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Caffeoyl-coenzyme 3 A-O-methyltransferase (CCoAOMT) plays a crucial role in the lignin synthesis in many higher plants. In this study, nine PbCCoAOMT genes in total were identified from pear, and classified into six categories. We treated pear fruits with hormones abscisic acid (ABA) and methyl jasmonate (MeJA) and salicylic acid (SA) and observed differential expression levels of these genes. Through qRT-PCR, we also preliminarily identified candidate PbCCoAOMT gene, potentially involved in lignin synthesis in pear fruits. Additionally, the overexpression of PbCCoAOMT1/2 in Arabidopsis and pear fruits increased in lignin content. Enzymatic assays showed that recombinant PbCCoAOMT1/2 proteins have similar enzymatic activity in vitro. The Y1H (Yeast one-hybrid) and dual luciferase (dual-LUC) experiments demonstrated that PbMYB25 can bind to the AC elements in the promoter region of the PbCCoAOMT1 gene. Our findings suggested that the PbCCoAOMT1 and PbCCoAOMT2 genes may contribute to the synthesis of lignin and provide insights into the mechanism of lignin biosynthesis and stone cell development in pear fruits., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Diapers are a staple care product for infants, yet concerns persist regarding the potential risks posed by dermal exposure to chemicals through their usage. This review provides a comprehensive summary of reported chemicals, highlighting the frequent detection of polychlorodibenzo-p-dioxins (PCDDs), phthalates (PAEs), volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs), bisphenols (BPs), organotins, and heavy metals. Disposable diapers commonly exhibit higher concentrations of VOCs, PAEs, BPs, and heavy metals than other chemicals. Our estimation reveals formaldehyde as posing the highest dermal exposure dose, reaching up to 0.018 mg/kg bw/day. Conversely, perfluorooctanoic acid (PFOA) exhibits lower exposure, but its non-cancer hazard quotient (0.062) is the highest. In most scenarios, the risk of chemical exposure through diapers for infants is deemed acceptable, while the risk is higher under some extreme exposure scenarios. Using the cancer slope factor recently suggested by U.S. EPA, the cancer risk in diapers raised by PFOA is 5.5 × 10 -5 . It should be noted that our estimation is approximately 1000-10,000 folds lower than some previous estimations. The high uncertainties associated with exposure and risk estimations are primarily raised by unclear parameters related to chemical migration coefficients, absorption factors, concentrations, and toxicity data for skin exposure, which requires research attention in future. Besides that, future research endeavors should prioritize the identification of potential toxic chemicals and the development of hygiene guidelines and standards., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Regulating secondary metabolite (SM) in Myxococcus xanthus bears the potential to influence the formation of important natural products with various biological activities. The authors of this study have previously found that the detectable levels of two proteins (4-hydroxyphenylpyruvate dioxygenase [HppD] and a Hsp90-like protein  [HtpG]) are affected by ROK inactivation. As evidence, the current study was designed to elucidate the possible role of these two proteins in regulating the SMs' biosynthesis in this bacterium. To begin with, inactivation of the corresponding genes was carried out, and two mutant strains (M. xanthus hppD - and htpG - ) were constructed. Subsequently, high-performance liquid chromatography coupled with mass spectrometry analysis for the metabolic extracts of the mutants revealed a significant reduction in the production of several SMs, like DKxanthene, myxalamide A, and myxochromide A, in comparison to the wild type. Furthermore, electrophoretic mobility shift assays using purified ROK protein suggested a direct binding on the genes' promoter region encoding the two proteins under study. It is therefore possible to conclude that hppD and htpG genes are implicated in the bacterium SMs' biosynthetic regulatory cascade, which seems to be directly regulated by the ROK protein. The present study provides additional evidence to a previous investigation showing the pleiotropic regulatory role of ROK on the production of SMs in M. xanthus., (© 2024 International Union of Biochemistry and Molecular Biology, Inc.)

How do cells coordinate the diverse elements that regulate their cholesterol homeostasis? Our model postulates that membrane cholesterol forms simple complexes with bilayer phospholipids. The phospholipids in the plasma membrane are of high affinity; consequently, they are fully complexed with the sterol. This sets the resting level of plasma membrane cholesterol. Cholesterol in excess of the stoichiometric equivalence point of these complexes has high chemical activity; we refer to it as active cholesterol. It equilibrates with the low affinity phospholipids in the intracellular membranes where it serves as a negative feedback signal to a manifold of regulatory proteins that rein in ongoing cholesterol accretion. We tested the model with a review of the literature regarding fourteen homeostatic proteins in enterocytes. It provided strong albeit indirect support for the following hypothesis. Active cholesterol inhibits cholesterol uptake and biosynthesis by suppressing both the expression and the activity of the gene products activated by SREBP-2; namely, HMGCR, LDLR and NPC1L1. It also reduces free cell cholesterol by serving as the substrate for its esterification by ACAT and for the synthesis of side-chain oxysterols, 27-hydroxycholesterol in particular. The oxysterols drive cholesterol depletion by promoting the destruction of HMGCR and stimulating sterol esterification as well as the activation of LXR. The latter fosters the expression of multiple homeostatic proteins, including four transporters for which active cholesterol is the likely substrate. By nulling active cholesterol, the manifold maintains the cellular sterol at its physiologic set point., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Lignocellulolytic clostridia employ multiple pairs of alternative σ/anti-σ (SigI/RsgI) factors to regulate cellulosomal components for substrate-specific degradation of cellulosic biomass. The current model has proposed that RsgIs use a sensor domain to bind specific extracellular lignocellulosic components and activate cognate SigIs to initiate expression of corresponding cellulosomal enzyme genes, while expression of scaffoldins can be initiated by several different SigIs. Pseudobacteroides cellulosolvens contains the most complex known cellulosome system and the highest number of SigI-RsgI regulons yet discovered. However, the function of many RsgI sensor domains and their relationship with the various enzyme types are not fully understood. Here, we report that RsgI4 from P. cellulosolvens employs a C-terminal module that bears distant similarity to the fibronectin type III (Fn3) domain and serves as the sensor domain. Substrate-binding analysis revealed that the Fn3-like domain of RsgI4 represents a novel carbohydrate-binding module (CBM) that binds to a wide range of polysaccharide types. Structure determination further revealed that the Fn3-like domain belongs to the type B group of CBMs with a predicted concave face for substrate binding. Promoter sequence analysis of cellulosomal genes revealed that SigI4 is responsible for cellulosomal regulation of major scaffoldins rather than enzymes, consistent with the broad substrate specificity of the RsgI4 sensor domain. Notably, scaffoldins are invariably required as cellulosome components regardless of the substrate type. These findings suggest that the intricate cellulosome system of P. cellulosolvens comprises a more elaborate regulation mechanism than other bacteria and thus expands the paradigm of cellulosome regulation., (© 2024 The Protein Society.)

