Effects of treatment with stem cell-derived extracellular vesicles in preclinical rodent models of intrauterine adhesion: A meta-analysis.

Background: Intrauterine adhesion (IUA) results from serious complications of intrauterine surgery or infection and mostly remains incurable. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have emerged as a potential new approach for the treatment of IUA; however, their impact is not fully understood. Here, we performed a meta-analysis summarizing the effects of sEVs on IUA in preclinical rodent models. Methods: This meta-analysis included searches of PubMed, EMBASE, Cochrane, and the Web of Science databases from January 1, 1997, to April 1, 2022, to identify studies reporting the therapeutic effect of sEVs on rodent preclinical animal models of IUA. We compared improvements in endometrial thickness, endometrial gland number, fibrosis area, embryo number, vascular endothelial growth factor (VEGF), transforming growth factor ß1 (TGFß1), and leukemia inhibitory factor (LIF) levels after treatment. Results: Our search included 100 citations, of which 7 met the inclusion criteria, representing 231 animals. Compared with that in the control group, the fibrosis area in the sEV-treated group was significantly reduced (standardized mean difference (SMD) = -6.87，95 % confidence interval (CI) = -9.67 to -4.07). The number of glands increased after the intervention (95 % CI, 3.72-7.68; P = 0.000). Endometrial thickness was significantly improved in the sEV-treated group (SMD = 2.57, 95 % CI, 1.62-3.52). Conclusions: This meta-analysis is highlighting that sEV treatment can improve the area of endometrial fibrosis, as well as VEGF, and LIF level, in a mouse IUA model. This knowledge of these findings will provide new insights into future preclinical research.

In vivo pharmacodynamic study of contezolid acefosamil, a prodrug of contezolid for oral and intravenous administration.

OBJECTIVES: Contezolid acefosamil is a novel O-acyl phosphoramidate prodrug of contezolid. In the current study, we aimed to systemically evaluate the efficacy of contezolid acefosamil against infections caused by multiple Gram-positive pathogens, and compare the efficacy of the prodrug by oral and intravenous administrations. METHODS: The in vivo pharmacodynamic efficacy of contezolid acefosamil was evaluated in mouse models of systemic (with five S. aureus, three S. pneumoniae and two S. pyogenes bacterial isolates) and thigh (with two S. aureus isolates) infections using linezolid as the reference agent. RESULTS: In both models, contezolid acefosamil administrated either orally or intravenously, demonstrated high antibacterial efficacy similar to linezolid, and the antibacterial efficacy of oral and intravenous contezolid acefosamil were comparable. CONCLUSIONS: The high aqueous solubility and great efficacy of contezolid acefosamil support its clinical development as an injectable and oral antibiotic suitable for serious Gram-positive infections.

Controllable atomic collision in a tight optical dipole trap.

Single atoms are interesting candidates for studying quantum optics and quantum information processing. Recently, trapping and manipulation of single atoms using tight optical dipole traps has generated considerable interest. Here we report an experimental investigation of the dynamics of atoms in a modified optical dipole trap with a backward propagating dipole trap beam, where a change in the two-atom collision rate by six times has been achieved. The theoretical model presented gives a prediction of high probabilities of few-atom loading rates under proper experimental conditions. This work provides an alternative approach to the control of the few-atom dynamics in a dipole trap and the study of the collective quantum optical effects of a few atoms.

Adjuvant icotinib versus observation in patients with completely resected EGFR-mutated stage IB NSCLC (GASTO1003, CORIN): a randomised, open-label, phase 2 trial.

Background: This phase 2 trial aimed to compare adjuvant icotinib with observation in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage IB non-small cell lung cancer (NSCLC). Methods: We performed a randomised, open-label, phase 2 trial from May 1, 2015 to December 29, 2020 at Sun Yat-sen University Cancer Center in China. Patients with completely resected, EGFR-mutant, stage IB (the 7th edition of TNM staging) NSCLC without adjuvant chemotherapy were randomised (1:1) to receive adjuvant therapy with icotinib (125 mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. The primary endpoint was 3-year disease-free survival (DFS). CORIN (GASTO1003) was registered with Clinicaltrials.gov, with the number NCT02264210. Findings: A total of 128 patients were randomised, with 63 patients in the icotinib group and 65 patients in the observation group. The median duration of follow-up was 39.9 months. The three-year DFS was significantly higher in the icotinib group (96.1%, 95% confidence interval [CI], 91.3-99.9) than in the observation group (84.0%, 95% CI, 75.1-92.9; P = 0.041). The DFS was significantly longer in the icotinib group than in the observation group, with a hazard ratio (HR) of 0.23 (95% CI, 0.07-0.81; P = 0.013). The OS data were immature, with three deaths in the observation arm. In the icotinib group, adverse events (AEs) of any grade were reported in 49 patients (77.8%), and grade 3 or greater AEs occurred in four patients (6.3%). No treatment-related deaths occurred. Interpretation: Our findings suggested that adjuvant icotinib improved the 3-year DFS in patients with completely resected EGFR-mutated stage IB NSCLC with a manageable safety profile. Funding: This study was sponsored by Betta Pharmaceutical Co., Ltd.

