it is important to understand the mechanisms of biofilm formation and develop novel strategies to treat biofilms more effectively. This review article begins with an introduction to biofilm formation in various clinical scenarios and their corresponding therapy. Established biofilm models used in research are then summarized. The potential targets which may assist in the development of new strategies for combating biofilms are further discussed. The novel technologies developed recently for the prevention and treatment of biofilms including antimicrobial surface coatings, physical removal of biofilms, development of new antimicrobial molecules, and delivery of antimicrobial agents are subsequently presented. Finally, directions for future studies are pointed out.

Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in clinics, the majority of these approaches seem to combine molecularly targeted drugs with chemotherapeutic agents. In this manuscript, we start by analyzing the list of FDA-approved molecularly targeted drugs for breast cancer to evaluate where molecular targeting stands in breast cancer treatment today. We will then provide an overview of other options currently under clinical trial or being investigated in pre-clinical studies.

Background: Colorectal cancer is the third most common cause of death among cancers in the world. Although improvements in various treatments have greatly improved the survival time of colorectal cancer patients, since colorectal cancer is often at an advanced stage when diagnosed, the prognosis of patients is still very poor. Since the ceRNA regulatory network was proposed in 2011, it has greatly promoted the study of the molecular mechanism of colorectal cancer occurrence and development.Objective: Exploring the new molecular mechanism of colorectal cancer occurrence and development and providing new targets for the diagnosis and treatment of colorectal cancer.Method: We analyzed the RNA-seq data of CRC from TCGA, such as differential expression analysis, weighted gene co-expression network analysis (WGCNA) and construction of ceRNA regulatory network.Results: We constructed a ceRNA network using RNA-seq data of CRC from TCGA. In the ceRNA regulatory network, 19 hub molecules with significant prognostic effects were ultimately identified, including 8 lncRNAs, 2 mRNAs and 9 miRNAs. These hub molecules constitute the lncRNA-miRNA, miRNA-mRNA or lncRNA-miRNA-mRNA axis.Conclusion: In this article, some new ceRNA regulatory axes have been discovered, which may potentially disclose new molecular mechanisms for the occurrence and development of colorectal cancer, thereby providing an important blueprint for the treatment and prognosis assessment of CRC patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate how Hydroxysafflor yellow A (HSYA) effects acute liver injury (ALI) and what transcriptional regulatory mechanisms it may employ. Methods: Rats were randomly divided into five groups (n = 10): Control, Model, HSYA-L, HSYA-M, and HSYA-H. In the control and model groups, rats were intraperitoneally injected with equivalent normal saline, while in the HSYA groups, they were also injected with different amounts of HSYA (10, 20, and 40 mg/kg/day) once daily for eight consecutive days. One hour following the last injection, the control group was injected into the abdominal cavity with 0.1 ml/100 g of peanut oil, and the other four groups got the same amount of a peanut oil solution containing 50% CCl4. Liver indexes were detected in rats after dissection, and hematoxylin and eosin (HE) dyeing was utilized to determine HSYA's impact on the liver of model rats. In addition, with RNASequencing (RNA-Seq) technology and quantitative real-time PCR (qRT-PCR), differentially expressed genes (DEGs) were discovered and validated. Furthermore, we detected the contents of anti-superoxide anion (anti-O2 -) and hydrogen peroxide (H2O2), and verified three inflammatory genes (Icam1, Bcl2a1, and Ptgs2) in the NF-kB pathway by qRT-PCR. Results: Relative to the control and HSYA groups, in the model group, we found 1111 DEGs that were up-/down-regulated, six of these genes were verified by qRT-PCR, including Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, and Creld2, indicated that these genes were obviously involved in the regulation of HSYA in ALI model. Membrane rafts, membrane microdomains, inflammatory response, regulation of cytokine production, monooxygenase activity, and iron ion binding were significantly enriched in GO analysis. KEGG analysis revealed that DEGs were primarily enriched for PPAR, retinol metabolism, NF-kB signaling pathways, etc. Last but not least, compared with the control group, the anti-O2 - content was substantially decreased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were considerably elevated in the model group. Compared with the model group, the anti-O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were substantially decreased in the HSYA group (p < 0.05). Conclusion: HSYA could improve liver function, inhibit oxidative stress and inflammation, and improve the degree of liver tissue damage. The RNA-Seq results further verified that HSYA has the typical characteristics of numerous targets and multiple pathway. Protecting the liver from damage by regulating the expression of Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, Creld2, and the PPAR, retinol metabolism, NF-kappa B signaling pathways. [ABSTRACT FROM AUTHOR]- content was substantially increased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were substantially decreased in the HSYA group (p < 0.05). Conclusion: HSYA could improve liver function, inhibit oxidative stress and inflammation, and improve the degree of liver tissue damage. The RNA-Seq results further verified that HSYA has the typical characteristics of numerous targets and multiple pathway. Protecting the liver from damage by regulating the expression of Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, Creld2, and the PPAR, retinol metabolism, NF-kappa B signaling pathways. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease with high morbidity and mortality, for which there is no available cure. Currently, it is generally believed that AD is a disease caused by multiple factors, such as amyloid-beta accumulation, tau protein hyperphosphorylation, oxidative stress, and inflammation. Multitarget prevention and treatment strategies for AD are recommended. Interestingly, naturally occurring dietary flavonoids, a class of polyphenols, have been reported to have multiple biological activities and anti-AD effects in several AD models owing to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties. In this review, we summarize and discuss the existing multiple pathogenic factors of AD. Moreover, we further elaborate on the biological activities of natural flavonoids and their potential mode of action and targets in managing AD by presenting a wide range of experimental evidence. The gathered data indicate that flavonoids can be regarded as prophylactics to slow the advancement of AD or avert its onset. Different flavonoids have different activities and varying levels of activity. Further, this review summarizes the structure–activity relationship of flavonoids based on the existing literature and can provide guidance on the design and selection of flavonoids as anti-AD drugs. [ABSTRACT FROM AUTHOR]