Healthy cells have developed a sophisticated network of antioxidant molecules to prevent the toxic accumulation of reactive oxygen species (ROS) generated by diverse environmental stresses. On the opposite, cancer cells often exhibit high levels of ROS and an altered levels of antioxidant molecules compared to normal cells. Among them, the antioxidant enzyme catalase plays an essential role in cell defense against oxidative stress through the dismutation of hydrogen peroxide into water and molecular oxygen, and its expression is often decreased in cancer cells. The elevation of ROS in cancer cells provides them proliferative advantages, and leads to metabolic reprogramming, immune escape and metastasis. In this context, catalase is of critical importance to control these cellular processes in cancer through various mechanisms. In this review, we will discuss the major progresses and challenges in understanding the role of catalase in cancer for this last decade. This review also aims to provide important updates regarding the regulation of catalase expression, subcellular localization and discuss about the potential role of microbial catalases in tumor environment. Finally, we will describe the different catalase-based therapies and address the advantages, disadvantages, and limitations associated with modulating catalase therapeutically in cancer treatment., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest to be disclosed., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

For public interest advocates engaged on issues of worker health and safety and environmental protections, regulatory cost-benefit analysis has long been seen as an obstacle to meaningful progress. In November 2023, the Biden administration overhauled Circular A-4, which provides guidance to agencies on how to perform cost-benefit analyses for their rules. The reforms seek to make cost-benefit analysis less biased against worker safety, public health, environmental, and other protective safeguards. As such, the new version of Circular A-4 offers important new levers to agencies to justify more stringent protections. By extension, those in the public interest community can use agency implementation of the new Circular A-4 as part of their advocacy efforts for specific rules they are tracking. This article seeks to support this tactic by providing a roadmap for advocates on how to incorporate into their comments critiques of agencies' cost-benefit analyses based on the Circular A-4 revisions., Competing Interests: Declaration of Conflicting InterestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Microcapsules encapsulating payloads are one of the most promising delivery methods. The mechanical properties of microcapsules often determine their application scenarios. For example, microcapsules with low mechanical strength are more widely used in biomedical applications due to their superior biocompatibility, softness, and deformability. In contrast, microcapsules with high mechanical strength are often mixed into the matrix to enhance the material. Therefore, characterizing and regulating the mechanical properties of microcapsules is essential for their design optimization. This paper first outlines four methods for the mechanical characterization of microcapsules: nanoindentation technology, parallel plate compression technology, microcapillary technology, and deformation in flow. Subsequently, the mechanisms of regulating the mechanical properties of microcapsules and the progress of applying microcapsules with different degrees of softness and hardness in food, textile, and pharmaceutical formulations are discussed. These regulation mechanisms primarily include altering size and morphology, introducing sacrificial bonds, and construction of hybrid shells. Finally, we envision the future applications and research directions for microcapsules with tunable mechanical properties., (Copyright © 2024. Published by Elsevier B.V.)

Caspase 9 (CASP9) is a well-known initiator caspase of intrinsic apoptosis. In humans, cIAP1 binds and induces degradation of the activated form of CASP9, but not pro-CASP9. In fish, the activity and regulation of CASP9 remain unknown. In this work, using flounder Paralichthys olivaceus as a representative species, we examined the regulatory mechanism of CASP9 in teleost. P. olivaceus CASP9 (PoCASP9) induced robust apoptosis, which was inhibited by P. olivaceus cIAP1 (PocIAP1). Unlike human cIAP1, PocIAP1 bound both pro- and active PoCASP9 and induced their degradation via the RING domain-involved proteasome pathway. In humans, the adaptor molecule CRADD cannot interact with CASP9. In contrast, P. olivaceus CRADD (PoCRADD) bound both pro- and active PoCASP9 via CARD-CARD interaction and enhanced apoptosis by promoting the cellular levels of pro- and active PoCASP9. Furthermore, PoCRADD abrogated the inhibition of PoCASP9 by PocIAP1 by preventing PocIAP1-PoCASP9 interaction. Together these results reveal a CASP9 regulation mechanism in teleost that differs from that in humans and demonstrate that teleost CASP9 is tightly and directly controlled by both negative and positive regulators that exert a regulation effect both before and after CASP9 activation. These findings advance our understanding of the regulation of CASP9-mediated apoptosis in vertebrates., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer is a disease that poses a serious threat to human health, the occurrence and development of which involves complex molecular mechanisms. Long non‑coding RNAs (lncRNAs) and RNA‑binding proteins (RBPs) are important regulatory molecules within cells, which have garnered extensive attention in cancer research in recent years. The binding of lncRNAs and RBPs plays a crucial role in the post‑transcriptional regulation of mRNA, affecting the synthesis of proteins related to cancer by regulating the stability of mRNA. This, in turn, regulates the malignant biological behaviors of tumor cells, such as proliferation and metastasis, and serves an important role in therapeutic resistance. The present study reviewed the role of lncRNA‑RBP interactions in the regulation of mRNA stability in various malignant tumors, with a focus on the molecular mechanisms underlying this regulatory interaction. The aim of the present review was to gain a deeper understanding of these molecular mechanisms to provide new strategies and insights for the precise treatment of cancer.