Nicotinamide mononucleotide ameliorates acute lung injury by inducing mitonuclear protein imbalance and activating the UPRmt.

Mitochondria need to interact with the nucleus under homeostasis and stress to maintain cellular demands and nuclear transcriptional programs. Disrupted mitonuclear interaction is involved in many disease processes. However, the role of mitonuclear signaling regulators in endotoxin-induced acute lung injury (ALI) remains unknown. Nicotinamide adenine dinucleotide (NAD+) is closely related to mitonuclear interaction with its central role in mitochondrial metabolism. In the current study, C57BL/6J mice were administrated with lipopolysaccharide 15 mg/kg to induce endotoxin-induced ALI and investigated whether the NAD+ precursor nicotinamide mononucleotide (NMN) could preserve mitonuclear interaction and alleviate ALI. After pretreatment with NMN for 7 days, NAD+ levels in the mitochondrial, nucleus, and total intracellular were significantly increased in endotoxemia mice. Moreover, supplementation of NMN alleviated lung pathologic injury, reduced ROS levels, increased MnSOD activities, mitigated mitochondrial dysfunction, ameliorated the defects in the nucleus morphology, and these cytoprotective effects were accompanied by preserving mitonuclear interaction (including mitonuclear protein imbalance and the mitochondrial unfolded protein response, UPRmt). Furthermore, NAD+-mediated mitonuclear protein imbalance and UPRmt are probably regulated by deacetylase Sirtuin1 (SIRT1). Taken together, our results indicated that NMN pretreatment ameliorated ALI by inducing mitonuclear protein imbalance and activating the UPRmt in an SIRT1-dependent manner.

Noiseless photonic non-reciprocity via optically-induced magnetization.

The realization of optical non-reciprocity is crucial for many applications, and also of fundamental importance for manipulating and protecting the photons with desired time-reversal symmetry. Recently, various new mechanisms of magnetic-free non-reciprocity have been proposed and implemented, avoiding the limitation of the strong magnetic field imposed by the Faraday effect. However, due to the difficulties in separating the signal photons from the drive laser and the noise photons induced by the drive laser, these devices exhibit limited isolation performances and their quantum noise properties are rarely studied. Here, we demonstrate an approach of magnetic-free non-reciprocity by optically-induced magnetization in an atom ensemble. Excellent isolation (highest isolation ratio is [Formula: see text]) is observed over a power dynamic range of 7 orders of magnitude, with the noiseless property verified by quantum statistics measurements. The approach is applicable to other atoms and atom-like emitters, paving the way for future studies of integrated photonic non-reciprocal devices.

Efficient Frequency Conversion in a Degenerate χ

Microresonators on a photonic chip could enhance nonlinear optics effects and thus are promising for realizing scalable high-efficiency frequency conversion devices. However, fulfilling phase matching conditions among multiple wavelengths remains a significant challenge. Here, we present a feasible scheme for degenerate sum-frequency conversion that only requires the two-mode phase matching condition. When the drive and the signal are both near resonance to the same telecom mode, an on-chip photon-number conversion efficiency up to 42% is achieved, showing a broad tuning bandwidth over 250 GHz. Furthermore, cascaded Pockels and Kerr nonlinear optical effects are observed, enabling the parametric amplification of the optical signal to distinct wavelengths in a single device. The scheme demonstrated in this Letter provides an alternative approach to realizing high-efficiency frequency conversion and is promising for future studies on communications, atom clocks, sensing, and imaging.

A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome.

BACKGROUND: Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. CASE PRESENTATION: In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband's mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. CONCLUSIONS: Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

Beilunmycin, a new virginiamycins antibiotic from mangrove-derived Streptomyces sp. 2BBP-J2 and the antibacterial activity by inhibiting protein translation.

