Global Regulator Research Articles

Inhibitory potential of Syzygium aromaticum against Fusarium oxysporum f. sp. lycopersici: In-vitro analysis and molecular docking studies

The antifungal potential of the extract of cloves (Syzygium aromaticum) was investigated in this study. The crude extracts of cloves and n-hexane, chloroform and n-butanol fractions were prepared. The antifungal activity of obtained fractions was studied at various concentrations ranging from 1.5 to 200.00 µg/mL. Thiophanate methyl (TM) was used as +ve control in this study. The fractions including methanolic, n-hexane, n-butanol, and chloroform significantly inhibited the growth of Fusarium oxysporum f.sp. lycopersici (FOL) ranging from 93.8 to 100 % when used at 200 µg/mL. The chloroform fraction showed 6.25 µg/mL MIC as compared to TM with 64 µg/mL MIC. GC/MS analysis showed that the chloroform fraction contained Eugenol, Phenol, 2,2′-methylenebis[6-(1,1-dimethylethyl)-4-methyl, 2,4-Di‑tert-butylphenol, n-Hexadecanoic acid, Phenol, and 2‑methoxy-4-(2-propenyl)- acetate. The findings of in-vitro antifungal analysis were further supported by molecular docking studies. Two virulence proteins of FOL i.e., global transcription regulator (SGE1) and DNA binding transcription factor (STE12) were docked with identified phytocompounds in the chloroform fraction by GC/MS analysis. Both of the receptors showed maximum binding affinities with 2-[2-(4-Phenyl-piperidin-1-yl)-ethyl]-isoindole-1,3‑dione (PED) (-12.054 kcal/mol) and 3,5-di‑tert-Butyl-4-hydroxyphenylpropionic acid (BHP) (-13.327 kcal/mol) respectively with strong hydrophilic/phobic interactions with active pocket residues. In conclusion, the chloroform fraction of S. aromaticum can be used to manage FOL.

AI in knowledge sharing, which ethical challenges are raised in decision-making processes for organisations?

PurposeThis study aims to identify and assess the key ethical challenges associated with integrating artificial intelligence (AI) in knowledge-sharing (KS) practices and their implications for decision-making (DM) processes within organisations.Design/methodology/approachThe study employs a mixed-methods approach, beginning with a comprehensive literature review to extract background information on AI and KS and to identify potential ethical challenges. Subsequently, a confirmatory factor analysis (CFA) is conducted using data collected from individuals employed in business settings to validate the challenges identified in the literature and assess their impact on DM processes.FindingsThe findings reveal that challenges related to privacy and data protection, bias and fairness and transparency and explainability are particularly significant in DM. Moreover, challenges related to accountability and responsibility and the impact of AI on employment also show relatively high coefficients, highlighting their importance in the DM process. In contrast, challenges such as intellectual property and ownership, algorithmic manipulation and global governance and regulation are found to be less central to the DM process.Originality/valueThis research contributes to the ongoing discourse on the ethical challenges of AI in knowledge management (KM) and DM within organisations. By providing insights and recommendations for researchers, managers and policymakers, the study emphasises the need for a holistic and collaborative approach to harness the benefits of AI technologies whilst mitigating their associated risks.

Multifaceted regulation of siderophore synthesis by multiple regulatory systems in Shewanella oneidensis

Siderophore-dependent iron uptake is a mechanism by which microorganisms scavenge and utilize iron for their survival, growth, and many specialized activities, such as pathogenicity. The siderophore biosynthetic system PubABC in Shewanella can synthesize a series of distinct siderophores, yet how it is regulated in response to iron availability remains largely unexplored. Here, by whole genome screening we identify TCS components histidine kinase (HK) BarA and response regulator (RR) SsoR as positive regulators of siderophore biosynthesis. While BarA partners with UvrY to mediate expression of pubABC post-transcriptionally via the Csr regulatory cascade, SsoR is an atypical orphan RR of the OmpR/PhoB subfamily that activates transcription in a phosphorylation-independent manner. By combining structural analysis and molecular dynamics simulations, we observe conformational changes in OmpR/PhoB-like RRs that illustrate the impact of phosphorylation on dynamic properties, and that SsoR is locked in the ‘phosphorylated’ state found in phosphorylation-dependent counterparts of the same subfamily. Furthermore, we show that iron homeostasis global regulator Fur, in addition to mediating transcription of its own regulon, acts as the sensor of iron starvation to increase SsoR production when needed. Overall, this study delineates an intricate, multi-tiered transcriptional and post-transcriptional regulatory network that governs siderophore biosynthesis.