The rising demand for quality education is current issues in the New Normal with management, which has to undergo a radical transformation in uplifting it since COVID-19 has adverse effects on education. This offers a challenge to all levels of Higher Educational Institutions (HEIs) managers. This study attempted to find out the strategies HEIs Presidents in attaining targets and priorities. Specifically, their management styles, their targets and priorities, and other strategies employed to the realization of the institution's targets and priorities. The study adopted a descriptive-analytic approach of quantitative and qualitative methods of research. This methods was used to confirm, validate, or corroborate findings. Information was generated from the responses of the respondents using focus group discussions (FGD) and documentary analysis from the responses of presidents, middle-level managers, selected teaching and non-teaching personnel, or a total of 411 respondents of ten (10) HEIs in Region V. The groups of respondents differed in their strategies especially on the assessment of the management styles of the Presidents and the majority them used autocratic style; The Presidents common targets and priorities are higher in accreditation level, academic excellence, community services, and attainment of VMGOs; aside from management styles, delegation and/or empowerment, consultations, constant monitoring, and follow-ups as other strategies in achieving the institutional targets and priorities; The management style can contribute to the realization of the institutions' targets and priorities; There is still a need to evaluate and equip future educational managers with the necessary knowledge, skills, and attitudes to manage an educational institution. [ABSTRACT FROM AUTHOR]

Epigenetics has emerged as a prime focus area in the field of cancer research. Lysine-specific demethylase 1A (LSD1), the first discovered histone demethylase, is mainly responsible for catalysing demethylation of histone 3 lysine 4 (H3K4) and H3K9 to activate or inhibit gene transcription. LSD1 is abnormally expressed in various cancers and participates in cancer proliferation, apoptosis, metastasis, invasion, drug resistance and other processes by interacting with regulatory factors. Therefore, it may serve as a potential therapeutic target for cancer. This review summarises the major oncogenic mechanisms mediated by LSD1 and provides a reference for developing novel and efficient anticancer strategies targeting LSD1. [ABSTRACT FROM AUTHOR]

Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both – the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups. [ABSTRACT FROM AUTHOR]

