Aberrant oncogene activation induces cellular senescence, an irreversible growth arrest that acts as a barrier against tumorigenesis. To identify microRNAs (miRNAs) involved in oncogene-induced ...senescence, we examined the expression of miRNAs in primary human TIG3 fibroblasts after constitutive activation of B-RAF. Among the regulated miRNAs, both miR-34a and miR-146a were strongly induced during senescence. Although members of the miR-34 family are known to be transcriptionally regulated by p53, we find that miR-34a is regulated independently of p53 during oncogene-induced senescence. Instead, upregulation of miR-34a is mediated by the ETS family transcription factor, ELK1. During senescence, miR-34a targets the important proto-oncogene MYC and our data suggest that miR-34a thereby coordinately controls a set of cell cycle regulators. Hence, in addition to its integration in the p53 pathway, we show that alternative cancer-related pathways regulate miR-34a, emphasising its significance as a tumour suppressor.
•Carboxylic acids (CAs) have powerful antimicrobial properties, specially at low pH.•Owing to their safety record, CAs are used by industry to assure safe food consumption.•The use of some CAs as ...antiseptics is done but still in a limited form.•CAs can be more explored as anti-infectious agents.
Carboxylic organic acids are intermediates of central carbon metabolic pathways (e.g. acetic, propionic, citric, and lactic acid) long known to have potent antimicrobial potential, mainly at acidic pHs. The food industry has been leveraging those properties for years, using many of these acids as preservatives to inhibit the growth of pathogenic and/or spoilage fungal and bacterial species. A few of these molecules (the most prominent being acetic acid) have been used as antiseptics since Hippocratic medicine, mainly to treat infected wounds in patients with burns. With the growth of antibiotic therapy, the use of carboxylic acids (and other chemical antiseptics) in clinical settings lost relevance; however, with the continuous emergence of multi-antibiotic/antifungal resistant strains, the search for alternatives has intensified. This prospective article raises awareness of the potential of carboxylic acids to control infections in clinical settings, considering not only their previous exploitation in this context (which we overview) but also the positive experience of their safe use in food preservation. At a time of great concern with antimicrobial resistance and the slow arrival of new antimicrobial therapeutics to the market, further exploration of organic acids as anti-infective molecules may pave the way to more sustainable prophylactic and therapeutic approaches.
Induction of the AR2 acid response system of
occurs at a moderately low pH (pH 5.5) and leads to high levels of resistance to pH levels below 2.5 in the presence of glutamate. Induction is mediated ...in part by the EvgAS two component system. Here, we show that the bacterial signaling molecule indole inhibits the induction of key promoters in the AR2 system and blocks the development of glutamate-dependent acid resistance. The addition of tryptophan, the precursor for indole biosynthesis, had the same effects, and this block was relieved in a
mutant, which is unable to synthesize indole. Expression of a constitutively active EvgS protein was able to relieve the inhibition caused by indole, consistent with EvgS being inhibited directly or indirectly by indole. Indole had no effect on autophosphorylation of the isolated cytoplasmic domain of EvgS. This is consistent with a model where indole directly or indirectly affects the ability of EvgS to detect its inducing signal or to transduce this information across the cytoplasmic membrane. The inhibitory activity of indole on the AR2 system is not related to its ability to act as an ionophore, and, conversely, the ionophore CCCP had no effect on acid-induced AR2 promoter activity, showing that the proton motive force is unlikely to be a signal for induction of the AR2 system.
Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP).
To determine whether ...enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants.
The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020.
Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age.
The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth.
A total of 101 infants (58 boys 57.4%; mean SD gestational age, 25.5 1.5 weeks) were included in the AA:DHA group, and 105 infants (59 boys 56.2%; mean SD gestational age, 25.5 1.4 weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 15.8% in the AA:DHA group vs 35 of 105 33.3% in the control group; adjusted relative risk, 0.50 95% CI, 0.28-0.91; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% 95% CI, 0.46-1.18 mol%; P < .001; overall mean difference in control group, 0.13 mol% 95% CI, 0.01-0.24 mol%; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 47.5% vs 48 of 105 45.7%) and of any grade of intraventricular hemorrhage (43 of 101 42.6% vs 42 of 105 40.0%). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died.