Intestinal carbapenem-resistant Klebsiella pneumoniae undergoes complex transcriptional reprogramming following immune activation

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) is a significant threat to public health worldwide. The primary reservoir for CR-Kp is the intestinal tract. There, the bacterium is usually present at low density but can bloom following antibiotic treatment, mostly in hospital settings. The impact of disturbances in the intestinal environment on the fitness, survival, expansion, and drug susceptibility of this pathogen is not well-understood, yet it may be relevant to devise strategies to tackle CR-Kp colonization and infection. Here, we adopted an in vivo model to examine the transcriptional adaptation of a CR-Kp clinical isolate to immune activation in the intestine. We report that as early as 6 hours following host treatment with anti-CD3 antibody, CR-Kp underwent rapid transcriptional changes including downregulation of genes involved in sugar utilization and amino acid biosynthesis and upregulation of genes involved in amino acid uptake and catabolism, antibiotic resistance, and stress response. In agreement with these findings, treatment increased the concentration of oxidative species and amino acids in the mouse intestine. Genes encoding for proteins containing the domain of unknown function (DUF) 1471 were strongly upregulated, however their deletion did not impair CR-Kp fitness in vivo upon immune activation. Transcription factor enrichment analysis identified the global regulator cAMP-Receptor Protein, CRP, as a potential orchestrator of the observed transcriptional signature. In keeping with the recognized role of CRP in regulating utilization of alternative carbon sources, crp deletion in CR-Kp resulted in strongly impaired gut colonization, although this effect was not amplified by immune activation. Thus, following intestinal colonization, which occurs in a CRP-dependent manner, CR-Kp can rapidly respond to immune cues by implementing a well-defined and complex transcriptional program whose direct relevance toward bacterial fitness warrants further investigation. Additional analyses utilizing this model may identify key factors to tackle CR-Kp colonization of the intestine.

The nucleoid protein HU positively regulates the expression of type VI secretion systems in Enterobacter cloacae.

T6SS is a nanomachine that functions as a weapon of bacterial destruction crucial for successful colonization in a specific niche. Enterobacter cloacae expresses two T6SSs required for bacterial competition, adherence, biofilm formation, and intestinal colonization. Expression of T6SS genes in pathogenic bacteria is controlled by multiple regulatory systems, including two-component systems, global regulators, and nucleoid proteins. Here, we reported that the HU nucleoid protein directly activates both T6SSs in E. cloacae, affecting the T6SS-related phenotypes. Our data describe HU as a new regulator involved in the transcriptional regulation of T6SS and its impact on E. cloacae pathogenesis.

MEMO1 binds iron and modulates iron homeostasis in cancer cells.

Mediator of ERBB2-driven cell motility 1 (MEMO1) is an evolutionary conserved protein implicated in many biological processes; however, its primary molecular function remains unknown. Importantly, MEMO1 is overexpressed in many types of cancer and was shown to modulate breast cancer metastasis through altered cell motility. To better understand the function of MEMO1 in cancer cells, we analyzed genetic interactions of MEMO1 using gene essentiality data from 1028 cancer cell lines and found multiple iron-related genes exhibiting genetic relationships with MEMO1. We experimentally confirmed several interactions between MEMO1 and iron-related proteins in living cells, most notably, transferrin receptor 2 (TFR2), mitoferrin-2 (SLC25A28), and the global iron response regulator IRP1 (ACO1). These interactions indicate that cells with high-MEMO1 expression levels are hypersensitive to the disruptions in iron distribution. Our data also indicate that MEMO1 is involved in ferroptosis and is linked to iron supply to mitochondria. We have found that purified MEMO1 binds iron with high affinity under redox conditions mimicking intracellular environment and solved MEMO1 structures in complex with iron and copper. Our work reveals that the iron coordination mode in MEMO1 is very similar to that of iron-containing extradiol dioxygenases, which also display a similar structural fold. We conclude that MEMO1 is an iron-binding protein that modulates iron homeostasis in cancer cells.

