FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect.

PURPOSE: Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs. METHODS: Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin. RESULTS: Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs. CONCLUSION: Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

Bta-miR-365-3p-targeted FKBP5 participates in the AMPK/mTOR signaling pathway in the regulation of preadipocyte differentiation in cattle.

Objective: MicroRNAs (miRNAs) are endogenous non-coding RNAs that can play a role in the post-transcriptional regulation of mammalian preadipocyte differentiation. However, the precise functional mechanism of its regulation of fat metabolism is not fully understood. Methods: We identified bta-miR-365-3p, which specifically targets the 3'untranslated region (3'UTR) of the FK506-binding protein 5 (FKBP5),and verified its mechanisms for regulating expression and involvement in adipogenesis. Results: In this study, we found that the overexpression of bta-miR-365-3p significantly decreased the lipid accumulation and triglyceride content in the adipocytes. Compared to inhibiting bta-miR-365-3p group, overexpression of bta-miR-365-3p can inhibit the expression of adipocyte differentiation-related genes C/EBPα and PPARγ. The dual-luciferase reporter system further validated the targeting relationship between bta-miR-365-3p and FKBP5. FKBP5 mRNA and protein expression were detected by qRT-PCR and Western blot. Overexpression of bta-miR-365-3p significantly down-regulated FKBP5 expression, while inhibition of bta-miR-365-3p showed the opposite, indicating that bta-miR-365-3p negatively regulates FKBP5. AMPK/mTOR signaling pathway is closely related to the regulation of cell growth and is involved in the development of bovine adipocytes. In this study, overexpression of bta-miR-365-3p significantly inhibited mRNA and protein expression of AMPK, mTOR, and SREBP1 genes, while the inhibition of bta-miR-365-3p expression was contrary to these results. Overexpression of FKBP5 significantly upregulated AMPK, mTOR, and SREBP1 gene expression, while inhibition of FKBP5 expression was contrary to the above experimental results. Conclusion: In conclusion, these results indicate that bta-miR-365-3p may be involved in the AMPK/mTOR signaling pathway in regulating Yanbian yellow cattle preadipocytes differentiation by targeting the FKBP5 gene.

Special economic zone and infant mortality: Evidence from China.

By exploiting the development of special economic zones (SEZs) in China as a quasi-natural experiment, this paper evaluates how such zones affect infant mortality. Difference-in-differences analysis reveals that SEZs significantly decrease the local infant mortality rate, and the impact is larger for male infants and infants with less-educated mothers. Further studies show that the SEZs, which acts as an economic growth shock, improve infant survival by increasing the local income. Furthermore, there is no supportive evidence that the SEZs significantly alter either women's fertility-associated behaviors or environmental pollution. These results highlight the previously ignored human capital-related consequences of place-based policies in China.

Modeling the pest-pathogen threats in a warming world for the red turpentine beetle (Dendroctonus valens) and its symbiotic fungus (Leptographium procerum).

BACKGROUND: Dendroctonus valens along with its symbiotic fungi have caused unprecedented damage to pines in China. Leptographium procerum, its primary symbiotic fungus, facilitates the invasion and colonization of the pest, thereby aggravating ecological threats. Assessing shifts in the niches and ranges of D. valens and its symbiotic fungus could provide a valuable basis for pest control. Here, we conducted niche comparisons between native and invasive populations of D. valens. Then, we employed standard ecological niche models and ensembles of small models to predict the potential distributions of D. valens and L. procerum under climate change conditions and to estimate areas of overlap. RESULTS: The niche of invasive population of D. valens in Chinese mainland only occupied a limited portion of the niche of native population in North America, leaving a substantial native niche unfilled and without any niche expansion. The suitable regions for D. valens are predicted in central and southern North America and central and northeastern Chinese mainland. The overlap with the suitable regions of L. procerum included eastern North America and the central and northeastern Chinese mainland under historical climatic scenarios. The regions susceptible to their symbiotic damage will shift northward in response to future climate change. CONCLUSIONS: Projected distributions of D. valens and its symbiotic fungus, along with areas vulnerable to their symbiotic damage, provide essential insights for devising strategies against this association. Additionally, our study contributes to comprehending how biogeographic approaches aid in estimating potential risks of pest-pathogen interactions in forests within a warming world. © 2024 Society of Chemical Industry.

Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice.

Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics; however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA sequencing, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe outer hair cell loss and progressive damage of synapses in inner hair cells were observed in Atoh1-Gpx4-/- mice. However, Fsp1-/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss.

Clinical study of NFNC in the treatment of acute exacerbation chronic obstructive pulmonary disease patients with respiratory failure.

BACKGROUND: Most patients with acute exacerbation chronic obstructive pulmonary disease (AECOPD) have respiratory failure that necessitates active correction and the improvement of oxygenation is particularly important during treatment. High flow nasal cannula (HFNC) oxygen therapy is a non-invasive respiratory aid that is widely used in the clinic that improves oxygenation state, reduces dead space ventilation and breathing effort, protects the loss of cilia in the airways, and improves patient comfort. AIM: To compare HFNC and non-invasive positive pressure ventilation in the treatment of patients with AECOPD. METHODS: Eighty AECOPD patients were included in the study. The patients were in the intensive care department of our hospital from October 2019 to October 2021. The patients were divided into the control and treatment groups according to the different treatment methods with 40 patients in each group. Differences in patient comfort, blood gas analysis and infection indices were analyzed between the two groups. RESULTS: After treatment, symptoms including nasal, throat and chest discomfort were significantly lower in the treatment group compared to the control group on the 3rd and 5th days (P < 0.05). Before treatment, the PaO2, PaO2/FiO2, PaCO2, and SaO2 in the two groups of patients were not significantly different (P > 0.05). After treatment, the same indicators were significantly improved in both patient groups but had improved more in the treatment group compared to the control group (P < 0.05). After treatment, the white blood cell count, and the levels of C-reactive protein and calcitonin in patients in the treatment group were significantly higher compared to patients in the control group (P < 0.05). CONCLUSION: HFNC treatment can improve the ventilation of AECOPD patients whilst also improving patient comfort, and reducing complications. HFNC is a clinically valuable technique for the treatment of AECOPD.

Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels.

The peroxisome is a ubiquitous organelle in rodent cells and plays important roles in a variety of cell types and tissues. It is previously indicated that peroxisomes are associated with auditory function, and patients with peroxisome biogenesis disorders (PBDs) are found to have hearing dysfunction, but the specific role of peroxisomes in hearing remains unclear. In this study, two peroxisome-deficient mouse models (Atoh1-Pex5-/- and Pax2-Pex5-/- ) are established and it is found that peroxisomes mainly function in the hair cells of cochleae. Furthermore, peroxisome deficiency-mediated negative effects on hearing do not involve mitochondrial dysfunction and oxidative damage. Although the mammalian target of rapamycin complex 1 (mTORC1) signaling is shown to function through peroxisomes, no changes are observed in the mTORC1 signaling in Atoh1-Pex5-/- mice when compared to wild-type (WT) mice. However, the expression of large-conductance, voltage-, and Ca2+ -activated K+ (BK) channels is less in Atoh1-Pex5-/- mice as compared to the WT mice, and the administration of activators of BK channels (NS-1619 and NS-11021) restores the auditory function in knockout mice. These results suggest that peroxisomes play an essential role in cochlear hair cells by regulating BK channels. Hence, BK channels appear as the probable target for treating peroxisome-related hearing diseases such as PBDs.

Pharmacokinetics of YK-1169 in healthy subjects and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation.

OBJECTIVE: This study (NCT05588531) aimed to evaluate the safety and pharmacokinetics of cefepime-avibactam (YK-1169) in healthy Chinese subjects and explore the optimal regimen for treating carbapenem-resistant Klebsiella pneumoniae (CRKP) based on the pharmacokinetic/pharmacodynamic evaluation. METHODS: YK-1169 single-ascending doses (0.5, 1.25, 2.5 or 3.75 g, 2-h infusion) and multiple doses (2.5 or 3.75 g every 8 h [q8h], 2-h infusion) given for 7 days were evaluated in pharmacokinetic studies. Subjects were randomized to receive cefepime (2 g), avibactam (0.5 g) or YK-1169 (2.5 g) to assess drug-drug interactions. The minimum inhibitory concentrations (MICs) of YK-1169 were determined by the broth microdilution method. Monte Carlo simulation was used to evaluate 10 different dose regimens. RESULTS: Cefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime Cmax,ss and AUC0-∞,ss were 9.20 and 16.0 µg/mL, 407.2 and 659.45 µg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. The avibactam Cmax,ss and AUC0-∞,ss were 0.545 and 0.837 µg/mL, 53.31 and 79.55 µg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. Cefepime and avibactam did not affect each other's pharmacokinetics. No serious adverse events occurred. All regimens achieved 90% probability of target attainment (PTA) goals when the MIC was ≤8 mg/L. The regimens of 2.5 (q8h, 2-h infusion), 3.75 (q8h, 2-, 3- and 4-h infusions) and 7.5 g (24-h continuous infusion) reached a 90% cumulative fraction of response. CONCLUSION: YK-1169 had good antibacterial activity against CRKP and could be an option for CRKP infections. The regimen of 2.5 g q8h intravenously guttae (ivgtt) 2 h should be considered in future clinical trials.

