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Abstract Background Antimicrobial resistance (AMR) is one of the most pressing global public health challenges; in particular, the rapid dissemination of carbapenem-resistant Enterobacterales (CRE) is emerging as a significant concern worldwide. Flies, serving as carriers of pathogens, pose a potential threat in the transmission of antibiotic-resistant bacteria (ARB) between animals and humans. The aim of this study was to evaluate and reveal the potential risk of AMR spread by flies. Methods A total of 450 flies were collected from four farms, four rural areas, and four urban areas in Dengfeng, Henan, China. To select CRE strains on the surface of flies, three flies sampled from the same geographical location were arbitrarily selected and placed into one tube of brain heart infusion broth (BHI), and the supernatant was screened using CHROMagar™ mSuperCARBA culture medium. Different colors and shapes of colonies were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA sequencing. Antimicrobial susceptibility testing for CRE strains was performed using broth microdilution. All CRE strains were whole-genome sequenced. Short-read sequencing was performed using MGISEQ-2000 and long-read sequencing was conducted using GridION. Results Totally, 150 BHI tubes were screened for CRE strains, and 33 strains were identified as CRE positive. In 24 mSuperCARBA plates, only one species of CRE strain was isolated from each plate. In three plates, two different species of CRE strains were identified in each plate. In one plate, three different species of CRE strains were simultaneously isolated. Carbapenem resistance genes were detected in 81.8% of CRE strains, and bla NDM−1 was predominant (66.7%). No significant correlations between carbapenem-resistant phenotypes and carbapenem resistance genes were observed. The complete genomes of all 33 strains were obtained. Genome analysis revealed that clonal transmission events may have occurred among different farms and rural areas. Phylogenetic analysis revealed that bla NDM−1 IncFII plasmids could break bacterial species barrier for cross-host transmission in diverse areas. Conclusions To understand and control the transmission of AMR from the perspective of One Health, it is imperative to enhance surveillance of ARB, antibiotic resistance genes, and antibiotic-resistant plasmids in flies.

Abstract Embedded Dynamic RAM (eDRAM) has become a key solution for large-capacity cache in high-performance processors. A heterogeneous two transistor capacitorless eDRAM (2T-eDRAM) that combines silicon and molybdenum disulfide (MoS2) is reported to address the short retention issue in conventional gain cell (GC) eDRAMs meanwhile eliminate the pillar capacitor in one transistor and one capacitor (1T1C) eDRAMs. The MoS2 write transistor with low OFF current (IOFF) enables long data retention, while the Si read transistor offers high drive current and logic compatibility. This combination enhances data retention by 1000 times and sense margin by 100 times respectively compared to full Si and MoS2 counterparts. A three-dimensional (3D) design stacking MoS2 on Si is demonstrated with back-end-of-line (BEOL) process to double integration density. With 6000 s data retention, 35 μA/μm sense margin, 5 ns access speeds, 3D integration and CMOS logic compatibility, this Si-MoS2 eDRAM marks a significant advancement in memory technology.

Abstract Background Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. Methods In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. Results We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Conclusions Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. Trial registration ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021.

Abstract With unintentional injuries being the leading mortality cause among children, the comprehensive evaluation of the unintentional injury burden concerning heat exposure remains unknown. Here we quantified the years lived with disability (YLD) due to unintentional child injuries in Guangzhou from 2016–2020 using the injury surveillance data. A Poisson regression model was employed to explore how various magnitudes of heat exposure could increase the injury burden in different children’s subgroups. Our findings suggest a positive link between heat exposure and childhood injuries. The successive heatwave led to a 16.8–23.8% higher risk of childhood injuries. Girls and preschoolers exhibited higher vulnerability to heat. Furthermore, heat exposure increased the road injury burden for preschoolers aged 3–6 years but not for adolescents. Our study links heat exposure to childhood unintentional injuries, providing insights into the demographic features and injury causes. This evidence can be used to inform healthy childhood development.

Abstract Background Psychological flexibility (PF) is defined as the ability to pursue valuable life goals despite the existence of distress. The Personalized Psychological Flexibility Index (PPFI) is a new measure of psychological flexibility that can address existing deficiencies. This study aimed to translate and validate the psychometric characteristics of the Chinese version of the PPFI among medical college students. Methods The study was conducted in two phases. Phase 1 involved the translation and cross-cultural adaptation of the PPFI according to guidelines recommended by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Phase 2 was a cross-sectional survey conducted on 945 medical college students in China. The psychometric performances of the scale were assessed using construct validity, divergent validity, criterion validity, incremental validity, internal consistency, and test-rest reliability. Results The exploratory factor analysis (EFA, n1 = 440) showed that the Chinese version of the PPFI consisted of 3 factors, with a total of 15 items. The confirmatory factor analysis (CFA, n2 = 440) showed that the three-factor structure fit well (χ2/ $$df$$ df =2.469, SRMR = 0.051, RMSEA = 0.058, GFI = 0.94, CFI = 0.985). The total Chinese PPFI score had a moderate positive association with the Comprehensive Assessment of Acceptance and Commitment Therapy (CompACT, r = 0.344) and a negative association with the Acceptance and Action Questionnaire-II (AAQ-II, r = -0.334). Furthermore, the Chinese PPFI demonstrated good internal consistency (Cronbach's α = 0.826) and test–retest reliability (ICC = 0.817, p

Although speech emotion recognition is challenging, it has broad application prospects in human-computer interaction. Building a system that can accurately and stably recognize emotions from human languages can provide a better user experience. However, the current unimodal emotion feature representations are not distinctive enough to accomplish the recognition, and they do not effectively simulate the inter-modality dynamics in speech emotion recognition tasks. This paper proposes a multimodal method that utilizes both audio and semantic content for speech emotion recognition. The proposed method consists of three parts: two high-level feature extractors for text and audio modalities, and an autoencoder-based feature fusion. For audio modality, we propose a structure called Temporal Global Feature Extractor (TGFE) to extract the high-level features of the time-frequency domain relationship from the original speech signal. Considering that text lacks frequency information, we use only a Bidirectional Long Short-Term Memory network (BLSTM) and attention mechanism to simulate an intra-modal dynamic. Once these steps have been accomplished, the high-level text and audio features are sent to the autoencoder in parallel to learn their shared representation for final emotion classification. We conducted extensive experiments on three public benchmark datasets to evaluate our method. The results on Interactive Emotional Motion Capture (IEMOCAP) and Multimodal EmotionLines Dataset (MELD) outperform the existing method. Additionally, the results of CMU Multi-modal Opinion-level Sentiment Intensity (CMU-MOSI) are competitive. Furthermore, experimental results show that compared to unimodal information and autoencoder-based feature level fusion, the joint multimodal information (audio and text) improves the overall performance and can achieve greater accuracy than simple feature concatenation.

Abstract Sarcomyxa edulis, a notable edible and medicinal mushroom indigenous to northeast China, is celebrated for its high nutritional value and delightful taste. In this study, white light as a control and examined the effects of red, green, and blue light on the agronomic traits, antioxidant capabilities, and nutritional composition of S. edulis. The results showed that different monochromatic light qualities affected the color of S. edulis pileus, with blue light demonstrating particular efficacy. Furthermore, blue light also regulated pileus length, whereas red light was instrumental in significantly increasing stalk length. Regarding antioxidant capacity, compared with red and green light, the activities of POD, SOD, and CAT were significantly improved by blue light irradiation, decreased MDA levels, and improved free radical scavenging potential. Additionally, blue light exposure led to an increase in the contents of 15 amino acids. Green light treatment reduced the crude fat content. For the first time, we found that light quality is a key factor in controlling the color of S. edulis. Blue light is an effective way to regulate the color and pileus size of S. edulis, and improve the antioxidant properties. The photobiological characteristics and the response of nutritional quality to light environment of S. edulis were clarified.

