Emergence of silent NDM-1 carbapenemase gene in carbapenem-susceptible Klebsiella pneumoniae: Clinical implications and epidemiological insights.

The global dissemination of carbapenemase genes, particularly blaNDM-1, poses a significant threat to public health. While research has mainly focused on strains with phenotypic resistance, the impact of silent resistance genes has been largely overlooked. This study documents the first instance of silent blaNDM-1 in a cluster of clonally related carbapenem-susceptible K. pneumoniae strains from a single patient. Despite initial effectiveness of carbapenem therapy, the patient experienced four recurrent lung infections over five months, indicating persistent K. pneumoniae infection. Genomic sequencing revealed all strains harbored blaNDM-1 on the epidemic IncX3 plasmid. A deletion within the upstream promoter region (PISAba125) of blaNDM-1 hindered its expression, resulting in phenotypic susceptibility to carbapenems. However, in vitro bactericidal assays and a mouse infection model showed that K. pneumoniae strains with silent blaNDM-1 exhibited significant tolerance to carbapenem-mediated killing. These findings demonstrate that silent blaNDM-1 can mediate both phenotypic susceptibility and antibiotic tolerance. In silico analysis of 1986 blaNDM sequences showed that 1956 (98.5%) retained the original promoter PISAba125. Given that previous genomic sequencing typically targets carbapenem-resistant strains, accurately assessing the prevalence of silent blaNDM remains challenging. This study highlights the hidden threat of silent resistance genes to clinical antimicrobial therapy and calls for enhanced clinical awareness and laboratory detection.

Replacement of sedentary behavior with various physical activities and the risk of incident depression: a prospective analysis of accelerator-measured and self-reported UK Biobank data.

PURPOSE: To examine the dose‒response relationships of sedentary behavior (SB) and physical activities (PAs) with depression, and to explore the effects of replacing SB with PAs on depression risk. METHODS: The study used data from UK Biobank aged 37 to 73 years. Light physical activity (LPA), moderate-to-vigorous activity (MVPA), sleep duration, and total sedentary behavior (TSB) were measured by accelerometers. Self-reported SB was also adopted when daily screen-sedentary behavior time (SSB) and leisure-sedentary behavior time (LSB) were the focus. Incident depression was obtained from the part of mental and behavioral disorders in the "first occurrence fields" of UK Biobank. A Cox proportional hazard model and isotemporal substitution model were performed to explore the associations of LPA, MVPA, TSB, LSB, SSB, and sleep on depression and the effects of replacing SB time with equal PA time. RESULTS: Highest levels of MVPA (HR = 0.58, 95%CI: 0.50-0.68) were associated with decreased depression risk compared with the lowest level (Q1). Longer SSB time (HR = 1.18, 95%CI: 1.06-1.32), LSB time (HR = 1.19, 95%CI: 1.07-1.32), and TSB time (HR = 1.17, 95%CI: 1.00-1.38) could increase depression risk significantly. Replacing 1h/day TSB, SSB, and LSB with MVPA brought the greatest risk reductions [31% (HR = 0.69, 95%CI: 0.62-0.77), 30% (HR = 0.70, 95%CI: 0.65-0.77), and 29% (HR = 0.71, 95%CI: 0.65-0.77)]. Under the same conditions, the effects of LPA replacement were also significant, but weaker than those of MVPA. Subgroup analyses showed that replacing 1h/d TSB with LPA could significantly decrease the depression risk for the females, but not for the males. CONCLUSION: Large benefits for reducing the risk of incident depression could be attained by replacing a period of TSB, SSB, or LSB with equal PA time, especially for MVPA. Regular PA and less SB were recommended for improving mental health.

Variations in bacterial community succession and assembly mechanisms with mine age across various habitats in coal mining subsidence water areas.

