Fifty-nine per cent of physically abused children in the present cohort had orofacial signs of abuse which would be easily visible to a dental practitioner. The commonest injuries were bruises and abrasions. This concurs with previous reports in the literature and highlights the important role of dental practitioners in the recognition of children who have been abused.
Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.
Depolarization of an individual mitochondrion or small
clusters
of mitochondria within cells has been achieved using a photoactivatable
probe. The probe is targeted to the matrix of the mitochondrion by
an alkyltriphenylphosphonium lipophilic cation and releases the protonophore
2,4-dinitrophenol locally in predetermined regions in response to
directed irradiation with UV light via a local photolysis system.
This also provides a proof of principle for the general temporally
and spatially controlled release of bioactive molecules, pharmacophores,
or toxins to mitochondria with tissue, cell, or mitochondrion specificity.
There is increasing interest in the effect of energy metabolism on oxidative stress, but much ambiguity over the relationship between the rate of oxygen consumption and the generation of reactive oxygen species (ROS). Production of ROS (such as hydrogen peroxide, H2O2) in the mitochondria is primarily inferred indirectly from measurements in vitro, which may not reflect actual ROS production in living animals. Here, we measured in vivo H2O2 content using the recently developed MitoB probe that becomes concentrated in the mitochondria of living organisms, where it is converted by H2O2 into an alternative form termed MitoP; the ratio of MitoP/MitoB indicates the level of mitochondrial H2O2
in vivo. Using the brown trout Salmo trutta, we tested whether this measurement of in vivo H2O2 content over a 24 h-period was related to interindividual variation in standard metabolic rate (SMR). We showed that the H2O2 content varied up to 26-fold among fish of the same age and under identical environmental conditions and nutritional states. Interindividual variation in H2O2 content was unrelated to mitochondrial density but was significantly associated with SMR: fish with a higher mass-independent SMR had a lower level of H2O2. The mechanism underlying this observed relationship between SMR and in vivo H2O2 content requires further investigation, but may implicate mitochondrial uncoupling which can simultaneously increase SMR but reduce ROS production. To our knowledge, this is the first study in living organisms to show that individuals with higher oxygen consumption rates can actually have lower levels of H2O2.
Here, we report that
wild type
Escherichia coli
ribosomes accept and elongate
precharged initiator tRNAs acylated
with multiple benzoic acids, including aramid precursors, as well
as malonyl (1,3-dicarbonyl) substrates to generate a diverse set of
aramid-peptide and polyketide-peptide hybrid molecules. This work
expands the scope of ribozyme- and ribosome-catalyzed chemical transformations,
provides a starting point for
in vivo
translation
engineering efforts, and offers an alternative strategy for the biosynthesis
of polyketide-peptide natural products.
Dentists in Scotland appear to be suspecting and referring more cases of child abuse/neglect than previously. The vast majority are willing to get involved in detecting neglect.
SummaryMitochondrial superoxide
(O2⋅−) underlies much oxidative damage and
redox signaling. Fluorescent probes can detect
O2⋅−, but are of limited applicability
in vivo, while in cells their usefulness is
constrained by side reactions and DNA intercalation. To overcome these
limitations, we developed a dual-purpose mitochondrial
O2⋅− probe, MitoNeoD, which can assess
O2⋅− changes
in vivo by mass spectrometry and
in vitro by fluorescence. MitoNeoD comprises a
O2⋅−-sensitive reduced phenanthridinium
moiety modified to prevent DNA intercalation, as well as a carbon-deuterium bond
to enhance its selectivity for O2⋅− over
non-specific oxidation, and a triphenylphosphonium lipophilic cation moiety
leading to the rapid accumulation within mitochondria. We demonstrated that
MitoNeoD was a versatile and robust probe to assess changes in mitochondrial
O2⋅− from isolated mitochondria to animal
models, thus offering a way to examine the many roles of mitochondrial
O2⋅− production in health and
disease.
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