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Microbiology Spectrum Jun 2024Acetic acid bacteria are used in many industrial processes such as the production of vinegar, vitamin C, the antidiabetic drug miglitol, and various artificial...
Acetic acid bacteria are used in many industrial processes such as the production of vinegar, vitamin C, the antidiabetic drug miglitol, and various artificial flavorings. These industrially important reactions are primarily carried out by an arsenal of periplasmic-facing membrane-bound dehydrogenases that incompletely oxidize their substrates and shuttle electrons directly into the respiratory chain. Among these dehydrogenases, GOX in was predicted to be a pyrroloquinoline quinone-dependent dehydrogenase of unknown function. However, after multiple analysis by a number of labs, no dehydrogenase activity has been detected. Reanalysis of GOX1969 sequence and structure reveals similarities to BamB, which functions as a subunit of the β-barrel assembly machinery complex that is responsible for the assembly of β-barrel outer membrane proteins in Gram-negative bacteria. To test if the physiological function of GOX1969 is similar to BamB in , we introduced the gene into an ∆ mutant. Growth deficiencies in the ∆ mutant were restored when was expressed on the plasmid pGox1969. Furthermore, increased membrane permeability conferred by deletion was restored upon expression, which suggests a direct link between GOX1969 and a role in maintaining outer membrane stability. Together, this evidence strongly suggests that GOX1969 is functionally acting as a BamB in . As such, functional information on uncharacterized genes will provide new insights that will allow for more accurate modeling of acetic acid bacterial metabolism and further efforts to design rational strains for industrial use.IMPORTANCE is an industrially important member of the acetic acid bacteria. Experimental characterization of putative genes is necessary to identify targets for further engineering of rational acetic acid bacteria strains that can be used in the production of vitamin C, antidiabetic compounds, artificial flavorings, or novel compounds. In this study, we have identified an undefined dehydrogenase GOX1969 with no known substrate and defined structural similarities to outer membrane biogenesis protein BamB in K12. Furthermore, we demonstrate that GOX1969 is capable of complementing knockout phenotypes in K12. Taken together, these findings enhance our understanding of physiology and expand the list of potential targets for future industrial strain design.
PubMed: 38916353
DOI: 10.1128/spectrum.01060-24 -
Nordisk Alkohol- & Narkotikatidskrift :... Jun 2024Harmful patterns of alcohol consumption, such as binge drinking, are prevalent among the student population at universities. Despite the risks of this behaviour, few...
Harmful patterns of alcohol consumption, such as binge drinking, are prevalent among the student population at universities. Despite the risks of this behaviour, few secondary prevention programmes have been created to meet the specific needs of this population. The PEERCARE programme is a peer-based prevention programme that seeks harm reduction for alcohol overuse in party environments, among other goals. To do so, a "chill-out" space is created by peer educators in party environments to limit the risks associated with alcohol overuse. This study sought to examine peer educators' experience with a chill-out space to identify their specific actions, difficulties and needs, and to consider possibilities for improvement. Nine engineering students from one French campus trained as peer educators (six men and three women; mean age 21 years) participated. Semi-structured interviews were used for data collection. The thematic analysis showed that the peer educators were highly engaged with this programme in response to alcohol overuse on their campus. The chill-out space was lauded for its non-judgemental and non-moralising nature. In addition, the numerous risk reduction activities that were enacted confirmed the benefits of these spaces during parties. The peer educators' experience was positive, and acting as managers of the chill-out space seemed to answer to a sense of competence recognitiontion. This study confirms the relevance of utilising chill-out spaces during parties and provides preliminary data on the deployment and management of peer-led chill-out space approaches. Expanding the implementation of such spaces to more educational institutions is recommended.
PubMed: 38903888
DOI: 10.1177/14550725231225597 -
Frontiers in Oncology 2024It has been reported that tumor immune microenvironment performs a vital role in tumor progress. However, acting mechanism of immune cell related genes (IRGs) in...
BACKGROUND
It has been reported that tumor immune microenvironment performs a vital role in tumor progress. However, acting mechanism of immune cell related genes (IRGs) in esophageal squamous cell carcinoma (ESCC) is uncertain.