Microorganisms play a pivotal role as catalysts in the biogeochemical cycles of aquatic ecosystems within coal mining subsidence areas. Despite their importance, the succession of microbial communities with increasing mine age, particularly across different habitats, and variations in phylogenetically-based community assembly mechanisms are not well understood. To address this knowledge gap, we collected 72 samples from lake sediments, water, and surrounding topsoil (0-20 cm) at various mining stages (early: 16 years, middle: 31 years, late: 40 years). We analyzed these samples using 16S rRNA gene sequencing and multivariate statistical methods to explore the dynamics and assembly mechanisms of bacterial communities. Our findings reveal that increases in phosphorus and organic matter in sediments, correlating with mining age, significantly enhance bacterial alpha diversity while reducing species richness (P < 0.001). Homogenizing selection (49.9 %) promotes species asynchrony-complementarity, augmenting the bacterial community's ability to metabolize sulfur, phosphorus, and organic matter, resulting in more complex-stable co-occurrence networks. In soil, elevated nitrogen and organic carbon levels markedly influence bacterial community composition (Adonis R2 = 0.761), yet do not significantly alter richness or diversity (P > 0.05). The lake's high connectivity with surrounding soil leads to substantial species drift and organic matter accumulation, thereby increasing bacterial richness in later stages (P < 0.05) and enhancing the ability to metabolize dissolved organic matter, including humic-like substances, fulvic acids, and protein-like materials. The assembly of soil bacterial communities is largely governed by stochastic processes (79.0 %) with species drift (35.8 %) significantly shaping these communities over a broad spatial scale, also affecting water bacterial communities. However, water bacterial community assembly is primarily driven by stochastic processes (51.2 %), with a substantial influence from habitat quality (47.6 %). This study offers comprehensive insights into the evolution of microbial community diversity within coal mining subsidence water areas, with significant implications for enhancing environmental management and protection strategies for these ecosystems.

Efficient narrowband yellow organic light-emitting diodes based on iridium(III) complexes with the rigid indolo[3,2,1-jk]carbazole unit.

Phosphorescent material with narrowband emission is crucial for advancing wide-color-gamut organic light-emitting diodes (OLEDs). In this work, two iridium(III) complexes, (PhthzICz)2Ir(tmd) and (thzICz)2Ir(tmd), using rigid 2-(benzothiazole-2-yl)indolo[3,2,1-jk]carbazole (PhthzICz) and 2-(thiazole-2-yl)indolo[3,2,1-jk]carbazole (thzICz) as cyclometalated ligands and 2,2,6,6-tetramethyl-3,5-heptanedione (tmd) as ancillary ligands, were synthesized. When these complexes were doped into the host material 3,3'-di(9H-carbazol-9-yl)-1,1'-biphenyl, the doped films exhibited yellow photoluminescence (PL) peaking at 537 and 531 nm, full width at half maximum (FWHM) bands of 35 and 60 nm, and PL quantum yields of 89.9% and 85.9%, respectively. OLEDs based on these two emitters display moderate performance characteristics with maximum external quantum efficiencies of 25.2% and 22.7%. Notably, the device based on (PhthzICz)2Ir(tmd) exhibits a narrow FWHM of 31 nm. Overall, the study highlights the practicality of incorporating rigid groups into the cyclometalated ligands of Ir(III) complexes as a viable strategy for achieving efficient Ir(III) complexes for OLEDs with narrow emission and high efficiency.

Bicyclol attenuates pulmonary fibrosis with silicosis via both canonical and non-canonical TGF-ß1 signaling pathways.

BACKGROUND: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. METHODS: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. RESULTS: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1ß, IL-6, TNF-α, and TGF-ß1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-ß1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. CONCLUSION: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-ß1, and consequently inhibits FMT and EMT via TGF-ß1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent.

Dexborneol Amplifies Pregabalin's Analgesic Effect in Mouse Models of Peripheral Nerve Injury and Incisional Pain.

Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the potentiation of pregabalin's analgesic effects by dexborneol, a neuroprotective bicyclic monoterpenoid compound. We performed animal experiments where pain models were induced using two methods: peripheral nerve injury, involving axotomy and ligation of the tibial and common peroneal nerves, and incisional pain through a longitudinal incision in the hind paw, while employing a multifaceted methodology that integrates behavioral pharmacology, molecular biology, neuromorphology, and lipidomics to delve into the mechanisms behind this potentiation. Dexborneol was found to enhance pregabalin's efficacy by promoting its transportation to the central nervous system, disrupting self-amplifying vicious cycles via the reduction of HMGB1 and ATP release, and exerting significant anti-oxidative effects through modulation of central lipid metabolism. This combination therapy not only boosted pregabalin's analgesic property but also notably decreased its side effects. Moreover, this therapeutic cocktail exceeded basic pain relief, effectively reducing neuroinflammation and glial cell activation-key factors contributing to persistent and chronic pain. This study paves the way for more tolerable and effective analgesic options, highlighting the potential of dexborneol as an adjuvant to pregabalin therapy.

Synergistic meso-ß regulation of porphyrins: squeezing the band gap into the near-infrared I/II region.

The development of novel near-infrared (NIR) materials with extremely small energy gaps and high stability is highly desirable in bioimaging and phototherapy. Here we report an effective strategy for narrowing the energy gaps of porphyrins by synergistic regulation of meso/ß substituents. The novel NIR absorbing/emitting meso-alkynyl naphthoporphyrins (Zn-TNP and Pt-TNP) are synthesized via the retro-Diels-Alder reaction. X-ray crystallography analysis confirms the highly distorted structures of the complexes. Both compounds exhibit intense Q bands around 800 nm, while Zn-TNP shows deep NIR fluorescence at 847 nm. Pt-TNP displays NIR-II room temperature phosphorescence peaking at 1106 nm with an extremely large Stokes shift of 314 nm, which are the longest wavelengths observed among the reported platinum porphyrinoids. Furthermore, Pt-TNP shows remarkable photostability and a notable capacity for synchronous singlet oxygen and heat generation under NIR light irradiation, demonstrating potential in combined photodynamic/photothermal therapy. A theoretical analysis reveals the progressive lifting of the HOMO by the ß-fused benzene ring, the decrease of the LUMO upon meso-alkynyl substitution, and energy-releasing pathways varying with metal ions. This dual regulation approach demonstrates great promise in designing innovative multifunctional NIR porphyrin materials.

Self-enhanced localized alkalinity at the encapsulated Cu catalyst for superb electrocatalytic nitrate/nitrite reduction to NH3 in neutral electrolyte.

The electrocatalytic nitrate/nitrite reduction reaction (eNOx-RR) to ammonia (NH3) is thermodynamically more favorable than the eye-catching nitrogen (N2) electroreduction. To date, the high eNOx-RR-to-NH3 activity is limited to strong alkaline electrolytes but cannot be achieved in economic and sustainable neutral/near-neutral electrolytes. Here, we construct a copper (Cu) catalyst encapsulated inside the hydrophilic hierarchical nitrogen-doped carbon nanocages (Cu@hNCNC). During eNOx-RR, the hNCNC shell hinders the diffusion of generated OH- ions outward, thus creating a self-enhanced local high pH environment around the inside Cu nanoparticles. Consequently, the Cu@hNCNC catalyst exhibits an excellent eNOx-RR-to-NH3 activity in the neutral electrolyte, equivalent to the Cu catalyst immobilized on the outer surface of hNCNC (Cu/hNCNC) in strong alkaline electrolyte, with much better stability for the former. The optimal NH3 yield rate reaches 4.0 moles per hour per gram with a high Faradaic efficiency of 99.7%. The strong-alkalinity-free advantage facilitates the practicability of Cu@hNCNC catalyst as demonstrated in a coupled plasma-driven N2 oxidization with eNOx-RR-to-NH3.

Is the Homologous Recombination Repair Mutation Defined by a 15-Gene Panel Associated with the Prognosis of Epithelial Ovarian Cancer?

BACKGROUND: There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. OBJECTIVE: We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. PATIENTS AND METHODS: We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. RESULTS: 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRm v HRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28-0.64) at all stages and 0.42 (0.27-0.65) at stages IIIC-IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24-0.68) at stages IIIC-IV. CONCLUSIONS: This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population.