One new virginiamycin derivative, 'beilunmycin' (1), and three known virginiamycin antibiotics, 16-hydroxy-virginiamycin M1 (2), virginiamycin M2 (3), and virginiamycin M1 (4), were isolated from the culture of a mangrove-derived endophytic Streptomyces sp. 2BBP-J2. The structures were characterized on the basis of their spectroscopic data, and the absolute configuration of 1 was established by ECD calculations. Compounds 1-4 exhibited antibacterial activities against Gram-positive bacteria, with MIC values in the range of 0.5-16 µg/ml. All the compounds demonstrated strong protein translation-stalling activity, with minimal concentrations detected with pDualrep2 in the range of 1.9-5.9 nmol.

Clinical and microbiological characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in a hospital from North China.

INTRODUCTION: The clinical and molecular characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in various provinces of China have been reported, however, there have been few reports in Hebei Province, North China. METHODOLOGY: The hvKp was identified by PCR amplification of hypervirulence-related genes, the hypermucoviscous phenotype was determined by the "string test", the drug susceptibility analysis was performed using the VITEK® 2 Compact Bacterial Identification and Monitoring System. Logistic regression was used to identify risk factors for hvKp infection. The molecular epidemiological characteristics of the strains were analyzed by pulsed-field gel electrophoresis (PFGE), and the capsular serotype of hvKp strain was detected by PCR. RESULTS: Overall, 52.21% (59/113) of K. pneumoniae isolates were hvKp, and the ratios of patients with older ages or a higher PMN cell count among hvKp infection were higher than those among classical Klebsiella pneumoniae (cKp) infection. hvKp are more susceptible to antibacterial drugs than cKp, and one ESBLs-producing hvKp strain was detected. The main capsular serotype of hvKp were K2, K57 and K1. PFGE indicated that the 59 strains of hvKp could be classified into 51 PFGE band types, forming 6 PFGE clusters. CONCLUSIONS: In this study, the detection rate of hvKp was 52.21% (59/113) identified by virulence genes. People with older ages or a higher PMN cell count are more likely to gain hvKp infection. ESBLs-producing hvKp is emerging, indicating the importance of epidemiologic surveillance and clinical awareness of this pathogen in this region.

All-optical thermal control for second-harmonic generation in an integrated microcavity.

Nonlinear optical effects in integrated microcavities have been studied extensively with the advantages of strong light-matter interaction, great scalability, and stability due to the small mode volume. However, the pump lasers stimulating nonlinear effects impose obstacles for practical applications, since the material absorption causes thermal resonance drift and instability. Here we experimentally demonstrate an all-optical control of the thermal behavior in optical microcavities for tunable doubly-resonant second-harmonic (SH) generation on an integrated photonic chip. Through an auxiliary control laser, the temperature of a selected microring can be efficiently changed, thus allowing precise frequency tuning of the doubly-resonant wavelength while eliminating the distortion of the lineshape induced by the thermo-optic effect. Although the phase-matching conditions will limit the tuning range of 55GHz, the technique is still potential to achieve a larger tuning range in combination with temperature regulation. Additionally, this approach has the advantage of quick reconfiguration, showing a fast modulation rate up to about 256 kHz. The theoretical model behind our experimental scheme is universal and applicable to other microcavity-enhanced nonlinear optical processes, and our work paves the way for controlling and utilizing the thermal effect in the applications of microcavities.

Design, Synthesis, and Bioactivity of Cyclic Lipopeptide Antibiotics with Varied Polarity, Hydrophobicity, and Positive Charge Distribution.

Twenty-three polymyxin analogs with variations at nine amino acid positions were synthesized and assessed for antimicrobial activity and renal cytotoxicity. Compounds M2, 14, S2, and 16 (MIC = 0.125-4 µg/mL) had similar or stronger activities against susceptible and drug-resistant strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii compared to polymyxin B (MIC = 1-2 µg/mL). Most synthesized compounds (50% cytotoxic concentration, CC50 ≥ 200 µg/mL) exhibited lower cytotoxicity than polymyxin B (CC50 = 99 ± 6 µg/mL). Polymyxin S2 showed high plasma stability in vitro and strong efficacy in a mouse systemic infection model (ED50 = 0.9 mg/kg) against NDM-1-producing Klebsiella pneumoniae, suggesting that it is a potential candidate for drug development. The activity and cytotoxicity results indicated that the amino acids at positions 2, 3, 6, and 7 might be replaced. Effects on activity and cytotoxicity linked to changes in the number of positively charged amino acids varied among different cyclopeptide skeletons, but the underlying mechanisms are unknown.

Development and validation of a sensitive LC-MS/MS method for the quantitation of IMB-YH-4py5-2H, an antituberculosis candidate, and its application to the pharmacokinetic study.

(E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 µm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1-100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections.

Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue.

Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125-32 µg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a ß-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight ß-lactamase-producing resistant Gram-negative bacteria.