Sputter deposition of multiprincipal element alloys (MPEAs) is a relatively new field of research with high functional potential. The multicomponent design space is immense and practically unexplored. An important obstacle for academic research of such sputtered films is the availability of single‐alloy targets and technical difficulties in using cosputtering of multiple metal targets or powder targets. This article focuses on the development of a simple powder metallurgy route, including cold uniaxial pressing of powder mixtures followed by pressureless sintering, for the preparation of targets made of two common base alloys forming simple solid solutions, i.e., FeNiCrCo and FeNiCrMn. In addition, targets of the former one containing 10 at% Al are also prepared. The sintered pellets are composed of randomly oriented crystallites with face‐centered cubic structures and an optimum chemical homogeneity. Oxide inclusions and residual porosity, inherent to consolidation and sintering of metal precursors, are observed and possible solutions to overcome these challenging problems are discussed. Nevertheless, encouraging results from preliminary deposition tests of FeNiCrCoAl0.4 using both direct current magnetron sputtering (DCMS) and high‐power impulse magnetron sputtering (HiPIMS) are presented. [ABSTRACT FROM AUTHOR]

Phosphorus (Pi) deficiency is an important factor affecting plant growth and development, and there are still some gaps in the understanding of the underlying molecular mechanism of the response to low-Pi stress in Pinus massoniana. Through an integrated high-throughput sequencing analysis of the miRNAome and transcriptome, a comprehensive study of the global miRNAs and mRNAs of P. massoniana seedling roots was conducted under Pi stress and Pi recovery. miRNAome analysis showed that 31 mRNAs (306 target genes) were differentially expressed in P. massoniana seedling roots under Pi stress and that 80 miRNAs (1091 target genes) were differentially expressed after Pi recovery. Comprehensive analyses of the miRNAome and transcriptome showed that miR399, miR11413-y, miR529-y, novel-m0045-3p and other miRNAs may participate in the response of P. massoniana to low-Pi stress by regulating target genes. Some genes and miRNAs were randomly selected for RT-qPCR validation, and the detected expression levels were basically consistent with the sequencing results. These results provide valuable information for a more comprehensive understanding of the low-Pi-tolerance adaptation mechanisms of P. massoniana as well as other conifers. [ABSTRACT FROM AUTHOR]

The growing incidence of neurodegenerative disorders in our populations is leading the research to identify potential biomarkers and targets for facilitating their early management and treatments. Biomarkers represent the crucial indicators of both physiological and pathological processes. Specific changes in molecular and cellular mechanisms of physiological processes result in biochemical alterations at systemic level, which can give us comprehensive information regarding the nature of any disease. In addition, any disease biomarker should be specific and reliable, able to consent of distinguishing the physiological condition of a tissue, organ, or system from disease, and be diverse among the various diseases, or subgroups or phenotypes of them. Accordingly, biomarkers can predict chances for diseases, facilitate their early diagnosis, and set guidelines for the development of new therapies for treating diseases and disease-making process. Here, we focus our attention on brain neurotrophic factor (BDNF)-tropomyosin receptor kinase (Trk) pathway, describing its multiple roles in the maintenance of central nervous system (CNS) health, as well as its implication in the pathogenesis of multiple sclerosis (MS). In addition, we also evidence the features of such pathway, which make of it a potential MS biomarker and therapeutic target. [ABSTRACT FROM AUTHOR]

Background: It is widely acknowledged that children with developmental language disorder (DLD) predominantly have difficulties in the areas of grammar and vocabulary, with preserved pragmatic skills. Consequently, few studies focus on the pragmatic skills of children with DLD, and there is a distinct lack of studies examining the effectiveness of pragmatic interventions. Aims: To carry out a systematic review of the literature on pragmatic interventions for children with DLD. Methods & Procedures: This systematic review was registered with PROSPERO (ID = CRD42017067239). A systematic search in seven databases yielded 1031 papers, of which 11 met our inclusion criteria. The included papers focused on interventions for children with DLD (mean = 3–18 years), enhancing oral language pragmatic skills, published between January 2006 and May 2020, and were based on a group‐study design such as randomized control trial or pre‐post‐testing. Study participants were monolingual speakers. The quality of papers was appraised using the Cochrane Risk of bias tool for randomized controlled trials. Outcomes & Results: There was a high degree of variability between the included intervention studies, especially regarding intensity, intervention targets and outcomes. The evidence suggested that pragmatic intervention is feasible for all models of delivery (individual, small and large group) and that interventions for pragmatic language are mostly focused on encouragement of conversation and narrative skills observed through parent–child interaction or shared book‐reading activities. Conclusions & Implications: This study highlights the importance of promoting and explicitly teaching pragmatic skills to children with DLD in structured interventions. A narrative synthesis of the included studies revealed that in addition to direct intervention, indirect intervention can also contribute to improving oral pragmatic skills of children with DLD. What this paper adds: What is already known on the subject?: An increasing number of studies have shown that difficulties in acquiring pragmatic language is not only present in children with autism. What this study adds to existing knowledge?: Interventions for pragmatic language in children with DLD are mostly focused on encouragement of conversation and narrative skills, very often through parent–child interaction or shared book‐reading activities. Interventions that target language pragmatic are feasible for all models of delivery (individual, small and large group). What are the potential or actual clinical implications of this work?: The efficacy of the existing studies varies, and it is difficult to give recommendations regarding the intensity and duration of the specific intervention. In addition to offering pragmatic intervention directly from a specialist, pragmatic interventions can also be carried out indirectly if the intervention is under the continuous supervision of a specialist. [ABSTRACT FROM AUTHOR]

The scientific work presents a concrete research carried out by the authors in order to implement some concepts of a technical and economic nature so that the readers can become aware of a certain way of presenting the problems regarding the durability development and sustainability of the road transport system. It proposes a study, carried out from a managerial point of view with engineering nuances, so that the concept of sustainable development in the addressed field can be viewed in a global context. The work as a whole is intended to be a theoretical approach with correlations in the field of engineering and management, essentially aiming at the sustainable development of the road transport. Finally, are presented some conclusions and further research directions in this way. [ABSTRACT FROM AUTHOR]

A herbal prescription in traditional Chinese medicine (TCM) has great complexity, with multiple components and multiple targets, making it extremely challenging to determine its bioactive compounds. Yinchenhao Tang (YCHT) has been extensively used for the treatment of jaundice disease. Although many studies have examined the efficacy and active ingredients of YCHT, there is still a lack of an in-depth systematic analysis of its effective components, mechanisms, and potential targets—especially one based on clinical patients. This study established an innovative strategy for discovering the potential targets and active compounds of YCHT based on an integrated clinical and animal experiment platform. The serum metabolic profiles and constituents of YCHT in vivo were determined by ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-ToF-MS)-based metabolomics combined with a serum pharmacochemistry method. Moreover, a compound–target–pathway network was constructed and analyzed by network pharmacology and ingenuity pathway analysis (IPA). We found that eight active components could modulate five key targets. These key targets were further verified by enzyme-linked immunosorbent assay (ELISA), which indicated that YCHT exerts therapeutic effects by targeting cholesterol 7α-hydroxylase (CYP7A1), multidrug-resistance-associated protein 2 (ABCC2), multidrug-resistance-associated protein 3 (ABCC3), uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and farnesoid X receptor (FXR), and by regulating metabolic pathways including primary bile acid biosynthesis, porphyrin and chlorophyll metabolism, and biliary secretion. Eight main effective compounds were discovered and correlated with the key targets and pathways. In this way, we demonstrate that this integrated strategy can be successfully applied for the effective discovery of the active compounds and therapeutic targets of an herbal prescription.

The Nuclear and Radiochemistry Group at Lawrence Livermore National Laboratory (LLNL) has developed a suite of diagnostics and techniques that can be used for astrophysics experiments at the National Ignition Facility (NIF). Capabilities have been developed to add material to the outside of NIF hohlraum assemblies as well as to the interior of NIF target capsules or the fill gas. The ability to place very small amounts of material close to the NIF target enables activation with very large, short-pulse neutron fluxes. The Solid Radiochemistry Diagnostic can be used to collect solid debris from a NIF shot within 2 h of the execution of a shot, and this can be analyzed for radioactive signatures with or without post-shot chemical processing. The Radiochemical Analysis of Gaseous Samples diagnostic system can be used to collect gaseous products produced during a NIF shot. Capsule doping and radiochemical analysis capabilities at NIF will be discussed. The application of these techniques to astrophysical measurements will be discussed as well as some preliminary results.

