Regulatory Responses Research Articles

Nano zinc oxide mediated resuscitation of aged Cajanus cajan via modulating aquaporin, cell cycle regulatory genes and hormonal responses.

Nanoparticle pretreatment improved the health ofaged Cajanus cajan seeds viz., regulation ofredox status, gene expression, andrestoration ofhormonal homeostasis. Ageing deteriorates the quality of seeds by lowering their vigor and viability, and terminating with loss of germination. These days, nanotechnology has been seen to revolutionize the agricultural sectors, and particularly nano zinc oxide (nZnO) has gained considerable interests due to its distinctive properties. The aim of the present work was to decipher the possibilities of using nZnO to rejuvenate accelerated aged (AA) seeds of Cajanus cajan. Both chemically (CnZnO) and green (GnZnO; synthesized using Moringa oleifera) fabricated nZnOs were characterized via standard techniques to interpret their purity, size, and shape. Experimental results revealed erratic germination with a decline in viability and membrane stability as outcomes of reactive oxygen intermediate (ROI) buildup in AA seeds. Application of nZnO substantially rebated the accrual of ROI, along with enhanced production of antioxidants, α-amylase activity, total sugar, protein and DNA content. Higher level of zinc was assessed qualitatively/ histologically and quantitatively in nZnO pulsed AA seeds, supporting germination without inducing toxicity. Meantime, augmentation in the gibberellic acid with a simultaneous reduction in the abscisic acid level were noted in nZnO invigorated seeds than that determined in the AA seeds, suggesting possible involvement of ROI in hormonal signalling. Furthermore, nZnO-subjected AA seeds unveiled differential expression of aquaporins and cell cycle regulatory genes. Summarizing, among CnZnO and GnZnO, later one holds better potential for a revival of AA seeds of Cajanus cajan by providing considerable tolerance against ageing-associated deterioration via recouping the cellular redox homeostasis, hormonal signaling, and alteration in expression patterns of aquaporin and cell cycle regulatory genes.

Sublingual allergen immunotherapy prevents house dust mite inhalant type 2 immunity through dendritic cell-mediated induction of Foxp3+ regulatory T cells

Sublingual allergen immunotherapy (SLIT) is an emerging treatment option for allergic asthma, and a potential disease modifying strategy for asthma prevention. The key cellular events leading to such long term tolerance remains to be fully elucidated. We administered prophylactic SLIT in a mouse model of house dust mite (HDM) driven allergic asthma. HDM extract was sublingually administered over 3 weeks followed by intratracheal sensitization and intranasal challenges with HDM. Prophylactic SLIT prevented allergic airway inflammation and hyperreactivity with a low lab-to-lab variation. The HDM specific Th2 (CD4 T helper) response was shifted by SLIT towards a regulatory and Th17 response in lung and mediastinal lymph node (MLN). By using Der p 1 specific CD4+ T cells (1-DER), we found that SLIT blocked 1-DER T cell recruitment to the MLN and dampened IL-4 secretion following intratracheal HDM sensitization. Sublingually administered Der p 1 protein activated 1-DER T cells in the cervical lymph node (CLN) via CCR7+ migratory dendritic cells (DC). DCs migrating from the oral submucosa to the CLN after SLIT induced Foxp3+ regulatory T cells. When mice were sensitized with HDM, prior prophylactic SLIT increased Der p 1 specific Tregs and lowered Th2 recruitment in the lung. By using Foxp3-DTR mice, Tregs were found to contribute to the immunoregulatory prophylactic effect of SLIT on type 2 immunity. These findings in a mouse model suggest that DC-mediated functional Treg induction in oral mucosa draining LNs is one of the driving mechanisms behind the disease modifying effect of prophylactic SLIT.