Poly(malic acid) (PMLA) as one of the important metabolites in Aureobasidium pullulans has great application in a variety of fields. LaeA, a global regulator capable of controlling fungal secondary metabolites, has been identified in A. pullulans. The involvement of LaeA in the biosynthesis of PMLA through direct or indirect means and its role in A. pullulans is currently unknown. Here we extracted and characterized the AplaeA gene from A. pullulans HIT-LCY3 T and resolved it by bioinformatics. The function of AplaeA was subsequently characterized by Rnai-LaeA and OEX-LaeA mutants. Based on phenotypic observations of the mutant strains, it was found that the gene had a large effect on the morphology and melanin production aspects of the strain, and that overexpression of the AplaeA gene resulted in a substantial increase in spore numbers. RT-qPCR combined with protein interactions results analyzed that ApLaeA positively regulates PMLA biosynthesis by controlling the expression of core genes of PMLA biosynthesis gene cluster and other related regulatory factors. Finally, OEX-LaeA was used as the starting strain to obtain the optimal fermentation conditions. These findings illustrate the regulatory mechanism of a hypothesized global regulator, LaeA, in A. pullulans HIT-LCY3 T , suggesting its potential application in industrial-scale PMLA biosynthesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Background: Medical device expenditures have increased in the 21st century, with cardiac devices comprising an outsized portion of the market. Meanwhile, the disproportionate share of FDA recalls of cardiac devices is often overshadowed. Using the FDA 510(k) premarket notification pathway and FDA recalls issued from 2000 to 2020, this project seeks to engage our understanding of innovation and recalls in the cardiac device space., Methods: 510(k) premarket notification submission dates, outcomes, and recalls from 1/1/2000 to 12/31/2019 were obtained from publicly available FDA data as a function of cardiac device innovation. We compared the annual number of 510(k) premarket clearances and FDA recalls from 1/1/2000 to 12/31/2009 to 1/1/2010 to 12/31/2019., Results: We found 343 moderate risk cardiac medical devices cleared for sale between the years 2000 and 2020. Comparing the last 10 years of the study period to the first, the yearly number of cleared devices decreased 39.7 %, from 21.4 to just 12.9 (p = 0.0019), defying positive trends in U.S. GDP and healthcare expenditures. Meanwhile, the number of FDA recalls issued for these devices increased 94.5 % from 7.3 to 14.2 recalls per year (p = 0.031). 215 device recalls were issued; 78 % Class II and 16 % Class I which constitute serious, potentially fatal recalls., Conclusions: While United States healthcare spending continues to trend upward, there was a distinct decrease in the number of new and updated cardiac devices entering the market between 2000 and 2020. Meanwhile, recalls of these devices have uncomfortably increased. Together, these trends suggest cardiac device innovation has become risk averse., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Heme, an iron-containing tetrapyrrole in hemoproteins, including: hemoglobin, myoglobin, catalase, cytochrome c, and cytochrome P450, plays critical physiological roles in different organisms. Heme-derived chemicals, such as biliverdin, bilirubin, and phycocyanobilin, are known for their antioxidant and anti-inflammatory properties and have shown great potential in fighting viruses and diseases. Therefore, more and more attention has been paid to the biosynthesis of hemoproteins and heme derivatives, which depends on the adequate heme supply in various microbial cell factories. The enhancement of endogenous biosynthesis and exogenous uptake can improve the intracellular heme supply, but the excess free heme is toxic to the cells. Therefore, based on the heme-responsive regulators, several sensitive biosensors were developed to fine-tune the intracellular levels of heme. In this review, recent advances in the: biosynthesis, acquisition, regulation, and upcycling of heme were summarized to provide a solid foundation for the efficient production and application of high-value-added hemoproteins and heme derivatives.

The production of cellulolytic enzymes in response to inducible carbon sources is mainly regulated at the transcriptional level in filamentous fungi. We have identified a cellobiose-response regulator (ClbR) controlling the expression of cellulolytic enzyme-encoding genes in Aspergillus aculeatus. However, the engineering potential of combining the deletion of transcriptional repressors with the overexpression of transcriptional activators to enhance enzyme production has not been analyzed. Here, we investigated the effect of the deletion of the transcriptional repressor creA and the overexpression of the transcriptional activator clbR in enzyme production in A. aculeatus. Here, we verified that a combination of creA deletion and clbR overexpression (Δc&OE) improved cellulase, β-1,4-xylanase, and β-glucosidase production. Cellulase and β-1,4-xylanase production increased 3.4- and 8.0-fold in Δc&OE compared with the host strain (MR12) at 96-h incubation, respectively. β-Glucosidase production in ΔcreA and Δc&OE increased approximately 5.0-fold compared with that in MR12 at 240-h incubation. Transcriptional analysis revealed that the increase in enzyme production was due to increased expression of cellobiohydrolase, endo-β-1,4-glucanase, β-1,4-xylanase, and β-glucosidase 1 (bgl1). Interestingly, bgl1 expression in ΔcreA increased in a dose-dependent manner in response to glucose. Thus, combinational manipulation of transcription factors improved cellulase, xylanase, and β-glucosidase production in A. aculeatus., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Nitrous oxide (N 2 O) is a potent greenhouse gas (GHG) and an ozone-depleting substance. The presence of plants in an ecosystem can either increase or decrease N 2 O emissions, or play a negligible role in driving N 2 O emissions. Here, we conducted a meta-analysis comparing ecosystem N 2 O emissions from planted and unplanted systems to evaluate how plant presence influences N 2 O emissions and examined the mechanisms driving observed responses. Our results indicate that plant presence reduces N 2 O emissions while it increases dinitrogen (N 2 ) emissions from ecosystems through decreases in soil nitrate concentration as well as increases in complete denitrification and mineral N immobilization. The response of N 2 O emissions to plant presence was universal across major terrestrial ecosystems - including forests, grassland and cropland - and it did not vary with N fertilization. Further, in light of the potential mechanisms of N 2 O formation in plant cells, we discussed how plant presence could enhance the emission of N 2 O from plants themselves. Improving our understanding of the mechanisms driving N 2 O emissions in response to plant presence could be beneficial for enhancing the robustness for predictions of our GHG sinks and sources and for developing strategies to minimize emissions at the ecosystem scale., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests that could appear to influence the work of this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Antimicrobial resistance (AMR) poses a significant global health threat, as it contributes to prolonged illness, higher mortality rates and increased healthcare costs. As traditional antibiotics become less effective, treatments such as bacteriophage therapy offer potential solutions. The question remains, however, on how to set research priorities in the face of a growing number of antibiotic-resistant pathogens, some common and/or dangerous. One standard way of making decisions about which research to prioritise is by using the disability-adjusted life year metric to estimate the current global impact of a disease or condition, combined with considerations of social justice although decisions made at a national level by governments, especially in low income countries with forecasting potential over future needs may look very different. Another approach is based on the needs of researchers and regulators given what we know about the technology itself. The biological characteristics of bacteriophage therapies set challenges to a universal and standardised prioritisation method. A proof of principle is still arguably needed. With a preliminary discussion of the scope and complexity of AMR and AMR therapeutics, we propose some implications of regulatory frameworks aiming to integrate bacteriophage therapy into mainstream medical practice while gathering scientific data on safety and efficacy, enhancing the collective action needed to combat AMR., (© 2024 The Author(s).)

Background: Although the majority of cannabinoid research has focused on delta-9-tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD), there is increasing interest in the therapeutic effects of other phytocannabinoid compounds (i.e., minor cannabinoids), as there is little known about their effects or interaction with CBD. The current study objective was to determine the concentrations of 15 minor cannabinoids in unregulated, over-the-counter CBD products. Methods: A cross-section sample of 80 local and national brands of hemp-derived oil products was purchased both online and in local retail outlets in central Kentucky. Epidiolex® was included as a regulated control. Samples from each product were extracted by solvent extraction and quantified by liquid-chromatography tandem mass-spectrometry. The targeted cannabinoids were: cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid, Δ 9 -tetrahydrocannabivarin, Δ 9 -tetrahydrocannabivarinic acid, Δ 9 -tetrahydrocannabinolic acid-A, Δ 8 -tetrahydrocannabinol (Δ 8 -THC), cannabigerol (CBG), cannabigerolic acid, cannabinol (CBN), cannabinolic acid, cannabicyclol (CBL), cannabicyclolic acid, cannabichromene (CBC) and cannabichromenic acid. Results: Among the unregulated products included in this analysis, the most frequently detected minor cannabinoids were CBDV (100% of samples tested), CBG (77%), CBC (72%), CBN (67%), CBL (67%), and CBDA (51%). Δ 8 -THC was not detected in any of the products tested. Concentrations of these cannabinoids varied widely from trace concentrations to several mg/mL (e.g., CBDA: 0.006-12.258 mg/mL). Conclusions: These data indicate CBD products often contain minor cannabinoids, although the array and concentrations of these cannabinoids vary widely across products. The concentrations of these minor cannabinoids are largely absent from product labels, leaving consumers uninformed about product contents.

