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Background: The ability of lignocellulose degradation for filamentous fungi is always attributed to their efficient CAZymes system with broader applications in bioenergy development. ADP-ribosylation factor GTPase-activating proteins (Arf-GAPs), pivotal in fungal morphogenesis, lack comprehensive studies on their regulatory mechanisms in lignocellulose utilization. Results: Here, the orthologs (TgGlo3 and TgGcs1) of Arf-GAPs in S. cerevisiae were characterized in Trichoderma guizhouense NJAU4742. The results indicated that overexpression of Tggcs1 (OE-Tggcs1) enhanced the lignocellulose utilization, whereas increased expression of Tgglo3 (OE-Tgglo3) elicited antithetical responses. On the fourth day of fermentation with rice straw as the sole carbon source, the activities of endoglucanase, cellobiohydrolase, xylanase, and filter paper of the wild-type strain (WT) reached 8.20 U mL−1, 4.42 U mL−1, 14.10 U mL−1, and 3.56 U mL−1, respectively. Compared to WT, the four enzymes activities of OE-Tggcs1 increased by 7.93%, 6.11%, 9.08%, and 12.92%, respectively, while those decreased to varying degrees of OE-Tgglo3. During the nutritional growth, OE-Tgglo3 resulted in the hyphal morphology characterized by sparsity and constriction, while OE-Tggcs1 led to a notable increase in vacuole volume. In addition, OE-Tggcs1 exhibited higher transport efficiencies for glucose and cellobiose thereby sustaining robust cellular metabolic rates. Further investigations revealed that Tgglo3 and Tggcs1 differentially regulated the transcription level of a dynamin-like GTPase gene (Tggtp), eliciting distinct redox states and apoptotic reaction, thus orchestrating the cellular response to lignocellulose utilization. Conclusions: Overall, these findings underscored the significance of TgArf-GAPs as pivotal regulators in lignocellulose utilization and provided initial insights into their differential modulation of downstream targets. [ABSTRACT FROM AUTHOR]

In the literature, macroscopic fundamental diagram (MFD)- or network fundamental diagram-based perimeter control approaches have been demonstrated as cost-effective means to improve traffic efficiency for urban traffic networks. This article proposes a new perimeter control approach, which extends previous approaches in two aspects. First, the proposed approach optimizes the allocation of perimeter metered flow considering the heterogeneity of network traffic flow distribution, which is inversely related to network production. Second, queue management is considered by the proposed approach so as to prevent queue spillback induced by perimeter control. The proposed control approach is well advanced for field application using only loop detector data. It adopts a hierarchical framework, where the upper level controller determines the total flow entering the protected network through perimeter links based on an MFD-based feedback regulator, while the lower level controller optimizes the distribution of the total metered flow among the perimeter links based on real-time network heterogeneity and perimeter queues. The proposed approach is tested and compared with state-of-the-art perimeter control approaches, using a real traffic network developed in the microscopic simulation software VISSIM. Results demonstrate that the proposed approach significantly reduces the overall network delay. Moreover, it outperforms other perimeter control approaches by maintaining low network heterogeneity within the protected network and preventing (or delaying) queue spillback at perimeter links. [ABSTRACT FROM AUTHOR]

Background: Candida albicans is an opportunistic pathobiont that manifests as candidiasis. Drug-resistant biofilms hinder current treatment of candidiasis. The morphological control of filamentous growth and biofilm formation is vital for the pathogenicity of C. albicans. This study aimed to investigate the antifungal activity of magnetic iron oxide nanoparticles (nano-Fe3 O4 ) against C. albicans, their ability to inhibit pre-formed biofilms, and to examine the expression levels of negative regulators, transcriptional repressors thymidine uptake 1 (TUP1), the negative transcriptional regulator of glucose repressed genes (NRG1), and target of rapamycin (TOR1) in C. albicans pre-formed biofilms after treatment with nano-Fe3 O4 . Methods: This study examines the antifungal activity of nano-Fe3 O4 against C. albicans, its ability to inhibit pre-formed biofilms, and investigates the expression levels of negative regulators, TUP1, NRG1, and TOR1 in C. albicans pre-formed biofilms after treatment with nano-Fe3 O4 . Results: Nano-Fe3 O4 at concentrations of 2× minimum inhibitory concentration (MIC), 1× MIC, and ½× MIC showed significant inhibitory effects on C. albicans pre-formed biofilm formation by 2,3-bis (2-methoxy-4-nitro-5 sulfophenyl)-5-[(phenylamino) carbonyl])-2H-tetrazolium hydroxide (XTT), crystal violet staining and light field microscopy with a MIC of 50 μg/mL. Gene expression profiling showed that nano-Fe3 O4 upregulates targets TUP1, NRG1, and TOR1 in C. albicans pre-formed biofilms. Conclusion: Our results suggest that nano-Fe3 O4 diminishes pre-formed biofilms and may subsequently reduce the pathogenicity of C. albicans, which can be responsible for biofilm-associated infections. TUP1, NRG1, and TOR1 may be possible molecular targets in C. albicans pre-formed biofilms after treatment with nano-Fe3 O4.

Regulators are responsible for overseeing organizations. Organizational behavior should be in line with laws and regulations. Therefore, regulators aim to influence behavior of regulatees, such as compliance (i.e., following rules and regulations), but also ethical behavior (i.e., doing the right thing, irrespective of the rules and regulations). However, little empirical evidence exists on the effectiveness of different types of regulatory actions. Also, most evidence focuses on compliance, despite an increasing demand for ethical behavior of organizations. A literature review was conducted to collect, summarize, and analyze empirical evidence on how regulators can stimulate regulatees’ compliant and ethical behavior. This paper uniquely covers multiple types of regulatory actions and also multiple types of underlying factors. To illustrate this, a novel framework was introduced, in which it was proposed that regulatory actions influence compliant and ethical behavior through regulatees’ capability, opportunity, and motivation. Combining the findings of 35 articles showed that studies on ‘deterrence’ and ‘cooperation’ demonstrated mixed results regarding their effectiveness, whereas ‘inspections’ were found more effective. Notably, psychological capability, social opportunity, and reflective motivation were more effective in stimulating behavior than physical capability, physical opportunity, and automatic motivation. A reflection on how regulators can use these unique insights to increase their effectiveness is given, as well as an aim to develop regulatory theory further.