Direct synthesis approach to design PDμ${\text{PD}}^\mu$ based smith predictor for integrating plants: Studied on a quadrotor UAV

AbstractThis article presents a simple yet novel method of designing a fractional‐order proportional derivative (namely, ) controller for all types of integrating plants. Considering the importance of the direct synthesis approach, the method obtains robust closed‐loop performance. The setpoint parameter is obtained using the multi‐optimization Pareto solution, considering the optimal values in control efforts and performance index together. The numerical investigations have shown improved servo and regulatory responses compared to recently published strategies with fractional orders. It is also known that classical PIDs cannot accurately follow a ramp setpoint. A real‐world situation also demands that the reference inputs become an acceleration ramp type. The proposed technique can handle rising ramp setpoints with plant uncertainty and measurement noise. Hardware verification is also performed on a quadrotor minidrone to check for real‐time issues.

혁신기술의 사업화와 규제개선

In the era of the Fourth Industrial Revolution, the pace of technological innovation is increasing rapidly. However, the speed of change in laws and regulations has not kept pace, resulting in the so-called regulatory lag. This is because innovative technologies and industries produce new and disruptive things in a remarkable speed, while the regulatory response is slow and lagging behind. This study surveyed 75 companies in the early demonstration stage of technology development to identify the regulatory challenges they have experienced in commercializing innovative technologies and suggested alternatives to solve them. The study found that companies in the early demonstration stage of technology development claimed the absence or lack of a certification system to prove the stability and performance of innovative products as the biggest regulatory obstacle. This shows that appropriate regulations are needed for SMEs' technological innovation rather than deregulation.

Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells.

Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents.

Responsible Business Conduct in Commodity Trading—A Multidisciplinary Review

AbstractResponsible business conduct (RBC)—the corporate activities and initiatives that proactively address corporate involvement in human rights, environmental, and governance threats—has become an increasingly used means to counteract and prevent adverse effects of global businesses. Unlike other business sectors whose adverse impacts and RBC efforts (or lack thereof) are well documented, a comprehensive understanding of the state of commodity trading (CT), has been missing. In response, this paper uses a multidisciplinary literature review to provide an integrative understanding of the current state of research on the relationship between CT and RBC. Based on a review of 131 articles, we advance a granular understanding of the current and prospective role of commodity traders in RBC by grouping extant research into three overarching themes: (1) industry self-regulation and co-regulatory initiatives, (2) government-led regulatory initiatives and policy responses, and (3) company-level management strategies impacting RBC practices. In addition to illustrating the themes through existing research and identifying gaps along the overarching themes, we use our literature review to suggest avenues for future research. The paper’s overarching contribution is, first, to synthesize previously fragmented findings into a coherent framework of CT and RBC. And second, to offer guidance on how scholarship in this important domain can be developed into a more mature, legitimate and practical stream of research.

Implications of Law’s Response to Mitochondrial Donation

Changes to Australian law in 2022 made Australia the second country to expressly permit the clinical use of mitochondrial donation (MD), a technology that makes heritable changes to the human genome. This paper considers these changes in the context of Australia’s broader controls on human embryo use to provide insights into future regulatory responses to other emerging genetic technologies, which could be used in reproduction.

Dual RNA sequencing of Helicobacter pylori and host cell transcriptomes reveals ontologically distinct host-pathogen interaction.

Simultaneous profiling of the dynamic interaction between Helicobacter pylori and the human gastric epithelium represents a novel strategy for identifying regulatory responses that drive pathogenesis. This study presents the first dual-transcriptome analysis of H. pylori when cocultured with gastric epithelial cells, revealing a bacterial adaptation strategy and a general repression of electron transportation-associated genes, both of which were modulated by cytotoxin-associated gene A (cagA). Temporal profiling of host mRNA signatures dissected the aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to H. pylori infection. We demonstrated a protective effect of gastric H. pylori colonization against chronic DSS-induced colitis through both in vitro and in vivo experiments. These findings significantly enhance our understanding of how H. pylori promotes infection and pathogenesis in the human gastric epithelium and provide evidence to identify targets for antimicrobial therapies.