Protein arginine methylation is a versatile post-translational protein modification that has notable cellular roles such as transcriptional activation or repression, cell signaling, cell cycle regulation, and DNA damage response. However, in spite of their extensive significance in the biological system, there is still a significant gap in understanding of the entire function of the protein arginine methyltransferases (PRMTs). It has been well-established that PRMTs form homo-oligomeric complexes to be catalytically active, but in recent years, several studies have showcased evidence that different members of PRMTs can have cross-talk with one another to form hetero-oligomeric complexes. Additionally, these heteromeric complexes have distinct roles separate from their homomeric counterparts. Here, we review and highlight the discovery of the heterodimerization of PRMTs and discuss the biological implications of these hetero-oligomeric interactions., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Reactive oxygen species (ROS) are among the most important signaling molecules, playing a significant role in plant growth, development, and responses to various environmental stresses. Respiratory burst oxidase homologs (RBOHs) are key enzymes in ROS production. Plants tightly regulate the activation and deactivation of RBOHs through various post-translational modifications (PTMs), including phosphorylation, ubiquitination, S-nitrosylation, and persulfidation. These PTMs fine-tune ROS production, ensuring normal plant growth and development while facilitating rapid responses to abiotic and biotic stresses. This review discusses the effects of different PTMs on RBOH function and their biological relevance. Additionally, we examine the evolutionary conservation of PTM sites and emphasize the complex interplay between multiple PTMs regulating RBOHs., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

nc886 is a regulatory noncoding RNA that is transcribed by RNA polymerase III (Pol III), is variably expressed in different biological contexts, and plays roles in inflammation and cancer. Epigenetic mechanisms play an intriguing role in regulating nc886 expression. As a maternally imprinted gene and metastable epiallele, nc866 exhibits polymorphic imprinting, with a methylation status that is influenced by environmental and biological factors. Consequently, the promoter DNA methylation status and the different resulting RNA expression levels of nc886 are associated with physiological and pathological conditions. In this review, we summarize the literature and explore the significance in relation to diverse roles of nc886.

Foodborne diseases, especially those caused by zoonotic agents, pose a significant threat to human health. Food business operators are therefore responsible for producing safe food. To do this, they must regularly carry out appropriate sample investigations to detect zoonotic agents in their food before it leaves the factory. Depending on the issue investigated, there may be legal requirements for food business operators, usually specifying minimum sample sizes, such as Commission Regulation (EU) No 2073/2005. However, in most cases there is no information on the precision, and therefore, on the significance of the results for these sample sizes. Regulatory veterinary authorities have a control function and, as a result, they are required to regularly evaluate the available investigations and their results. In addition, in certain crisis situations (e.g., foodborne outbreaks or suspected food contamination), authorities may guide food business operators in their investigations and conduct their own investigations to assess food safety measures. In such cases, as there are no legally defined sample sizes to be taken, the appropriate sample sizes must be determined by the authorities. This can lead to a conflict between the need for feasibility and the need for conclusiveness of the investigation potentially being a challenge for the regulatory authority in charge. This paper highlights the importance of thoughtful study design and the critical communication of available results by veterinary authorities on the background of a use case involving Listeria monocytogenes findings in a crisis situation. Using the minimum sample size, n=5, required by Regulation (EU) No 2073/2005 for the pathogen Listeria monocytogenes as a guide, the uncertainties associated with small sample sizes are highlighted. It also aims to facilitate the evaluation of studies performed and the assessment of further sample sizes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate post-transcription and influence various biological processes across species. Despite various studies of miRNAs in vertebrates, plants, and other organisms, miRNA data in aquatic invertebrates are insufficient. In this study, we identified miRNAs from four aquatic invertebrate species that are widely used in aquatic toxicology: the rotifer Brachionus koreanus, the water flea Daphnia magna, the cyclopoid copepod Paracyclopina nana, and the harpacticoid copepod Tigriopus japonicus, using next-generation sequencing and in silico analysis. We identified total 188, 41, 47, and 100 miRNAs from each species, and target genes were predicted based on 3'-untranslated region information. Target prediction and functional annotation results provided the biological processes of these miRNAs in various development-related mechanisms, signaling transduction, and metabolism-related pathways. Moreover, the network between the miRNAs and their targets concerning defense-related and antioxidant genes suggests the suitability of miRNAs as biomarkers in ecotoxicological studies., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Health and social care employees may be involved in professional regulatory proceedings because their alleged behaviour raises health or conduct concerns. Employees, patients or service users may also be involved in a regulatory tribunal as witnesses. This study is about the role of employers in supporting them in this process., Methods: Taking an organisational support perspective, we interviewed 25 senior employees in health and social care organisations in the UK who are responsible for managing the employer's role in the proceedings. Template analysis was used to analyse the transcripts., Results: Support for patients was limited to that offered during an employer's complaints process, and only one employer gave some support during the regulatory process if the patient or service user initiated regulatory proceedings. Support for employees in tribunals was little different to that offered during an initial investigation by the employer. However, where additional support for being involved in a regulatory tribunal was offered to employees, it most often came from the senior employees' own experience of the stressfulness of being a witness in these proceedings. Employers were not aware of training resources that would better support their employees to engage with professional regulatory proceedings., Conclusions: Employers offer limited support to employees who are involved in professional regulatory proceedings, and the support offered may depend more on senior employee's individual experience of involvement in regulatory proceedings to exercise this discretion. Patients, service users and other public witnesses receive almost no support from health and social care employers during professional regulatory proceedings., (© 2024. The Author(s).)

Situated within the context of increasing "adult regulatory practices" in skateboarding, this article draws attention to and interrogates the ways normative ideas of "youth," "adolescence," and "youth/adolescent development" often interplay with such efforts. In doing so, this article offers a critique, from a Critical Youth Studies perspective, of dominant, developmentalist notions of youth that typically cast young people as deficits in need of specific forms of intervention and surveillance. The article concludes with areas of inquiry emergent from critiques of dominant renderings of youth to be considered when engaging in processes of forming regulatory programs, policies, and practices related to skateboarding., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Petrone.)