The Golgi-sialyltransferase ST6Gal1 (βgalactosidase α2,6 sialyltransferase 1), adds the negatively charged sugar, sialic acid, to the terminal galactose of N-glycosylated proteins. Upregulation of ST6Gal1 is observed in many malignancies, and a large body of research has determined that ST6Gal1-mediated α2,6 sialylation impacts cancer hallmarks. ST6Gal1 affects oncogenic behaviors including sustained proliferation, enhanced self-renewal, epithelial-to-mesenchymal transition, invasion, and chemoresistance. However, there are relatively few ST6GaL1 related signaling pathways that are well-established to mediate these biologies: greater delineation of specific targets and signaling mechanisms that are orchestrated by ST6Gal1 is needed. The aim of this review is to provide a summary of our current understanding of select oncogenic signaling pathways and targets affected by ST6Gal1.

The growing incidence of neurodegenerative disorders in our populations is leading the research to identify potential biomarkers and targets for facilitating their early management and treatments. Biomarkers represent the crucial indicators of both physiological and pathological processes. Specific changes in molecular and cellular mechanisms of physiological processes result in biochemical alterations at systemic level, which can give us comprehensive information regarding the nature of any disease. In addition, any disease biomarker should be specific and reliable, able to consent of distinguishing the physiological condition of a tissue, organ, or system from disease, and be diverse among the various diseases, or subgroups or phenotypes of them. Accordingly, biomarkers can predict chances for diseases, facilitate their early diagnosis, and set guidelines for the development of new therapies for treating diseases and disease-making process. Here, we focus our attention on brain neurotrophic factor (BDNF)–tropomyosin receptor kinase (Trk) pathway, describing its multiple roles in the maintenance of central nervous system (CNS) health, as well as its implication in the pathogenesis of multiple sclerosis (MS). In addition, we also evidence the features of such pathway, which make of it a potential MS biomarker and therapeutic target.

Tenbensel and colleagues identify that a target for emergency department (ED) stays in New Zealand met with gaming in response from local hospitals. The result is in line with studies in other jurisdictions. The enthusiasm for targets and tight performance measurement in some health systems reflects a lack of trust in professionals to do the right thing for altruistic reasons. However such measurement systems have failed to address this loss of trust and may, ironically, have worsened the situation. A more promising approach for both improving performance and restoring trust may depend upon collaboration and partnership between consumers, local providers, and central agencies in agreeing and tracking appropriate local responses to high level national goals rather than imposing tight, and potentially misleading measures from the centre.

Biodiversity conservation is at a crossroads. A number of trends are converging with the potential to transform our understanding of nature and how we conserve it. First, conservation policy makers are advocating increasingly ambitious global biodiversity targets, such as the agreement to protect 30% of terrestrial, inland water, and of coast and marine areas by 2030 made at the December 2022 Conference of the Parties to the Convention on Biological Diversity. Second, recognizing that governments do not have sufficient resources to reach these ambitious targets, they are turning to private finance and innovative financing mechanisms for help. Third, technological advances are enabling new ways of surveilling people, species, and ecosystems, measuring conservation outcomes, and targeting funding. Finally, long-standing concerns over the alienation of Indigenous Peoples and local communities from land and resources, and the colonial legacy of conservation, have been amplified by widespread contemporary awareness of racism more generally. Nascent critiques of conservation are incorporating but also moving beyond calls for participatory or rights-based approaches to conservation to push for the complete decolonization of conservation, alternatives to capitalist approaches to conservation, and other radical reforms. Collectively, these shifts are both reinforcing traditional conservation practice and power relationships and opening up space to expand understandings of collaborative management, environmental caretaking, and sustainable livelihoods and dramatically reform conservation. In this article, we draw on decades of research studying conservation governance in sites that range from villages to international meetings in order to examine this critical historical moment in conservation politics. We argue that conservation is at an ontological and epistemic moment during which the meaning of biodiversity, how to know it, how to conserve it, and who should conserve it is being fundamentally transformed. As transnational movements seek to transform our political economic system and to decolonize conservation, the consolidation of elite power among actors in finance, technology, governments, and big nongovernmental organizations abstracts conservation from localized contexts, drawing attention away from ensuring effective conservation on the ground and failing to challenge the root causes of biodiversity loss. Thus, continued vigilance is needed to keep equity, rights, justice, and livelihoods at the forefront of conservation.