Structure and gene expression changes of the gill and liver in juvenile black porgy (Acanthopagrus schlegelii) under different salinities

Black porgy (Acanthopagrus schlegelii) is an important marine aquaculture species in China. It is an ideal object for the cultivation of low-salinity aquaculture strains in marine fish and the study of salinity tolerance mechanisms in fish because of its strong low-salinity tolerance ability. Gill is the main osmoregulatory organ in fish, and the liver plays an important role in the adaptation of the organism to stressful environments. In order to understand the coping mechanisms of the gills and livers of black porgy in different salinity environments, this study explored these organs after 30 days of culture in hypoosmotic (0.5 ppt), isosmotic (12 ppt), and normal seawater (28 ppt) at histologic, physiologic, and transcriptomic levels. The findings indicated that gill exhibited a higher number of differentially expressed genes than the liver, emphasizing the gill's heightened sensitivity to salinity changes. Protein interaction networks and enrichment analyses highlighted energy metabolism as a key regulatory focus at both 0.5 ppt and 12 ppt salinity in gills. Additionally, gills showed enrichment in ions, substance transport, and other metabolic pathways, suggesting a more direct regulatory response to salinity stress. The liver's regulatory patterns at different salinities exhibited significant distinctions, with pathways and genes related to metabolism, immunity, and antioxidants predominantly activated at 0.5 ppt, and molecular processes linked to cell proliferation taking precedence at 12 ppt salinity. Furthermore, the study revealed a reduction in the volume of the interlamellar cell mass (ILCM) of the gills, enhancing the contact area of the gill lamellae with water. At 0.5 ppt salinity, hepatic antioxidant enzyme activity increased, accompanied by oxidative stress damage. Conversely, at 12 ppt salinity, gill NKA activity significantly decreased without notable changes in liver structure. These results underscore the profound impact of salinity on gill structure and function, highlighting the crucial role of the liver in adapting to salinity environments.

From the Great Recession to the COVID-19 Pandemic: A Financial History of the United States 2010-2020 —A Comparison of the Government’s Response to the Two Financial Crises that Bookended the 2010 to 2020 Decade

This article compares the government's legislative and regulatory response to each of the two financial crises that bookended the 2010-2020 decade and how the response to the COVID-19 crisis was affected by various provisions of the Dodd-Frank Wall Street Reform and Consumer Protection Act enacted in 2010 in response to the 2008 financial crisis. The article concludes with six lessons we learned from these two financial crises experienced in relatively short order: act fast, act with force, act on multiple fronts, regain or retain citizens' confidence in the financial system, ensure access to liquidity, and aid those who are struggling.

Differential expression of immune-related biomarkers in primary cultures from Atlantic salmon (Salmo salar) exposed to processed Paecilomyces variotii with or without inactivated Moritella viscosa

Paecilomyces variotii (a filamentous fungus), is a promising novel protein source in fish feeds due to its high nutritional value. Also, P. variotii has Microbial-Associated Molecular Patterns (MAMPs) such as glucans and nucleic acids that could modulate the host's immune response. To understand the potential bioactive properties of this fungus in Atlantic salmon (Salmo salar), our study was conducted to evaluate the gene expression of immune-related biomarkers (e.g., cytokines, effector molecules and receptors) on primary cultures from salmon head kidney (HKLs) and spleen leukocytes (SLs) exposed to either UV inactivated or fractions from P. variotii with or without inactivated Moritella viscosa (a skin pathogen in salmonids). Moreover, the effect of the fermentation conditions and down-stream processing on the physical ultrastructure and cell wall glucan content of P. variotii was characterized. The results showed that drying had a significant effect on the cell wall ultrastructure of the fungi and the choice of fermentation has a significant effect on the quantity of β-glucans in P. variotii. Furthermore, stimulating Atlantic salmon HKLs and SLs with P. variotii and its fractions induced gene expression related to pro-inflammatory (tnfα, il1β) and antimicrobial response (cath2) in HKLs, while response in SLs was related to both pro-inflammatory and regulatory response (tnfα, il6 and il10). Similarly, the stimulation with inactivated M. viscosa alone led to an up-regulation of genes related to pro-inflammatory (tnfα, il1β, il6) antimicrobial response (cath2), intra-cellular signalling and recognition of M. viscosa (sclra, sclrb) and a suppression of regulatory response (il10) in both HKLs and SLs. Interestingly, the co-stimulation of cells with P. variotii and M. viscosa induced immune homeostasis (il6, tgfβ) and antimicrobial response (cath2) in SLs at 48h. Thus, P. variotii induces immune activation and cellular communication in Atlantic salmon HKLs and SLs and modulates M. viscosa induced pro-inflammatory responses in SLs. Taken together, the results from physical and chemical characterization of the fungi, along with the differential gene expression of key immune biomarkers, provides a theoretical basis for designing feeding trials and optimize diets with P. variotii as a functional novel feed ingredient for Atlantic salmon.