Background: The Jun proto-oncogene ( JUN ), also referred to as C-JUN , is an integral component of the JNK signaling pathway, which is crucial for the formation and differentiation of spermatogonial stem cells (SSCs). Investigations into the transcriptional regulation of chicken JUN can offer a molecular foundation for elucidating its mechanistic role in SSCs. Methods: In this study, we successfully cloned a 2000 bp upstream sequence of the JUN transcription start site and constructed a series of pGL3 recombinant vectors containing JUN promoters of varying lengths. Results: We verified the promoter activity of the 2000 bp upstream sequence by assessing the fluorescence intensity of DF-1 and identified the promoter activities of different regions via dual-luciferase assays. The transcription of JUN and its promoter region spanning -700 to 0 bp was modulated by an activator of the JNK signaling pathway. Bioinformatics analysis revealed that this -700 to 0 bp region was highly conserved among avian species and predicted the presence of binding sites for Wilms tumor 1 ( WT1 ) and CCAAT/enhancer binding protein alpha ( CEBPA ). The JNK signaling pathway activator was found to upregulate the expression of these transcription factors in DF-1 cells. Through the deletion of binding sites and the overexpression of WT1 and CEBPA , we demonstrated that WT1 inhibited the transcription of JUN , while CEBPA promoted it. Conclusions: In conclusion, the -700 to 0 bp region is the key region of the JUN promoter, with WT1 inhibiting JUN transcription. The results of the study not only provide ideas for exploring the regulatory mechanism of JUN in chicken SSCs, but also lay an important foundation for the study of avian SSCs.

Following an outbreak of Cronobacter sakazakii infection in infant formula, the US Food and Drug Administration commissioned a series of reports and then undertook a major reorganization of its food program. This article describes the changes that went into effect on 1 October 2024, why those changes are likely to improve the new Human Foods Program, and additional work that must be undertaken to enhance the agency's impact upon public health.

Carotenoids are a large class of isoprenoid compounds which are biosynthesized by plants, algae, along with certain fungi, bacteria and insects. In plants, carotenoids provide crucial functions in photosynthesis and photoprotection. Furthermore, carotenoids also serve as precursors to apocarotenoids, which are derived through enzymatic and non-enzymatic cleavage reactions. Apocarotenoids encompass a diverse set of compounds, including hormones, growth regulators, and signaling molecules which play vital roles in pathways associated with plant development, stress responses, and plant-organismic interactions. Regulation of carotenoid biosynthesis indirectly influences the formation of apocarotenoids and bioactive effects on target pathways. Recent discovery of a plethora of new bioactive apocarotenoids across kingdoms has increased interest in expanding knowledge of the breadth of apocarotenoid function and regulation. In this review, we provide insights into the regulation of carotenogenesis, specifically linked to the biosynthesis of apocarotenoid precursors. We highlight plant studies, including useful heterologous platforms and synthetic biology tools, which hold great value in expanding discoveries, knowledge and application of bioactive apocarotenoids for crop improvement and human health. Moreover, we discuss how this field has recently flourished with the discovery of diverse functions of apocarotenoids, thereby prompting us to propose new directions for future research., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In general, the initiation or closure of antibiotic biosynthesis is determined by regulatory proteins, but most of their mechanisms of action remain unknown. The 2-deoxystreptamine-containing aminoglycosides (2-DOS AGs) form a unique category among antibiotics. Genomic analysis revealed that a group of hypothetical regulatory genes represented by neoI are widely distributed in the biosynthetic gene clusters (BGCs) of natural products from Streptomyces species, including several 2-DOS AGs. Only limited knowledge is available for the roles of NeoI-type regulators although neomycin and some of the related AGs have been developed as therapeutic drugs for decades. This study focuses on the functional determination of neoI and its homologues situated in the BGCs of six AGs. We found that the yield of neomycin in neoI disruption mutant (ΔneoI) increased by 50% compared to the wild-type (WT) strain ((420.6±44.1) mg L -1 ), while it was partially restored by the complementation of neoI, demonstrating that NeoI acted as a repressor in neomycin biosynthesis. Further electrophoretic mobility shift assays (EMSAs) and DNase I footprinting assays indicated that NeoI could specifically bind to the promoter region between neoE and neoI with conserved nucleotides (5'-CVHYMRCHDKAGYGGACR-3'), as determined by site-directed mutagenesis. Interestingly, cross-bindings of the NeoI homologues from the six different BGCs to their corresponding DNA targets were manifested, and the five exogenous NeoI homologues could complement NeoI function of repressing neomycin biosynthesis. Our results suggested that NeoI-type regulators represent widespread and conservative regulatory characteristics in the biosynthesis of 2-DOS AGs, which would be significant for optimizing the biosynthetic pathways of valuable commercialized aminoglycoside antibiotics., (© 2024. Science China Press.)

The Zrt/Irt-like protein (ZIP) family consists of ubiquitously expressed divalent d -block metal transporters that play central roles in the uptake, secretion, excretion, and distribution of several essential and toxic metals in living organisms. The past few years has witnessed rapid progress in the molecular basis of these membrane transport proteins. In this critical review, we summarize the research progress at the molecular level of the ZIP family and discuss the future prospects. Furthermore, an evolutionary path for the unique ZIP fold and a new classification of the ZIP family are proposed based on the presented structural and sequence analyses.

Kiwifruit growth and development are severely affected by various biotic and abiotic stresses, especially cold stress and the bacterial disease caused by Pseudomonas syringae pv. actinidiae (Psa). Metallothioneins (MTs) are a group of cysteine-rich proteins that play crucial roles in stress response, metal detoxification, and homeostasis in plants. However, the protective role of these MTs in kiwifruit remains to be elucidated. In the present study, four AcMT genes were identified in the Hongyang kiwifruit genome, namely, two Type 2 isoforms ( AcMT2 and AcMT2a ) and two Type 3 isoforms ( AcMT3a and AcMT3b ) located separately on four different chromosomes. The hormones and stress response cis -elements within the promoter regions of these AcMTs were characterized. It was revealed that the four AcMT genes exhibited different expression patterns in different tissues: AcMT2 and AcMT2a were expressed at much higher levels in the fruit, male flower, female flower, root, and bark, while AcMT3a was expressed mainly in the fruit and AcMT3b was expressed highly in the bark. The expression patterns of these AcMT genes after exposure to Psa infection and different phytohormones, including gibberellic acid A3(GA 3 ), ethylene (ET), and abscisic acid (ABA), were evaluated. It was revealed that in response to Psa infection, the main AcMTs in each tissue (those with expression levels higher compared to the other MTs in that tissue) were downregulated during the early stage in kiwifruits, followed by a recovery phase. In addition, most AcMTs were downregulated after exposure to ET and GA 3 , while type 2 AcMTs ( AcMT2 and AcMT2a ) were upregulated after treatment with ABA. The overexpression of AcMTs in Escherichia coli presented a higher tolerance to H 2 O 2 , heavy metals, low temperature, and high temperature. Collectively, these findings demonstrated the protective roles of AcMTs in terms of stress resistance conferred through plant hormone-related signal pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Song, Yang, He, Xin and Huang.)