Abstract Background The ability of lignocellulose degradation for filamentous fungi is always attributed to their efficient CAZymes system with broader applications in bioenergy development. ADP-ribosylation factor GTPase-activating proteins (Arf-GAPs), pivotal in fungal morphogenesis, lack comprehensive studies on their regulatory mechanisms in lignocellulose utilization. Results Here, the orthologs (TgGlo3 and TgGcs1) of Arf-GAPs in S. cerevisiae were characterized in Trichoderma guizhouense NJAU4742. The results indicated that overexpression of Tggcs1 (OE-Tggcs1) enhanced the lignocellulose utilization, whereas increased expression of Tgglo3 (OE-Tgglo3) elicited antithetical responses. On the fourth day of fermentation with rice straw as the sole carbon source, the activities of endoglucanase, cellobiohydrolase, xylanase, and filter paper of the wild-type strain (WT) reached 8.20 U mL−1, 4.42 U mL−1, 14.10 U mL−1, and 3.56 U mL−1, respectively. Compared to WT, the four enzymes activities of OE-Tggcs1 increased by 7.93%, 6.11%, 9.08%, and 12.92%, respectively, while those decreased to varying degrees of OE-Tgglo3. During the nutritional growth, OE-Tgglo3 resulted in the hyphal morphology characterized by sparsity and constriction, while OE-Tggcs1 led to a notable increase in vacuole volume. In addition, OE-Tggcs1 exhibited higher transport efficiencies for glucose and cellobiose thereby sustaining robust cellular metabolic rates. Further investigations revealed that Tgglo3 and Tggcs1 differentially regulated the transcription level of a dynamin-like GTPase gene (Tggtp), eliciting distinct redox states and apoptotic reaction, thus orchestrating the cellular response to lignocellulose utilization. Conclusions Overall, these findings underscored the significance of TgArf-GAPs as pivotal regulators in lignocellulose utilization and provided initial insights into their differential modulation of downstream targets.

This study investigates the effect of Environmental, Social, and Governance (ESG) scores on bank performance in five Association of Southeast Asian Nations (ASEAN) countries: Indonesia, Malaysia, Singapore, Thailand, and the Philippines. This study aims to examine the effect of ESG scores on bank financial performance and investigate whether the influence of bank ownership can strengthen both. This study uses a sample of 26 banks in 5-ASEAN countries during 2016–2021. This amount is the result of data sorting conducted on 86 banks by adjusting to the research sample criteria. Using multiple linear regression analysis, this study shows that ESG scores have a significant positive effect on bank financial performance as measured by Return on Assets (ROA), Return on Equity (ROE), and Price to Book Value (PBV). Furthermore, this study found that the positive impact of ESG scores on bank performance is stronger for state-owned banks compared to private banks. However, bank ownership does not affect the relationship between ESG scores and ROA. These findings suggest that law enforcement by the government through regulators plays an important role in encouraging banks to view ESG as a driving value to improve their performance.

Phosphate ore is the dominating natural resource for the production of fertilizers and phosphorous chemical products. Flotation is the most widely employed technique to enrich apatite and remove the impurities for the separation of the phosphate ore. The flotation reagents play an important role in this efficient separation of phosphate ores. In the last few decades, great progress has been achieved in the flotation reagents for phosphate ores. However, a critical review on this theme has rarely been reported in recent years. Thus, the goal of this paper is to critically analyze the published literature on the flotation reagents for phosphate ores, mainly ranging from 2010 to 2024, including the regulators, depressors, collectors, and frothers. Additionally, the interaction mechanisms between the reagents and mineral surfaces were analyzed. It is concluded that sulfuric acids and its derivatives play a leading role in the depression of phosphate minerals. Highly selective biobased depressants have become potential carbonate inhibitors. Additionally, the derivatization and synthesis of multi-functional compounds and identifying the biobased frothers are the main development trends of collectors and frothers. Overall, a high-quality concentrate with a 31.05% grade and 98.21% recovery at pH 5 was achieved using lecithin as an ecofriendly amphoteric collector and sulfuric acid as the depressor when the feed contained 24.49% P2O5, which was superior to other flotation indexes of similar phosphate ores. This review will help researchers to document knowledge gaps and provide a reference for the efficient and green beneficiation of phosphate ores in the future. [ABSTRACT FROM AUTHOR]

To date the mainstreaming of equality and human rights law into public sector organisations has been underwhelming with the implementation of these norms being ad hoc and inconsistent. Existing research on factors that influence implementation has been either too general or too disjointed. This article has two aims to advance research on the implementation of equality and human rights: (i) to outline factors that influence the implementation of these norms and (ii) provide a more settled foundations for future research on equality and human rights implementation. It does this through interviews, undertaken in 2018–2019, with individuals responsible for leading the implementation of equality and human rights law within public sector organisations (specifically regulators, inspectorates and ombudsmen) in England and Wales. On the basis of this, the article makes suggestions for how the implementation of equality and human rights can be advanced further through changes to the regulatory environment. [ABSTRACT FROM AUTHOR]

For centuries, Gram‐negative pathogens have infected the human population and been responsible for numerous diseases in animals and plants. Despite advancements in therapeutics, Gram‐negative pathogens continue to evolve, with some having developed multi‐drug resistant phenotypes. For the successful control of infections caused by these bacteria, we need to widen our understanding of the mechanisms of host–pathogen interactions. Gram‐negative pathogens utilise an array of effector proteins to hijack the host system to survive within the host environment. These proteins are secreted into the host system via various secretion systems, including the integral Type III secretion system (T3SS). The T3SS spans two bacterial membranes and one host membrane to deliver effector proteins (virulence factors) into the host cell. This multifaceted process has multiple layers of regulation and various checkpoints. In this review, we highlight the multiple strategies adopted by these pathogens to regulate or maintain virulence via the T3SS, encompassing the regulation of small molecules to sense and communicate with the host system, as well as master regulators, gatekeepers, chaperones, and other effectors that recognise successful host contact. Further, we discuss the regulatory links between the T3SS and other systems, like flagella and metabolic pathways including the tricarboxylic acid (TCA) cycle, anaerobic metabolism, and stringent cell response. [ABSTRACT FROM AUTHOR]