Ammopiptanthus mongolicus is an ancient remnant species from the Mediterranean displaying characteristics such as high-temperature tolerance, drought resistance, cold resistance, and adaptability to impoverished soil. In the case of high-temperature tolerance, heat shock transcription factors (HSFs) are integral transcriptional regulatory proteins exerting a critical role in cellular processes. Despite extensive research on the HSF family across various species, there has been no analysis specifically focused on A. mongolicus. In this study, we identified 24 members of the AmHSF gene family based on the genome database of A. mongolicus, which were unevenly distributed over 9 chromosomes. Phylogenetic analysis showed that these 24 members can be categorized into 5 primary classes consisting of a total of 13 subgroups. Analysis of the physical and chemical properties revealed significant diversity among these proteins. With the exception of the AmHSFB3 protein, which is localized in the cytoplasm, all other AmHSF proteins were found to be situated in the nucleus. Comparison of amino acid sequences revealed that all AmHSF proteins contain a conserved DNA-binding domains structure, and the DNA-binding domains and oligomerization domains of the AmHSF gene exhibit conservation with counterparts across diverse species; we investigated the collinearity of AmHSF genes in relation to those of three other representative species. Through GO enrichment analysis, evidence emerged that AmHSF genes are involved in heat stress responses and may be involved in multiple transcriptional regulatory pathways that coordinate plant growth and stress responses. Finally, through a comprehensive analysis using transcriptome data, we examined the expression levels of 24 AmHSFs under 45 °C. The results revealed significant differences in the expression profiles of AmHSFs at different time intervals during exposure to high temperatures, highlighting their crucial role in responding to heat stress. In summary, these results provide a better understanding of the role and regulatory mechanisms of HSF in the heat stress response of A. mongolicus, meanwhile also establishing a foundation for further exploration of the biological functions of AmHSF in the adversity response of A. mongolicus.

Abstract Plant U-box genes play an important role in the regulation of plant hormone signal transduction, stress tolerance, and pathogen resistance; however, their functions in coffee (Coffea canephora L.) remain largely unexplored. In this study, we identified 47 CcPUB genes in the C. canephora L. genome, clustering them into nine groups via phylogenetic tree. The CcPUB genes were unevenly distributed across the 11 chromosomes of C. canephora L., with the majority (11) on chromosome 2 and none on chromosome 8. The cis-acting elements analysis showed that CcPUB genes were involved in abiotic and biotic stresses, phytohormone responsive, and plant growth and development. RNA-seq data revealed diverse expression patterns of CcPUB genes across leaves, stems, and fruits tissues. qRT-PCR analyses under dehydration, low temperature, SA, and Colletotrichum stresses showed significant up-regulation of CcPUB2, CcPUB24, CcPUB34, and CcPUB40 in leaves. Furthermore, subcellular localization showed CcPUB2 and CcPUB34 were located in the plasma membrane and nucleus, and CcPUB24 and CcPUB40 were located in the nucleus. This study provides valuable insights into the roles of PUB genes in stress responses and phytohormone signaling in C. canephora L., and provided basis for functional characterization of PUB genes in C. canephora L.

Abstract Erectile dysfunction (ED) is prevalent among males experiencing fertility challenges, yet attitudes towards actively treating ED in this group are under-researched. From a cohort of 1256 men with reproductive needs, 303 were identified with ED. The survey encompassed 296 respondents who correctly completed the second questionnaire, revealing that 50.3% sought ED treatment, with higher ED severity increasing the likelihood of seeking treatment. Infertile men were more likely to seek treatment than those with pregnancy loss (OR 3.18, 95% CI 1.74–5.83). Men with normal semen parameters were more open to ED therapy (OR 3.02, 95% CI 1.69–5.36), whereas those undergoing Assisted Reproduction Treatment were less inclined (OR 0.32, 95% CI 0.18–0.58). PDE-5 inhibitors (PDE-5Is) were preferred by 51.0% of those seeking treatment, with 29.7% of men with pregnancy loss and 60.1% of infertile men choosing PDE-5Is as their first option. Concerns included potential adverse effects of PDE-5Is on fetal health (78.7% of men with pregnancy loss) and on sperm quality (44.2% of infertile men). In conclusion, the different fertility requirements, semen parameters, and whether received ART are significant factors influencing the acceptance of treatment, PDE-5Is utilization among individuals in men with couple pregnancy loss is notably limited.

Abstract Metasurfaces with tunable functionalities are greatly desired for modern optical system and various applications. To increase the operating channels of polarization-multiplexed metasurfaces, we proposed a structure of N cascaded dual-channel metasurfaces to achieve 2 N electrically switchable channels without intrinsic loss or cross-talk for certain functionalities, including beam steering, vortex beam generation, lens, etc. As proof of principles, we have implemented a 3-layer setup to achieve 8 channels. In success, we have demonstrated two typical functionalities of vortex beam generation with switchable topological charge of l = −3 ~ +4 or l = −1 ~ −8, and beam steering with the deflection direction switchable in an 8×1 line or a 4×2 grid. We believe that our proposal would provide a practical way to significantly increase the scalability and extend the functionality of polarization-multiplexed metasurfaces. Although this method is not universal, it is potential for the applications of LiDAR, glasses-free 3D display, OAM (de)multiplexing, and varifocal meta-lens.

Abstract Background Sleep and physical activity (PA) are thought to be interconnected with the development of rheumatoid arthritis (RA). However, the precise nature and extent of these relationships have yet to be fully quantified. This study aimed to quantify the longitudinal effects of sleep behaviors, PA, and genetic susceptibility on the incidence of RA and to estimate the combined effects and interactions among these exposures. Methods A total of 363,211 adults were derived from a large European cohort. We incorporated five sleep behaviors (sleep duration, insomnia, snoring, chronotype, and daytime sleepiness) to generate sleep patterns, which were defined based on healthy sleep scores. Multivariate-adjusted Cox proportional hazard models were conducted to assess the individual and combined associations of sleep patterns, PA, and genetic susceptibility with the risk of RA occurrence. Multiplicative and additive interactions were estimated by P interaction and relative excess risk due to interaction (RERI) between each of the two exposures. Results During a follow-up of 12.5 years, 4262 RA cases were ascertained. A healthy sleep pattern was associated with a decreased risk of RA in a dose-response manner, with an adjusted hazard ratio (HR) of 0.79 (95% confidence interval [CI] = 0.75–0.84), independent of traditional risk factors and genetic predisposition. Under the restricted cubic splines model, a non-linear association was detected for PA and RA risk. Participants in the intermediate quintile 3 showed the lowest risk for developing RA, with a HR 95% CI of 0.84 (0.76–0.92). Moreover, there was an additive interaction effect of intermediate sleep pattern and PA, with a 0.45 (95% CI = 0.02–0.87) RERI of developing RA. Additionally, individuals at high genetic risk had the greatest 10-year absolute risk reduction (10.58 per 1000 person-years) when adopting both favorable behaviors. Conclusions A healthy sleep pattern and moderate PA were associated with a reduced risk of developing RA, which can offset the deleterious effects of predisposing genetic components. Implementing these modifiable lifestyle factors into public health practices is beneficial for RA prevention.