METHODS
TCGA-ESCC, GSE23400, GSE26886, GSE75241, and GSE196756 datasets were gained via public databases. First, differentially expressed genes (DEGs) between ESCC and control samples from GSE23400, GSE26886, and GSE75241 were screened out by differential expression analysis, and overlapping DEGs were identified. Single-cell transcriptome data of GSE196756 were applied to explore immune cells that might be involved in regulation of ESCC. Then, weighted gene co-expression network analysis was applied to screen IRGs. Next, differentially expressed IRGs (DE-IRGs) were identified by overlapping IRGs and DEGs, and were incorporated into univariate Cox, least absolute shrinkage and selection operator, and multivariate Cox to acquire prognosis-related genes, and ESCC samples were grouped into high-/low-risk groups on the basis of median risk score. Finally, the role of prognosis model in immunotherapy was analyzed.
RESULTS
Totally 248 DEGs were yielded by overlapping 3,915 DEGs in GSE26886, 459 DEGs in GSE23400, and 1,641 DEGs in GSE75241. Single-cell analysis found that B cells, dendritic cells, monocytes, neutrophils, natural killer cells, and T cells were involved in ESCC development. Besides, MEred, MEblack, MEpink, MEblue and MEbrown modules were considered as key modules because of their highest correlations with immune cell subtypes. A total of 154 DE-IRGs were yielded by taking intersection of DEGs and genes in key modules. Moreover, CTSC, ALOX12, and RMND5B were identified as prognosis-related genes in ESCC. Obviously, Exclusion and TIDE scores were notably lower in high-risk group than in the other one, indicating that high-risk group was more responsive to immunotherapy.
CONCLUSIONS
Through bioinformatic analysis, we identified a prognosis model consisting of IRGs (CTSC, ALOX12, and RMND5B) in ESCC, providing new ideas for studies related to treatment and prognosis of ESCC.
PubMed: 38903709
DOI: 10.3389/fonc.2024.1370801 -
Cureus May 2024Background Levalbuterol is a short-acting β-agonist (SABA) indicated for treating or preventing asthma exacerbation. It was included in the 2020 Chinese National...
Estimating the Economic Impact of Levalbuterol's Potential Transition From the National Reimbursement Drug List for the Treatment of Pediatric Asthma in China: A Budget Impact Analysis.
Background Levalbuterol is a short-acting β-agonist (SABA) indicated for treating or preventing asthma exacerbation. It was included in the 2020 Chinese National Reimbursement Drug List (NRDL). This study estimates the economic impact of levalbuterol's status change within and withdrawal from the NRDL in treating pediatric asthma from a publicly funded medical insurance perspective. Methodology A prevalence-based budget impact model was developed. The analysis compared a a levalbuterol scenario to a levalbuterol. Epidemiological data were obtained from the existing literature. Cost data were estimated based on the drug dosage in clinical trials, real-world settings, and expert opinions. Scenario analysis considered the same length of stay (LOS) in the two groups. One-way sensitivity analyses were carried out to show the impact of varying individual parameters. Results In the base-case analysis, compared to the scenario, the preservation of levalbuterol resulted in cost savings of ¥82.8 million in China over three years. In the scenario analysis, savings decreased to ¥76.1 million over three years. Sensitivity analysis showed that, for the most part, the results were robust to changes in input parameter values. Conclusions Using levalbuterol may lead to substantial cost savings for Chinese society.
PubMed: 38903381
DOI: 10.7759/cureus.60640 -
The Journal of Biological Chemistry Jun 2024Aberrant regulation of signal transduction pathways can adversely derail biological processes for tissue development. One such process is the embryonic eyelid closure...
Aberrant regulation of signal transduction pathways can adversely derail biological processes for tissue development. One such process is the embryonic eyelid closure that is dependent on the Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1). Map3k1 knockout in mice results in defective eyelid closure and an autosomal recessive eye-open at birth phenotype. We have shown that in utero exposure to dioxin, a persistent environmental toxicant, induces the same eye defect in Map3k1 heterozygous but not wild type pups. Here we explore the mechanisms of the Map3k1 (gene) and dioxin (environment) interactions (GxE) underlying defective eyelid closure. We show that, acting through the Aryl Hydrocarbon Receptor (AHR), dioxin activates Epidermal Growth Factor Receptor (EGFR) signaling, which in turn depresses MAP3K1-dependent Jun N-terminal Kinase (JNK) activity. The dioxin mediated JNK repression is moderate but is exacerbated by Map3k1 heterozygosity. Therefore, dioxin exposed Map3k1 embryonic eyelids have a marked reduction of JNK activity, accelerated differentiation and impeded polarization in the epithelial cells. Knocking out Ahr or Egfr in eyelid epithelium attenuates the open-eye defects in dioxin-treated Map3k1 pups, whereas knockout of Jnk1 and S1pr that encodes the Sphigosin-1-phosphate (S1P) receptors upstream of the MAP3K1-JNK pathway potentiates the dioxin toxicity. Our novel findings show that the crosstalk of AHR, EGFR and S1P-MAP3K1-JNK pathways determines the outcome of dioxin exposure. Thus, gene mutations targeting these pathways are potential risk factors for the toxicity of environmental chemicals.