Pharmacokinetics, Safety, and Immunogenicity of Intravenous and Subcutaneous Single-Dose QX002N Injection in Healthy Subjects: A Randomized, Open, Parallel, Single-Center, Phase I Study.

INTRODUCTION: Interleukin-17A (IL-17A) plays a crucial role in the pathogenesis of ankylosing spondylitis (AS), although not all patients respond to traditional IL-17A antibody treatments. QX002N injection, as a new monoclonal antibody targeting IL-17A, has shown potential in treating AS, offering a new treatment option for patients who do not respond well to existing therapies. METHODS: A randomized, open, parallel, single-center, phase I study was conducted to assess the pharmacokinetics, safety, and immunogenicity of single doses of QX002N injection administered intravenously (IV) or subcutaneously (SC) to healthy Chinese volunteers. Blood samples were collected at specified time intervals, and then serum concentrations of QX002N were analyzed by enzyme-linked immunosorbent assay. RESULTS: Pharmacokinetic analysis of the drug concentration-time data showed that the mean maximum observed serum QX002N concentration (Cmax) was 110 and 33.9 µg/ml, respectively. The average area under the drug concentration-time curves from 0 to the time of the last quantifiable concentration (AUClast) were 52,656 and 36,269 µg·h/ml, respectively and the average area under the drug concentration-time curves from 0 to infinity (AUCinf) were 54,867 and 38,194 µg·h/ml, respectively. The absolute bioavailability of QX002N after SC injection was 69.6%. CONCLUSIONS: Immunogenicity was assessed and all the subjects in this study were Anti-drug antibody (ADA)-negative, which means no subjects appeared to develop immunogenicity to QX002N. All the results testify to the safety of QX002N injection, which is satisfactory after IV or SC dosing in healthy subjects. TRIAL REGISTRATION: www.chinadrugtirals.org.cn , CTR20220430.

A decade of insight: bibliometric analysis of gut microbiota's role in osteoporosis (2014-2024).

Purpose: Osteoporosis represents a profound challenge to public health, underscoring the critical need to dissect its complex etiology and identify viable targets for intervention. Within this context, the gut microbiota has emerged as a focal point of research due to its profound influence on bone metabolism. Despite this growing interest, the literature has yet to see a bibliometric study addressing the gut microbiota's contribution to both the development and management of osteoporosis. This study aims to fill this gap through an exhaustive bibliometric analysis. Our objective is to uncover current research hotspots, delineate key themes, and identify future research trends. In doing so, we hope to provide direction for future studies and the development of innovative treatment methods. Methods: Relevant publications in this field were retrieved from the Web of Science Core Collection database. We used VOSviewer, CiteSpace, an online analysis platform and the R package "Bibliometrix" for bibliometric analysis. Results: A total of 529 publications (including 351 articles and 178 reviews) from 61 countries, 881 institutions, were included in this study. China leads in publication volume and boast the highest cumulative citation. Shanghai Jiao Tong University and Southern Medical University are the leading research institutions in this field. Nutrients contributed the largest number of articles, and J Bone Miner Res is the most co-cited journal. Of the 3,166 scholars who participated in the study, Ohlsson C had the largest number of articles. Li YJ is the most co-cited author. "Probiotics" and "inflammation" are the keywords in the research. Conclusion: This is the first bibliometric analysis of gut microbiota in osteoporosis. We explored current research status in recent years and identified frontiers and hot spots in this research field. We investigate the impact of gut microbiome dysregulation and its associated inflammation on OP progression, a topic that has garnered international research interest in recent years. Additionally, our study delves into the potential of fecal microbiota transplantation or specific dietary interventions as promising avenues for future research, which can provide reference for the researchers who focus on this research filed.

Conflicting Aromaticity in Trirhodium(I) Rosarin.

