We rationally engineered an elegant entropy‐driven DNA nanomachine with three‐dimensional track and applied it for intracellular miRNAs imaging. The proposed nanomachine is activated by target miRNA ...binding to drive a walking leg tethered to gold nanoparticle with a high density of DNA substrates. The autonomous and progressive walk on the DNA track via the entropy‐driven catalytic reaction of intramolecular toehold‐mediated strand migration leads to continuous disassembly of DNA substrates, accompanied by the recovery of fluorescence signal due to the specific release of a dye‐labeled substrate from DNA track. Our nanomachine outperforms the conventional intermolecular reaction‐based gold nanoparticle design in the context of an improved sensitivity and kinetics, attributed to the enhanced local effective concentrations of working DNA components from the proximity‐induced intramolecular reaction. Moreover, the nanomachine was applied for miRNA imaging inside living cells.
Walk on a DNA track: An elegant entropy‐driven DNA nanomachine with a three‐dimensional track was rationally engineered (see picture). The nanomachine was applied for microRNA imaging inside living cells.
Synthetic molecular machines have received increasing attention because of their great ability to mimic natural biological motors and create novel modes of motion. However, very few examples have ...been implemented with real autonomous movement inside living cells, due to the challenges of the driving force and highly integrated system design. In this work, we report an elegant, highly integrated DNA nanomachine that can be powered by endogenous ATP molecules and autonomously operated inside living cells without any auxiliary additives. It assembles all components on a single gold nanoparticle (AuNP) including a hairpin-locked swing arm encoding a start triggered by an intracellular target molecule and a two-stranded DNA track responding to the motion of the swing arm. When the intracellular target activates the nanomachine
the unlocking swing arm, the machine autonomously and progressively operates on the established DNA track
intramolecular toehold-mediated strand migration and internal ATP binding. This paper also demonstrates the machine's bioanalytical application for specific microRNA (miRNA) imaging in living cells.
Hypnotics have been reported to be associated with dementia. However, the relationship between insomnia, hypnotics and dementia is still controversial. We sought to examine the risk of dementia in ...patients with long-term insomnia and the contribution of hypnotics.
Data was collected from Taiwan's Longitudinal Health Insurance Database. The study cohort comprised all patients aged 50 years or older with a first diagnosis of insomnia from 2002 to 2007. The comparison cohort consisted of randomly selected patients matched by age and gender. Each patient was individually tracked for 3 years from their insomnia index date to identify whether the patient had a first diagnosis of dementia. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
We identified 5693 subjects with long-term insomnia and 28,465 individuals without. After adjusting for hypertension, diabetes mellitus, hyperlipidemia, and stroke, those with long-term insomnia had significantly higher risks of dementia (HR, 2.34; 95% CI, 1.92-2.85). Patients with long-term insomnia and aged 50 to 65 years had a higher increased risk of dementia (HR, 5.22; 95% CI, 2.62-10.41) than those older than 65 years (HR, 2.33; 95% CI, 1.90-2.88). The use of hypnotics with a longer half-life and at a higher prescribed dose predicted a greater increased risk of dementia.
Patients with long-term use of hypnotics have more than a 2-fold increased risk of dementia, especially those aged 50 to 65 years. In addition, the dosage and half-lives of the hypnotics used should be considered, because greater exposure to these medications leads to a higher risk of developing dementia.
The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. ...tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7CHT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.
The potential relationship between anaesthesia, surgery and onset of dementia remains elusive.
To determine whether the risk of dementia increases after surgery with anaesthesia, and to evaluate ...possible associations among age, mode of anaesthesia, type of surgery and risk of dementia.
The study cohort comprised patients aged 50 years and older who were anaesthetised for the first time since 1995 between 1 January 2004 and 31 December 2007, and a control group of randomly selected patients matched for age and gender. Patients were followed until 31 December 2010 to identify the emergence of dementia.
Relative to the control group, patients who underwent anaesthesia and surgery exhibited an increased risk of dementia (hazard ratio = 1.99) and a reduced mean interval to dementia diagnosis. The risk of dementia increased in patients who received intravenous or intramuscular anaesthesia, regional anaesthesia and general anaesthesia.
The results of our nationwide, population-based study suggest that patients who undergo anaesthesia and surgery may be at increased risk of dementia.
Increasing evidence has shown that immune checkpoint inhibitors are associated with hyperprogressive disease (HPD). HPD usually resulted in dramatically reduced survival duration, which limited the ...opportunity to administer other therapies.
A heavily pretreated lung adenocarcinoma patient experienced rapid progression of rib metastasis soon after immune checkpoint inhibitor -based combination therapy.
On the basis of radiographic and pathological findings, the patient was diagnosed with HPD.
We treated the patient with iodine-125 radioactive particle implantation to the metastatic lesions in the chest wall.
The metastatic lesions shrank significantly 1 month later.
Early detection and adequate treatment are essential for prolonged survival when HPD occurs.
Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several ...clinical trials of "universal" drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens.
Initiation of symbiotic nodules in legumes requires cytokinin signaling, but its mechanism of action is largely unknown. Here, we tested whether the failure to initiate nodules in the Medicago ...truncatula cytokinin perception mutant cre1 (cytokinin response1) is due to its altered ability to regulate auxin transport, auxin accumulation, and induction of flavonoids. We found that in the cre1 mutant, symbiotic rhizobia cannot locally alter acro- and basipetal auxin transport during nodule initiation and that these mutants show reduced auxin (indole-3-acetic acid) accumulation and auxin responses compared with the wild type. Quantification of flavonoids, which can act as endogenous auxin transport inhibitors, showed a deficiency in the induction of free naringenin, isoliquiritigenin, quercetin, and hesperetin in cre1 roots compared with wild-type roots 24 h after inoculation with rhizobia. Coinoculation of roots with rhizobia and the flavonoids naringenin, isoliquiritigenin, and kaempferol, or with the synthetic auxin transport inhibitor 2,3,5,-triiodobenzoic acid, rescued nodulation efficiency in cre1 mutants and allowed auxin transport control in response to rhizobia. Our results suggest that CRE1-dependent cytokinin signaling leads to nodule initiation through the regulation of flavonoid accumulation required for local alteration of polar auxin transport and subsequent auxin accumulation in cortical cells during the early stages of nodulation.
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