Abstract Background With the backdrop of global climate change, the impact of climate change on respiratory diseases like asthma is receiving increasing attention. However, the effects of temperature and diurnal temperature range (DTR) on asthma are complex, and understanding these effects across different seasons, age groups, and sex is of utmost importance. Methods This study utilized asthma hospitalization data from Lanzhou, China, and implemented a distributed lag nonlinear model (DLNM) to investigate the relationship between temperature and DTR and asthma hospitalizations. It considered differences in the effects across various seasons and population subgroups. Results The study revealed that low temperatures immediately increase the risk of asthma hospitalization (RR = 1.2010, 95% CI: 1.1464, 1.2580), and this risk persists for a period of time. Meanwhile, both high and low DTR were associated with an increased risk of asthma hospitalization. Lower temperatures (RR = 2.9798, 95% CI: 1.1154, 7.9606) were associated with higher asthma risk in the warm season, while in the cold season, the risk significantly rose for the general population (RR = 3.6867, 95% CI: 1.7494, 7.7696), females (RR = 7.2417, 95% CI: 2.7171, 19.3003), and older individuals (RR = 18.5425, 95% CI: 5.1436, 66.8458). In the warm season, low DTR conditions exhibited a significant association with asthma hospitalization risk in males (RR = 7.2547, 95% CI: 1.2612, 41.7295) and adults aged 15–64 (RR = 9.9494, 95% CI: 2.2723, 43.5643). Children also exhibited noticeable risk within specific DTR ranges. In the cold season, lower DTR increases the risk of asthma hospitalization for the general population (RR = 3.1257, 95% CI: 1.4004, 6.9767). High DTR significantly increases the risk of asthma hospitalization in adults (RR = 5.2563, 95% CI: 2.4131, 11.4498). Conclusion This study provides crucial insights into the complex relationship between temperature, DTR, and asthma hospitalization, highlighting the variations in asthma risk across different seasons and population subgroups.

Abstract The family of coinage-metal-based cyclic trinuclear complexes exhibits abundant photophysical properties, promising for diverse applications. However, their utility in biochemistry is often hindered by large particle size and strong hydrophobicity. Meanwhile, the investigation into multi-photon excited luminescence within this family remained undocumented, limiting their potential in bio-imaging. Herein, we unveil the multi-photon excited luminescent properties of pyrazolate-based trinuclear gold(I) clusters, facilitated by excimeric gold(I)···gold(I) interactions, revealing a nonlinear optical phenomenon within this family. Furthermore, to address issues of poor biocompatibility, we employ electrospinning coupled with hydroxypropyl-beta-cyclodextrin as the matrix to fabricate a flexible, durable, transparent, and red emissive film with a photoluminescence quantum yield as high as 88.3%. This strategy not only produces the film with sufficient hydrophilicity and stability, but also achieves the downsizing of trinuclear gold(I) clusters from microscale to nanoscale. Following the instantaneous dissolution of the film in the media, the released trinuclear gold(I) nanoparticles have illuminated cells and bacteria through a real-time, non-toxic, multi-photon bio-imaging approach. This achievement offers a fresh approach for utilizing coinage-metal-based cyclic trinuclear complexes in biochemical fields.

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-β, secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.

ObjectiveTo analyze the trend of hepatitis B incidence among residents of Xizang Autonomous Region from 2018 to 2022, to provide a reference for the development of hepatitis B prevention and control strategies. MethodsData on reported hepatitis B incidence among residents of Xizang Autonomous Region from 2018 to 2022 were collected from the Hepatitis B Surveillance System of the China Information System for Disease Control and Prevention, and the trend of hepatitis B incidence in the population during this period was analyzed. ResultsThe reported annual incidence rate (1/100 000) of hepatitis B among residents of Xizang Autonomous Region was 80.14, 111.07, 121.69, 129.10, and 100.20 in 2018, 2019, 2020, 2021, and 2022, respectively, with an overall increasing trend (χ2trend = 48.225, Ptrend < 0.001), and the rate increased for both male (72.84 to 86.38) and female (87.60 to 103.43) residents (both Ptrend < 0.001) and for residents aged 40 – 49 years (80.88 to 117.74), 50 – 59 years (83.40 to 116.74), and ≥ 60 years (81.30 to 188.44) (all Ptrend < 0.001) over the period; but the rate decreased for residents aged 0 – 9 years (30.72 to 13.92) and 30 – 39 years (105.60 to 104.54) (both Ptrend < 0.05). The reported annual incidence rate (1/100 000) of hepatitis B increased during the period for residents of all prefecture-level administrative divisions of Xizang Autonomous Region, including Lhasa (145.37 to 150.36), Shigatse (8.90 to12.59), Changdu (87.18 to 143.64), Naqu (47.29 to 93.41), and Ali (155.03 to 348.36) (all Ptrend < 0.05), except for residents in Linzhi, whose rate decreased from 181.65 to 118.53 (χ2trend = 9.890, Ptrend = 0.002). Both the reported incidence rates (1/100 000) of chronic hepatitis B and unclassified hepatitis B among residents of Xizang Autonomous Region showed an increasing trend over the 5-year period, from 58.26 and 13.49 to 65.32 and 21.55 (both Ptrend < 0.001). ConclusionThe overall reported incidence rate of hepatitis B, including chronic and unclassified hepatitis B, among residents of Xizang Autonomous Region showed an upward trend from 2018 to 2022 and the residents aged 40 years and above are the key population for hepatitis B prevention and control in this region.

A 61-kb biosynthetic gene cluster (BGC), which is accountable for the biosynthesis of hibarimicin (HBM) B from Microbispora rosea subsp. hibaria TP-A0121, was heterologously expressed in Streptomyces coelicolor M1154, which generated a trace of the target products but accumulated a large amount of shunt products. Based on rational analysis of the relevant secondary metabolism, directed engineering of the biosynthetic pathways resulted in the high production of HBM B, as well as new HBM derivates with improved antitumor activity. These results not only establish a biosynthetic system to effectively synthesize HBMs—a class of the largest and most complex Type-II polyketides, with a unique pseudo-dimeric structure—but also set the stage for further engineering and deep investigation of this complex biosynthetic pathway toward potent anticancer drugs.

Abstract The study explored the impact of pretreatment serum albumin-to-alkaline phosphatase ratio (AAPR) and changes in tumor blood supply on pathological complete response (pCR) in breast cancer (BC) patients following neoadjuvant chemotherapy (NACT). Additionally, a nomogram for predicting pCR was established and validated. The study included BC patients undergoing NACT at Yongchuan Hospital of Chongqing Medical University from January 2019 to October 2023. We analyzed the correlation between pCR and clinicopathological factors, as well as tumor ultrasound features, using chi-square or Fisher's exact test. We developed and validated a nomogram predicting pCR based on regression analysis results. The study included 176 BC patients. Logistic regression analysis identified AAPR [odds ratio (OR) 2.616, 95% confidence interval (CI) 1.140–5.998, P = 0.023], changes in tumor blood supply after two NACT cycles (OR 2.247, 95%CI 1.071–4.716, P = 0.032), tumor histological grade (OR 3.843, 95%CI 1.286–10.659, P = 0.010), and HER2 status (OR 2.776, 95%CI 1.057–7.240, P = 0.038) as independent predictors of pCR after NACT. The nomogram, based on AAPR, changes in tumor blood supply after two NACT cycles, tumor histological grade, and HER2 status, demonstrated a good predictive capability.