Aromaticity is one of the most important and widely used concepts in chemistry. Among the various experimentally discovered and theoretically predicted compounds that possess different types of aromaticity, conflicting aromaticity, where aromatic and antiaromatic electron delocalization is present in one molecule simultaneously, remains one of the most controversial and elusive concepts, although theoretically predicted 15 years ago. In this work, we synthesized a novel conflicting aromatic trirhodium complex that contains a σ-aromatic metal fragment surrounded by the π-antiaromatic organic ligand and characterized it by nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, and X-ray single crystal structure analysis. Experimental characterization and quantum chemical calculations confirm the unique conflicting aromaticity of the synthesized trirhodium molecule. Thus, this novel conflicting aromatic molecule expands the family of aromatic compounds. This discovery will enable researchers to develop and understand the phenomena of conflicting aromaticity in chemistry.

In Situ Analysis of Interfacial Morphological and Chemical Evolution in All-Solid-State Lithium-Metal Batteries.

Visualizing lithium (Li) ions and understanding Li plating/stripping processes as well as evolution of solid electrolyte interface (SEI) are critical for optimizing all-solid-state Li metal batteries (ASSLMB). However, the buried solid-solid interfaces present a challenge for detection which preclude the employment of multiple analysis techniques. Herein, by employing complementary in situ characterizations, morphological/chemical evolution, Li plating/stripping dynamics and SEI dynamics were efficiently decoupled and Li ion behavior at interface between different solid-state electrolytes (SSE) was successfully detected. The innovative combining experiments of in situ atomic force microscopy and in situ X-ray photoelectron spectroscopy on Li metal anode revealed interfacial morphological/chemical evolution and decoupled Li plating/stripping process from SEI evolution. Though Li plating speed in Li10GeP2S12 (LGPS) was higher than Li3PS4 (LPS), speed of SSE decomposition was similar and ~85% interfacial SSE turned into SEI during plating and remained unchanged in stripping. To leverage strengths of different SSEs, an LPS-LGPS-LPS sandwich electrolyte was developed, demonstrating enhanced ionic conductivity and improved interfacial stability with less SSE decomposition (25%). Using in situ Kelvin Probe Force Microscopy, Li-ion behavior at interface between different SSEs was effectively visualized, uncovering distribution of Li ions at LGPS|LPS interface under different potentials.

Bayesian analysis of physiologically based toxicokinetic (PBTK) modeling for pentachlorophenol exposure in pregnant women.

Pentachlorophenol (PCP) is a persistent organic compound that is widely present in the environment. The estimation of internal exposure levels for a given external exposure using toxicokinetic models is key to the human health risk assessment of PCP. The present study developed a physiologically based multicompartmental pharmacokinetic (PBTK) model to describe and predict the behavior of pentachlorophenol (PCP) in an organism. The model consists of stomach, intestines, adipose tissue, kidneys and fast- and poorly perfused tissues that are interconnected via blood circulation. We constructed a PBTK model of PCP in rats and extrapolated it to human dietary PCP exposure. The toxicokinetic data of PCP in human tissues and excreta were obtained from the published literature. Based on the collected PCP dietary survey and internal exposure data of pregnant women in Shanghai, Bayesian statistical analysis was performed for the model using Markov chain Monte Carlo (MCMC) simulation. The posterior distributions of the sensitive parameters were estimated, and the model was parameter optimized and validated using the pregnant women's test dataset. The results showed that the root mean square error (RMSE) improved 37.3% compared to the original model, and a systematic literature search revealed that the optimized model achieved acceptable prediction results for other datasets in China. A PCP metabolism model based on the exposure characteristics of pregnant women in China was constructed in the present study. The model provides a theoretical basis for the study of PCP toxicity and risk assessment.

A social-ecological approach for identifying and mapping ecosystem service trade-offs and conservation priorities in peri-urban areas.