This study addresses the critical need for innovation in the healthcare sector, particularly in Japan's functional food industry, amid rising chronic diseases and healthcare costs. It explores the complex relationship between regulatory design and corporate behaviour, focusing on how companies' compliance strategies influence their research and development (R&D) investments. A mixed-method approach was used, analysing data from 15 major dietary supplement companies and 74 products under Japan's Foods with Function Claims (FFCs) regulation. The study reveals a correlation between companies' engagement in the FFCs system and their preference for conducting in-house clinical trials, indicative of higher R&D investments ( R = 0.66, p = 0.007), and that between the latter variable and average product sales, which is a measure of returns on regulatory compliance ( R = 0.66, p = 0.008). Companies actively complying with FFCs regulations tend to conduct R&D and accumulate knowledge in-house, to innovate and differentiate their products, gaining competitive advantages. The study also highlights the role of a company's size, market presence, and industry origins in shaping regulatory strategies, with firms from other industries using FFCs regulations to explore new business opportunities. The research underscores the importance of flexible regulatory frameworks that encourage R&D investment, leading to innovation and competitive advantages in the healthcare sector.

Neurotechnology and Artificial Intelligence (AI) have developed rapidly in recent years with an increasing number of applications and AI-enabled devices that are about to enter the market. While promising to substantially improve quality of life across various severe medical conditions, there are also concerns that the convergence of these technologies, e.g., in the form of intelligent neuroprostheses, may have undesirable consequences and compromise cognitive liberty, mental integrity, or mental privacy. Therefore, various international organizations, such as the Organization for Economic Cooperation and Development (OECD) or United Nations Educational, Scientific and Cultural Organization (UNESCO), have formed initiatives to tackle such questions and develop recommendations that mitigate risks while fostering innovation. In this context, a first international conference on the ethics and regulation of intelligent neuroprostheses was held in Berlin, Germany, in autumn 2023. The conference gathered leading experts in neuroscience, engineering, ethics, law, philosophy as well as representatives of industry, policy making and the media. Here, we summarize the highlights of the conference, underline the areas in which a broad consensus was found among participants, and provide an outlook on future challenges in development, deployment, and regulation of intelligent neuroprostheses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Buthut, Starke, Akmazoglu, Colucci, Vermehren, van Beinum, Bublitz, Chandler, Ienca and Soekadar.)

Cellular retinoic acid binding protein 2 (CRABP2) transports retinoic acid from the cytoplasm to the nucleus where it then transfers its cargo to retinoic acid receptor-containing complexes leading to activation of gene transcription. We demonstrate using purified proteins that CRABP2 is also a cyclin D3-specific binding protein and that the CRABP2 cyclin D3 binding site and the proposed CRABP2 nuclear localization sequence overlap. Both sequences are within the helix-loop-helix motif that forms a lid to the retinoic acid binding pocket. Mutations within this sequence that block both cyclin D3 and retinoic acid binding promote formation of a CRABP2 structure in which the retinoic acid binding pocket is occupied by an alternative lid conformation. Structural and functional analysis of CRABP2 and cyclin D3 mutants combined with AlphaFold models of the ternary CDK4/6-cyclin D3-CRABP2 complex supports the identification of an α-helical protein binding site on the cyclin D3 C-terminal cyclin box fold., Competing Interests: Declaration of interests Some work in the authors’ laboratory is supported by a research grant from Astex Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Root-synthesized secondary metabolites are critical quality-conferring compounds of foods, plant-derived medicines, and beverages. However, information at a single-cell level on root-specific secondary metabolism remains largely unexplored. L-Theanine, an important quality component of tea, is primarily synthesized in roots, from which it is then transported to new shoots of tea plant. In this study, we present a single-cell RNA sequencing (scRNA-seq)-derived map for the tea plant root, which enabled cell-type-specific analysis of glutamate and ethylamine (two precursors of theanine biosynthesis) metabolism, and theanine biosynthesis, storage, and transport. Our findings support a model in which the theanine biosynthesis pathway occurs via multicellular compartmentation and does not require high co-expression levels of transcription factors and their target genes within the same cell cluster. This study provides novel insights into theanine metabolism and regulation, at the single-cell level, and offers an example for studying root-specific secondary metabolism in other plant systems., Competing Interests: SL, YZ, SZ, YW, MH, YD, JG, BZ, TY, EX, XW, WL, ZZ No competing interests declared, (© 2024, Lin, Zhang et al.)

One of the debilitating causes of high mortality in the case of tuberculosis and other bacterial infections is the resistance development against standard drugs. There are limited studies so far to describe how a bacterial second messenger molecule can directly participate in distinctive antibiotic tolerance characteristics of a cell in a mechanism-dependent manner. Here we show that intracellular cyclic di-AMP (c-di-AMP) concentration can modulate drug sensitivity of Mycobacterium smegmatis by interacting with an effector protein or interfering with the 5'-UTR regions in mRNA of the genes and thus causing transcriptional downregulation of important genes in the pathways. We studied four antibiotics with different mechanisms of action: rifampicin, ciprofloxacin, erythromycin, and tobramycin and subsequently found that the level of drug sensitivity of the bacteria is directly proportional to the c-di-AMP concentration inside the cell. Further, we unraveled the underlying molecular mechanisms to delineate the specific genes and pathways regulated by c-di-AMP and hence result in differential drug sensitivity in M. smegmatis., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Objectives: Medico-legal and regulatory culture has a significant impact on medical practitioners, including the decision of graduates to enter high-risk specialties. This study explores the impact of the current medico-legal and regulatory culture in Ireland on the decision of graduate entry medical students to enter one high risk specialty, obstetrics and gynecology., Study Design: We conducted a survey of 146 final-year, graduate-entry medical students pre- and post- a 6-week rotation in obstetrics and gynecology in Ireland. Participants were asked to rate the influence (on a four-point scale) of factors such as fear of being sued, being reported to the regulatory body or criminal prosecution on their decision to pursue a career in obstetrics or gynaecology. Data were matched pre- and post-rotation and McNemar-Bowker's test was used to test for differences in related data. All analysis was conducted using SPSS for Windows version 25., Results: The responses of 72 students to both questionnaires could be matched (response rate 49.3%). The majority of participants pre-rotation reported that fear of being sued (74%), fear of being reported to the regulatory body (70%) and fear of criminal prosecution (55%) were factors influencing their decision (somewhat or to a great extent) to pursue a career in obstetrics. There were no significant changes post-rotation. Compared to obstetrics, lower proportions of participants pre-rotation considered fear of being sued (54%), fear of being reported to the regulatory body (50%) and fear of criminal prosecution (40%) as factors influencing their decision to pursue a career in gynecology. There were no significant changes post-rotation., Conclusions: Medico-legal and regulatory culture is shaping the perceptions of graduate entry medical students of obstetrics and gynecology and influencing their decision to pursue a career in the speciality. Understanding the impact of medico-legal culture on career choices including a high-risk specialty such as obstetrics and gynecology is important from both a policy and reform context, and if the healthcare service is to recruit and retain adequate numbers to ensure the safe provision of healthcare., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Indole-3-carbinol (I3C), a compound found in cruciferous vegetables, has shown significant efficacy in treating both cancerous and non-cancerous diseases. Its primary derivative, 3,3'-diindolylmethane (DIM), formed during digestion, also exhibits similar therapeutic benefits. In liver disorders, I3C and DIM exhibit dual roles by inhibiting and promoting hepatocellular carcinoma (HCC) and providing relief for nonmalignant liver diseases, such as acute liver injury (ALI), hepatic fibrosis, nonalcoholic fatty liver disease (NAFLD), and alcohol-related liver disease (ALD). Mechanistically, I3C and DIM modulate various pathophysiological processes, including cell proliferation, apoptosis, oxidative stress, and lipogenesis. This review aims to enhance researchers' understanding of the regulatory roles of I3C and DIM in these liver diseases and explore the potential of plant-derived substances in liver disease treatment., (Copyright © 2024. Published by Elsevier Masson SAS.)