Abstract Alternative polyadenylation (APA) plays a crucial role in cancer biology. Here, we used data from the 3′aQTL-atlas, GTEx, and the China Nanjing Lung Cancer GWAS database to explore the association between apaQTL/eQTL-SNPs and the risk of lung adenocarcinoma (LUAD). The variant T allele of rs277646 in NIT2 is associated with an increased risk of LUAD (OR = 1.12, P = 0.015), lower PDUI values, and higher NIT2 expression. The 3′RACE experiment showed multiple poly (A) sites in NIT2, with the rs277646-T allele causing preferential use of the proximal poly (A) site, resulting in a shorter 3′UTR transcript. This leads to the loss of the hsa-miR-650 binding site, thereby affecting LUAD malignant phenotypes by regulating the expression level of NIT2. Our findings may provide new insights into understanding and exploring APA events in LUAD carcinogenesis.

Abstract Background Anxiety disorders are one of the most common mental disorders. Ghrelin is a critical orexigenic brain-gut peptide that regulates food intake and metabolism. Recently, the ghrelin system has attracted more attention for its crucial roles in psychiatric disorders, including depression and anxiety. However, the underlying neural mechanisms involved have not been fully investigated. Methods In the present study, the effect and underlying mechanism of ghrelin signaling in the nucleus accumbens (NAc) core on anxiety-like behaviors were examined in normal and acute stress rats, by using immunofluorescence, qRT-PCR, neuropharmacology, molecular manipulation and behavioral tests. Results We reported that injection of ghrelin into the NAc core caused significant anxiolytic effects. Ghrelin receptor growth hormone secretagogue receptor (GHSR) is highly localized and expressed in the NAc core neurons. Antagonism of GHSR blocked the ghrelin-induced anxiolytic effects. Moreover, molecular knockdown of GHSR induced anxiogenic effects. Furthermore, injection of ghrelin or overexpression of GHSR in the NAc core reduced acute restraint stress-induced anxiogenic effects. Conclusions This study demonstrates that ghrelin and its receptor GHSR in the NAc core are actively involved in modulating anxiety induced by acute stress, and raises an opportunity to treat anxiety disorders by targeting ghrelin signaling system.

Abstract The nonconventional yeast Kluyveromyces marxianus has potential for industrial production, but the lack of advanced synthetic biology tools for precise engineering hinders its rapid development. Here, we introduce a CRISPR-Cas9-mediated multilocus integration method for assembling multiple exogenous genes. Using SlugCas9-HF, a high-fidelity Cas9 nuclease, we enhance gene editing precision. Specific genomic loci predisposed to efficient integration and expression of heterologous genes are identified and combined with a set of paired CRISPR-Cas9 expression plasmids and donor plasmids to establish a CRISPR-based biosynthesis toolkit. This toolkit enables genome integration of large gene modules over 12 kb and achieves simultaneous quadruple-locus integration in a single step with 20% efficiency. As a proof-of-concept, we apply the toolkit to screen for gene combinations that promote heme production, revealing the importance of HEM4Km and HEM12Sc. This CRISPR-based toolkit simplifies the reconstruction of complex pathways in K. marxianus, broadening its application in synthetic biology.

Purpose This study examined the diagnostic value of high-frequency ultrasound (HFUS) features in differentiating between benign and malignant skin lesions. Methods A total of 1,392 patients with 1,422 skin lesions who underwent HFUS examinations were included in an initial dataset (cohort 1) to identify features indicative of malignancy. Qualitative clinical and HFUS characteristics were recorded for all lesions. To determine which HFUS and clinical features were suggestive of malignancy, univariable and multivariable logistic regression analyses were employed. The diagnostic performance of HFUS features combined with clinical information was evaluated. This assessment was validated using internal data (cohort 2) and multicenter external data (cohort 3). Results Features significantly associated with malignancy included age above 60 years; lesion location in the head, face, and neck or genital regions; changes in macroscopic appearance; crawling or irregular growth pattern; convex or irregular base; punctate hyperechogenicity; blood flow signals; and feeding arteries. The area under the receiver operating characteristic curve, sensitivity, and specificity of HFUS features combined with clinical information were 0.946, 92.5%, and 86.9% in cohort 1; 0.870, 93.1%, and 80.8% in cohort 2 (610 lesions); and 0.864, 86.2%, and 86.6% in cohort 3 (170 lesions), respectively. However, HFUS is not suitable for evaluating lesions less than 0.1 mm in thickness or lesions exhibiting surface hyperkeratosis. Conclusion In a clinical setting, the integration of HFUS with clinical information exhibited good diagnostic performance in differentiating malignant and benign skin lesions. However, its utility was limited in evaluating extremely thin lesions and those exhibiting hyperkeratosis.

Objective To explore the mechanism which drives nimbolide (NIM) in treating acute pneumonia caused by Staphylococcus aureus (S. auteus). Methods A mouse model of acute pneumonia caused by S. auteus was constructed through endotracheal intubation. After NIM treatment, the survival rate was observed, the amount of bacteria in the lung was tested by plate culture, and the expression of inflammatory cytokines in the lung tissues was detected with ELISA. After primary cultured peritoneal macrophages (PM) were infected with S. auteus, the effect of NIM on the expression of inflammatory cytokines and activation of inflammatory pathway were studied with ELISA and Western blotting, respectively. The effect of RNF114 knockdown by lentiviral shRNA infection on inflammation responses in PM was explored with ELISA and Western blotting. Results Acute infection of S. auteus in the lung could cause acute death in the mice, while NIM treatment significantly improved the survival rate and down-regulated the levels of inflammatory cytokines in the lung. However, it had no effect on the lung colonization of S. auteus in the short term. The results of in vitro experiments indicated that NIM may regulate RNF114 function to down-regulate the phosphorylation level of ERK, inhibit the activation of MAPK pathway, and thus suppress the expression of inflammatory cytokines. Conclusion NIM may inhibit the activation of MAPK pathway by regulating the function of RNF114, and thus suppress the expression of inflammatory cytokines in the lung, and finally inhibit the death of mice with acute pulmonary hyperinflammation caused by S. auteus.

Abstract Background The standard care for resectable non-small cell lung cancer (NSCLC) involves perioperative therapy combining chemotherapy and immune checkpoint inhibitors, typically lasting 6 to 12 months. However, the optimal treatment strategies for potentially resectable squamous cell lung carcinoma (SCC) remain unclear. This Phase 2 trial aimed to assess the efficacy and safety of a condensed four-cycle perioperative treatment regimen with tislelizumab combined with chemotherapy in patients with potentially resectable stage III SCC. Methods Patients with potentially resectable stage IIIA-IIIB (N2) SCC received intravenous tislelizumab, albumin-bound paclitaxel, and carboplatin for up to four cycles. The primary endpoints were major pathologic response (MPR) and incidence of treatment-related adverse events. Safety and potential biomarkers for efficacy prediction were also assessed. Results Among 35 enrolled patients, 32 underwent surgery with R0 resection achieved in all cases. MPR was achieved in 24 patients and pathological complete response (pCR) in 14 patients. Radiographic objective response was observed in 31 patients. The 12-month and 24-month event-free survival rate was 85.7 and 61.0%, respectively. Four patients experienced grade 3 or 4 adverse events. Tumor tissue based next-generation sequencing revealed the potential associations between several biomarkers and pathological response, including tumor neoantigen burden score, 18-gene expression profile score, CD8 + T cells, M1/M2 macrophages ratio and interferon‐gamma expression level. Besides, circulating tumor DNA (ctDNA) dynamics and concentration were also associated with pathological response and the presence of ctDNA at postoperative month 1 was a strong predictor for disease relapse. Furthermore, metagenomic sequencing in bronchoalveolar lavage fluid demonstrated Streptococcus was the most abundant genus in the pCR group. Conclusions A condensed four-cycle perioperative treatment regimen of tislelizumab combined with chemotherapy demonstrated promising efficacy and manageable toxicities in potentially resectable stage III SCC. Specific biomarkers showed potential for predicting treatment efficacy and the mechanism of superior antitumor response of pCR patients was preliminarily and indirectly explored. Trial registration ClinicalTrials.gov, NCT05024266. Registered August 27, 2021.