Dyslexia-Related Hearing Loss Occurs Mainly through the Abnormal Spontaneous Electrical Activity of Spiral Ganglion Neurons.

Dyslexia is a reading and spelling disorder due to neurodevelopmental abnormalities and is occasionally found to be accompanied by hearing loss, but the reason for the associated deafness remains unclear. This study finds that knockout of the dyslexia susceptibility 1 candidate 1 gene (Dyx1c1-/- ) in mice, the best gene for studying dyslexia, causes severe hearing loss, and thus it is a good model for studying the mechanism of dyslexia-related hearing loss (DRHL). This work finds that the Dyx1c1 gene is highly expressed in the mouse cochlea and that the spontaneous electrical activity of inner hair cells and type I spiral ganglion neurons is altered in the cochleae of Dyx1c1-/- mice. In addition, primary ciliary dyskinesia-related phenotypes such as situs inversus and disrupted ciliary structure are seen in Dyx1c1-/- mice. In conclusion, this study gives new insights into the mechanism of DRHL in detail and suggests that Dyx1c1 may serve as a potential target for the clinical diagnosis of DRHL.

Macrophage-mediated immune response aggravates hearing disfunction caused by the disorder of mitochondrial dynamics in cochlear hair cells.

Mitochondrial dynamics is essential for maintaining the physiological function of the mitochondrial network, and its disorders lead to a variety of diseases. Our previous study identified mitochondrial dynamics controlled anti-tumor immune responses and anxiety symptoms. However, how mitochondrial dynamics affects auditory function in the inner ear remains unclear. Here, we show that the deficiency of FAM73a or FAM73b, two mitochondrial outer membrane proteins that mediate mitochondrial fusion, leads to outer hair cells (HCs) damage and progressive hearing loss in FVB/N mice. Abnormal mitochondrial fusion causes elevated oxidative stress and apoptosis of HCs in the early stage. Thereafter, the activation of macrophages and CD4+ T cell is found in the mutant mice with the increased expression of the inflammatory cytokines IL-12 and IFN-γ compared with control mice. Strikingly, a dramatically decreased number of macrophages by Clophosome®-A-Clodronate Liposomes treatment alleviates the hearing loss of mutant mice. Collectively, our finding highlights that FAM73a or FAM73b deficiency affects HCs survival by disturbing the mitochondrial function, and the subsequent immune response in the cochleae worsens the damage of HCs.

Sitafloxacin pharmacokinetics/pharmacodynamics against multidrug-resistant bacteria in a dynamic urinary tract infection in vitro model.