Background: The Oryza sativa cultivar Kitaake is a promising new model rice for research due to its short life cycle (9 weeks), adaptability to greenhouse conditions, readily accepts foreign genes, and its complete genome sequence is accessible, providing a valuable blueprint for researchers. However, its major RNA interference (RNAi) gene families (DCLs, AGOs, RDRs) have not yet been studied. These gene families influence target-specific protein-coding gene expression and biotic and abiotic stresses, regulating plant growth and development. Objectives: This study aims to identify and characterize RNAi gene families from the Kitaake rice. Methods: This study has been designed by in-silico analysis to explore major RNAi genes highlighting their molecular functions, phylogenetic groups, regulatory factors, and other vital characteristics of Kitaake rice corresponding to OsRNAi genes. Results: This study has identified 10 DCLs, 21 AGOs, and 7 RDRs as major RNAi proteins of Kitaake rice corresponding to OsRNAi by BLASTP search. Domain analysis has been revealed the RNase III, PAZ, and Piwi domains are related to gene silencing processes. According to synteny study, Kitaake and rice have the most homology in 33 RNAi gene pairs, suggesting they share a chromosomal order and similar functions. The majority of OsKRNAi proteins have been located in the nucleus and chloroplast, which are related to gene silencing. Gene silencing and ribonuclease III activity are key terms from gene ontology (GO) analysis, which is part of the gene silencing process. Gene regulatory analysis has identified some important transcription factors including ERE, which participates in DNA binding and microRNAs (miRNAs) including 'Osa-MIR168' improves rice resistance to blast disease. The investigation of cis-acting regulatory elements in OsKRNAi genes has shown various crucial components, including MBS, W-box, LTR, ABRE, ARE that are linked with the different stresses. Genes (such as OsKAGO1d) were found to be overexpressed in target of rapamycin (TOR), increasing susceptibility to pathogens. Conclusion: The findings of this study may be useful resources for further experimental investigation on the improvement of Kitaake rice crop against different stresses.

Cells must rapidly adapt to changes in nutrient conditions through responsive signalling cascades to maintain homeostasis. One of these adaptive pathways results in the post-translational modification of proteins by O-GlcNAc. O-GlcNAc modifies thousands of nuclear and cytoplasmic proteins in response to nutrient availability through the hexosamine biosynthetic pathway. O-GlcNAc is highly dynamic and can be added and removed from proteins multiple times throughout their life cycle, setting it up to be an ideal regulator of cellular processes in response to metabolic changes. Here, we describe the link between cellular metabolism and O-GlcNAc, and we explore O-GlcNAc’s role in regulating cellular processes in response to nutrient levels. Specifically, we discuss the mechanisms of elevated O-GlcNAc levels in contributing to diabetes and cancer, as well as the role of decreased O-GlcNAc levels in neurodegeneration. These studies form a foundational understanding of aberrant O-GlcNAc in human disease and provide an opportunity to further improve disease identification and treatment.

Abstract Regulatory marketing authorisation is not enough to ensure patient access to new medicinal products. Health Technology Assessment bodies may require data on effectiveness, relative effectiveness, and cost-effectiveness. Healthcare systems may require data on clinical utility, savings, and budget impact. Furthermore, the exact requirements of these bodies vary country by country and sometimes even region to region, resulting in a patchwork of different data requirements to achieve effective, reimbursed patient access to new therapies. In addition, clinicians require data to make informed clinical management decisions. This requirement is of key importance in rare diseases where there is often limited data and clinical experience at the time of regulatory approval. This paper describes an innovative initiative that is called Project SATURN: Systematic Accumulation of Treatment practices and Utilization, Real world evidence, and Natural history data for the rare disease Osteogenesis Imperfecta. The objective of this project is to generate a common core dataset by utilising existing data sources to meet the needs of the various stakeholders and avoiding fragmentation through multiple approaches (e.g., a series of individual national requests/approaches, and unconnected with the regulators’ potential requirements). It is expected that such an approach will reduce the time for patient access to life-changing medications. Whilst Project SATURN applies to Osteogenesis Imperfecta, it is anticipated that the principles could also be applied to other rare diseases and reduce the time for patient access to new medications.

The integration of digital technologies in the financial industry holds significant promise for enhancing the effectiveness and availability of financial services. However, it is also confronted with various financial and organisational limitations that must be resolved. The objective of this study is to examine the financial and organisational limitations that occur during the implementation of digital technologies in financial management. In order to accomplish this objective, various techniques such as analysis, synthesis, generalisation, systematisation, and statistical methods were employed. The study revealed that the implementation of digital technologies in the financial sector encounters substantial obstacles and constraints. An inherent challenge arises from the incongruity between emerging digital technologies and antiquated traditional management models, resulting in deficiencies and vulnerabilities in organisational management. The study emphasises the significance of organisations modifying their management models in order to achieve optimal utilisation of digital tools. The findings also demonstrate the significance of organisational elements such as culture, competencies, digital resources, senior management support, and organisational structure in shaping choices to embrace and execute digital technologies. Thus, the study helps to solve current issues related to the introduction of digital technologies in the financial sector and contributes to improving its efficiency and sustainability. The practical significance of the study is to increase the understanding of financial and organisational constraints that arise during the introduction of digital technologies in financial management and to contribute to the development of more effective approaches to digital financial management