Fusion is inherently safer than fission due to the absence of nuclear chain reactions. However, operating fusion power plants will not be risk free. There will still be numerous hazards that will need careful management in order to safely build, operate and ultimately decommission a fusion power plant. Ensuring a robust safety demonstration that covers all radiological and non-radiological hazards is therefore vitally important for the future permissioning and consenting of fusion power plants. The safety case for the STEP prototype plant will be developed in line with a set of safety philosophies, safety functional requirements and design safety principles to ensure that the safety case production process is consistent and robust.This article is part of the theme issue 'Delivering Fusion Energy - The Spherical Tokamak for Energy Production (STEP)'.

Introduction: Plasmodium falciparum is the most damaging malaria pathogen and brings a heavy burden to global health. Host switching and morphological changes in P. falciparum are dependent on an effective gene expression regulatory system. C5 methylation of cytosines is a common RNA modification in eukaryotes, and the NSUN family are essential m 5 C modification executors. Currently, little is known about this family in Plasmodium spp. In this study, we focus on exploring the function of PfNSUN1 protein., Methods: An efficient CRISPR/Cas9 gene editing technique was applied to construct the PfNSUN1 knockdown strain. The knockdown efficiency was confirmed by growth curves and western blot experiments. The knockdown transcriptome data was acquired to find differentially expressed genes, and target genes of PfNSUN1 protein were identified by RNA immunoprecipitation and high-throughput sequencing experiments., Results: The efficiency of PfNSUN1 protein down-regulated was about 34%. RNA-seq data revealed that differentially expressed genes were mainly down-regulated. And there were 224, 278, 556 genes that were down-regulated with more than 2-fold changes and p-adj<0.05 at ring, trophozoite and schizont stages, respectively. PfNSUN1 protein was significantly enriched on 154 target genes, including 28S ribosomal RNA and pfap2-g5 transcription factor., Discussion: PfNSUN1 is a crucial RNA post-transcriptional modification protein in P. falciparum . It plays a pivotal role in regulating gene expression and parasite growth by targeting 28S ribosomal RNA and pfap2-g5 transcription factor., Competing Interests: Author QJ is employed by Hunan Xingchen Biotechnology Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tang, Fan, Lu, Jiang, Cheng, Zhang, Shen and Shang.)

Autism spectrum disorder (ASD) is a highly heterogeneous disorder characterized by impairments in social, communicative, and restrictive behaviors. Over the past 20 years, research has highlighted the role of the immune system in regulating neurodevelopment and behavior. In ASD, immune abnormalities are frequently observed, such as elevations in pro-inflammatory cytokines, alterations in immune cell frequencies, and dysregulated mechanisms of immune suppression. The adaptive immune system - the branch of the immune system conferring cellular immunity - may be involved in the etiology of ASD. Specifically, dysregulated T cell activity, characterized by altered cellular function and increased cytokine release, presence of inflammatory phenotypes and altered cellular signaling, has been consistently observed in several studies across multiple laboratories and geographic regions. Similarly, mechanisms regulating their activation are also disrupted. T cells at homeostasis coordinate the healthy development of the central nervous system (CNS) during early prenatal and postnatal development, and aid in CNS maintenance into adulthood. Thus, T cell dysregulation may play a role in neurodevelopment and the behavioral and cognitive manifestations observed in ASD. Outside of the CNS, aberrant T cell activity may also be responsible for the increased frequency of immune based conditions in the ASD population, such as allergies, gut inflammation and autoimmunity. In this review, we will discuss the current understanding of T cell biology in ASD and speculate on mechanisms behind their dysregulation. This review also evaluates how aberrant T cell biology affects gastrointestinal issues and behavior in the context of ASD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Policymakers aiming to increase access to health care while simultaneously keeping costs low and quality high are considering expanding the practice authority and prescriptive authority of nurse practitioners in order to address primary care shortages. While we know this increases access, some researchers argue that the expansion of job autonomy of nurse practitioners can compromise the quality and safety of rendered medical services. This paper investigates quality and safety outcomes in prescribing behaviors of nurse practitioners who have prescribed opioids for Medicare Part D beneficiaries using a unique source of policy variation, nurse practitioners with the ability to prescribe medication who move to either states with or without physician supervision. We find that scope of practice expansions do not compromise quality and safety in terms of potential abuse or misuse of prescriptive authority., (© 2024 John Wiley & Sons Ltd.)