Considering both ecological and social dimensions in the assessment of ecosystem services (ESs) can facilitate acceptable and inclusive management strategies, especially in peri-urban areas characterized by intricate human-ecosystem interactions. A limited body of research, however, has mapped the plural values of ESs and their different types of trade-offs in such areas. This research aimed to execute an interdisciplinary analysis of the biophysical and social values of ESs in peri-urban Shanghai, China, through a social-ecological approach that integrates spatial biophysical assessment with participatory mapping. Trade-off analysis in both ES types and ES valuations were then conducted, and multicriteria decision-making was applied for conservation. Our results reveal that trade-off intensities were lower within the social values compared to the biophysical values. Within both value dimensions, relatively stronger trade-offs were found between food production and other ESs. Areas with both high biophysical and social values were infrequently observed across ESs. Based on the characteristics of diverse values, our study identified priority conservation areas and provided management implications. We argue that adopting the integrated social-ecological perspective in sustainable environmental management contributes to the realization of harmonious coexistence between people and nature in peri-urban areas.

Causal relationship between thyroid dysfunction and gastric cancer: a two-sample Mendelian randomization study.

Backgroud: Gastric cancer is one of the most common cancers worldwide, and its development is associated with a variety of factors. Previous observational studies have reported that thyroid dysfunction is associated with the development of gastric cancer. However, the exact relationship between the two is currently unclear. We used a two-sample Mendelian randomization (MR) study to reveal the causal relationship between thyroid dysfunction and gastric cancer for future clinical work. Materials and methods: This study is based on a two-sample Mendelian randomization design, and all data are from public GWAS databases. We selected hyperthyroidism, hypothyroidism, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) as exposures, with gastric cancer as the outcome. We used three statistical methods, namely Inverse-variance weighted (IVW), MR-Egger, and weighted median, to assess the causal relationship between thyroid dysfunction and gastric cancer. The Cochran's Q test was used to assess the heterogeneity among SNPs in the IVW analysis results, and MR-PRESSO was employed to identify and remove IVs with heterogeneity from the analysis results. MR-Egger is a weighted linear regression model, and the magnitude of its intercept can be used to assess the horizontal pleiotropy among IVs. Finally, the data were visualized through the leave-one-out sensitivity test to evaluate the influence of individual SNPs on the overall causal effect. Funnel plots were used to assess the symmetry of the selected SNPs, forest plots were used to evaluate the confidence and heterogeneity of the incidental estimates, and scatter plots were used to assess the exposure-outcome relationship. All results were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). P<0.05 represents statistical significance. Results: According to IVW analysis, there was a causal relationship between hypothyroidism and gastric cancer, and hypothyroidism could reduce the risk of gastric cancer (OR=0.936 (95% CI:0.893-0.980), P=0.006).This means that having hypothyroidism is a protective factor against stomach cancer. This finding suggests that hypothyroidism may be associated with a reduced risk of gastric cancer.Meanwhile, there was no causal relationship between hyperthyroidism, FT4, and TSH and gastric cancer. Conclusions: In this study, we found a causal relationship between hypothyroidism and gastric cancer with the help of a two-sample Mendelian randomisation study, and hypothyroidism may be associated with a reduced risk of gastric cancer, however, the exact mechanism is still unclear. This finding provides a new idea for the study of the etiology and pathogenesis of gastric cancer, and our results need to be further confirmed by more basic experiments in the future.

Time-domain slicing optical frequency domain reflectometry.

A time-domain slicing (TDS) optical frequency domain reflectometry is proposed for large strain sensing with better spatial resolution. Compared with the conventional frequency domain slicing (FDS) method, the TDS with a Burg spectrum estimation is capable of enhancing the similarity of a local spectrum under large strain and mostly suppressing the fake peaks during the strain resolving. The experimental results demonstrated that it enables measurements of strain ranging from 600 to 4200 µÎµ with a spatial resolution of 2.4 mm and a narrow optical frequency scanning range of only 10 nm. Moreover, the measurement accuracy is improved by six times by decreasing the root mean square error (RMSE) from 8.6611 to 1.3396 µÎµ without any hardware modification.

Poly(ethylene oxide)-based composite solid electrolyte for long cycle life solid-state lithium metal batteries: Improvement of interface stability through a dual mechanism.