Global output feedback regulation of time-varying nonlinear systems via the dual-gain method

Global output feedback regulation of time-varying nonlinear systems via the dual-gain method

Effects of erythromycin on biofilm formation and resistance mutation of Escherichia coli on pristine and UV-aged polystyrene microplastics

Microplastics (MPs) and antibiotics co-occur widely in the environment and pose combined risk to microbial communities. The present study investigated the effects of erythromycin on biofilm formation and resistance mutation of a model bacterium, E. coli, on the surface of pristine and UV-aged polystyrene (PS) MPs sized 1–2 mm. The properties of UV-aged PS were significantly altered compared to pristine PS, with notable increases in specific surface area, carbonyl index, hydrophilicity, and hydroxyl radical content. Importantly, the adsorption capacity of UV-aged PS towards erythromycin was approximately 8-fold higher than that of pristine PS. Biofilms colonizing on UV-aged PS had a greater cell count (5.6 × 108 CFU mg−1) and a higher frequency of resistance mutation (1.0 × 10−7) than those on pristine PS (1.4 × 108 CFU mg−1 and 1.4 × 10−8, respectively). Moreover, erythromycin at 0.1 and 1.0 mg L−1 significantly (p < 0.05) promoted the formation and resistance mutation of biofilm on both pristine and UV-aged PS. DNA sequencing results confirmed that the biofilm resistance was attributed to point mutations in rpoB segment of the bacterial genome. qPCR results demonstrated that both UV aging and erythromycin repressed the expression levels of a global regulator rpoS in biofilm bacteria, as well as two DNA mismatch repair genes mutS and uvrD, which was likely to contribute to increased resistance mutation frequency.

Iron starvation increases the production of the Pseudomonas aeruginosa RsmY and RsmZ sRNAs in static conditions.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that induces virulence gene expression in response to host-mediated iron starvation. Recently, our laboratory showed that some virulence factors are responsive to iron limitation in static but not shaking growth conditions. One of these is the HSI-2-type six secretion system (T6SS), which is also induced during chronic infection. Iron regulation of T6SS was partially impacted by the iron-responsive PrrF sRNA and completely dependent upon the Pseudomonas quinolone signal (PQS) biosynthetic gene pqsA. Here, we analyzed the impact of iron on the expression of two small regulatory RNAs (sRNAs), RsmY and RsmZ, that activate the expression of T6SS by sequestering the RsmA translation inhibitor. Our results demonstrate that iron starvation induces the expression of RsmY and RsmZ in static but not shaking cultures. We further show that this induction occurs through the rsmY and rsmZ promoters and is dependent upon PqsA. Disruption of either the pqsR gene also eliminated iron-dependent regulation of rsmY and rsmZ promoter activity. Taken together, our results show novel targets of iron regulation that are specific to static growth, highlighting the importance of studying regulatory mechanisms in static communities that may be more representative of growth during chronic infection.IMPORTANCEIron is a central component of various bacterial metabolic pathways making it an important host-acquired nutrient for pathogens to establish infection. Previous iron regulatory studies primarily relied on shaking bacterial cultures; while these ensure cultural homogeneity, they do not reflect growth conditions during infection. We recently showed that static growth of Pseudomonas aeruginosa promotes iron-dependent regulation of a type six secretion system (T6SS), a virulence factor that is induced during chronic infections. In the current study, we found that static growth also promotes iron-dependent regulation of the RsmY and RsmZ sRNAs, which are global regulators that affect T6SS during chronic P. aeruginosa lung infection. Hence, our work demonstrates the Rsm sRNAs as potential effectors of iron regulation during static growth that may also be relevant in chronic infection.

Healthcare Integrated Information System in Indonesia

The United States (US), leads the world in medical science and technology. Lead by clear definitions in almost all sectors of clinical research, training and governance practices. Likewise, the pharmaceutical and medical device (medical equipment) manufacturers are considered one of the leading in the world. Therefore, many of the definitions and rules have also been adopted into global regulations by the world health organization, the World Health Organization (WHO). Currently, these rules have been implemented into the health information system (HIS), which further rapidly being adopted and used in many countries. Nowadays, health facilities (HF) around the world have used HIS, which are basic or have reached an advanced level. This paper will describe how the development of HIS and applied products from utilization of information technology (IT) in Indonesia, along with the opportunities and challenges in the future.