PubMed: 38897570
DOI: 10.1016/j.jbc.2024.107486 -
Journal of Clinical Medicine May 2024Stress during a pandemic increases the risk of alcohol consumption, which may require pharmacological management. An observational single-center retrospective study...
Stress during a pandemic increases the risk of alcohol consumption, which may require pharmacological management. An observational single-center retrospective study was conducted from 1 January 2018 to 31 December 2021, and divided into 2-year periods (2018-2019 and 2020-2021). This study focused on calls to one of the emergency departments (EDs) of seven hospitals in the Bari (Italy) metropolitan area for patients requiring emergency services (ESs) who were either admitted or not admitted, due to their refusal. A 30% reduction in emergency calls for alcohol-related issues and a 41.17% reduction in calls for patients who refused to be admitted to the ED were observed during the pandemic. During the pandemic, an inverse association was found between pharmacological treatment and number of calls coded green (non-critical) and yellow (fairly critical) in patients admitted to EDs. An inverse association was also found for calls coded green in patients not admitted to EDs and pharmacological treatment. Metadoxine was administered in almost all alcohol-related emergencies, primarily in conjunction with drugs acting on the gastrointestinal tract, irrespective of age, the period considered, and whether patients were admitted or not admitted to the ED. ES is the first and only out-of-hospital service encountered by numerous patients with alcohol-use disorders who refuse to be admitted to the ED. These patients should be directed by ES personnel to a multidisciplinary program to receive treatment for drinking, improve their quality of life, and reduce sanitation costs.
PubMed: 38892768
DOI: 10.3390/jcm13113057 -
International Journal of Molecular... May 2024Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine...
Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.
Topics: Deoxyadenosines; Humans; Neoplasms; Cyclic AMP; Molecular Dynamics Simulation; Adenosine Triphosphate; Signal Transduction; Computer Simulation; Adenylyl Cyclases
PubMed: 38891880
DOI: 10.3390/ijms25115692 -
SAGE Open Nursing 2024Contraceptive switching from a more effective to a less effective method is a concern, especially in developing countries with high unmet needs for family planning....
INTRODUCTION
Contraceptive switching from a more effective to a less effective method is a concern, especially in developing countries with high unmet needs for family planning. Indeed, the lack of understanding regarding the reasons behind contraceptive switching behavior in the study area poses a significant challenge in effectively addressing this issue.
OBJECTIVE
This study aimed to assess the magnitude and factors associated with long-acting contraceptive switching in Mizan-Aman town, southwest Ethiopia.
METHODS
A community-based cross-sectional study was conducted, involving 345 women randomly selected from the population of married women in their reproductive age group. Data collection was conducted through interviewer-administered questionnaires. Bivariate and multivariable logistic regression analyses were employed to ascertain factors linked with contraceptive method switching status. Statistical significance was determined at a -value of less than .05.
RESULTS
Out of the 345 participants interviewed, the prevalence of switching from long-acting to short-acting contraceptives was 28.4%, 95% CI (13.6%, 33.2%). Upon adjusting for confounding variables, factors significantly associated with contraceptive switching included women aged 31-35 [adjusted odds ratio (AOR) = 0.58; 95% CI (0.36, 0.74)] and aged 41-49 [AOR = 0.54; 95% CI (0.48, 0.82)], those with formal education [AOR = 0.79; 95% CI (0.52, 0.87)], those desiring future pregnancy [AOR = 2.12; 95% CI (1.98, 3.38)], experiencing complications from previous method use [AOR = 3.67; 95% CI (2.57, 7.40)], and encountering stockouts of their preferred contraceptive choice [AOR = 2.01; 95% CI (1.39, 3.24)].