The minimum distance models have undoubtedly represented a significant advance for the establishment of targets in Data Envelopment Analysis (DEA). These models may help in defining improvement plans that require the least overall effort from the inefficient Decision Making Units (DMUs). Despite the advantages that come with Closest Targets, in some cases unsatisfactory results may be given, since improvement plans, even in that context, differ considerably from the actual performances. This generally occurs because all the effort employed to reach the efficient DEA frontier is channeled into just a few variables. In certain contexts these exorbitant efforts in some inputs/outputs become unapproachable. In fact, proposals for sequential improvement plans can be found in the literature. It could happen that the sequential improvement plans continue to be so demanding in some variable that it would be difficult to achieve such targets. We propose an alternative approach where the improvement plans require similar efforts in the different variables that participate in the analysis. In the absence of information about the limitations of improvement in the different inputs/outputs, we consider that a plausible and conservative solution would be the one where an equitable redistribution of efforts would be possible. In this paper, we propose different approaches with the aim of reaching an impartial distribution of efforts to achieve optimal operating levels without neglecting the overall effort required. Therefore, we offer different alternatives for planning improvements directed towards DEA efficient targets, where the decision-maker can choose the one that best suits their circumstances. Moreover, and as something new in the benchmarking DEA context, we will study which properties satisfy the targets generated by the different models proposed. Finally, an empirical example used in the literature serves to illustrate the methodology proposed. [ABSTRACT FROM AUTHOR]

The plants of Amaryllidaceae family, such as Amaryllis belladonna L., have been used as herbal remedies for thousands of years to address various disorders, including diseases that might today be identified as cancer. The objective of this work was to evaluate the potential of three Amaryllidaceae alkaloids against four cancer cell lines. The alkaloids lycorine, 1- O -acetylcaranine, and montanine were evaluated in vitro against colon adenocarcinoma cell line (HCT-116) and breast carcinoma cell lines (MCF-7, MDAMB231, and Hs578T). Computational experiments (target prediction and molecular docking) were conducted to gain a deeper comprehension of possible interactions between these alkaloids and potential targets associated with these tumor cells. Montanine presented the best results against HCT-116, MDAMB231, and Hs578T cell lines, while lycorine was the most active against MCF-7. In alignment with the target prediction outcomes and existing literature, four potential targets were chosen for the molecular docking analysis: CDK8, EGFR, ER-alpha, and dCK. The docking scores revealed two potential targets for the alkaloids with scores similar to co-crystallized inhibitors and substrates: CDK8 and dCK. A visual analysis of the optimal docked configurations indicates that the alkaloids may interact with some key residues in contrast to the other docked compounds. This observation implies their potential to bind effectively to both targets. In vitro and in silico results corroborate with data literature suggesting the Amaryllidaceae alkaloids as interesting molecules with antitumoral properties, especially montanine, which showed the best in vitro results against colorectal and breast carcinoma. More studies are necessary to confirm the targets and pharmaceutical potential of montanine against these cancer cell lines. [Display omitted] [ABSTRACT FROM AUTHOR]

• Vital signaling pathways for pancreatic cancer (PC) growth, metastasis, and resistance are reviewed. • Interplay of selected signaling pathways in PC progression is discussed. • Small molecular inhibitors, including their advantages and challenges are explored. • Diverse small molecular inhibitors in current PC clinical trials are assessed. Pancreatic cancer (PC), a disease with high heterogeneity and a dense stromal microenvironment, presents significant challenges and a bleak prognosis. Recent breakthroughs have illuminated the crucial interplay among RAS, epidermal growth factor receptor (EGFR), and hedgehog pathways in PC progression. Small molecular inhibitors have emerged as a potential solution with their advantages of oral administration and the ability to target intracellular and extracellular sites effectively. However, despite the US FDA approving over 100 small-molecule targeted antitumor drugs, challenges such as low response rates and drug resistance persist. This review delves into the possibility of using small molecules to treat persistent or spreading PC, highlighting the challenges and the urgent need for a diverse selection of inhibitors to develop more effective treatment strategies. This review unveils groundbreaking strategies for using small molecules to treat pancreatic cancer (PC). It explores innovative approaches to overcome the challenges posed by the dense stroma, offering the potential for enhanced drug delivery and improved patient outcomes. [ABSTRACT FROM AUTHOR]