The blood-testis barrier (BTB) is formed adjacent to the seminiferous basement membrane. It is a distinct ultrastructure, partitioning testicular seminiferous epithelium into apical (adluminal) and basal compartments. It plays a vital role in developing and maturing spermatocytes into spermatozoa via reorganizing its structure. This enables the transportation of preleptotene spermatocytes across the BTB, from basal to adluminal compartments in the seminiferous tubules. Several bioactive peptides and biomolecules secreted by testicular cells regulate the BTB function and support spermatogenesis. These peptides activate various downstream signaling proteins and can also be the target themself, which could improve the diffusion of drugs across the BTB. The gap junction (GJ) and its coexisting junctions at the BTB maintain the immunological barrier integrity and can be the "gateway" during spermatocyte transition. These junctions are the possible route for toxicant entry, causing male reproductive dysfunction. Herein, we summarize the detailed mechanism of all the regulators playing an essential role in the maintenance of the BTB, which will help researchers to understand and find targets for drug delivery inside the testis. [ABSTRACT FROM AUTHOR]

Regulatory marketing authorisation is not enough to ensure patient access to new medicinal products. Health Technology Assessment bodies may require data on effectiveness, relative effectiveness, and cost-effectiveness. Healthcare systems may require data on clinical utility, savings, and budget impact. Furthermore, the exact requirements of these bodies vary country by country and sometimes even region to region, resulting in a patchwork of different data requirements to achieve effective, reimbursed patient access to new therapies. In addition, clinicians require data to make informed clinical management decisions. This requirement is of key importance in rare diseases where there is often limited data and clinical experience at the time of regulatory approval. This paper describes an innovative initiative that is called Project SATURN: Systematic Accumulation of Treatment practices and Utilization, Real world evidence, and Natural history data for the rare disease Osteogenesis Imperfecta. The objective of this project is to generate a common core dataset by utilising existing data sources to meet the needs of the various stakeholders and avoiding fragmentation through multiple approaches (e.g., a series of individual national requests/approaches, and unconnected with the regulators' potential requirements). It is expected that such an approach will reduce the time for patient access to life-changing medications. Whilst Project SATURN applies to Osteogenesis Imperfecta, it is anticipated that the principles could also be applied to other rare diseases and reduce the time for patient access to new medications. [ABSTRACT FROM AUTHOR]

Background: The crosstalk between genomic alterations and metabolic dysregulation in bladder cancer is largely unknown. A deep understanding of the interactions between cancer drivers and cancer metabolic changes will provide novel opportunities for targeted therapeutic strategies. Methods: Three primary bladder cancer specimens with paired normal tissues or blood samples were subjected to whole-exome sequencing, DNA methylation array and whole-transcriptome sequencing by next-generation sequencing technology. We applied the methods to multi-omics data combining the Cancer Genome Atlas (TCGA) bladder cancer samples, including somatic mutation, DNA copy number, DNA methylation and gene expression profile for validation. Results: We identified 34 mutated cancer driver genes in bladder cancer. KDM6A was the most significantly mutated cancer driver gene. Metabolic pathways were enriched in both differentially methylated regions (DMRs) and differentially expressed genes. Twenty-nine DMRs in the TSS200 region were highly correlated with the upregulation of gene expression, and 24 DMRs in the genome were highly correlated with the downregulation of gene expression. A total of 201 genes had highly correlated DNA methylation and expression. Thirty-four genes, including the known metabolic genes CXXC5, PRR5, ABCB8 and BAHD1, were further validated in the TCGA cohort. Multi-omics alterations identified two new candidate driver genes, WIPI2 and GFM2, that warrant future studies. Conclusions: This study provides a comprehensive and systematic analysis, focusing on identifying key regulatory factors that may lead to cancer metabolic heterogeneity. Further understanding and verification of the cancer genes driving metabolic reprogramming and their role in the progression of bladder cancer will help to identify new therapeutic targets. [ABSTRACT FROM AUTHOR]

It is a period of substantial change for the ever-growing cross-border payments space, with numerous new trends emerging, along with new technologies, new market entrants and participants, and unprecedented regulatory collaboration around the G20 Roadmap for Enhancing Cross-border Payments. This paper discusses the drivers for the changes underway, explains the continued context of elevated compliance risks in the cross-border payments space, and calls for the entire ecosystem, including banks, service providers, new entrants and regulators, to focus on building and fostering a strong culture of compliance. This imperative is even more critical for new entrants who may not be subject to the same level of stringency within their current applicable regulatory regime and who may believe that this gives them more flexibility than other service providers. Building and fostering such a culture of compliance will have numerous benefits, including the reduction of crime. This paper argues that the universal commitment to such a culture of compliance among all parties involved in the ecosystem must begin with the adoption of an inquisitive compliance mindset, that is, a mindset that acknowledges the critical importance of compliance requirements, the rationale for their adoption and a willingness to ask questions and get detailed responses on an ongoing basis. Such a dynamic understanding would facilitate any future changes required by evolving regulations. [ABSTRACT FROM AUTHOR]

Abstract Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. In the process of CKD, with the gradual loss of renal function, the incidence of various life-threatening complications, such as cardiovascular diseases, cerebrovascular accident, infection and stroke, is also increasing rapidly. Unfortunately, existing treatments exhibit limited ability to halt the progression of kidney injury in CKD, emphasizing the urgent need to delve into the precise molecular mechanisms governing the occurrence and development of CKD while identifying novel therapeutic targets. Renal fibrosis, a typical pathological feature of CKD, plays a pivotal role in disrupting normal renal structures and the loss of renal function. Ferroptosis is a recently discovered iron-dependent form of cell death characterized by lipid peroxide accumulation. Ferroptosis has emerged as a potential key player in various diseases and the initiation of organ fibrosis. Substantial evidence suggests that ferroptosis may significantly contribute to the intricate interplay between CKD and its progression. This review comprehensively outlines the intricate relationship between CKD and ferroptosis in terms of iron metabolism and lipid peroxidation, and discusses the current landscape of pharmacological research on ferroptosis, shedding light on promising avenues for intervention. It further illustrates recent breakthroughs in ferroptosis-related regulatory mechanisms implicated in the progression of CKD, thereby providing new insights for CKD treatment. Video Abstract

Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. In the process of CKD, with the gradual loss of renal function, the incidence of various life-threatening complications, such as cardiovascular diseases, cerebrovascular accident, infection and stroke, is also increasing rapidly. Unfortunately, existing treatments exhibit limited ability to halt the progression of kidney injury in CKD, emphasizing the urgent need to delve into the precise molecular mechanisms governing the occurrence and development of CKD while identifying novel therapeutic targets. Renal fibrosis, a typical pathological feature of CKD, plays a pivotal role in disrupting normal renal structures and the loss of renal function. Ferroptosis is a recently discovered iron-dependent form of cell death characterized by lipid peroxide accumulation. Ferroptosis has emerged as a potential key player in various diseases and the initiation of organ fibrosis. Substantial evidence suggests that ferroptosis may significantly contribute to the intricate interplay between CKD and its progression. This review comprehensively outlines the intricate relationship between CKD and ferroptosis in terms of iron metabolism and lipid peroxidation, and discusses the current landscape of pharmacological research on ferroptosis, shedding light on promising avenues for intervention. It further illustrates recent breakthroughs in ferroptosis-related regulatory mechanisms implicated in the progression of CKD, thereby providing new insights for CKD treatment. BfoF46qaBLtgVmJXm1oAqY Video Abstract [ABSTRACT FROM AUTHOR]

Most biosynthetic gene clusters (BGCs) of Actinobacteria are either silent or expressed less than the detectable level. The non-genetic approaches including biological interactions, chemical agents, and physical stresses that can be used to awaken silenced pathways are compared in this paper. These non-genetic induction strategies often need screening approaches, including one strain many compounds (OSMAC), reporter-guided mutant selection, and high throughput elicitor screening (HiTES) have been developed. Different types of genetic manipulations applied in the induction of cryptic BGCs of Actinobacteria can be categorized as genome-wide pleiotropic and targeted approaches like manipulation of global regulatory systems, modulation of regulatory genes, ribosome and engineering of RNA polymerase or phosphopantheteine transferases. Targeted approaches including genome editing by CRISPR, mutation in transcription factors and modification of BGCs promoters, inactivation of the highly expressed biosynthetic pathways, deleting the suppressors or awakening the activators, heterologous expression, or refactoring of gene clusters can be applied for activation of pathways which are predicted to synthesize new bioactive structures in genome mining studies of Acinobacteria. In this review, the challenges and advantages of employing these approaches in induction of Actinobacteria BGCs are discussed. Further, novel natural products needed as drug for pharmaceutical industry or as biofertilizers in agricultural industry can be discovered even from known species of Actinobactera by the innovative approaches of metabolite biosynthesis elicitation. [ABSTRACT FROM AUTHOR]

This study was conducted to gauge the nature and level of organizational legitimacy of private higher education institutions (PHEIs) in Ethiopia through the perspectives of regulators involved in accrediting and auditing private institutions. The study adopted a mixed-methods approach, particularly the explanatory sequential design, and used questionnaire, documentary evidence, and interview as principal means of data collection. One hundred and twenty-one regulators were involved in the survey and ten regulators participated in the in-depth interview. The findings revealed that both the overall rating of PHEIs and the various categories of legitimacy identified as procedural, consequential, structural, personal, and linkage received average ratings by regulators. This denotes a threshold level of acceptance suggesting the need for a more substantial legitimacy level that the Ethiopian private higher education sector should attain if it seeks to earn heightened credibility and active support from stakeholders. Conclusions and implications of the study at the nexus of theory, policy, and practice are discussed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of this research was to explore the importance of N6-methyladenosine (m6A) methylation-associated genes concerning the clinical outcome of patients with renal cell carcinoma (RCC) by employing the Cancer Genome Atlas (TCGA) database along with various bioinformatics methodologies. MATERIALS AND METHODS: The transcriptome and clinical data of RCC patients were obtained from the TCGA database. We identified the differential expression of 13 genes and selected potential predictive genes for further analysis of their prognostic values. RESULTS: Ten genes (YTHDC2, FTO, YTHDF2, METTL3, KIAA1429, ZC3H13, METTL14, ALKBH5, WTAP, and RBM15) exhibited altered expression levels in RCC. Subgroup analysis based on m6A methylation-related gene expression levels revealed no significant differences in survival rates, but significant differences were observed in grade, T stage, and gender. Five potential predictors (FTO, RBM15, YTHDC2, ZC3H13b, and ALKBH5) demonstrated independent predictive value. Multivariate analysis selected two regulators (METTL14 and METTL3), and based on these, prognostic signals for RCC were constructed, independent of potential confounding factors. The model clearly distinguished between samples with good and poor prognoses. CONCLUSIONS: The expression levels of m6A methylation-related genes in RCC patients were found to differ and were associated with survival rates and prognosis. These findings suggest that m6A methylation-related genes could serve as prognostic indicators and promising therapeutic targets for RCC patients. [ABSTRACT FROM AUTHOR]

Abstract Mitochondria are the main sources of energy production for muscle tissues, including skeletal, cardiac, or smooth muscle, to support their activities. Mitochondrial dysfunction and dysregulation of their quality control systems are significant characteristics in aged muscle. Increasing evidence indicates that natural products, especially phytochemicals, can prevent or improve age‐related muscle disorders. Among them, some dietary components specifically regulate mitochondrial quality control (MQC) to play their efficacy. However, the content of related studies is currently not systematically reviewed. In this review, composition, changes, and associated regulators in the MQC network during muscle aging were summarized by comprehensive literature retrieval. Subsequently, the effects and mechanisms of dietary active ingredients on this control network were described. This review showed that mitochondrial dysfunction is a common feature in different types of muscle aging. And four main ways of MQC are involved in maintaining mitochondrial homeostasis and they form a tight and integral system, for muscle‐healthy aging. The benefits of specific endogenous metabolites and exogenous components on aged muscle health are mediated in the above ways. Dietary phytochemicals including phenols, terpenoids, and alkaloids, unfold their influential roles in delaying muscle aging via promoting mitochondrial biogenesis and mitophagy. These findings suggest that MQC is a promising action site against muscle aging and food or herbal‐derived natural products are representative potential interventions. More clinical studies in the future are worthy of future investigation of these natural products.

