Tetracyclines are among the most used antibiotics in livestock worldwide. Resistance is widely disseminated in Escherichia coli, where it is generally mediated by tetracycline efflux pumps, such as ...TetA. Expression of tetracycline efflux pumps is tightly controlled by the repressor TetR, which has been shown to be tetracycline-responsive at sub-MIC tetracycline concentrations. The objective of this study was to investigate the effects of increasing tetracycline concentrations on the growth of TetA-producing E. coli, and to determine how expression of tetA and tetR related to each other in different growth phases in the presence of tetracycline.
A tetracycline resistant E. coli strain containing tetA and tetR on the chromosome was constructed and cultured in the presence of increasing concentrations of tetracycline. Expression of tetR and tetA was measured at four time points in different growth phases by quantitative real-time PCR. The TetA-producing E. coli exhibited prolonged lag phase with increasing concentrations of tetracycline, while expression of tetA and tetR increased and decreased, respectively, with increasing tetracycline concentration. The levels of tetA and tetR mRNA varied depending on growth phase, resulting in a gradual decrease of the tetA/tetR ratio from approximately 4 in the lag phase to approximately 2 in the stationary phase.
This study shows that the expression of tetR and tetA is tetracycline concentration- and growth phase-dependent, contributing to improved understanding of the relationships between E. coli growth, tetracycline exposure and expression of tetracycline resistance.
•Users who engaged with an employer-provided digital menopause health application reported a significant associated decrease in the severity of their menopause symptoms over time.•The frequency of ...application engagement was associated with the subsequent reduction in menopausal symptom severity.•As menopausal symptom severity decreased, a significant concurrent reduction in work impairment was observed, suggesting a beneficial impact of symptom management on work productivity.
The aim of the study was to evaluate the change in menopause symptoms and work impairment among a cohort of UK working women who utilised an employer-provided digital menopause health application offering education and personalised support.
We adopted a retrospective, single-arm, longitudinal approach by analysing data from 11,870 users of the Peppy Health menopause application. Users reported their menopause symptoms and work impairment on day 0 and after 90 and 180 days of application use.
Menopause symptoms were measured by the Menopause Rating Scale, while work impairment was measured by a single question.
A significant decrease in the severity of menopause symptoms was observed in users across menopause stages, except for premenopausal users who saw lower severity and no change over time. Improvement in menopause symptoms was positively associated with the degree of application engagement. Work impairment also significantly reduced over time for menopausal users, and a significant association was observed between a reduction in menopause symptoms and a decline in work impairment.
Our findings show that engaging with a digital menopause application is associated with an improvement in menopause symptoms, which lends initial support for the use of personalised digital solutions to help working women through the menopause transition.
•Exposure to metals/elements may be a risk factor for neurodevelopmental disorders.•We examined gestational levels of metals/elements and ADHD and autism in children.•Several metals and elements ...appeared to increase ADHD or autism risk.•Population levels of these chemicals may adversely affect neurodevelopment.
Prenatal exposure to toxic metals or variations in maternal levels of essential elements during pregnancy may be a risk factor for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring.
We investigated whether maternal levels of toxic metals and essential elements measured in mid-pregnancy, individually and as mixtures, were associated with childhood diagnosis of ADHD or ASD.
This study is based on the Norwegian Mother, Father and Child Cohort Study and included 705 ADHD cases, 397 ASD cases and 1034 controls. Cases were identified through linkage with the Norwegian Patient Registry. Maternal concentrations of 11 metals/elements were measured in blood at week 17 of gestation; cadmium; cesium; cobalt; copper; lead; magnesium; manganese; selenium; zinc; total arsenic; and total mercury. Multivariable adjusted logistic regression models were used to examine associations between quartile levels of individual metals/elements and outcomes. We also investigated non-linear associations using restricted cubic spline models. The joint effects of the metal/element mixture on ASD and ADHD diagnoses were estimated using a quantile-based g-computation approach.
For ASD, we identified positive associations (increased risks) in the second quartile of arsenic OR = 1.77 (CI: 1.26, 2.49) and the fourth quartiles of cadmium and manganese OR = 1.57 (CI: 1.07 2.31); OR = 1.84 (CI: 1.30, 2.59), respectively. In addition, there were negative associations between cesium, copper, mercury, and zinc and ASD. For ADHD, we found increased risk in the fourth quartiles of cadmium and magnesium OR = 1.59 (CI: 1.15, 2.18); OR = 1.42 (CI: 1.06, 1.91). There were also some negative associations, among others with mercury. In addition, we identified non-linear associations between ASD and arsenic, mercury, magnesium, and lead, and between ADHD and arsenic, copper, manganese, and mercury. There were no significant findings in the mixture approach analyses.
Results from the present study show several associations between levels of metals and elements during gestation and ASD and ADHD in children. The most notable ones involved arsenic, cadmium, copper, mercury, manganese, magnesium, and lead. Our results suggest that even population levels of these compounds may have negative impacts on neurodevelopment. As we observed mainly similarities among the metals’ and elements’ impact on ASD and ADHD, it could be that the two disorders share some neurochemical and neurodevelopmental pathways. The results warrant further investigation and replication, as well as studies of combined effects of metals/elements and mechanistic underpinnings.
•Users who signed up to a menopause digital health app reported more severe menopause symptoms than the general European population.•Severity of menopause symptoms was associated with work ...impairment, taking time off and a desire to leave work.•Feeling supported was inversely associated with work impairment and a desire to leave employment.
The aim of the current study was to determine the demographic characteristics and workplace experiences of users of a menopause application in the UK.
A retrospective observational study of data extracted from the information submitted by 21,555 users of the Peppy Health menopause application during registration.
Menopause symptoms were measured using the Menopause Rating Scale. The other questionnaire items assessed workplace impairment, work absence, thoughts about reducing hours or leaving work, feelings of support and disclosure confidence.
Users were predominately peri- and postmenopausal women between the ages of 40 and 60. The users reported menopause symptoms that were more severe than in the general population. Symptom severity was associated with work impairment and wanting to reduce hours worked or leave employment, and feeling supported was associated with less impairment.
The menopause application is reaching women in the workplace who are experiencing severe symptoms and who are likely to benefit from targeted support. Among the users of a menopause application, the presence of severe menopause symptoms can have a significantly negative effect on work and future participation in paid employment. The results also indicate the potential role of support to mitigate some of the negative impact.
Herein, we report a photomediated hydro- and deuterodecarboxylation of different primary, secondary, and tertiary carboxylic acids catalyzed by an organic pyrimidopteridine photoredox catalyst. The ...reaction was optimized by a statistical design of experiment (DoE). Under optimized reaction conditions, the conversion of commercially available nonsteroidal anti-inflammatory drugs (NSAIDs) in tablet form and on gram scale was realized. The scope of the application comprises primary, secondary, and tertiary aliphatic biologically active carboxylic acids. A deuterium incorporation of up to 95% by using D2O as inexpensive deuterium source was achieved. A sensitivity assessment as well as experiments aiding the elucidation of the reaction mechanism are discussed.
We characterized the global transcriptome of Escherichia coli MG1655:: tetA grown in the presence of ½ MIC (14 mg/L) of OTC, and for comparison WT MG1655 strain grown with 1//2 MIC of OTC (0.25 mg/L ...OTC). 1646 genes changed expression significantly (FDR > 0.05) in the resistant strain, the majority of which (1246) were also regulated in WT strain. Genes involved in purine synthesis and ribosome structure and function were top-enriched among up-regulated genes, and anaerobic respiration, nitrate metabolism and aromatic amino acid biosynthesis genes among down-regulated genes. Blocking of the purine-synthesis- did not affect resistance phenotypes (MIC and growth rate with OTC), while blocking of protein synthesis using low concentrations of chloramphenicol or gentamicin, lowered MIC towards OTC. Metabolic-modeling, using a novel model for MG1655 and continuous weighing factor that reflected the degree of up or down regulation of genes encoding a reaction, identified 102 metabolic reactions with significant change in flux in MG1655:: tetA when grown in the presence of OTC compared to growth without OTC. These pathways could not have been predicted by simply analyzing functions of the up and down regulated genes, and thus this work has provided a novel method for identification of reactions which are essential in the adaptation to growth in the presence of antimicrobials.
Elucidating the factors governing the functional compatibility of horizontally transferred genes is important to understand bacterial evolution, including the emergence and spread of antibiotic ...resistance, and to successfully engineer biological systems. In silico efforts and work using single-gene libraries have suggested that sequence composition is a strong barrier for the successful integration of heterologous genes. Here we sample 200 diverse genes, representing >80% of sequenced antibiotic resistance genes, to interrogate the factors governing genetic compatibility in new hosts. In contrast to previous work, we find that GC content, codon usage, and mRNA-folding energy are of minor importance for the compatibility of mechanistically diverse gene products at moderate expression. Instead, we identify the phylogenetic origin, and the dependence of a resistance mechanism on host physiology, as major factors governing the functionality and fitness of antibiotic resistance genes. These findings emphasize the importance of biochemical mechanism for heterologous gene compatibility, and suggest physiological constraints as a pivotal feature orienting the evolution of antibiotic resistance.
We report a sequential one-pot preparation of aromatic trifluoromethyl ketones starting from readily accessible aryl bromides and fluorosulfates, the latter easily prepared from the corresponding ...phenols. The methodology utilizes low pressure carbon monoxide generated
from COgen to generate Weinreb amides as reactive intermediates that undergo monotrifluoromethylation affording the corresponding aromatic trifluoromethyl ketones (TFMKs) in good yields. The stoichiometric use of CO enables the possibility for accessing
C-isotopically labeled TFMK by switching to the use of
COgen.
The applicability of a heteroaromatic photoredox catalyst in an additive-free photo-mediated hydroamination of stilbenes is described. Initiated by the excitation of a highly potent organic ...pyrimidopteridine photoredox catalyst (E*PrPPT*/PrPPT· – = +2.10 V vs SCE in MeCN), the photo-mediated hydroamination of stilbenes was enabled using unprotected, primary aliphatic, allylic, benzylic amines for the synthesis of various α-phenyl phenethylamine derivatives. Notably, the stereogenic center of α-chiral amines was fully preserved. Both starting materials serve as competent quenching partners. Fluorescence- and competitive fluorescence-quenching experiments as well as electron paramagnetic resonance spectroscopic analysis and density functional theory calculations allowed a plausible reaction mechanism to be deduced.
Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent.
We investigated whether prenatal ...exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD).
This study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach.
Odds of ASD was significantly elevated in PFOA quartile 2 OR = 1.71 (95% CI: 1.20, 2.45) compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 OR = 1.54 (95% CI: 1.16, 2.04) compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD OR = 0.76 (95% CI: 0.64, 0.90) as well as the carboxylate mixture OR = 0.79 (95% CI: 0.68, 0.93) and the sulfonate mixture OR = 0.84 (95% CI: 0.73, 0.96).
Prenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development.
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