Abstract Background The atherogenic index of plasma (AIP) is a simple and reliable marker of insulin resistance and is closely associated with various cardiovascular diseases (CVDs). However, the relationships between AIP and left ventricular (LV) geometric indicators have not been adequately assessed. This study was carried out to investigate the association between AIP and LV geometric abnormalities in obstructive sleep apnea (OSA) patients. Methods This retrospective cross-sectional study included a total of 618 OSA patients (57.3 ± 12.4 years, 73.1% males, BMI 28.1 ± 4.2 kg/m2) who underwent echocardiography. Patients with OSA were diagnosed with clinical symptoms and an apnea-hypopnea index ≥ 5.0. LV hypertrophy (LVH) was defined as left ventricular mass index (LVMIh2.7) ≥ 50.0 g/m2.7 for men and 47.0 g/m2.7 for women. AIP was calculated as log10 (TG/HDL-C). Results Compared with the non-LVH group, AIP was significantly higher in the LVH group (0.19 ± 0.29 vs 0.24 ± 0.28, P = 0.024) and the concentric LVH group (0.18 ± 0.29, 0.19 ± 0.30, 0.20 ± 0.26 and 0.29 ± 0.29 in the control, concentric remodeling, eccentric hypertrophy and concentric hypertrophy groups, respectively, P = 0.021). Meanwhile, in the group of patients with the highest AIP tertile, the levels of LVMIh2.7 (42.8 ± 10.5, 43.2 ± 9.3 and 46.1 ± 12.1 in the T1, T2 and T3 groups, respectively, P = 0.003), and the prevalence of LVH (25.2%, 24.0% and 34.6% in the T1, T2 and T3 groups, respectively, P = 0.032) and concentric LVH (10.7%, 9.8% and 20.2% in the T1, T2 and T3 groups, respectively, P = 0.053) were higher compared with those in the other groups. Positive correlations between AIP and LV geometric indicators including the LVMIh2.7, LVMIBSA, LV mass (LVM), diastolic left ventricular inner diameter (LVIDd), diastolic left ventricular posterior wall thickness (PWTd) and diastolic interventricular septal thickness (IVSTd), were revealed according to correlation analysis (P

Abstract The ubiquitination-mediated protein degradation exerts a vital role in the progression of multiple tumors. NEDD4L, which belongs to the E3 ubiquitin ligase NEDD4 family, is related to tumor genesis, metastasis and drug resistance. However, the anti-tumor role of NEDD4L in esophageal carcinoma, and the potential specific recognition substrate remain unclear. Based on public esophageal carcinoma database and clinical sample data, it was discovered in this study that the expression of NEDD4L in esophageal carcinoma was apparently lower than that in atypical hyperplastic esophageal tissue and esophageal squamous epithelium. Besides, patients with high expression of NEDD4L in esophageal carcinoma tissue had longer progression-free survival than those with low expression. Experiments in vivo and in vitro also verified that NEDD4L suppressed the growth and metastasis of esophageal carcinoma. Based on co-immunoprecipitation and proteome analysis, the NEDD4L ubiquitination-degraded protein ITGB4 was obtained. In terms of the mechanism, the HECT domain of NEDD4L specifically bound to the Galx-β domain of ITGB4, which modified the K915 site of ITGB4 in an ubiquitination manner, and promoted the ubiquitination degradation of ITGB4, thus suppressing the malignant phenotype of esophageal carcinoma.

Abstract Interactions are mandatory for online or offline music and dance education to improve understandability and learning efficacy. The course designed for such artistic education incorporates multi-point interactions and monotonous presentations. The validation of the key factor: interactivity is thus mandatory for enhancing efficiency. This article introduces an interactivity validation method (IVM) using combined fuzzy neural network (FNN) to aid artistic course development. The output of the existing course and its evaluation criteria are considered in enhancing its grade. The fuzzy performs interaction classification as mandatory and trivial based on the student’s performance. The neural network identifies the chances for maximum performance by increasing or decreasing the interaction rate. If a saturated performance is achieved at a high or low interactivity, then the further course design is performed based on the saturated interactivity factor. The failing factors are used for training the neural network for modifying the interactivity rate from the current course development suggestion. Such a process is keen on classifying and validating the impact of interactivity over artistic course design.

Abstract Background Syntaxin6 (STX6) is a SNARE (Soluble N-ethylmaleimide-sensitive factor attachment protein receptors) protein complex located in the trans-Golgi network and endosomes, which is closely associated with a variety of intracellular membrane transport events. STX6 has been shown to be overexpressed in a variety of human malignant tumors such as esophageal, colorectal, and renal cell carcinomas, and participates in tumorigenesis and development. Methods Based on clinical public database and clinical liver samples analysis, the expression of STX6 in hepatocellular carcinoma (HCC) tissues was investigated. The effects of STX6 on proliferation, migration and invasion of HCC cell in vitro and in vivo were evaluated through gain- and loss-of-function studies. We further performed RNA-seq analysis and protein interactome analysis, to further decifer the detailed mechanisms of STX6 in the regulation of the JAK-STAT pathway in HCC. Results STX6 expression was upregulated in HCC tissues and its expression was highly correlated with the high histological grade of the tumor. STX6 promoted HCC cell proliferation, migration and invasion both in vitro and in vivo. Mechanistically, STX6 mediated tumor progression depending on promoting the activation of JAK-STAT signaling pathway. Receptor for activated protein kinase C (RACK1) as an essential adaptor protein mediating STX6 regulation of JAK-STAT pathway. Specifically, STX6 interacted with RACK1 and then recruited signal transducer and activator of transcription 3 (STAT3) to form a protein-binding complex and activates STAT3 transcriptional activity. Conclusions This study provided a novel concept that STX6 exerted oncogenic effects by activating the STAT3 signaling pathway, and STX6 might be a promising therapeutic target for HCC.

IntroductionThe integration of artificial intelligence (AI) in pathogenic microbiology has accelerated research and innovation. This study aims to explore the evolution and trends of AI applications in this domain, providing insights into how AI is transforming research and practice in pathogenic microbiology.MethodsWe employed bibliometric analysis and topic modeling to examine 27,420 publications from the Web of Science Core Collection, covering the period from 2010 to 2024. These methods enabled us to identify key trends, research areas, and the geographical distribution of research efforts.ResultsSince 2016, there has been an exponential increase in AI-related publications, with significant contributions from China and the USA. Our analysis identified eight major AI application areas: pathogen detection, antibiotic resistance prediction, transmission modeling, genomic analysis, therapeutic optimization, ecological profiling, vaccine development, and data management systems. Notably, we found significant lexical overlaps between these areas, especially between drug resistance and vaccine development, suggesting an interconnected research landscape.DiscussionAI is increasingly moving from laboratory research to clinical applications, enhancing hospital operations and public health strategies. It plays a vital role in optimizing pathogen detection, improving diagnostic speed, treatment efficacy, and disease control, particularly through advancements in rapid antibiotic susceptibility testing and COVID-19 vaccine development. This study highlights the current status, progress, and challenges of AI in pathogenic microbiology, guiding future research directions, resource allocation, and policy-making.