In this letter we propose a new computational method for designing optimal regulators for high-dimensional nonlinear systems. The proposed approach leverages physics-informed machine learning to solve high-dimensional Hamilton-Jacobi-Bellman equations arising in optimal feedback control. Concretely, we augment linear quadratic regulators with neural networks to handle nonlinearities. We train the augmented models on data generated without discretizing the state space, enabling application to high-dimensional problems. We use the proposed method to design a candidate optimal regulator for an unstable Burgers' equation, and through this example, demonstrate improved robustness and accuracy compared to existing neural network formulations.

In contrast to some low-molar-mass per- and polyfluoroalkyl substances (PFASs), which are well established to be toxic, persistent, bioaccumulative, and mobile, fluoropolymers (FPs) are water-insoluble, safe, bioinert, and durable. These niche high-performance polymers fulfil the 13 polymer-of-low-concern (PLC) criteria in their recommended conditions of use. In addition, more recent innovations (e.g., the use of non-fluorinated surfactants in aqueous radical (co)polymerization of fluoroalkenes) from industrial manufacturers of FPs are highlighted. This review also aims to show how these specialty polymers endowed with outstanding properties are essential (even irreplaceable, since hydrocarbon polymer alternatives used in similar conditions fail) for our daily life (electronics, energy, optics, internet of things, transportation, etc.) and constitute a special family separate from other "conventional" C1–C10 PFASs found everywhere on Earth and its oceans. Furthermore, some information reports on their recycling (e.g., the unzipping depolymerization of polytetrafluoroethylene, PTFE, into TFE), end-of-life FPs, and their risk assessment, circular economy, and regulations. Various studies are devoted to environments involving FPs, though they present a niche volume (with a yearly production of 330,300 t) compared to all plastics (with 460 million t). Complementary to other reviews on PFASs, which lack of such above data, this review presents both fundamental and applied strategies as evidenced by major FP producers. [ABSTRACT FROM AUTHOR]

Key Takeaways: Public water systems should assess their compliance with regulatory requirements and be prepared for additional scrutiny from regulators. The US Environmental Protection Agency may apply pressure to include climate‐related assessments in Section 1433 risk and resilience plans. Regulators have the authority to seek information from utilities and inspect facilities. Utilities operating in overburdened communities should be especially aware of regulatory requirements and be prepared for more inspections. [ABSTRACT FROM AUTHOR]

Copyright of Journal: American Water Works Association is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The COVID-19 pandemic caused considerable disruption to the development, regulatory evaluation, production, and distribution of medicinal products. Key healthcare stakeholders were under pressure to develop and review medicinal products to address the health emergency, while preserving the continuity of activities to ensure patient access to other medicinal products. In the light of this challenging situation, the National Regulatory Authorities (NRAs) and the biopharmaceutical industry applied and utilized product development and regulatory agilities to accelerate the development and authorization of safe, effective and quality COVID-19 vaccines and treatments as well as other non-COVID-19 medicinal products. On the basis of the literature review and primary research conducted, this review article gathered insights on experiences and challenges in the use of agilities related to regulatory assessment of initial marketing and post-approval change (PAC) applications, oversight of product manufacturing quality and supply chain continuity, and product development/clinical trial processes during the early phases of the COVID-19 pandemic. Agilities were thus implemented in an emergency context characterized by the lack of medicinal products to help tackle a disease that was devastating for the global public health. This review article concludes that useful lessons can be learned from these insights to improve product development practices and regulatory processes during both normal and health emergency times. Standard regulatory frameworks during normal times can be enhanced by leveraging digitalization, further simplifying and harmonizing requirements, and using reliance mechanisms which can help to increase efficiency in regulatory decision-making regarding medicinal products. During health emergencies, such as a pandemic, maximizing global coordination, collaboration, reliance, and harmonization of regulatory requirements and guidance are important to facilitate the rapid development and assessment of key medicinal products to address the health emergency. [ABSTRACT FROM AUTHOR]

Regulations and regulatory change management (RCM) are critical for safeguarding organisations and the overall economy by providing operating guardrails for managing risks. This paper discusses the purpose of regulations, the role of regulators and the need for proactive adoption of a robust RCM framework. It provides a practitioner's perspective for establishing in-house RCM operations, outlining opportunities for adopting regulatory technology to support efficient compliance and organisational growth needs. [ABSTRACT FROM AUTHOR]

The use of data and evidence from real clinical practice (RWD / RWE) is becoming more and more relevant to the healthcare system when making critical decisions in the field of drug circulation regulation, as well as making decisions on the inclusion or non-inclusion of a drug in government funding programs.This article discusses the role of clinical registries as one of the most important sources of RWD / RWE. Definitions of terminology are given, and various types of registers are described according to the type of information collected, methods of its collection, storage, and processing. It also shows the possibility of using registers in decision-making, describes the mechanisms for consolidating information from various types of registers, as well as obtaining data for analysis from other sources, shows the importance of correct collection and validation of data collected in the register.The article also briefly describes the local experience in the development, implementation, and maintenance of registers on the example of a number of disorders.It was prepared using guidelines prepared by the Office of Medical Policy of the Center for Drug Evaluation and Research in collaboration with the Center for Biological Evaluation and Research and the US Food and Drug Administration»s Center of Excellence in Oncology.

Non-verbal semiotics is one of the leading areas of modern communication research. The study is devoted to the topical interdisciplinary issue - the relationship between non-verbal semiotics and Russian grammar. The aim of the research is to characterize the representation of the temporal forms of the Russian verb in describing the kinesic behaviour of literary characters. The elements of nonverbal semiotics were analysed in the stories by A.P. Chekhov “Death of an Official”, “Chameleon”, “Thick and Thin”, “Horse Name”, “Surgery”. The following methods were used as the main ones: descriptive, semantic explication, differential, analytical. The methodological foundations of kinesics as an integrative science were considered, the correlation between the verbal realization of kinema and the temporal forms of the Russian verb was revealed. It has been proved that the most recurrent manifestations of non-verbal semiotics in Chekhov's stories are communicative emblems (in particular, etiquette and ritual), symptomatic emblems and dynamic descriptors, nominated with the help of aspect and tense forms of the Russian verb. Emblems-illustrators are quantitatively less represented in the analyzed stories. They are prospective for further research on the example of Russian literary classics.