As an alternative to one drug-one target approaches, systems biology methods can provide a deeper insight into the holistic effects of drugs. Network-based approaches are tools of systems biology, that can represent valuable methods for visualizing and analysing drug-protein and protein–protein interactions. In this study, a KNIME workflow is presented which connects drugs to causal target proteins and target proteins to their causal protein interactors. With the collected data, networks can be constructed for visualizing and interpreting the connections. The last part of the workflow provides a topological enrichment test for identifying relevant pathways and processes connected to the submitted data. The workflow is based on openly available databases and their web services. As a case study, compounds of DILIRank were analysed. DILIRank is the benchmark dataset for Drug-Induced Liver Injury by the FDA, where compounds are categorized by their likeliness of causing DILI. The study includes the drugs that are most likely to cause DILI ("mostDILI") and the ones that are not likely to cause DILI ("noDILI"). After selecting the compounds of interest, down- and upregulated proteins connected to the mostDILI group were identified; furthermore, a liver-specific subset of those was created. The downregulated sub-list had considerably more entries, therefore, network and causal interactome were constructed and topological pathway enrichment analysis was performed with this list. The workflow identified proteins such as Prostaglandin G7H synthase 1 and UDP-glucuronosyltransferase 1A9 as key participants in the potential toxic events disclosing the possible mode of action. The topological network analysis resulted in pathways such as recycling of bile acids and salts and glucuronidation, indicating their involvement in DILI. The KNIME pipeline was built to support target and network-based approaches to analyse any sets of drug data and identify their target proteins, mode of actions and processes they are involved in. The fragments of the pipeline can be used separately or can be combined as required. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis is one of the most important processes of cancer deterioration via nurturing an immunosuppressive tumor environment (TME). Targeting tumor angiogenesis has been widely accepted as a cancer intervention approach, which is also synergistically associated with immune therapy. However, drug resistance is the biggest challenge of anti-angiogenesis therapy, which affects the outcomes of anti-angiogeneic agents, and even combined with immunotherapy. Here, emerging targets and representative candidate molecules from ethnopharmacology (including traditional Chinese medicine, TCM) have been focused, and they have been proved to regulate tumor angiogenesis. Further investigations on derivatives and delivery systems of these molecules will provide a comprehensive landscape in preclinical studies. More importantly, the molecule library of ethnopharmacology meets the viability for targeting angiogenesis and TME simultaneously, which is attributed to the pleiotropy of pro-angiogenic factors (such as VEGF) toward cancer cells, endothelial cells, and immune cells. We primarily shed light on the potentiality of ethnopharmacology against tumor angiogenesis, particularly TCM. More research studies concerning the crosstalk between angiogenesis and TME remodeling from the perspective of botanical medicine are awaited. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a class of non-coding short RNAs with ∼22 nts in length, which play important roles in the regulation of numerous biological processes in animals. In this study, two small RNA libraries from fatty (S01) and normal livers (S02) from Holstein Dairy Cow (HDC) were sequenced through deep sequencing. A total of 12,964,411 and 15,426,289 clean reads were obtained, representing 370 known and 182 novel miRNAs, respectively. The characterization, expression pattern, potential functions and target genes of these miRNAs were investigated. Analysis identified 66 upregulated and seven downregulated differentially expressed miRNAs (DIE-miRNAs). To verify the sequencing results, 10 DIE-miRNAs were selected for qRT-PCR, and the results were confirmed to be consistent with the miRNA sequencing. In addition, a total of 5,578 targets of the 73 DIE-miRNAs were predicted. GO analysis revealed that DIE-miRNAs targets are associated with cellular process, cell part and molecular transducer activity. KEGG pathway analysis showed that Arrhythmogenic right ventricular cardiomyopathy, Axon guidance, Ether lipid metabolism and Cocaine addiction were closely associated with liver metabolism. These findings will provide valuable information for further functional verification of miRNAs between normal and fatty liver, as might exploit new attractive miRNAs biomarkers for diseases detection in HDC. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC) transplantation is the only curative therapy for many diseases. HSCs from umbilical cord blood (UCB) source have many advantages over from bone marrow. However, limited HSC dose in a single CB unit restrict its widespread use. Over the past two decades, ex vivo HSC expansion with small molecules has been an effective approach for obtaining adequate HSCs. Till now, several small-molecule compounds have entered the phase I/II trials, showing safe and favorable pharmacological profiles. As HSC expansion has become a hot topic over recent years, many newly identified small molecules along with novel biological mechanisms for HSC expansion would help solve this challenging issue. Here, we will give an overview of HSC biology, discovery and medicinal chemistry development of small molecules, natural products targeting for HSC expansion, and their recent clinical progresses, as well as potential protein targets for HSC expansion. Hematopoietic stem cell (HSC) could be ex vivo expanded by small molecules, which is a safe strategy for obtaining adequate HSCs, bringing hope for serious hematologic diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a common neurological disorder associated with high disability rates and mortality rates. At present, recombinant tissue plasminogen activator (r-tPA) is the only US(FDA)-approved drug for IS. However, due to the narrow therapeutic window and risk of intracerebral hemorrhage, r-tPA is currently used in less than 5% of stroke patients. Natural compounds have been widely used in the treatment of IS in China and have a wide range of therapeutic effects on IS by regulating multiple targets and signaling pathways. The keywords "ischemia stroke, traditional Chinese Medicine, Chinese herbal medicine, natural compounds" were used to search the relevant literature in PubMed and other databases over the past five years. The results showed that JAK/STAT, NF-κB, MAPK, Notch, Nrf2, and PI3K/Akt are the key pathways, and SIRT1, MMP9, TLR4, HIF-α are the key targets for the natural compounds from traditional Chinese medicine in treating IS. This study aims to update and summarize the signaling pathways and targets of natural compounds in the treatment of IS, and provide a base of information for the future development of effective treatments for IS. [ABSTRACT FROM AUTHOR]