The global nitrogen regulator GlnR is a direct transcriptional repressor of the key gluconeogenic gene pckA in actinomycetes.

The GlnR regulator of actinomycetes controls nitrogen metabolism genes and many other genes involved in carbon, phosphate, and secondary metabolisms. Currently, the known GlnR-regulated genes in carbon metabolism are involved in the transport of carbon sources, the assimilation of short-chain fatty acid, and the 2-methylcitrate cycle, although little is known about the relationship between GlnR and the TCA cycle and gluconeogenesis. Here, based on the biochemical and genetic results, we identified GlnR as a direct transcriptional repressor of pckA, the gene that encodes phosphoenolpyruvate carboxykinase, a key enzyme for gluconeogenesis, thus highlighting that GlnR plays a central and complex role for dynamic orchestration of cellular carbon, nitrogen, and phosphate fluxes and bioactive secondary metabolites in actinomycetes to adapt to changing surroundings.

Ensuring Fair Compensation: Analyzing and Adjusting Freight Forwarder Liability Limits

Background: Due to the absence of unified global regulations, defining the service and legal role of freight forwarders is challenging. This, as well as the lack of a standardized limit to the freight forwarder’s liability for loss or damage to the cargo, introduces misunderstandings into his relationship with the client. The purpose of this study is to analyze the most widely used limit for freight forwarder’s liability, set in Special Drawing Rights (SDR) units, and to adjust it, which will allow for maintaining the purchasing power of the compensation amount over different periods of time. Methods: In this study, two methods of adjusting the liability limit were proposed. In accordance with the first one, the limit was adjusted considering the impact of dollar inflation on the SDR unit. The second method involves changes in the limit of liability, taking into account changes in world prices for goods. Results: The result of this study showed that the second method is more functional, helping to preserve the purchasing power of the liability limit most effectively over time. Conclusions: This study revealed the fluctuating purchasing power of the forwarder’s liability limit over time and suggests utilizing a methodology tied to changes in global goods’ prices for adjustment.

Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

A Point Mutation in Cassette Relieves the Repression Regulation of CcpA Resulting in an Increase in the Degradation of 2,3-Butanediol in Lactococcus lactis.

In lactic acid bacteria, the global transcriptional regulator CcpA regulates carbon metabolism by repressing and activating the central carbon metabolism pathway, thus decreasing or increasing the yield of certain metabolites to maximize carbon flow. However, there are no reports on the deregulation of the inhibitory effects of CcpA on the metabolism of secondary metabolites. In this study, we identified a single-base mutant strain of Lactococcus lactis N8-2 that is capable of metabolizing 2,3-butanediol. It has been established that CcpA dissociates from the catabolite responsive element (cre) site due to a mutation, leading to the activation of derepression and expression of the 2,3-butanediol dehydrogenase gene cluster (butB and butA). Transcriptome analysis and quantitative polymerase chain reaction (Q-PCR) results showed significant upregulation of transcription of butB and butA compared to the unmutated strain. Furthermore, micro-scale thermophoresis experiments confirmed that CcpA did not bind to the mutated cre. Furthermore, in a bacterial two-plasmid fluorescent hybridization system, it was similarly confirmed that the dissociation of CcpA from cre eliminated the repressive effect of CcpA on downstream genes. Finally, we investigated the differing catalytic capacities of the 2,3-butanediol dehydrogenase gene cluster in L. lactis N8-1 and L. lactis N8-2 for 2,3-butanediol. This led to increased expression of butB and butA, which were deregulated by CcpA repression. This is the first report on the elimination of the deterrent effect of CcpA in lactic acid bacteria, which changes the direction of enzymatic catalysis and alters the direction of carbon metabolism. This provides new perspectives and strategies for metabolizing 2,3-butanediol using bacteria in synthetic biology.

