Chlorine disinfection to drinking water plays an important role in preventing and controlling waterborne disease outbreaks globally. Nevertheless, little is known about why it enriches the antibiotic resistance genes (ARGs) in bacteria after chlorination. Here, ARGs released from killed antibiotic-resistant bacteria (ARB), and culturable chlorine-injured bacteria produced in the chlorination process as the recipient, were investigated to determine their contribution to the horizontal transfer of ARGs during disinfection treatment. We discovered Escherichia coli, Salmonella aberdeen, Pseudomonas aeruginosa and Enterococcus faecalis showed diverse resistance to sodium hypochlorite, and transferable RP4 could be released from killed sensitive donor consistently. Meanwhile, the survival of chlorine-tolerant injured bacteria with enhanced cell membrane permeabilisation and a strong oxidative stress-response demonstrated that a physiologically competent cell could be transferred by RP4 with an improved transformation frequency of up to 550 times compared with the corresponding untreated bacteria. Furthermore, the water quality factors involving chemical oxygen demand (COD Mn), ammonium nitrogen and metal ions (Ca 2+ and K +) could significantly promote above transformation frequency of released RP4 into injured E. faecalis. Our findings demonstrated that the chlorination process promoted the horizontal transfer of plasmids by natural transformation, which resulted in the exchange of ARGs across bacterial genera and the emergence of new ARB, as well as the transfer of chlorine-injured opportunistic pathogen from non-ARB to ARB. Considering that the transfer elements were quite resistant to degradation through disinfection, this situation poses a potential risk to public health.

Abstract-Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the ␣7 nicotinic acetylcholine receptor (␣7nAChR) in inflammation has recently been identified. We tested the hypothesis that ␣7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the ␣7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and ␣7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-␣, interleukin-1␤, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the ␣7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor B. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in ␣7nAChR Ϫ/Ϫ mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension. (Hypertension. 2011;57:298-307.) • Online Data Supplement Key Words: acetylcholine Ⅲ ␣7 nicotinic acetylcholine receptor Ⅲ inflammation Ⅲ hypertension Ⅲ end-organ damage H ypertension is a major risk factor for myocardial infarction, heart failure, stroke, and kidney dysfunction. Endorgan damage (EOD), including cardiac hypertrophy and myocyte dysfunction, vascular remodeling, and renal lesions, is a crucial mediatory link between hypertension and the development of these cardiovascular events. 1 Therefore, a better understanding of the mechanisms leading to hypertensive EOD could provide new avenues for prevention of cardiovascular events. Inflammation is very important in the genesis and development of EOD. 2,3 Furthermore, the reninangiotensin system can contribute to EOD, at least partly by promoting inflammation. 4 -7 However, cardiovascular inflammation and EOD can also occur without renin-angiotensin system activation, 8 so other mechanisms must also operate.Recent evidence indicates that neuronal 9 -11 cholinergic systems influence inflammatory responses by controlling the release of tumor necrosis factor (TNF)-␣, interleukin-(⌱L)-1␤, and IL-6 and that nonneuronal acetylcholine synthesis and rele...

Our previous study showed that high levels of HMGB1 existed in rats following cardiopulmonary bypass (CPB)-induced acute lung injury (ALI) and neutralization of high-mobility group box 1(HMGB1) reduced CPB-induced ALI. However, the mechanism by which CPB increases HMGB1 secretion is unclear. Recent studies have shown that inflammasome-mediated cell pyroptosis promotes HMGB1 secretion. This study aimed to investigate the relationship between inflammasome-mediated pyroptosis and HMGB1 in CPB-related ALI. We employed oxygen-glucose deprivation (OGD)-induced alveolar macrophage (AM) NR8383 pyroptosis to measure HMGB1 secretion. We found that OGD significantly increased the levels of caspase-1 cleaved p10, IL-1β and ASC expression, caspase-1 activity and the frequency of pyroptotic AM, and promoted the cytoplasm transportation and secretion of HMGB1, which were significantly mitigated by ASC silencing or pre-treatment with glyburide (a Nlrp3 inhibitor) in AM. CPB also increased the expression levels of Nlrp3, ASC, caspase-1 P10, and IL-1β, and the percentages of AM pyroptosis in the lungs of experimental rats accompanied by increased levels of serum and bronchoalveolar lavage fluid (BALF) HMGB1. Treatment with glyburide significantly mitigated the CPB-increased ASC, caspase-1 p10 and IL-1β expression, and the percentages of AM pyroptosis in the lungs, as well as the levels of HMGB1 in serum and BALF in rats. Therefore, our data indicated that the Nlrp3/ASC-mediated AM pyroptosis increased HMGB1 secretion in ALI induced by CPB. These findings may provide a therapeutic strategy to reduce lung injury and inflammatory responses during CPB.

BTO/MoS2@CA , with the integration of charge‐enhanced enzymatic activity, pH‐responsive CA release‐mediated H2O2 self‐supply, and GSH depletion, enables out‐of‐balance redox homeostasis, leading to effective tumor ferroptosis. As demonstrated by Yawei Lv, Xin Yu, Jing Liu, Chunying Chen et al. in their Research Article (e202217448), charge is one of the important contributing factors for nanozyme activity, which has not been mentioned previously.