Background: Coarse grains are rich in fiber, minerals, and other beneficial nutrients but are consumed at low levels in modern populations. The factors that influence coarse grain consumption in current living and dietary environments are not fully understood. Objectives: This study aimed to explore the knowledge and behavior related to coarse grain consumption and identify the influencing factors among Chinese citizens. Methods: Six focus group discussions were conducted with 39 participants aged 18–65 years from diverse social backgrounds in Xi'an, China. All discussions were transcribed verbatim and analyzed using inductive thematic analysis. Results: The majority of participants demonstrated insufficient knowledge about coarse grains, including their definitions, health benefits, and recommended intake. A small number of the participants reported regular consumption. The barriers to coarse grain consumption were poor sensory properties, insufficient cooking skills and time, limited availability of ready-to-eat foods, established dietary habits, and high prices. Additionally, new barriers included psychological burden, concerns about food safety, the impact of processing methods on health benefits, and special health conditions. Health benefits and family influence emerged as the 2 primary factors motivating coarse grain consumption. Most participants expressed a positive attitude toward partially replacing staple foods with coarse grains. Enhancing health education, innovating food processing methods, improving labeling systems, and strengthening safety supervision have been recommended for increasing coarse grain consumption. Conclusions: A gap exists between health awareness and healthy behaviors regarding coarse grain consumption; thus, collaborative efforts among government agencies, educational institutions, nutrition societies, the food industry, policymakers, and health professionals are essential to overcome these challenges.

Damping-off disease in chili (Capsicum annum L.) cultivation is a significant global issue, severely affecting seeds, seedlings, and young plants, regardless of the location of cultivation, whether in greenhouses or open fields. Despite chili being a widely popular vegetable used in various cuisines globally, farmers face challenges in meeting the growing demand due to the extensive damage caused by this disease, ranging from 20 to 85%. The shelf life and quality of mature pods are also severely affected. Damping-off disease is mainly caused by soil-borne fungus from the Pythium species, with additional contributions from Phytophthora, Fusarium, and Rhizoctonia species. These pathogens’ adaptability to diverse environmental conditions and resistance to synthetic fungicides make controlling damping-off on a commercial scale challenging. However, integrated disease management has shown promising results as a remedial approach. In this review, we discuss the current state of chili diseases, the nature of the pathogens causing damping-off, the epidemiology of the disease, and various control mechanisms. In this review, we broadly discuss the current state of chili diseases, the nature of the pathogens causing damping-off, the epidemiology of the disease, and various control mechanisms. Furthermore, we highlight the importance and efficacy of integrated disease management techniques, along with future prospects in unexplored areas, such as host–pathogen interaction and sustainable disease control measures. The information in this review aims to assist chili growers in understanding the epidemiology and management of damping-off in chili cultivation.

Fatty acyl desaturases (Fads) are crucial enzymes that catalyze the rate-limiting step of the desaturation reactions by introducing a double bond into to pre-existing fatty acyl chains. As a group of key enzymes involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), Fads have been well investigated in teleost fishes but they are still rarely known in chondrichthyans. In this study, we first identified a fatty acyl desaturases gene (fads2) from the Chinese sturgeon (Acipenser sinensis), a critically endangered cartilaginous species in China, by combining with bioinformatic analyses and molecular cloning methods. Then, the spatio-temporal distribution patterns, functional characteristics and transcriptional changes of this gene in response to different nutritional conditions were investigated. The coding sequences of the fads2 gene was 1350 bp in length, encoding a protein of 449 amino acids. Multiple protein sequences alignment, genetic synteny and phylogenetic analyses further suggested that fads2 gene was evolutionary conserved. Functional characterization by heterologous expression in yeast showed that Fads2 exhibited Δ6 and Δ8 bifunctional desaturation activities, and possessed capacities to convert 18:2n-6, 18:3n-3, 20:2n-6 and 20:3n-3–18:3n-6, 18:4n-3, 20:3n-6 and 20:4n-3, respectively. In vivo experiment, diets full with C18 PUFA but not LC-PUFA significantly induced the expression levels of fads2 in Chinese sturgeon brain and liver tissues. Our findings suggest that fads2 is an evolutionary and functionally conserved desaturase in Chinese sturgeon, and which plays important roles in regulation of endogenous LC-PUFAs biosynthesis. In summary, these findings will provide a new insight into the evolutionary history of key enzymes of LC-PUFA biosynthesis in vertebrates.

Background: Clearance of human papillomavirus (HPV) among adolescent men who have sex with men (MSM) is not well studied. This study aimed to evaluate the clearance of HPV DNA and antibodies among adolescent MSM. Methods: In our cohort study, we enrolled adolescent MSM in Melbourne between October 2010 and September 2013. At baseline, 3, 6, and 12 months, anal and penile swabs for HPV DNA and serum for HPV antibodies against genotypes 6, 11, 16, and 18, were collected. Definite clearance was defined as HPV DNA (same site) /antibodies for the same genotype undetected following a positive HPV DNA /antibodies test at baseline or month 3. Possible clearance was defined as HPV DNA (same site) /antibodies for the same genotype undetected at month 12 following a positive HPV DNA/antibodies test at month 6. Overall clearance was defined as either definite or possible clearance. The agreement between HPV DNA clearance and antibodies clearance was calculated. Results: A total of 183 MSM were included (median age: 19 years, interquartile [IQR]: 18 to 20). At the anus, overall clearance rate was 21.6 (95 % confidence interval[CI]: 7.9 to 47.0), 44.8 (19.3 to 88.3), 51.9 (20.9 to 106.9) and 33.7 (7.0 to 98.5) per 1000 person months (PM) for HPV 6, 11, 16 and 18. At the penis, overall clearance rate was 64.5 (13.3 to 188.5), 71.3 (14.7 to 208.2), 96.5 (31.3 to 225.3) and 333.3 (8.4 to 1857.2) per 1000 PM for HPV 6, 11, 16 and 18. For antibodies, overall clearance rate was 22.2 (9.6 to 43.7), 18.8 (3.9 to 55.0), 10.8 (0.3 to 60.1) and 19.0 (2.3 to 68.8) per 1000 PM. Agreement between anal/penile HPV DNA clearance and antibodies clearance was low: kappa = -0.18 (95 % CI: −0.28 to 0.08)/-0.13 (−0.24 to −0.02), 0.04 (−0.29 to 0.36)/0.22 (−0.32 to 0.76), −0.10 (−0.27 to 0.08)/-0.14 (−0.37 to 0.10) and −0.14 (−0.28 to 0.01)/-0.14 (−0.33 to 0.06) for HPV 6, 11, 16 and 18, respectively. Conclusion: Clearance rates of HPV DNA were low and varied by genotypes and anatomical sites among adolescent MSM. Antibodies against HPV were stable during the study period.