CARTEL TO PLAYER: OPEC DYNAMICS IN THE GLOBAL OIL MARKET

The OPEC, since its establishment in 1960 as a cartel and regime, has been largely controlling the global energy supply and price regulations, and thus, playing a pivotal role in the global geopolitics of energy security. However, the journey of this inter-governmental organisation till date, as a predominant energy cartel, from cartel dominance and regional geopolitics to global competition and climate change challenges, has not been an easy one. Although OPEC has been going through ups and downs in the global energy market, the requirement of petroleum resources by the global community for economic growth and the developmental process cannot be ignored. Therefore, the role of OPEC is likely to be prominent at least till the mid-2030s as indicated by various energy reports. This research paper is intended to test the hypothesis that in spite of internal dissent and discontent, price war and rise of OPEC+, exploration of shale energy, focus for energy transition, OPEC will have an unmatchable share in the global energy basket and remain a dominant player in the global energy market and geopolitics, at least for the near future. The paper also focuses on how the Russia-Ukraine war has united OPEC and non-OPEC suppliers further to control the global energy market Which benefits both.

Transcriptional and Metabolic Response of a Strain of Escherichia coli PTS- to a Perturbation of the Energetic Level by Modification of [ATP]/[ADP] Ratio.

The intracellular [ATP]/[ADP] ratio is crucial for Escherichia coli's cellular functions, impacting transport, phosphorylation, signaling, and stress responses. Overexpression of F1-ATPase genes in E. coli increases glucose consumption, lowers energy levels, and triggers transcriptional responses in central carbon metabolism genes, particularly glycolytic ones, enhancing carbon flux. In this contribution, we report the impact of the perturbation of the energetic level in a PTS- mutant of E. coli by modifying the [ATP]/[ADP] ratio by uncoupling the cytoplasmic activity of the F1 subunit of the ATP synthase. The disruption of [ATP]/[ADP] ratio in the evolved strain of E. coli PB12 (PTS-) was achieved by the expression of the atpAGD operon encoding the soluble portion of ATP synthase F1-ATPase (strain PB12AGD+). The analysis of the physiological and metabolic response of the PTS- strain to the ATP disruption was determined using RT-qPCR of 96 genes involved in glucose and acetate transport, glycolysis and gluconeogenesis, pentose phosphate pathway (PPP), TCA cycle and glyoxylate shunt, several anaplerotic, respiratory chain, and fermentative pathways genes, sigma factors, and global regulators. The apt mutant exhibited reduced growth despite increased glucose transport due to decreased energy levels. It heightened stress response capabilities under glucose-induced energetic starvation, suggesting that the carbon flux from glycolysis is distributed toward the pentose phosphate and the Entner-Duodoroff pathway with the concomitant. Increase acetate transport, production, and utilization in response to the reduction in the [ATP]/[ADP] ratio. Upregulation of several genes encoding the TCA cycle and the glyoxylate shunt as several respiratory genes indicates increased respiratory capabilities, coupled possibly with increased availability of electron donor compounds from the TCA cycle, as this mutant increased respiratory capability by 240% more than in the PB12. The reduction in the intracellular concentration of cAMP in the atp mutant resulted in a reduced number of upregulated genes compared to PB12, suggesting that the mutant remains a robust genetic background despite the severe disruption in its energetic level.

Convergent genetic adaptation of Escherichia coli in minimal media leads to pleiotropic divergence.

Adaptation in an environment can either be beneficial, neutral or disadvantageous in another. To test the genetic basis of pleiotropic behaviour, we evolved six lines of E. coli independently in environments where glucose and galactose were the sole carbon sources, for 300 generations. All six lines in each environment exhibit convergent adaptation in the environment in which they were evolved. However, pleiotropic behaviour was observed in several environmental contexts, including other carbon environments. Genome sequencing reveals that mutations in global regulators rpoB and rpoC cause this pleiotropy. We report three new alleles of the rpoB gene, and one new allele of the rpoC gene. The novel rpoB alleles confer resistance to Rifampicin, and alter motility. Our results show how single nucleotide changes in the process of adaptation in minimal media can lead to wide-scale pleiotropy, resulting in changes in traits that are not under direct selection.