Solid-state lithium metal batteries (SSLMBs) are promising candidates for safe and high-energy-density next-generation applications. However, harmful interfacial decomposition and uneven Li deposition lead to poor ion transport, a short cycle life, and battery failure. Herein, we propose a novel poly(ethylene oxide) (PEO)-based composite solid electrolyte (CSE) containing succinonitrile (SN) and zinc oxide (ZnO) nanoparticles (NPs), which improves interface stability through a dual mechanism. (1) By anchoring bis(trifluoromethanesulfonyl)imide (TFSI) anions to ZnO, a reliable solid electrolyte interface (SEI) later with abundant LiF can be obtained to inhibit interface decomposition. (2) The immobilization of escaping SN molecules in the SEI layer by ZnO NPs promotes the self-polymerization of SN and facilitates charge transfer through the interface. As a result, the ion conductivity of the stainless steel-symmetrical battery reaches 1.1 × 10-4 S cm-1 at room temperature, and a LiFePO4 (LFP) full battery exhibits ultrahigh stability (800 cycles) at 0.5 C. Thus, the present study provides valuable insights for the development of advanced PEO-based SSLMBs.

Optomechanical Frequency Comb Based on Multiple Nonlinear Dynamics.

Phonon-based frequency combs that can be generated in the optical and microwave frequency domains have attracted much attention due to the small repetition rates and the simple setup. Here, we experimentally demonstrate a new type of phonon-based frequency comb in a silicon optomechanical crystal cavity including both a breathing mechanical mode (∼GHz) and flexural mechanical modes (tens of MHz). We observe strong mode competition between two approximate flexural mechanical modes, i.e., 77.19 and 90.17 MHz, resulting in only one preponderant lasing, while maintaining the lasing of the breathing mechanical mode. These simultaneous observations of two-mode phonon lasing state and significant mode competition are counterintuitive. We have formulated comprehensive theories to elucidate this phenomenon in response to this intriguing outcome. In particular, the self-pulse induced by the free carrier dispersion and thermo-optic effects interacts with two approximate flexural mechanical modes, resulting in the repetition rate of the comb frequency-locked to exact fractions of one of the flexural mechanical modes and the mode hopping between them. This phonon-based frequency comb has at least 260 comblines and a repetition rate as low as a simple fraction of the flexural mechanical frequency. Our demonstration offers an alternative optomechanical frequency comb for sensing, timing, and metrology applications.

Elucidation of Palmarumycin Spirobisnaphthalene Biosynthesis Reveals a Set of Previously Unrecognized Oxidases and Reductases.

Spirobisnaphthalenes (SBNs) are a class of highly oxygenated, fungal bisnaphthalenes containing a unique spiroketal bridge, that displayed diverse bioactivities. Among the reported SBNs, palmarumycins are the major type, which are precursors for the other type of SBNs structurally. However, the biosynthesis of SBNs is unclear. In this study, we elucidated the biosynthesis of palmarumycins, using gene disruption, heterologous expression, and substrate feeding experiments. The biosynthetic gene cluster for palmarumycins was identified to be distant from the polyketide synthase gene cluster, and included two cytochrome P450s (PalA and PalB), and one short chain dehydrogenase/reductase (PalC) encoding genes as key structural genes. PalA is an unusual, multifunctional P450 that catalyzes the oxidative dimerization of 1,8-dihydroxynaphthalene to generate the spiroketal linkage and 2,3-epoxy group. Chemical synthesis of key intermediate and in vitro biochemical assays proved that the oxidative dimerization proceeded via a binaphthyl ether. PalB installs the C-5 hydroxy group, widely found in SBNs. PalC catalyzes 1-keto reduction, the reverse 1-dehydrogenation, and 2,3-epoxide reduction. Moreover, an FAD-dependent oxidoreductase, encoded by palD, which locates outside the cluster, functions as a 1-dehydrogenase. These results provided the first genetic and biochemical evidence for the biosynthesis of palmarumycin SBNs.