Introduction: Despite intensive research, preterm birth (PTB) rates have not decreased significantly in recent years due to a lack of understanding of the underlying causes and insufficient treatment options for PTB. We are committed to finding promising biomarkers for the treatment of PTB. Methods: An extensive search of the literature was conducted with MEDLINE/PubMed, and in total, 151 studies were included and summarized in the present review. Results: Substantial evidence supports that the infection and/or inflammatory cascade associated with infection is an early event in PTB. Toll-like receptor (TLR) is a prominent pattern recognition receptor (PRR) found on both immune and non-immune cells, including fetal membrane cells. The activation of TLR downstream molecules, followed by TLR binding to its ligand, is critical for infection and inflammation, leading to the involvement of the TLR signaling pathway in PTB. TLR ligands are derived from microbial components and molecules released by damaged and dead cells. Particularly, TLR4 is an essential TLR because of its ability to recognize lipopolysaccharide (LPS). In this comprehensive overview, we discuss the role of TLR signaling in PTB, focus on numerous host-derived genetic and epigenetic regulators of the TLR signaling pathway, and cover ongoing research and prospective therapeutic options for treating PTB by inhibiting TLR signaling. Conclusion: This is a critical topic because TLR-related molecules and mechanisms may enable obstetricians to better understand the physiological changes in PTB and develop new treatment and prevention strategies. [ABSTRACT FROM AUTHOR]

Iron is a mineral micronutrient essential for survival and vital functions in many biological processes in living organisms. Iron plays a crucial role as a cofactor of iron-sulfur clusters in energy metabolism and biosynthesis by binding with enzymes and transferring electrons to targets. Iron can also impair cellular functions by damaging organelles and nucleic acids by producing free radicals from redox cycling. Iron-catalyzed reaction products can induce active-site mutations in tumorigenesis and cancer progression. However, the boosted pro-oxidant iron form may contribute to cytotoxicity by increasing soluble radicals and highly reactive oxygen species via the Fenton reaction. An increased redox-active labile iron pool is required for tumor growth and metastasis, but the increased cytotoxic lipid radicals also lead to regulated cell death, such as ferroptosis. Therefore, this may be a major target for selectively killing cancer cells. This review intends to understand altered iron metabolism in cancers and discuss iron-related molecular regulators highly associated with iron-induced cytotoxic radical production and ferroptosis induction, focusing on head and neck cancer. [ABSTRACT FROM AUTHOR]

In the nanotechnology era, nanotechnology applications have been intensifying their prospects to embrace all the vigorous sectors persuading human health and animal. The safety and concerns regarding the widespread use of engineered nanomaterials (NMs) and their potential effect on human health still require further clarification. Literature elucidated that NMs exhibited significant adverse effects on various molecular and cellular alterations. Epigenetics is a complex process resulting in the interactions between an organism's environment and genome. The epigenetic modifications, including histone modification and DNA methylation, chromatin structure and DNA accessibility alteration, regulate gene expression patterns. Disturbances of epigenetic markers induced by NMs might promote the sensitivity of humans and animals to several diseases. Also, this paper focuses on the epigenetic regulators of some dietary nutrients that have been confirmed to stimulate the epigenome and, more exactly, DNA histone modifications and non-histone proteins modulation by acetylation, and phosphorylation inhibition, which counteracts oxidative stress generations. The present review epitomizes the recent evidence of the potential effects of NMs on histone modifications, in addition to in vivo and in vitro cytosine DNA methylation and its toxicity. Furthermore, the part of epigenetic fluctuations as possible translational biomarkers for uncovering untoward properties of NMs is deliberated. [ABSTRACT FROM AUTHOR]

Despite the importance of sell-side analysts in the capital markets, we know little about the effectiveness of routine monitoring of the sell-side industry. We examine the attributes of sell-side research issued by analysts before and after their brokerage faces regulatory sanctions. We find that after a sanction, analysts at sanctioned brokerages lower their stock recommendations, both in absolute terms and relative to the recommendations of other analysts following the same firms. These analysts are also more likely than analysts at other brokerages to downgrade a company’s stock after the receipt of unfavorable information about the firm. Importantly, we document that analysts at nonsanctioned brokerages also reduce the optimism of their stock recommendations when a peer analyst’s brokerage is sanctioned, consistent with spillovers as a result of routine regulatory monitoring. Our study provides evidence that regulatory action against sell-side brokerages is associated with a reduction in sell-side analysts’ positive bias.

Both Foliar nutrients and phytohormones application have crucial roles in enhancing the yield of plants and meeting the increasing demand for food. To evaluate the effects of a foliar fertilizer and growth regulators on quality and quantity yields of saffron (Crocus sativus L.), a complete block randomized experiment was conducted on the experimental farm in Farooj in 2020-2021. This study consisted of seven treatments: 1-Control, 2- Gibberellin (200 ppm), 3-Auxin (200 ppm), 4- foliar spraying of Fruit Set (specific fertilizer containing 8.75% N as NO3−, 4.37% Zn, and 10% B, 6%K, and 6% sea weed extract at a rate of 0.5 L/ha + gibberellin (200ppm), 5-Fruit Set foliar fertilizer (0.5 L/ha), 6- N-phenyl-phthalamic acid (200 mg/L as irrigation), and 7-N-phenyl-phthalamic acid (spraying with 200 mg/L). It was found that the Fruit Set treatment resulted in the highest flower height (10.33 cm) and the auxin treatment resulted in 46 % increase in leaf height over the control treatment. In the Fruit Set + gibberellin treatment, the highest flower weight (2790g) was achieved, and the highest number of mother corms (15 pieces) was obtained in the auxin and gibberellin treatment. It also was observed that the mother corm weight (44 grams) and diameter (14 cm) were highest in gibberellin treatment (47%), and auxin treatment produced the largest number of daughter corms (32 pieces). Fruit Set + gibberellin, Fruit Set, auxin, and gibberellin significantly increased flower weight by 93%, 67%, 78%, and 77%. The Fruit Set treatment was found to be most effective in terms of crocin levels. Overall, the results of this research showed positive effects of gibberellin on quantitative yield and auxin on the number of daughter corms. In addition, the application of the Fruit Set improved the flowering and quality characteristics of saffron.