Simple Summary: The One Health concept to toxoplasmosis highlights that the health of humans is closely related to the health of animals and our common environment. Toxoplasmosis outcomes might be severe and fatal in patients with immunodeficiency, diabetes, and pregnant women and infants. Consequently, the development of effective vaccine and diagnostic strategies is urgent for the elimination of this disease. Proteomics analysis has allowed the identification of key proteins that can be utilized in the development of novel disease diagnostics and vaccines. This work presents relevant proteins found in the proteome of the life cycle-specific stages of Toxoplasma parasites. In fact, it brings together the main functionality key proteins from Toxoplasma parasites coming from proteomic approaches that are most likely to be useful in improving the disease management, and critically proposes innovative directions to finally develop promising vaccines and diagnostics tools. Toxoplasma gondii is a pathogenic protozoan parasite that infects the nucleated cells of warm-blooded hosts leading to an infectious zoonotic disease known as toxoplasmosis. The infection outcomes might be severe and fatal in patients with immunodeficiency, diabetes, and pregnant women and infants. The One Health approach to toxoplasmosis highlights that the health of humans is closely related to the health of animals and our common environment. The presence of drug resistance and side effects, the further improvement of sensitivity and specificity of serodiagnostic tools and the potentiality of vaccine candidates to induce the host immune response are considered as justifiable reasons for the identification of novel targets for the better management of toxoplasmosis. Thus, the identification of new critical proteins in the proteome of Toxoplasma parasites can also be helpful in designing and test more effective drugs, vaccines, and diagnostic tools. Accordingly, in this study we present important proteins found in the proteome of the life cycle-specific stages of Toxoplasma parasites that are potential diagnostic or vaccine candidates. The current study might help to understand the complexity of these parasites and provide a possible source of strategies and biomolecules that can be further evaluated in the pathobiology of Toxoplasma parasites and for diagnostics and vaccine trials against this disease. [ABSTRACT FROM AUTHOR]