Abstract Background and Objective To explore the association between protein quantitative trait loci (pQTL‐SNPs) and the risk of LUAD. Methods “Blood +” high depth blood proteomics analysis was performed on plasma from female LUAD patients and female healthy controls, and combined with proteomics data from tumors and adjacent non‐tumor tissues of female LUAD patients to screen proteins uniformly expressed in plasma and tissues. pQTL‐SNPs were then screened through multiple databases and subjected to multilevel screening. The associations between selected pQTL‐SNPs and LUAD risk were evaluated by Female Lung Cancer Consortium in Asia GWAS (FLCCA GWAS). Enzyme linked immunosorbent assay (ELISA) is used to determine the levels of candidate protein. Results A total of 7 pQTL‐SNPs were significantly associated with altered LUAD risk (p 1, p

Abstract Background Imbalances in alkali elements (AEs) and alkaline earth elements (AEEs) cause reproductive disorders. However, it remains unclear whether AEs/AEEs in follicular fluid have a relationship with the serious reproductive disorder known as diminished ovarian reserve (DOR). Methods A nested case‒control study was carried out in China. Follicular fluid samples from 154 DOR patients and 154 controls were collected and assessed for nine AEs/AEE levels. Both the mixed and single effects of the elements on DOR were estimated with a Bayesian kernel machine (BKMR) and logistic regressions. Results The DOR group had higher median concentrations of Li, Na, and K in follicular fluid (all P values

Objective To establish a high-throughput screening system to obtain key Staphylococcus aureus (S.aureus) secretory proteins which required for S.aureus survival in macrophages. Methods Based on our validated eukaryotic expression vector library of S.aureus secretory proteins, DNA transfection was used to obtain an RAW264.7 macrophage array expressing S.aureus secretory proteins. After the RAW264.7 cells were infected with S.aureus, the extracellular bacteria were removed to observe the intracellular surviving situation of S.aureus. Finally, the screening results were validated by the overexpression and knockout S.aureus of corresponding secretory proteins. Results The optimal transfection dose (1.0 μg/well) of plasmids for RAW264.7, multiplicity of infection (MOI, 1.0), and infection time (4 h after removing extracellular bacteria of S.aureus) were established respectively. To validate the screening results, the corresponding overexpression and knockout strains were constructed. And hypothetical protein and Serine protease E were found to promote the survival of intracellular S.aureus. Conclusion We successfully construct a screening system for key secreted secretory proteins which required for S.aureus surviving in macrophages, which may advance the study of the intracellular surviving mechanism of S. aureus.

Abstract Background The effects of female chromosomal polymorphisms (FCPs) on various aspects of reproductive health have been investigated, yet the findings are frequently inconsistent. This study aims to clarify the role of FCPs on the outcomes of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods This retrospective cohort study comprised 951 couples with FCPs and 10,788 couples with normal karyotypes who underwent IVF/ICSI treatment at Peking University Third Hospital between 2015 and 2021. The exposure was FCPs. The embryological outcomes and clinical outcomes were compared. Results The FCPs, as a whole, compromised the oocyte maturation rate (76.0% vs. 78.8%, P = 0.008), while they did not adversely affect other IVF/ICSI outcomes. Further detailed analyses showed that every type of FCPs contributed to the lower oocyte maturation rate, particularly the rare FCPs (69.0% vs. 78.8%, P = 0.008). The female qh + was associated with a higher normal fertilization rate (63.0% vs. 59.2%, adjusted P = 0.022), a higher clinical pregnancy rate (37.0% vs. 30.7%, adjusted P = 0.048), and a higher live birth rate (27.0% vs.19.0%, adjusted P = 0.003) in couples undergoing IVF. Conversely, in couples undergoing ICSI, female qh + was found to be related to a lower normal fertilization rate (58.8% vs. 63.8%, P = 0.032), a comparable clinical pregnancy rate (25.7% vs. 30.9%, P = 0.289), and a comparable live birth rate (19.8% vs. 19.2%, P = 0.880) compared to the control group. Additionally, an increased risk of preterm birth was observed in women undergoing IVF with multiple polymorphisms (62.5% vs. 16.9%, adjusted P

Abstract Background Although papillary thyroid cancer (PTC) patients are known to have an excellent prognosis, up to 30% of patients experience disease recurrence after initial treatment. Accurately predicting disease prognosis remains a challenge given that the predictive value of several predictors remains controversial. Thus, we investigated whether machine learning (ML) approaches based on comprehensive predictors can predict the risk of structural recurrence for PTC patients. Methods A total of 2244 patients treated with thyroid surgery and radioiodine were included. Twenty-nine perioperative variables consisting of four dimensions (demographic characteristics and comorbidities, tumor-related variables, lymph node (LN)-related variables, and metabolic and inflammatory markers) were analyzed. We applied five ML algorithms—logistic regression (LR), support vector machine (SVM), extreme gradient boosting (XGBoost), random forest (RF), and neural network (NN)—to develop the models. The area under the receiver operating characteristic (AUC-ROC) curve, calibration curve, and variable importance were used to evaluate the models’ performance. Results During a median follow-up of 45.5 months, 179 patients (8.0%) experienced structural recurrence. The non-stimulated thyroglobulin, LN dissection, number of LNs dissected, lymph node metastasis ratio, N stage, comorbidity of hypertension, comorbidity of diabetes, body mass index, and low-density lipoprotein were used to develop the models. All models showed a greater AUC (AUC = 0.738 to 0.767) than did the ATA risk stratification (AUC = 0.620, DeLong test: P

Abstract Background Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. Methods Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. Results We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. Conclusions This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Objective To investigate the correlation between heart rate variability (HRV) and the degree of nervousness before blood donation. Methods The psychological state of 253 blood donors before blood donation was assessed by the self-rating anxiety scale (SAS) and the degree of nervousness and their HRV were measured. The correlation between the SAS score, the degree of nervousness and the HRV parameters was analyzed, and the differences were compared among different types of donors by multivariate linear regression. Results A total of 247 blood donors were included in the study. Five HRV parameters in blood donors aged 18-24 were higher than in those aged 25 years and above(all P

Abstract Kluyveromyces marxianus is a food‐safe yeast with great potential for producing heterologous proteins. Improving the yield in K. marxianus remains a challenge and incorporating large‐scale functional modules poses a technical obstacle in engineering. To address these issues, linear and circular yeast artificial chromosomes of K. marxianus (KmYACs) were constructed and loaded with disulfide bond formation modules from Pichia pastoris or K. marxianus. These modules contained up to seven genes with a maximum size of 15 kb. KmYACs carried telomeres either from K. marxianus or Tetrahymena. KmYACs were transferred successfully into K. marxianus and stably propagated without affecting the normal growth of the host, regardless of the type of telomeres and configurations of KmYACs. KmYACs increased the overall expression levels of disulfide bond formation genes and significantly enhanced the yield of various heterologous proteins. In high‐density fermentation, the use of KmYACs resulted in a glucoamylase yield of 16.8 g/l, the highest reported level to date in K. marxianus. Transcriptomic and metabolomic analysis of cells containing KmYACs suggested increased flavin adenine dinucleotide biosynthesis, enhanced flux entering the tricarboxylic acid cycle, and a preferred demand for lysine and arginine as features of cells overexpressing heterologous proteins. Consistently, supplementing lysine or arginine further improved the yield. Therefore, KmYAC provides a powerful platform for manipulating large modules with enormous potential for industrial applications and fundamental research. Transferring the disulfide bond formation module via YACs proves to be an efficient strategy for improving the yield of heterologous proteins, and this strategy may be applied to optimize other microbial cell factories.