OBJECTIVES: Sitafloxacin is one of the newer generation fluoroquinolones with highly active against multidrug-resistant (MDR) bacteria. Our objectives were to identify the sitafloxacin pharmacokinetic/pharmacodynamic (PK/PD) index and breakpoints against MDR isolate in the urinary tract infection model. METHODS: Forty-eight MDR isolates underwent sitafloxacin and levofloxacin microdilution susceptibility testing. A 24 h in vitro model was established that simulated the healthy subjects urodynamics of sitafloxacin fumarate injection. Ten MDR isolates (four carbapenem-resistant Escherichia coli, three carbapenem-resistant P. aeruginosa and three vancomycin-resistant E. faecium) were selected. The drug efficacy was quantified by the change in log colony counts within 24 h. A sigmoid Emax model was fitted to the killing effect data. Monte Carlo simulations were performed to assess target attainment for the sitafloxacin fumarate doses of 100 and 200 mg q24h. RESULTS: Analysis indicated that the MICs of sitafloxacin were all significantly lower than that of levofloxacin (P < 0.01). The UAUC0-24h/MIC targets required to achieve stasis, 1-log10 killing and 2-log10 killing were 63.60, 79.49 and 99.45 (carbapenem-resistant E. coli), 60.85, 90.31 and 128.95 (carbapenem-resistant P. aeruginosa), 65.91, 77.81 and 103.11 (vancomycin-resistant E. faecium). Monte Carlo simulation showed the infusion of sitafloxacin fumarate 100 mg q24h was able to achieve 90% probability of target attainment against bacteria with MIC of 8 mg/L for the common complicated urinary tract infections. CONCLUSIONS: Sitafloxacin fumarate injection is an alternative therapeutic agent for the treatment of UTIs caused by MDR isolates.

The Factors Influencing Public Satisfaction with Community Services for COVID-19: Evidence from a Highly Educated Community in Beijing.

The satisfaction of highly educated citizens with community services for COVID-19 represents the attitude of the middle class and plays an important role in both the social and political stability of a country. The aim of this paper was to determine which factors influence public satisfaction with COVID-19 services in a highly educated community. Through a literature review and using the American Customer Satisfaction Index (ACSI) model, this paper constructed a public satisfaction model of community services for COVID-19 and proposed relevant research hypotheses. A community with many highly educated residents in Beijing was selected as the case study, where 450 official questionnaires were distributed based on the age ratio of residents, with 372 valid questionnaires being collected from May 2021 to July 2021. The study results obtained by a structural equation model (SEM) show that: (1) public satisfaction is significantly and positively influenced by quality perception (0.305 **), public demand (0.295 **), and service maturity (0.465 ***); (2) public satisfaction has a significantly positive effect on service image (0.346 ***) and public trust (0.232 **), and service image significantly affects public trust (0.140 *); (3) service maturity is positively influenced by public demand (0.460 ***) and quality perception (0.323 *); and (4) public demand is positively influenced by quality perception (0.693 ***) (* p < 0.05; ** p < 0.01; *** p < 0.00). The conclusions of the study can provide suggestions and recommendations to improve the satisfaction of highly educated residents with community healthcare services during the COVID-19 pandemic.

Does Monitoring Total and Free Polymyxin B1 Plasma Concentrations Predict Polymyxin B-Induced Nephrotoxicity? A Retrospective Study in Critically Ill Patients.

INTRODUCTION: The correlation between total and free polymyxin B (PMB including PMB1 and PMB2) exposure in vivo and acute kidney injury (AKI) remains obscure. This study explores the relationships between plasma exposure of PMB1 and PMB2 and nephrotoxicity, and investigates the risk factors for PMB-induced acute kidney injury (AKI) in critically ill patients. METHODS: Critically ill patients who used PMB and met the criteria were enrolled. The total plasma concentration and plasma binding of PMB1 and PMB2 were analysed by liquid chromatography-tandem mass spectrometry and equilibrium dialysis. RESULTS: A total of 89 patients were finally included, and AKI developed in 28.1% of them. The peak concentration of PMB1 (Cmax (B1)) (adjusted odds ratio (AOR) = 1.68, 95% CI 1.08-2.62, p = 0.023), baseline BUN level (AOR = 1.08, 95% CI 1.01-1.16, p = 0.039) and hypertension (AOR = 3.73, 95% CI 1.21-11.54, p = 0.022) were independent risk factors for PMB-induced AKI. The area under the ROC curve of the model was 0.799. When Cmax (B1) was 5.23 µg/ml or more, the probability of AKI was higher than 50%. The ratio of PMB1/PMB2 decreased after PMB preparation entered into the body. The protein binding rate in critically ill patients indicated significant individual differences. Free Cmax (B) and free Cmax (B1) levels in the AKI group were significantly (p < 0.05) higher than those in the non-AKI group. Total and free concentrations of PMB in patients showed a positive correlation. CONCLUSIONS: Both the ROC curve and logistic regression model showed that Cmax (B1) was a good predictor for the probability of PMB-induced AKI. Early therapeutic drug monitoring (TDM) of PMB should be considered in critically ill patients. Compared with Cmin (B), Cmax (B) and Cmax (B1) may be helpful for the early prediction of PMB-induced AKI in critically ill patients.