Recent years have witnessed a series of special rectification activities of Internet finance, which has successfully controlled the overall risk and improved the situation of disorderly development and ecological deterioration in the Internet finance industry. However, the task of preventing and defusing risks in the Internet finance sector remains arduous, and the regulatory system adapted to the characteristics of Internet finance needs to be improved. In this context, it is important to summarize and refine the experience, form rules and regulations, and establish a sound long-term mechanism for Internet financial regulation. As this is not only the basic requirement for preventing and defusing financial risks but also the reliable guarantee for building an inclusive financial system in China. However, existing literature has focused minimally on the evolution of China's Internet financial regulation, the formation of long-term mechanisms and its key influencing factors. This study constructs a tripartite evolutionary game model among Internet financial enterprises, analyzes the strategy choices between the stakeholders, dissects the dynamic evolution process of Internet financial regulation, explores the key factors that influence the formation of the permanent mechanism of Internet financial regulation, and adopts MATLAB software to conduct numerical simulations on the evolutionary trajectories of the three participants and their sensitivity to key parameters. Results show that:(1)there exist four evolutionary stable strategies, among which the Internet financial enterprises adopt “legal operation”, the consumers adopt “participating in regulation” and the financial regulators adopt “positive regulation” is the optimal evolutionary stable strategy;(2)the key factors influencing the participants' strategy choices have significant differences, the strategy choices of the Internet financial enterprises are mainly influenced by the costs of their “legal operation” strategy, the punishment of financial regulators to the Internet financial enterprises, and the consumers' reputation effect; the strategy choices of consumers are mainly influenced by the cost and reward of their “participating in regulation” strategy, and the cost of financial regulators to provide the access for consumers; the strategy choices of financial regulators is mainly influenced by the reward given to consumers and the enhancement of social credibility of “positive regulation”;(3)the dynamic game between the three participants makes the Internet financial regulation scheme in China have obvious stage characteristics, the permanent Internet financial regulation mechanism can be achieved by the formation of a mixed regulation situation with the continuous improvement of the financial regulators formal regulations and the perfection of reputation mechanism. The contributions of this study are threefold. First, this study includes consumers, an important stakeholder of Internet finance regulation, into the framework of evolutionary game analysis, which makes up for the lack of analysis of consumers' role in Internet financial regulation in previous studies; Second, this study analyzes the evolution path and stability of the three participants from the perspective of evolutionary game, thereby revealing the behavioral and strategic relationships among the participants, and exploring the dynamic evolution path of China's Internet financial regulation. Third, combined with the constraint conditions of the evolutionary stability strategy, this study discusses the influence of the key parameters, which provides a theoretical basis and decision-making reference for the construction of the permanent mechanism of China's Internet financial regulation. This study, to a certain extent, reveals the inherent logic of the phased changes in China's Internet financial regulation and identifies the key factors influencing the formation of a permanent mechanism of Internet financial regulation. As a result, this study can serve as a crucial reference for financial regulators to formulate targeted strategies to promote the transition of Internet financial regulation to a mature stage and form a permanent mechanism of Internet financial regulation. [ABSTRACT FROM AUTHOR]

Copyright of Nonferrous Metals (Mineral Processing Section) is the property of Beijing Research Institute of Mining & Metallurgy Technology Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A review of the control laws (models) of alternating current arc steelmaking furnaces' (ASF) electric modes (EM) is carried out. A phase-symmetric three-component additive fuzzy model of electrode movement control signal formation is proposed. A synthesis of fuzzy inference systems based on the Sugeno model for the implementation of the proposed additive three-component fuzzy law of arc length control is performed. A structural computer Simulink model of the EM control system in a high-power arc steelmaking furnace of the DSP-200 type with an ARDM-T-12 arcs power regulator is created. Computer research into control dynamics indicators under the influence of deterministic perturbations and also integral indicators of energy efficiency when handling stationary random arc lengths fluctuations (corresponding to various technological stages of melting) are carried out. A comparative analysis of dynamics indicators, energy efficiency, and electromagnetic compatibility of the proposed fuzzy and known differential model of ASF arc lengths control is carried out. The implementation of the proposed fuzzy three-component additive control model in comparison with the existing deterministic differential one reduces the dispersion of voltages, currents, and arcs powers, reduces electrical losses in an arc furnace high-power network by 10–22% and increases the average arc power by 0.9–1.5%. [ABSTRACT FROM AUTHOR]

Key Takeaways: A constellation of factors, both environmental and operational, is threatening many water utilities' ability to succeed. Improvement can come from multiple channels in terms of sufficient utility planning, guidance from the water industry, and support from stakeholders and regulators. The Water 2050 initiative takes a long view of ensuring optimal water system operation through the lens of technology, sustainability, economics, governance, and social and demographic issues. [ABSTRACT FROM AUTHOR]

The increasing threat of cyberattacks has resulted in increased efforts by both the U.K. government and regulatory authorities to coordinate efforts to influence cybersecurity risk management practices in the U.K. insurance sector, focusing on cyber risk underwriters. This paper provides an evaluation of these arrangements. It first provides a descriptive overview of the key U.K. regulatory authorities and the evolution of their efforts over the past decade, as well as the scope for broader collaborations with industry and member-based associations and international organisations. It then evaluates the effectiveness of these efforts by providing a multi-method study of the incidence, nature and evolution of cost of data breaches, investment in computer systems and software intangible assets at risk of cyberattack, and a content analysis of annual reports of both U.K. regulators and a sample of U.K. insurers. The findings suggest that while both the total costs of data breaches and the size of investment in computer systems and software intangibles at risk of cyberattack have gradually increased over time, the degree of engagement with cyber as a reporting issue by both cyber insurers and financial regulators has not. It is concluded that while these efforts have been apparently successful in avoiding a large-scale, systemic cyberattack on the U.K. insurance industry, there are significant gaps and overlaps in the system of cyber regulatory oversight. [ABSTRACT FROM AUTHOR]