Aptasensors for the Detection of Environmental Contaminants of High Concern in Water Bodies: A Systematic Review

With the advancement of technology and increasing industrial activity, anthropogenic contaminants are currently detected where there is no record of their presence or insufficient information about their toxicological impact. Consequently, there are not sufficiently robust local or global regulations, the ecotoxicological and human health risks are critical, and they may not be routinely monitored despite being ubiquitous. The interest in studying environmental contaminants, including micropollutants and emerging contaminants, in complex environmental water samples has grown in the last decade. Due to the concentrations in which they are typically found in the environment and the rapid global dispersion, the detection procedures for these substances must be capable of measuring very low concentrations. Many efforts have been made to improve remediation procedures or develop novel analytical methods for their determination. Although there are several robust and reliable standard analytical techniques for their monitoring, pollutant contamination requires simple and inexpensive methods for massive, in situ monitoring campaigns. In this regard, biosensors have emerged as devices with high selectivity, sensitivity, easy operation, and short analysis times. Aptasensors are biosensors based on a nucleic acid recognition element (aptamer). Due to their synthetic nature, stability, and easy production, aptamers are frequently employed to develop bioassays. This work presents a systematic review of the trends in using aptasensors for detecting environmental contaminants present in environmental water samples, as well as the estimation of the potential technological contribution these devices might give to environmental monitoring.

Characterization of a pleiotropic regulator MtrA in Streptomyces avermitilis controlling avermectin production and morphological differentiation

BackgroundThe macrolide antibiotic avermectin, a natural product derived from Streptomyces avermitilis, finds extensive applications in agriculture, animal husbandry and medicine. The mtrA (sav_5063) gene functions as a transcriptional regulator belonging to the OmpR family. As a pleiotropic regulator, mtrA not only influences the growth, development, and morphological differentiation of strains but also modulates genes associated with primary metabolism. However, the regulatory role of MtrA in avermectin biosynthesis remains to be elucidated.ResultsIn this study, we demonstrated that MtrA, a novel OmpR-family transcriptional regulator in S. avermitilis, exerts global regulator effects by negatively regulating avermectin biosynthesis and cell growth while positively controlling morphological differentiation. The deletion of the mtrA gene resulted in an increase in avermectin production, accompanied by a reduction in biomass and a delay in the formation of aerial hyphae and spores. The Electrophoretic Mobility Shift Assay (EMSA) revealed that MtrA exhibited binding affinity towards the upstream region of aveR, the intergenic region between aveA1 and aveA2 genes, as well as the upstream region of aveBVIII in vitro. These findings suggest that MtrA exerts a negative regulatory effect on avermectin biosynthesis by modulating the expression of avermectin biosynthesis cluster genes. Transcriptome sequencing and fluorescence quantitative PCR analysis showed that mtrA deletion increased the transcript levels of the cluster genes aveR, aveA1, aveA2, aveC, aveE, aveA4 and orf-1, which explains the observed increase in avermectin production in the knockout strain. Furthermore, our findings demonstrate that MtrA positively regulates the cell division and differentiation genes bldM and ssgC, while exerting a negative regulatory effect on bldD, thereby modulating the primary metabolic processes associated with cell division, differentiation and growth in S. avermitilis, consequently impacting avermectin biosynthesis.ConclusionsIn this study, we investigated the negative regulatory effect of the global regulator MtrA on avermectin biosynthesis and its effects on morphological differentiation and cell growth, and elucidated its transcriptional regulatory mechanism. Our findings indicate that MtrA plays crucial roles not only in the biosynthesis of avermectin but also in coordinating intricate physiological processes in S. avermitilis. These findings provide insights into the synthesis of avermectin and shed light on the primary and secondary metabolism of S. avermitilis mediated by OmpR-family regulators.

The European Union's Regulatory Power: Refining and Illustrating the Concept With the Case of the Transfer of EU Geographical Indication Rules to Japan

AbstractThe European Union's (EU) regulatory power is an increasing focus of scholarly attention, but the lack of a consistent definition leaves room for refinement. Studies investigating the EU's role as a global regulatory actor yield different interpretations, some viewing the EU as a global market regulator, some as a power residing in the trade–regulatory nexus and others as a law‐making entity that creates widely emulated rules. This article refines the definition of the EU's regulatory power by presenting a conceptual framework for better understanding the EU's regulatory actorness, encompassing its ends and means as a general regulator and/or a regulatory power. Using the proposed framework to analyse the transfer of EU geographical indication (GI) rules to Japan, this study finds that the EU's regulatory power is particularly conditioned on the interest constellation between the EU and a third country. Regarding the EU's goal of exercising regulatory power, interest promotion seems to take priority over rule exporting or norm sharing.