Despite the growing concerns about pesticide pollution, a comprehensive global understanding continues to be hampered by a lack of data from less developed countries. Ethiopia, being a typical agricultural country, is one of the top consumers of pesticides in sub-Saharan Africa. This study conducted a nationwide analysis to assess pesticide water pollution and human health risks in Ethiopia based on the available data. Additionally, the study evaluated the effectiveness of the Pesticide Risks in the Tropics for Man, Environment, and Trade (PRIMET) model, which is currently used for pesticide regulatory risk assessment in Ethiopia. The scoring approach was employed to map the site-specific pollution status based on clearly defined individual pesticide concentrations, excluding mixtures (n = 99). The pollution scores varied significantly among sites, with higher scores observed in the Rift Valley region. Acute and chronic health risks were identified for some commonly detected pesticides at their maximum concentrations. Epidemiological studies conducted in Ethiopia also demonstrated that pesticide exposure is associated with acute poisoning, respiratory health problems, neurobehavioral symptoms, and breast cancer. Furthermore, the study found that the existing regulatory framework likely underestimates pesticide risks in 35 % of the cases, raising concerns about the reliability of the PRIMET model in its current version. Overall, the results emphasize the need for increased attention to pesticide regulation and management in Ethiopia and other countries with similar scenarios, including regular monitoring, implementation of residue limits, post-application evaluations, and recalibration of the PRIMET model. This study provides valuable scientific information and insights into pesticide pollution and can serve as a baseline for ensuring agricultural and environmental sustainability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cytotoxic accumulation of loosely bound mitochondrial Fe2+ is a hallmark of Friedreich's Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe2+ associated with FA or the neurological disorders Parkinson's disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe3+ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe2+ or exceptionally high affinities (i.e. ≤10-31) for non-pathologic Fe3+ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe2+-targeted therapeutics, we compared traditional Fe3+ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe2+ binding affinities (Kd's of 1-4  µM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe3+(0.46-9.59 µM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe2+ coordination using H2O. ATH434 significantly stabilized bound Fe2+ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe2+ and Fe3+ position it to sequester excess Fe2+ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores., (© The Author(s) 2024. Published by Oxford University Press.)

Malate dehydrogenases (MDHs) have been extensively studied since the 1960s due to their key roles in carbon metabolism and pathways such as redox balance and lipid synthesis. Recently, there has been renewed interest in these enzymes with the discovery of their role in the metabolic changes that occur during cancer and a widespread community of undergraduate teaching laboratories addressing MDH research questions, the Malate Dehydrogenase CUREs Community (MCC). This special issue describes different facets of MDH, including its physiological role, its structure-function relationships, its regulation through post-translational modifications, and perspectives on its evolutionary history. There are two human isoforms: a cytoplasmic isoform that carries out formation of NAD+ for glycolysis, and a mitochondrial isoform that plays a major role in the citric acid cycle. Although the sequences of these two isoforms vary, the structures of the enzymes are similar, and studies suggest that each isoform may form complexes with other enzymes in common pathways. Experimental and theoretical advances have helped to characterize the post-translational modifications of MDH, allowing us to ask more complex questions involving the regulation of the enzyme and substrate promiscuity in the context of cancer. Additionally, there are many unresolved questions on the role of malate dehydrogenase in other organisms, especially in parasites. The review articles in this issue seek to shed light on the latest advances in our understanding of MDH and highlight areas for future studies., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The marine bacterium Vibrio parahaemolyticus is a major cause of seafood-borne gastroenteritis in humans and of acute hepatopancreatic necrosis disease in shrimp. Bile acids, produced by the host and modified into secondary bile acids by commensal bacteria in the gastrointestinal tract, induce the virulence factors leading to disease in humans and shrimp. Here, we show that secondary bile acids also activate this pathogen's type VI secretion system 1, a toxin delivery apparatus mediating interbacterial competition. This finding implies that Vibrio parahaemolyticus exploits secondary bile acids to activate its virulence factors and identify the presence of commensal bacteria that it needs to outcompete in order to colonize the host.IMPORTANCEBacterial pathogens often manipulate their host and cause disease by secreting toxic proteins. However, to successfully colonize a host, they must also remove commensal bacteria that reside in it and may compete with them over resources. Here, we find that the same host-derived molecules that activate the secreted virulence toxins in a gut bacterial pathogen, Vibrio parahaemolyticus , also activate an antibacterial toxin delivery system that targets such commensal bacteria. These findings suggest that a pathogen can use one cue to launch a coordinated, trans -kingdom attack that enables it to colonize a host., Competing Interests: The authors declare no conflict of interest.

Cellular metabolism comprises a complex network of biochemical anabolic and catabolic processes that fuel the growth and survival of living organisms. The enzyme malate dehydrogenase (MDH) is most known for its role in oxidizing malate to oxaloacetate (OAA) in the last step of the tricarboxylic acid (TCA) cycle, but it also participates in the malate-aspartate shuttle in the mitochondria as well as the glyoxylate cycle in plants. These pathways and the specific reactions within them are dynamic and must be carefully calibrated to ensure a balance between nutrient/energy supply and demand. MDH structural and functional complexity requires a variety of regulatory mechanisms, including allosteric regulation, feedback, and competitive inhibition, which are often dependent on whether the enzyme is catalyzing its forward or reverse reaction. Given the role of MDH in central metabolism and its potential as a target for therapeutics in both cancer and infectious diseases, there is a need to better understand its regulation. The involvement of MDH in multiple pathways makes it challenging to identify which effectors are critical to its activity. Many of the in vitro experiments examining MDH regulation were done decades ago, and though allosteric sites have been proposed, none to date have been specifically mapped. This review aims to provide an overview of the current knowledge surrounding MDH regulation by its substrate, products, and other intermediates of the TCA cycle while highlighting all the gaps in our understanding of its regulatory mechanisms., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Central line-associated bloodstream infections (CLABSIs) can result in worse outcomes and high hospitalization cost for patients. This study aimed to assess the effectiveness of multi-department cooperation, intelligent prevention, and supervision (MDCIPS) in reducing the incidence of CLABSIs and improving the clinical outcomes of the patients. Key issues were identified through a literature review and survey on the status quo. A MDCIPS model was thus built. A total of 440 patients with indwelling central venous catheters (CVCs) were enrolled in the study. The control group ( n  = 219) received conventional infection-control managements, while the intervention group ( n  = 221) received MDCIPS interventions in addition to conventional infection-control managements. The number of CLABSIs patients, incidence of CLABSIs, average length of hospital stay, average total hospitalization cost, and disease outcomes were compared between the two groups. The intervention group had a significant reduction in the number and incidence of CLABSIs (0[0%] vs. 4[1.33%], P  < 0.05). Two of the four patients with CLABSIs in the control group died. The average length of hospital stay was significantly longer in the control group than the intervention group (17 days vs. 13 days, P  < 0.001). The average hospitalization cost in the control group was much higher than that in the intervention group (92.8 thousand yuan vs. 65.2 thousand yuan, P  < 0.001). Patient outcome was improved in the intervention group than the control group ( P  = 0.001). In summary, the MDCIPS model effectively reduces the incidence of CLABSIs, alleviates the patients' economic burden, and improves the clinical outcomes of the patients., Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-024-01760-8., Competing Interests: Conflicts of InterestsThe authors declare of no conflicts of interests., (© The Author(s), under exclusive licence to Indian Society of Hematology and Blood Transfusion 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)