CONCLUSION AND RECOMMENDATION
The study area exhibited a notable prevalence of switching from long-acting contraceptives. Complications arising from prior method use and the unavailability of preferred contraceptive options emerged as significant factors influencing this switching behavior. Thus, it underscores the importance of providing counseling and ongoing support to women, ensuring access to safer and more effective modern contraceptive methods.
PubMed: 38887366
DOI: 10.1177/23779608241262908 -
Retrovirology Jun 2024An essential regulatory hub for retroviral replication events, the 5' untranslated region (UTR) encodes an ensemble of cis-acting replication elements that overlap in a... (Review)
Review
An essential regulatory hub for retroviral replication events, the 5' untranslated region (UTR) encodes an ensemble of cis-acting replication elements that overlap in a logical manner to carry out divergent RNA activities in cells and in virions. The primer binding site (PBS) and primer activation sequence initiate the reverse transcription process in virions, yet overlap with structural elements that regulate expression of the complex viral proteome. PBS-segment also encompasses the attachment site for Integrase to cut and paste the 3' long terminal repeat into the host chromosome to form the provirus and purine residues necessary to execute the precise stoichiometry of genome-length transcripts and spliced viral RNAs. Recent genetic mapping, cofactor affinity experiments, NMR and SAXS have elucidated that the HIV-1 PBS-segment folds into a three-way junction structure. The three-way junction structure is recognized by the host's nuclear RNA helicase A/DHX9 (RHA). RHA tethers host trimethyl guanosine synthase 1 to the Rev/Rev responsive element (RRE)-containing RNAs for m7-guanosine Cap hyper methylation that bolsters virion infectivity significantly. The HIV-1 trimethylated (TMG) Cap licenses specialized translation of virion proteins under conditions that repress translation of the regulatory proteins. Clearly host-adaption and RNA shapeshifting comprise the fundamental basis for PBS-segment orchestrating both reverse transcription of virion RNA and the nuclear modification of m7G-Cap for biphasic translation of the complex viral proteome. These recent observations, which have exposed even greater complexity of retroviral RNA biology than previously established, are the impetus for this article. Basic research to fully comprehend the marriage of PBS-segment structures and host RNA binding proteins that carry out retroviral early and late replication events is likely to expose an immutable virus-specific therapeutic target to attenuate retrovirus proliferation.
Topics: Virus Replication; RNA, Viral; Humans; HIV-1; 5' Untranslated Regions; Binding Sites; Gene Expression Regulation, Viral; Reverse Transcription; Retroviridae
PubMed: 38886829
DOI: 10.1186/s12977-024-00646-x -
Journal of Ethnopharmacology Jun 2024Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease....
ETHNOPHARMACOLOGICAL RELEVANCE
Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease. The decoction has demonstrated its capability to protect arteries and resist atherosclerosis. Its mechanisms for anti-atherosclerosis effect, nevertheless, remain unknown.
AIMS OF THE STUDY
The goal of the present study is to explore the effectiveness of ZSXBGZD acting on atherosclerosis and its key components based on experimental verification and network pharmacology analysis.
MATERIALS AND METHODS
The ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and databases were used to identify chemical components in ZSXBGZD. Network pharmacological analysis and molecular docking were implemented in order to reveal the possible therapeutic targets of ZSXBGZD. To form the model of atherosclerosis, we gave Apolipoprotein E knocked out mice a high-fat diet. H&E staining was performed to observe the effects of ZSXBGZD on atherosclerosis. Immunofluorescence and Western blot were used to investigate whether ZSXBGZD could affect autophagy, apoptosis, AGE-RAGE signaling pathway and other related mechanisms.
RESULTS
In total, 30 core compounds were screened through intersecting UPLC-Q-TOF-MS and the databases. The anti-atherosclerotic effect of ZSXBGZD might relate to the AGE-RAGE signaling pathway via network pharmacology analysis. ZSXBGZD could inhibit apoptosis, activate autophagy and ease inflammation by modifying AGE-RAGE signaling pathway to reduce the area of atherosclerotic plaque.
CONCLUSION
ZSXBGZD could treat atherosclerosis by regulating autophagy and apoptosis via adjusting the AGE-RAGE signaling pathway.
PubMed: 38885915
DOI: 10.1016/j.jep.2024.118466