Gstm1/Gstt1 is essential for reducing cisplatin ototoxicity in CBA/CaJ mice.

Cisplatin is a widely used chemotherapeutic agent. However, its clinical utility is limited because of cisplatin-induced ototoxicity. Glutathione S-transferase (GST) was found to play a vital role in reducing cisplatin ototoxicity in mice. Deletion polymorphisms of GSTM1 and GSTT1, members of the GST family, are common in humans and are presumed to be associated with cisplatin-induced hearing impairment. However, the specific roles of GSTM1 and GSTT1 in cisplatin ototoxicity are not completely clear. Here, under cisplatin treatment, simultaneous deletion of Gstm1 and Gstt1 lead to a more profound hearing loss in CBA/CaJ mice (Gstm1/Gstt1-DKO) than in wild-type mice. The Gstm1/Gstt1-DKO mice, in which phase II detoxification genes were upregulated, exhibited more severe oxidative stress and higher outer hair cell apoptosis in the cochleae than the control mice. Thus, our study revealed that Gstm1 and Gstt1 protect auditory hair cells from cisplatin-induced ototoxicity in the CBA/CaJ mice, and genetic screening for GSTM1 and GSTT1 polymorphisms could help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.

Thermally enhanced bioremediation: A review of the fundamentals and applications in soil and groundwater remediation.

Thermally enhanced bioremediation (TEB), a new concept proposed in recent years, explores the combination of thermal treatment and bioremediation to address the challenges of the low efficiency and long duration of bioremediation. This study presented a comprehensive review regarding the fundamentals of TEB and its applications in soil and groundwater remediation. The temperature effects on the bioremediation of contaminants were systematically reviewed. The thermal effects on the physical, chemical and biological characteristics of soil, and the corresponding changes of contaminants bioavailability and microbial metabolic activities were summarized. Specifically, the increase in temperature within a suitable range can proliferate enzymes enrichment, extracellular polysaccharides and biosurfactants production, and further enhancing bioremediation. Furthermore, a systematic evaluation of TEB applications by utilizing traditional in situ heating technologies, as well as renewable energy (e.g., stored aquifer thermal energy and solar energy), was provided. Additionally, TEB has been applied as a biological polishing technology post thermal treatment, which can be a cost-effective method to address the contaminants rebounds in groundwater remediation. However, there are still various challenges to be addressed in TEB, and future research perspectives to further improve the basic understanding and applications of TEB for the remediation of contaminated soil and groundwater are presented.

Evaluation of the in vitro synergy of polymyxin B-based combinations against polymyxin B -resistant gram-negative bacilli.

OBJECTIVES: This study aimed to evaluate the in vitro synergy of polymyxin B (PMB) combined with 11 other antibiotics against PMB-resistant gram-negative bacilli (GNBs). METHODS: Thirty-six clinical isolates of PMB-resistant GNBs were used. The MICs of all the antimicrobials tested were determined by the broth microdilution method and the checkerboard assay method. Carbapenemase genes were detected by PCR. In vitro synergy results were interpreted using the fractional inhibitory concentration index (FICI). Four combinations that showed positive interactions were subsequently evaluated in a time-kill study. RESULTS: Among the 36 strains, 15 harboured the carbapenemase gene, and blaKPC was the predominant carbapenemase. The resistance rates of the 36 strains to tigecycline, meropenem, ceftazidime, and cefepime were 100% (36/36), 97% (35/36), 94% (34/36), and 97% (35/36), respectively. For Enterobacteriaceae and Pseudomonas aeruginosa, the resistance rates to aztreonam and ceftazidime-avibactam (avibactam at a fixed concentration of 4 mg/L) were 95% (19/20) and 25% (5/20), respectively. The PMB-based combinations exhibited synergism to a certain degree. The most synergistic combinations were PMB plus meropenem-avibactam (avibactam at a fixed concentration of 4 mg/L) and PMB plus tigecycline, with the synergy rates of 83.3% and 80.6%, respectively. Compared to tazobactam- and sulbactam-based ß-lactam-ß-lactamase inhibitor combinations (BL-BLIs), PMB with avibactam-based BL-BLIs exhibited a better synergistic effect. For Acinetobacter baumannii, PMB plus sulbactam exhibited a strong synergism with a 2∼7-fold MIC reduction of PMB. In time-kill studies, the highest degree of synergism was observed for PMB with cefepime-avibactam on all the tested isolates. For isolates with low-level resistance to PMB, PMB combined with other partner antimicrobials also showed a certain degree of synergism. CONCLUSIONS: PMB in combination with tigecycline and avibactam-based BL-BLIs could be a potential clinical option for clinical treatment of infections caused by PMB -resistant GNBs.