This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants.
ClinicalTrials.gov Identifier: NCT03201588.
The EvgS/EvgA two-component system of
is activated in response to low pH and alkali metals and regulates many genes, including those for the glutamate-dependent acid resistance system and a number of ...efflux pumps. EvgS, the sensor kinase, is one of five unconventional histidine kinases (HKs) in
and has a large periplasmic domain and a cytoplasmic PAS domain in addition to phospho-acceptor, HK and dimerization, internal receiver, and phosphotransfer domains. Mutations that constitutively activate the protein at pH 7 map to the PAS domain. Here, we built a homology model of the periplasmic region of EvgS, based on the structure of the equivalent region of the BvgS homologue, to guide mutagenesis of potential key residues in this region. We show that histidine 226 is required for induction and that it is structurally colocated with a proline residue (P522) at the top of the predicted transmembrane helix that is expected to play a key role in passing information to the cytoplasmic domains. We also show that the constitutive mutations in the PAS domain can be further activated by low external pH. Expression of the cytoplasmic part of the protein alone also gives constitutive activation, which is lost if the constitutive PAS mutations are present. These findings are consistent with a model in which EvgS senses both external and internal pH and is activated by a shift from a tight inactive to a weak active dimer, and we present an analysis of the purified cytoplasmic portion of EvgS that supports this.
One of the ways bacteria sense their environment is through two-component systems, which have one membrane-bound protein to do the sensing and another inside the cell to turn genes on or off in response to what the membrane-bound protein has detected. The membrane-bound protein must thus be able to detect the stress and signal this detection event to the protein inside the cell. To understand this process, we studied a protein that helps
to survive exposure to low pH, which it must do before taking up residence in the gastrointestinal tract. We describe a predicted structure for the main sensing part of the protein and identify some key residues within it that are involved in the sensing and signaling processes. We propose a mechanism for how the protein may become activated and present some evidence to support our proposal.
AbstractUntil recently, the sunflower star,
, was a dominant and common predator in a wide variety of benthic habitats in the northeast Pacific. Then, in 2013, its populations began to plummet across ...its entire range as a result of the spread of a phenomenon known as sea star wasting disease, or sea star wasting. Although dozens of sea star species were impacted by this wasting event,
seems to have suffered the greatest losses and is now listed by the International Union for the Conservation of Nature as the first critically endangered sea star. In order to learn more about the life history of this endangered predator and to explore the potential for its restoration, we have initiated a captive rearing program to attempt complete life-cycle (egg-to-egg) culture for
. We report our observations on holding and distinguishing individual adults, reproductive seasonality, larval development, inducers of settlement, and early juvenile growth and feeding. These efforts will promote and help guide conservation interventions to protect remaining populations of this species in the wild and facilitate its ultimate return.
The bacterial cell wall is essential for viability, but despite its ability to withstand internal turgor must remain dynamic to permit growth and division. Peptidoglycan is the major cell wall ...structural polymer, whose synthesis requires multiple interacting components. The human pathogen
is a prolate spheroid that divides in three orthogonal planes. Here, we have integrated cellular morphology during division with molecular level resolution imaging of peptidoglycan synthesis and the components responsible. Synthesis occurs across the developing septal surface in a diffuse pattern, a necessity of the observed septal geometry, that is matched by variegated division component distribution. Synthesis continues after septal annulus completion, where the core division component FtsZ remains. The novel molecular level information requires re-evaluation of the growth and division processes leading to a new conceptual model, whereby the cell cycle is expedited by a set of functionally connected but not regularly distributed components.
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