BackgroundAcute lung injury (ALI) is considered to be the major cause of respiratory failure in critically ill patients. Clinical studies have found that in patients with sepsis and after hemorrhage, the elevated level of high mobility group box-1(HMGB-1) in their circulation is highly associated with ALI, but the underlying mechanism remains unclear. Extracellular HMGB-1 has cytokine-like properties and can bind to Toll-like Receptor-4 (TLR4), which was reported to play an important role in the pathogenesis of ALI. The aim of this study was to determine whether HMGB-1 directly contributes to ALI and whether TLR4 signaling pathway is involved in this process.MethodsRecombinant human HMGB-1 (rhHMGB-1) was used to induce ALI in male Sprague-Dawley rats. Lung specimens were collected 2 h after HMGB-1 treatment. The levels of TNF-α, IL-1β, TLR4 protein, and TLR4 mRNA in lungs as well as pathological changes of lung tissue were assessed. In cell studies, the alveolar macrophage cell line, NR8383, was collected 24 h after rhHMGB-1 treatment and the levels of TNF-α and IL-1β in cultured medium as well as TLR4 protein and mRNA levels in the cell were examined. TLR4-shRNA-lentivirus was used to inhibit TLR4 expression, and a neutralizing anti-HMGB1 antibody was used to neutralize rhHMGB-1 both in vitro and in vivo.ResultsFeatures of lung injury and significant elevation of IL-1β and TNF-α levels were found in lungs of rhHMGB-1-treated animals. Cultured NR8383 cells were activated by rhHMGB-1 treatment and resulted in the release of IL-1β and TNF-α. TLR4 expression was greatly up-regulated by rhHMGB-1. Inhibition of TLR4 or neutralization of HMGB1 with a specific antibody also attenuated the inflammatory response induced by HMGB-1 both in vivo and in vitro.ConclusionHMGB-1 can activate alveolar macrophages to produce proinflammatory cytokines and induce ALI through a mechanism that relies on TLR-4.

The potential risks of nano-materials and the spread of antibiotic resistance genes (ARGs) have become two major global public concerns. Studies have confirmed that nano-alumina can promote the spread of ARGs mediated by plasmids. Nano-titanium dioxide (TiO(2)), an excellent photocatalytic nano-material, has been widely used and is often present in aqueous environments. At various nano-material concentrations, bacterial density, matting time, and matting temperature, nano-TiO(2) can significantly promote the conjugation of RP4 plasmid in Escherichia coli. We developed a mathematical model to quantitatively describe the conjugation process and used this model to evaluate the effects of nano-TiO(2) on the spread of ARGs. We obtained analytical solutions for total and resistant bacteria, which were enumerated by the abundance of genetic loci unique to the plasmid and the chromosome using qPCR. Our results showed that the mathematic model was able to fit the experimental data well and can be used to quantitatively evaluate the effects of nano-TiO(2). According to our model, the presence of nano-TiO(2) decreased the bacterial growth rate from 0.0360 to 0.0323 min(-1) and increased the conjugative transfer rate from 6.69 × 10(-12) to 3.93 × 10(-10 )mL cell(-1) min(-1). These results indicate that nano-TiO(2) inhibited bacterial growth and promoted conjugation simultaneously. The data for morphology and mRNA expression also demonstrated this phenomenon. Our results confirm that environmental nano-TiO(2) may cause the spread of ARGs and thus poses an environmental risk. In addition, we provide a potential method for monitoring changes in ARGs that result from conjugation and evaluating the effects of antimicrobial substances on ARG expression.

BackgroundThe incidence of intertrochanteric hip fracture is expected to increase as the global population ages. It is one of the most important causes of mortality and morbidities in the geriatric population. The incidence of reverse oblique and transverse intertrochanteric (AO/OTA 31-A3) fractures is relatively low; however, the incidence of implant failure in AO/OTA 31-A3 fractures is relatively high compared with that in AO/OTA 31-A1 and A2 fractures. To date, the risk factors for implant failure in AO/OTA 31-A3 fractures treated with proximal femoral nail antirotation (PFNA) have remained ambiguous. The purpose of this study was to identify the predictive factors of implant failure in AO/OTA 31-A3 fractures treated with PFNA.MethodsThe data of all patients who underwent surgery for trochanteric fractures at our institution between January 2006 and February 2018 were retrospectively reviewed. All AO/OTA 31-A3 fractures treated with PFNA were included. Logistic regression analysis of potential predictors of implant failure was performed. Potential predictors included age, sex, body mass index, fracture type, reduction method, status of posteromedial support and lateral femoral wall, reduction quality, tip-apex distance and position of the helical blade in the femoral head.ResultsOne hundred four (9.3%) patients with AO/OTA 31-A3 fractures were identified. Forty-five patients with AO/OTA 31-A3 fractures treated with PFNA were suitable for our study. Overall, implant failure occurred in six (13.3%) of forty-five patients. Multivariate analysis identified poor reduction quality (OR, 28.70; 95% CI, 1.91–431.88; p = 0.015) and loss of posteromedial support (OR, 18.98; 95% CI, 1.40–257.08; p = 0.027) as factors associated with implant failure.ConclusionsPoor reduction quality and loss of posteromedial support are predictors of implant failure in reverse oblique and transverse intertrochanteric fractures treated with PFNA.

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