P(III) vs P(V): A P(V) Reagent for Thiophosphoramidate Linkages and Application to an Asymmetric Synthesis of a Cyclic Dinucleotide STING Agonist.

A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.

Nemonoxacin Enhances Antibacterial Activity and Anti-Resistance Mutation Ability of Vancomycin against Methicillin-Resistant Staphylococcus aureus in an In Vitro Dynamic Pharmacokinetic/Pharmacodynamic Model.

Reduced susceptibility and emergence of resistance to vancomycin in methicillin-resistant Staphylococcus aureus (MRSA) have led to the development of various vancomycin-based combinations. Nemonoxacin is a novel nonfluorinated quinolone with antibacterial activity against MRSA. The present study aimed to investigate the effects of nemonoxacin on antibacterial activity and the anti-resistant mutation ability of vancomycin for MRSA and explore whether quinolone resistance genes are associated with a reduction in the vancomycin MIC and mutant prevention concentration (MPC) when combined with nemonoxacin. Four isolates, all with vancomycin MICs of 2 µg/mL, were used in a modified in vitro dynamic pharmacokinetic/pharmacodynamic model to investigate the effects of nemonoxacin on antibacterial activity (isolates M04, M23, and M24) and anti-resistant mutation ability (isolates M04, M23, and M25, all with MPCs of ≥19.2 µg/mL) of vancomycin. The mutation sites of gyrA, gyrB, parC, and parE of 55 clinical MRSA isolates were sequenced. We observed that in M04 and M23, the combination of vancomycin (1 g given every 12 h [q12h]) and nemonoxacin (0.5 g once daily [qd]) showed a synergistic bactericidal activity and resistance enrichment suppression. All clinical isolates resistant to nemonoxacin harbored gyrA (S84→L) mutation; gyrA (S84→L) and parC (E84→K) mutations were the two independent risk factors for the unchanged vancomycin MPC in combination. Nemonoxacin enhances the bactericidal activity and suppresses resistance enrichment ability of vancomycin against MRSA, with an MIC of 2 µg/mL. Our in vitro data support the combination of nemonoxacin and vancomycin for the treatment of MRSA infection with a high MIC.

YY1 and RTCB in mouse uterine decidualization and embryo implantation.

As a multifunctional transcription factor, YY1 regulates the expression of many genes essential for early embryonic development. RTCB is an RNA ligase that plays a role in tRNA maturation and Xbp1 mRNA splicing. YY1 can bind in vitro to the response element in the proximal promoter of Rtcb and regulate Rtcb promoter activity. However, the in vivo regulation and whether these two genes are involved in the mother-fetal dialogue during early pregnancy remain unclear. In this study, we validated that YY1 bound in vivo to the proximal promoter of Rtcb in mouse uterus of early pregnancy. Moreover, via building a variety of animal models, our study suggested that both YY1 and RTCB might play a role in mouse uterus decidualization and embryo implantation during early pregnancy.

Mechanism and Prevention of Ototoxicity Induced by Aminoglycosides.

Aminoglycosides, a class of clinically important drugs, are widely used worldwide against gram-negative bacterial infections. However, there is growing evidence that aminoglycosides can cause hearing loss or balance problems. In this article, we mainly introduce the main mechanism of ototoxicity induced by aminoglycosides. Genetic analysis showed that the susceptibility of aminoglycosides was attributable to mutations in mtDNA, especially A1555G and C1494T mutations in 12S rRNA. In addition, the overexpression of NMDA receptors and the formation of free radicals also play an important role. Understanding the mechanism of ototoxicity induced by aminoglycosides is helpful to develop new therapeutic methods to protect hearing. In this article, the prevention methods of ototoxicity induced by aminoglycosides were introduced from the upstream and downstream aspects.