Abstract Background For women diagnosed with HR-HPV DNA positivity in community hospitals, the necessity of investigating the potential presence of multiple HR-HPV infections upon referral to tertiary medical institutions remains unclear. Methods In our cohort, women tested positive for HR-HPV DNA during examinations in community hospitals, were subsequently referred to tertiary medical facilities, reevaluated HR-HPV genotype and categorized based on cytological and histopathological results. The risk of cytologic/histopathology abnormalities and ≧ high grade squamous intraepithelial lesion(HSIL) or Cervical Intraepithelial Neoplasia (CIN) 2 associated with individual genotypes and related multiple HPV infections are calculated. Results A total of 1677 women aged between 21 and 77 were finally included in the present study. The cytology group included 1202 women and the histopathological group included 475 women with at least one HR-HPV infection of any genotype. We only observed a higher risk of low grade cytological abnormalities in women with multiple infections than those in corresponding single infections (for all population with an OR of 1.85[1.39–2.46]; p

Abstract Many climate models simulate near-surface air temperatures that are too low in the Arctic compared to the observation-based ERA5 reanalysis data, a bias that was noted in the Inter-governmental Panel on Climate Change Sixth Assessment Report (IPCC AR6). Here we present a high-resolution, satellite-derived dataset of near-surface air temperatures for the Arctic sea-ice region (1982–2020). We use it as a benchmark to reevaluate climate reanalyses and model simulations in CMIP6 (Coupled Model Intercomparison Project 6). We find that the CMIP6 simulations in the central Arctic, with generally thicker ice and snow, align well with satellite observations, with an annual mean bias of less than ± 1 °C over sea ice. By contrast, climate reanalyses like ERA5 exhibit widespread warm biases exceeding 2 °C in the same region. We conclude that reliance on ERA5 reanalysis as a reference may have led to an underestimation of climate model reliability in the Arctic region.

Changes in leukocyte populations may confound the disease-associated miRNA signals in the blood of cancer patients. We aimed to develop a method to detect differentially expressed miRNAs from lung cancer whole blood samples that are not influenced by variations in leukocyte proportions. The Ref-miREO method identifies differential miRNAs unaffected by changes in leukocyte populations by comparing the within-sample relative expression orderings (REOs) of miRNAs from healthy leukocyte subtypes and those from lung cancer blood samples. Over 77% of the differential miRNAs observed between lung cancer and healthy blood samples overlapped with those between myeloid-derived and lymphoid-derived leukocytes, suggesting the potential impact of changes in leukocyte populations on miRNA profile. Ref-miREO identified 16 differential miRNAs that target 19 lung adenocarcinoma-related genes previously linked to leukocytes. These miRNAs showed enrichment in cancer-related pathways and demonstrated high potential as diagnostic biomarkers, with the LASSO regression models effectively distinguishing between healthy and lung cancer blood or serum samples (all AUC > 0.85). Additionally, 12 of these miRNAs exhibited significant prognostic correlations. The Ref-miREO method offers valuable candidates for circulating biomarker detection in cancer that are not affected by changes in leukocyte populations.

ABSTRACTObjectives: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress.Methods: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo.Results: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models.Discussion: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

Abstract We investigate the role of the subpolar North Atlantic (SPNA) for downstream predictability, using two decadal climate prediction systems. We use the subpolar extreme cold and fresh anomaly event developing in winter 2013/2014 as initial conditions and evaluate ensemble predictions of the two systems in the following decade. In addition, we perform ensemble pacemaker experiments where the models are forced toward observed ocean temperature and salinity anomalies in the SPNA from November 2014 through December 2019. The pacemaker experiments show improved skill along the Atlantic Water pathway, compared with the standard decadal predictions, and we therefore conclude that the correct description of the ocean in the SPNA is the key. The enhanced skill is most prominent in subsurface salinity in the form of propagating anomalies.

BackgroundThe demand for fertility-sparing surgery (FSS) is increasing among patients with early-stage cervical cancer (CC). This study aimed to evaluate the feasibility of local excision as an alternative to hysterectomy in stage I CC patients aged 15–39 years—commonly referred to as adolescents and young adults (AYAs)—with varying clinicopathological characteristics.MethodsUsing the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients diagnosed between 2000 and 2020. We examined treatment interventions across different age groups, degrees of histological types, tumor differentiation, and tumor stages. The effect of local excision vs. hysterectomy was assessed by comparing overall survival (OS) and disease-specific survival (DSS) rates.ResultsA total of 10,629 stage I AYA cervical cancer patients were included in this study. Among these patients, 24.5% underwent local excision for fertility preservation, while 67.3% underwent radical hysterectomy. For patients with cervical squamous cell carcinoma (SCC), long-term outcomes favored local excision over hysterectomy, and a similar trend was observed in those with adenosquamous cell carcinoma (ASCC). However, the prognosis was comparable among patients with cervical adenocarcinoma (AC). In patients with well- and moderate- differentiated tumors, local excision demonstrated superior OS compared to hysterectomy. No significant differences in prognosis were found between the two surgical interventions for patients with poorly differentiated and undifferentiated tumors. In stage IA patients, local excision was considered a viable alternative to hysterectomy. In stage IB1–IB2, FSS yielded prognostic outcomes comparable to those of hysterectomy. Conversely, patients with stage IB3 exhibited significantly shorter 5-year OS and DSS following local excision than those who underwent hysterectomy.ConclusionIn stage IA–IB2 (diameter ≤4 cm) AYA patients, local excision may serve as a viable option for fertility preservation. The histological type of SCC, AC, and ASCC, along with differentiation, should not serve as restrictive factors in determining fertility preservation strategies for these patients. Patients with early-stage, well- or moderately-differentiated SCC may benefit from local excision surgery, even when fertility preservation is not the primary objective.

Proton exchange membrane water electrolysis (PEMWE) plays a critical role in practical hydrogen production. Except for the electrode activities, the widespread deployment of PEMWE is severely obstructed by the poor electron-proton permeability across the catalyst layer (CL) and the inefficient transport structure. In this work, the PEDOT:F (Poly(3,4-ethylenedioxythiophene):perfluorosulfonic acid) ionomers with mixed proton-electron conductor (MPEC) were fabricated, which allows for a homogeneous anodic CL structure and the construction of a highly efficient triple-phase interface. The PEDOT:F exhibits strong perfluorosulfonic acid (PFSA) side chain extensibility, enabling the formation of large hydrophilic ion clusters that form proton-electron transport channels within the CL networks, thus contributing to the surface reactant water adsorption. The PEMWE device employing membrane electrode assembly (MEA) prepared by PEDOT:F-2 demonstrates a competitive voltage of 1.713 ​V under a water-splitting current of 2 ​A ​cm−2 (1.746 ​V at 2A cm−2 for MEA prepared by Nafion D520), along with exceptional long-term stability. Meanwhile, the MEA prepared by PEDOT:F-2 also exhibits lower ohmic resistance, which is reduced by 23.4 ​% and 17.6 ​% at 0.1 ​A ​cm−2 and 1.5 ​A ​cm−2, respectively, as compared to the MEA prepared by D520. The augmentation can be ascribed to the superior proton and electron conductivity inherent in PEDOT:F, coupled with its remarkable structural stability. This characteristic enables expeditious mass transfer during electrolytic reactions, thereby enhancing the performance of PEMWE devices.