Microdialysis combined with liquid chromatography-tandem mass spectrometry for the quantitation of gemifloxacin and its application to a muscle penetration study in healthy and MRSA-infected rats.

Pharmacological efficacy is based on the drug concentration in target tissues, which usually cannot be represented by the plasma concentration. The purpose of this study was to compare the pharmacokinetic characteristics of gemifloxacin in plasma and skeletal muscle and evaluate its tissue penetration in both healthy and MRSA (methicillin-resistant Staphylococcus aureus)-infected rats. A microdialysis (MD) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine free gemifloxacin concentrations in rat plasma and skeletal muscle simultaneously. The in vivo recoveries of MD were 23.21% ± 3.42% for skeletal muscle and 20.62% ± 3.19% for plasma, and were concentration independent. We provided evidence that the method developed here meets FDA requirements. Additionally, this method was successfully applied to the determination of free gemifloxacin in rats. Muscle and blood dialysates were collected after an 18 mg/kg intravenous bolus dose. The mean areas under the concentration-time curves (AUCs) from 0 to 9 h for skeletal muscle and plasma were 3641.50 ± 915.65 h*ng/mL and 7068.32 ± 1964.19 h*ng/mL in MRSA-infected rats and 3774.72 ± 700.36 h*ng/mL and 6927.49 ± 1714.86 h*ng/mL in healthy rats, respectively. There was no significant difference (P>0.05) in gemifloxacin exposure between healthy rats and MRSA-infected rats for plasma or muscle. The low ratio of AUC0-9 muscle to AUC0-9 plasma suggested lower drug exposure in skeletal muscle than in plasma for both healthy and MRSA-infected rats. Our study suggested that the administration of gemifloxacin according to drug levels in plasma to treat local infection is unreasonable and might result in an inadequate dose regimen.

Infrared laser locking to a rubidium saturated absorption spectrum via a photonic chip frequency doubler.

To extend the coherence of quantum transitions for laser locking, as well as increase the compactness and stability of the experimental setup, we propose to utilize photonic integrated resonators with high second-harmonic (SH) generation efficiencies as reliable frequency doublers that link the desired frequencies with the frequency references. In this Letter, a sufficiently strong SH signal up to microwatts was generated by a photonic integrated frequency doubler using a milliwatt infrared (IR) laser source. Furthermore, an increased SH generation bandwidth covering Rb85 and Rb87D2 transition lines, as well as saturated absorption spectroscopy, was demonstrated by tuning the pump power and chip temperature. Here we present, to the best of our knowledge, the first successful locking of an IR laser to Rb saturated absorption lines via a photonic chip frequency doubler.

Evolution and Antibacterial Evaluation of 8-Hydroxy-cycloberberine Derivatives as a Novel Family of Antibacterial Agents Against MRSA.

Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25⁻0.5 µg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg-1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 µg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.

Cavity-enhanced optical controlling based on three-wave mixing in cavity-atom ensemble system.

Cavity-enhanced optical controlling is experimentally observed with a low-control laser power in a cavity-atom ensemble system. Here, the three-level atoms are coupled with two optical modes of a Fabry-Perot cavity, where a new theoretical model is developed to describe the effective three-wave mixing process between spin-wave and optical modes. By adjusting either temperature or cavity length, we demonstrate the precise frequency tuning of the hybrid optical-atomic resonances. When the doubly-resonant condition is satisfied, the probe laser can be easily modulated by a control laser. In addition, interesting non-Hermitian physics are predicted theoretically and demonstrated experimentally, and all-optical switching is also achieved. Such a doubly-resonant cavity-atom ensemble system without a specially designed cavity can be used for future applications, such as optical signal storage and microwave-to-optical frequency conversion.

Synthesis and Biological Evaluation of Quinoline Derivatives as a Novel Class of Broad-Spectrum Antibacterial Agents.

Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G⁺) and Gram-negative (G-) bacteria, taking compound 1 as the lead. Among the target compounds, quinolone coupled hybrid 5d exerted the potential effect against most of the tested G⁺ and G- strains with MIC values of 0.125⁻8 µg/mL, much better than those of 1. Molecular-docking assay showed that compound 5d might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound 5d was selected for the further investigation, with an advantage of a dual-target mechanism of action.

Antibacterial Activity and Structure-Activity Relationship of a Series of Newly Synthesized Pleuromutilin Derivatives.

A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram-positive pathogens. In this work, a five-membered heterocyclic moiety, a pyrimidine-heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether-containing pleuromutilin derivatives exert a more potency activity than the sulfoxide-type derivatives against Gram-positive pathogens. The structure-activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives.