Traumatic brain injury (TBI) is closely and bi-directionally linked with alcohol use, as by some estimates intoxication is the direct or indirect cause of one-third to one-half of all TBI cases. ...Alcohol use following injury can reduce the efficacy of rehabilitation and increase the chances for additional injury. Finally, TBI itself may be a risk factor for the development of alcohol use disorders. Children who suffer TBIs have poorer life outcomes and more risk of substance abuse. We used a standardized closed-head injury to model mild traumatic brain injuries. We found that mice injured as juveniles but not during adulthood exhibited much greater alcohol self-administration in adulthood. Further, this phenomenon was limited to female mice. Using behavioral testing, including conditioned place preference assays, we showed that early injuries increase the rewarding properties of alcohol. Environmental enrichment administered after injury reduced axonal degeneration and prevented the increase in drinking behavior. Additionally, brain-derived neurotrophic factor gene expression, which was reduced by TBI, was normalized by environmental enrichment. Together, these results suggest a novel model of alterations in reward circuitry following trauma during development.
The stringent response is a stress signalling system mediated by the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) in response to nutrient deprivation. Recent ...research highlights the complexity and broad range of functions that these alarmones control. This Review provides an update on our current understanding of the enzymes involved in ppGpp, pppGpp and guanosine 5'-monophosphate 3'-diphosphate (pGpp) (collectively (pp)pGpp) turnover, including those shown to produce pGpp and its analogue (pp)pApp. We describe the well-known interactions with RNA polymerase as well as a broader range of cellular target pathways controlled by (pp)pGpp, including DNA replication, transcription, nucleotide synthesis, ribosome biogenesis and function, as well as lipid metabolism. Finally, we review the role of ppGpp and pppGpp in bacterial pathogenesis, providing examples of how these nucleotides are involved in regulating many aspects of virulence and chronic infection.
The stringent response is a survival mechanism used by bacteria to deal with stress. It is coordinated by the nucleotides guanosine tetraphosphate and pentaphosphate (p)ppGpp, which interact with ...target proteins to promote bacterial survival. Although this response has been well characterized in proteobacteria, very little is known about the effectors of this signaling system in Gram-positive species. Here, we report on the identification of seven target proteins for the stringent response nucleotides in the Gram-positive bacterium Staphylococcus aureus. We demonstrate that the GTP synthesis enzymes HprT and Gmk bind with a high affinity, leading to an inhibition of GTP production. In addition, we identified five putative GTPases—RsgA, RbgA, Era, HflX, and ObgE—as (p)ppGpp target proteins. We show that RsgA, RbgA, Era, and HflX are functional GTPases and that their activity is promoted in the presence of ribosomes but strongly inhibited by the stringent response nucleotides. By characterizing the function of RsgA in vivo, we ascertain that this protein is involved in ribosome assembly, with an rsgA deletion strain, or a strain inactivated for GTPase activity, displaying decreased growth, a decrease in the amount of mature 70S ribosomes, and an increased level of tolerance to antimicrobials. We additionally demonstrate that the interaction of ppGpp with cellular GTPases is not unique to the staphylococci, as homologs from Bacillus subtilis and Enterococcus faecalis retain this ability. Taken together, this study reveals ribosome inactivation as a previously unidentified mechanism through which the stringent response functions in Gram-positive bacteria.
Among more than 35,000 health care workers, those who received two doses of BNT162b2 vaccine had a high level of protection against Covid-19, regardless of the between-dose interval, but efficacy ...began to wane after 6 months. Immunity in vaccinated, previously infected persons was more effective and durable (>1 year) than that in vaccinated persons who had not been infected.
Ribosome assembly cofactors are widely conserved across all domains of life. One such group, the ribosome-associated GTPases (RA-GTPase), act as molecular switches to coordinate ribosome assembly. We ...previously identified the Staphylococcus aureus RA-GTPase Era as a target for the stringent response alarmone (p)ppGpp, with binding leading to inhibition of GTPase activity. Era is highly conserved throughout the bacterial kingdom and is essential in many species, although the function of Era in ribosome assembly is unclear. Here we show that Era is not essential in S. aureus but is important for 30S ribosomal subunit assembly. Protein interaction studies reveal that Era interacts with the 16S rRNA endonuclease YbeY and the DEAD-box RNA helicase CshA. We determine that both Era and CshA are required for growth at suboptimal temperatures and rRNA processing. Era and CshA also form direct interactions with the (p)ppGpp synthetase RelSau, with RelSau positively impacting the GTPase activity of Era but negatively affecting the helicase activity of CshA. We propose that in its GTP-bound form, Era acts as a hub protein on the ribosome to direct enzymes involved in rRNA processing/degradation and ribosome subunit assembly to their site of action. This activity is impeded by multiple components of the stringent response, contributing to the slowed growth phenotype synonymous with this stress response pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Seafood mislabelling and species substitution, compounded by a convoluted seafood supply chain with significant traceability challenges, hinder efforts towards more sustainable, responsible, and ...ethical fishing and business practices. We conducted the largest evaluation of the quality and accuracy of labels for 672 seafood products sold in Australia, assessing six seafood groups (i.e., hoki, prawns, sharks and rays, snapper, squid and cuttlefish, and tuna) from fishmongers, restaurants, and supermarkets, including domestically caught and imported products. DNA barcoding revealed 11.8% of seafood tested did not match their label with sharks and rays, and snappers, having the highest mislabelling rate. Moreover, only 25.5% of products were labelled at a species-level, while most labels used vague common names or umbrella terms such as 'flake' and 'snapper'. These poor-quality labels had higher rates of mislabelling than species-specific labels and concealed the sale of threatened or overfished taxa, as well as products with lower nutritional quality, reduced economic value, or potential health risks. Our results highlight Australia's weak seafood labelling regulations and ambiguous non-mandatory naming conventions, which impede consumer choice for accurately represented, sustainable, and responsibly sourced seafood. We recommend strengthening labelling regulations to mitigate seafood mislabelling and substitution, ultimately improving consumer confidence when purchasing seafood.
Elevated sputum eosinophil counts predict asthma exacerbations and responsiveness to inhaled corticosteroids but are impractical to measure in primary care. We investigated the relation between blood ...eosinophil count and prospective annual asthma outcomes for a large UK cohort.
This historical cohort study used anonymised medical record data to identify primary care patients with asthma aged 12-80 years with 2 years of continuous records, including 1 year before (baseline) and 1 year after (outcome) their most recent eosinophil count. Negative binomial regression was used to compare outcome exacerbation rates and logistic regression to compare odds of asthma control for patients with blood eosinophil counts of 400 cells per μL or less versus greater than 400 cells per μL, adjusting for age, sex, body-mass index, smoking status, and Charlson comorbidity index. The study is registered at ClinicalTrials.gov, number NCT02140541.
Overall, 20 929 (16%) of 130 248 patients had blood eosinophil counts greater than 400 cells per μL. During the outcome year, these patients experienced significantly more severe exacerbations (adjusted rate ratio RR 1·42, 95% CI 1·36-1·47) and acute respiratory events (RR 1·28, 1·24-1·33) than those with counts of 400 cells per μL or less. They also had significantly lower odds of achieving overall asthma control (OR 0·74, 95% CI 0·72-0·77), defined as limited reliever use and no asthma-related hospital attendance or admission, acute course of oral corticosteroids, or prescription for antibiotics. Exacerbation rates increased progressively with nine ascending categories of blood eosinophil count as compared with a reference category of 200 cells per μL or less.
Patients with asthma and blood eosinophil counts greater than 400 cells per μL experience more severe exacerbations and have poorer asthma control. Furthermore, a count-response relation exists between blood eosinophil counts and asthma-related outcomes. Blood eosinophil counts could add predictive value to Global Initiative for Asthma control-based risk assessment.
Teva Pharmaceuticals.
The stringent response is a conserved bacterial stress response mechanism that allows bacteria to respond to nutritional challenges. It is mediated by the alarmones pppGpp and ppGpp, nucleotides that ...are synthesized and hydrolyzed by members of the RSH superfamily. Whilst there are key differences in the binding targets for (p)ppGpp between Gram-negative and Gram-positive bacterial species, the transient accumulation of (p)ppGpp caused by nutritional stresses results in a global change in gene expression in all species. The RSH superfamily of enzymes is ubiquitous throughout the bacterial kingdom, and can be split into three main groups: the long-RSH enzymes; the small alarmone synthetases (SAS); and the small alarmone hydrolases (SAH). Despite the prevalence of these enzymes, there are important differences in the way in which they are regulated on a transcriptional and post-translational level. Here we provide an overview of the diverse regulatory mechanisms that are involved in governing this crucial signalling network. Understanding how the RSH superfamily members are regulated gives insights into the varied important biological roles for this signalling pathway across the bacteria.
PDF