Drug shortages in Israel, revisited: a bitter pill to swallow.

In 2017, we published an article addressing drug shortages (DS) in Israel, exploring regulatory perspectives, challenges, and potential solutions. Since then, DS remain a significant concern for patients, healthcare providers, and policymakers globally. In this updated article, we revisit the topic, providing new insights, data, and analysis on the current DS landscape in Israel, efforts to mitigate them, and propose strategies to combat this escalating issue. We conducted a comprehensive search of the Israeli Ministry of Health (MOH) DS database, spanning from 2014 to the present. We extracted DS numbers and theirreasons. Further searches on the Israeli MOH website, pharmaceutical division archives, and the internet yielded official MOH publications and correspondence regarding regulatory responses to DS from 2017 onwards. Additionally, two specific cases of DS were examined to analyze their handling. Recent activities and publications from the Israeli MOH aimed at reducing DS were also reviewed. Between 2014 and 2022, DS surged 2.66-fold. Total DS were 3228; 672 due to commercial reasons, and 2556 to operational reasons (20.5% and 79.5% respectively). The average duration of intermittent DS increased 1.56-fold, from 85 to 133days. Manufacturers informed the MOH 22days prior to actual shortage on average. Analyzing 2022's DS (640) by ATC groups, prominent categories included nervous system drugs (18%), drugs acting on the alimentary tract and metabolism (14%), and dermatologicals (11%). Operational DS in 2022 (n = 564) were primarily due to stock delivery delays (38%), stock over-utilization (12%), and raw material shortages (9%). Sixteen official MOH publications on DS were identified from 2017 onwards. Moreover, two high-impact DS case studies were examined. Despite routine monitoring by the Israeli MOH and updating the DS policy throughout this period, DS persist, intensifying annually and posing serious health risks. This trend mirrors international patterns, affecting countries globally. In Israel's uniquely structured healthcare system, with its swift stakeholder cooperation and implementation capabilities, more effective DS management is conceivable. We propose ten universally applicable rules to address DS challenges.

Epigenetic control of microglial immune responses.

Microglia, the major population of brain-resident macrophages, are now recognized as a heterogeneous population comprising several cell subtypes with different (so far mostly supposed) functions in health and disease. A number of studies have performed molecular characterization of these different microglial activation states over the last years making use of "omics" technologies, that is transcriptomics, proteomics and, less frequently, epigenomics profiling. These approaches offer the possibility to identify disease mechanisms, discover novel diagnostic biomarkers, and develop new therapeutic strategies. Here, we focus on epigenetic profiling as a means to understand microglial immune responses beyond what other omics methods can offer, that is, revealing past and present molecular responses, gene regulatory networks and potential future response trajectories, and defining cell subtype-specific disease relevance through mapping non-coding genetic variants. We review the current knowledge in the field regarding epigenetic regulation of microglial identity and function, provide an exemplary analysis that demonstrates the advantages of performing joint transcriptomic and epigenomic profiling of single microglial cells and discuss how comprehensive epigenetic analyses may enhance our understanding of microglial pathophysiology.

Regulatory avoidance responses to private Country-by-Country Reporting

Regulatory avoidance responses to private Country-by-Country Reporting

CRISPRi-induced transcriptional regulation of IAH1 gene and its influence on volatile compounds profile in Kluyveromyces marxianus DU3.

Mezcal is a traditional Mexican distilled beverage, known for its marked organoleptic profile, which is influenced by several factors, such as the fermentation process, where a wide variety of microorganisms are present. Kluyveromyces marxianus is one of the main yeasts isolated from mezcal fermentations and has been associated with ester synthesis, contributing to the flavors and aromas of the beverage. In this study, we employed CRISPR interference (CRISPRi) technology, using dCas9 fused to the Mxi1 repressor factor domain, to down-regulate the expression of the IAH1 gene, encoding for an isoamyl acetate-hydrolyzing esterase, in K. marxianus strain DU3. The constructed CRISPRi plasmid successfully targeted the IAH1 gene, allowing for specific gene expression modulation. Through gene expression analysis, we assessed the impact of IAH1 down-regulation on the metabolic profile of volatile compounds. We also measured the expression of other genes involved in volatile compound biosynthesis, including ATF1, EAT1, ADH1, and ZWF1 by RT-qPCR. Results demonstrated successful down-regulation of IAH1 expression in K. marxianus strain DU3 using the CRISPRi system. The modulation of IAH1 gene expression resulted in alterations in the production of volatile compounds, specifically ethyl acetate, which are important contributors to the beverage's aroma. Changes in the expression levels of other genes involved in ester biosynthesis, suggestingthat the knockdown of IAH1 may generate intracellular alterations in the balance of these metabolites, triggering a regulatory response. The application of CRISPRi technology in K. marxianus opens the possibility of targeted modulation of gene expression, metabolic engineering strategies, and synthetic biology in this yeast strain.

From static to dynamic: The influence of mechanotransduction on skin equivalents analyzed by bioimaging and RNAseq

In this study, we explore the impact of mechanical stimuli on skin models using an innovative skin-on-a-chip platform, addressing the limitations of conventional transwell-cultured skin equivalents. This platform facilitates cyclic mechanical stimulation through compression and stretching, combined with automated media perfusion. Our findings, using bioimaging and bulk RNA sequencing, reveal increased expression of Keratin 10 and Keratin 14, indicating enhanced skin differentiation and mechanical integrity. The increase in desmosomes and tight junctions, observed through Claudin-1 and Desmoplakin 1 & 2 analysis, suggests improved keratinocyte differentiation due to mechanical stimulation. Gene expression analyses reveal a nuanced regulatory response, suggesting a potential connection to the Hippo pathway, indicative of a significant cellular reaction to mechanical stimuli. The results show the important influence of mechanical stimulation on skin model integrity and differentiation, demonstrating the potential of our microfluidic platform in advancing skin biology research and pharmaceutical testing.

Data privacy challenges and regulatory responses in cross-border cryptocurrencytransactions: A comparative analysis

Data privacy challenges and regulatory responses in cross-border cryptocurrencytransactions: A comparative analysis

Nanoplastics increase in vitro oestrogenic activity of neurotherapeutic drugs.

Environmental pollution with plastic nanoparticles (PNPs) has rendered hazard assessment of unintentional human exposure to neurotherapeutic drugs through contaminated water and food ever more complicated. Due to their small size, PNPs can easily enter different cell types and cross different biological barriers, while their high surface-to-volume ratio enables higher adsorption of chemicals. This is how PNPs take the role of a Trojan horse as they enhance bioaccumulation of many different pollutants. One of the health concerns related to water pollution with neurotherapeutic drugs is endocrine disruption, already evidenced for the anticonvulsant drug carbamazepine (Cbz) and antidepressant fluoxetine (Flx). Our study aimed to evaluate endocrine disrupting effects of Cbz and Flx in mixtures with polystyrene nanoparticles (PSNPs) using the in vitro luciferase assay to measure oestrogen receptor activity in T47D-KBluc cells treated with Cbz-PSNPs or Flx-PSNPs mixtures and compare it with the activities observed in cells treated with individual mixture components (Cbz, Flx, or PSNPs). Dose ranges used in the study were 0.1-10 mg/L, 1-100 µmol/L, and 0.1-10 µmol/L for PSNPs, Cbz, and Flx, respectively. Our findings show that none of the individual components activate oestrogen receptors, while the mixtures induce oestrogen receptor activity starting with 0.1 mg/L for PSNPs, 10 µmol/L for Cbz, and 0.5 µmol/L for Flx. This is the first study to evidence that PSNPs increase oestrogen receptor activity induced by neurotherapeutic drugs at their environmentally relevant concentrations and calls for urgent inclusion of complex mixtures in health hazard assessments to inform regulatory response.

Business In (Action): The International Chamber of Commerce and Climate Change from Stockholm to Rio

This paper engages with the literature that has looked at the historical response to climate change among industries positioned to have had a far-reaching impact on changing the course of the climate crisis. While much of the historical research in this domain has focused on the role of big oil companies, the utility industry and conservative think tanks in the manufacturing of doubt regarding climate science and opposing ambitions climate policies, our focus is on the International Chamber of Commerce (ICC) – the world’s largest transnational business association. Unlike individual multinational corporations, the ICC developed a close ties and collaborations with the United Nations Environment Programme (UNEP), which made ICC positioned to influence international policy discussions. This study finds that the ICC developed a dual strategy, which set aside climate change as the focus for discussion and business action. One strategy, led by ICC Environment Committee, involved intense collaboration with the United Nations and developing a business agenda for sustainable development. At the same time, the creation of the International Panel of Climate Change (IPCC) in 1988 and the Intergovernmental Negotiating Committee for a Framework Convention on Climate Change (INC) in 1991, gave rise to a parallel strategy, led by ICC’s related oil companies. As this study finds, the ICC’s Energy Committee developed close ties to the Global Climate Coalition, a front group designed to combat the scientific evidence of climate change. The paper concludes that the ICC was able to delay meaningful regulatory response to climate change the between 1988-1992 by forming a broad coalition of competing interests and collaborating with agencies established under the auspices of the United Nations.

Algorithmic Trading and AI: A Review of Strategies and Market Impact

This review explores the dynamic intersection of algorithmic trading and artificial intelligence (AI) within financial markets. It delves into the evolution, strategies, and broader market impact of algorithmic trading fueled by AI technologies. Examining the symbiotic relationship between advanced algorithms and AI, the review navigates through the various strategies employed, shedding light on their implications for market efficiency, liquidity, and overall stability. From high-frequency trading to machine learning-driven predictive analytics, this review unveils the multifaceted landscape of algorithmic trading in the era of AI, presenting both opportunities and challenges for financial markets. The review begins by tracing the historical development of algorithmic trading, emphasizing the paradigm shift with the integration of AI. From traditional programmatic trading to the emergence of sophisticated algorithms driven by machine learning and deep learning, the evolution sets the stage for a comprehensive understanding of the subject. An in-depth analysis of diverse algorithmic trading strategies unfolds, covering areas such as trend following, statistical arbitrage, market making, and sentiment analysis. The incorporation of AI introduces adaptive learning capabilities, enabling algorithms to evolve and optimize strategies based on real-time market conditions. Exploring the impact of algorithmic trading on financial markets, the review examines how AI-driven strategies contribute to market efficiency, liquidity provision, and price discovery. It dissects the implications for traditional market structures, regulatory considerations, and the potential risks associated with algorithmic dominance. Acknowledging the transformative power of algorithmic trading with AI, the review critically assesses the challenges and ethical considerations. From algorithmic bias to systemic risks, the review delves into the darker corners of this technological advancement, prompting a reflection on the need for responsible and transparent practices. The review concludes by peering into the future trajectory of algorithmic trading fueled by AI. Anticipated innovations, regulatory responses, and the evolving landscape of financial markets are discussed, offering insights into the ongoing transformation and potential disruptions in the realm of algorithmic trading. In essence, this review provides a nuanced perspective on the intricate relationship between algorithmic trading and AI, offering a comprehensive understanding of their strategies and the transformative impact on financial markets.