Search

Abstract The pursuit of obtaining enzymes with high activity and stability remains a grail in enzyme evolution due to the stability-activity trade-off. Here, we develop an isothermal compressibility-assisted dynamic squeezing index perturbation engineering (iCASE) strategy to construct hierarchical modular networks for enzymes of varying complexity. Molecular mechanism analysis elucidates that the peak of adaptive evolution is reached through a structural response mechanism among variants. Furthermore, this dynamic response predictive model using structure-based supervised machine learning is established to predict enzyme function and fitness, demonstrating robust performance across different datasets and reliable prediction for epistasis. The universality of the iCASE strategy is validated by four sorts of enzymes with different structures and catalytic types. This machine learning-based iCASE strategy provides guidance for future research on the fitness evolution of enzymes.

Abstract Background Active cytomegalovirus (CMV) infection is associated with poor prognosis in septic patients with critical illness. Patients of septic category are highly likely to benefit from prophylactic antiviral therapy. Nevertheless, the clinical characteristics for CMV reactivation are lacking among septic patients requiring mechanical ventilation. The aim of this study was to investigate the incidence, risk factors, and clinical outcomes regarding active CMV infection in mechanically ventilated patients with sepsis. Methods A single-center, retrospective cohort study conducted from January 2021 to December 2023 that included septic patients on mechanical ventilation at the intensive care unit (ICU) of a national hospital. Study participants were divided into active and non-active CMV infection groups based on CMV DNAemia within a 28-day hospitalization period in ICU. Clinical features, laboratory findings, treatment measures, and clinical outcomes were compared between the two groups. Results Among 118 septic patients, 21 (17.8%) exhibited active CMV infection within 28-day ICU admission. Hemoglobin served as an independent risk factor and predictor for active CMV infection (P

Abstract Background Allergic rhinitis (AR) subjects might have their microenvironment changed due to pathogenesis and living environment. Whether the nasal microbe in AR children differs from healthy subjects and how it interplays with dermal, oral and indoor dust microbe needs to be elucidated. Methods In this case–control study, we analyzed and compared the bacterial characterization and associations in nasal, dermal, oral swab samples and dust samples in 62 children with physician-diagnosed AR(cases) and 51 age- and gender-matched healthy ones with no history of allergic diseases(controls). Full-length 16S rRNA sequencing(swabs) and shotgun metagenomics(dust) were applied. Bacterial diversity, composition, abundance difference characteristics and fast expectation–maximization for microbial source tracking(FEAST) analysis were performed and compared between cases and controls. Results The α-diversity of dust microorganisms in AR was lower than that in control group (P = 0.034), and the β-diversity indices of microorganisms in nasal cavity (P = 0.020), skin (P = 0.001) and dust (P = 0.004) were significantly different from those in control group. At species levels, a total of 10, 15, 12, and 15 bacterial species were differentially enriched in either cases or controls in nasal, dermal, oral, and dust samples, respectively(Linear Discriminant Analysis(LDA) score > 2, P

Abstract Background Heart failure with improved ejection fraction (HFimpEF) has been regarded as a new heart failure (HF) type in 2022. However, studies on the impact of left ventricular ejection fraction (LVEF) trajectories on the prognosis of patients with HFimpEF are scarce. In this study, we investigated dynamic trajectories of LVEF and different clinical outcomes in HFimpEF. Methods and results This was a multi-center study included patients diagnosed with HF with reduced ejection fraction (HFrEF) between January 1, 2015, and October 31, 2022. Enrolled patients were divided into HFimpEF and persistent HFrEF groups. To further investigate different LVEF trajectories in HFimpEF patients, they were classified into persistent HFimpEF and transient HFimpEF subgroups. Adverse clinical outcomes encompassed all-cause death, cardiovascular death, and HF-related rehospitalization. A total of 734 patients were included (HFimpEF: n = 162; persistent HFrEF: n = 572). Cox regression analysis revealed that compared with persistent HFrEF, patients with HFimpEF experienced a lower risk of all-cause and cardiovascular death. Subgroup analysis determined that only 113 (69.75%) patients maintained an LVEF exceeding 40%. Cox regression analysis revealed that persistent HFimpEF patients had a lower risk of all-cause and cardiovascular death compared to those with transient HFimpEF. Finally, multivariate logistic analysis showed that gender and high-density lipoprotein cholesterol levels were independent predictors of persistent HFimpEF. Conclusions HFimpEF does not accurately represent HF recovery, given that there are different trajectories of LVEF in HFimpEF. Patients with persistent HFimpEF experience better clinical outcomes, highlighting clinicians should identify clinical modifiable factors to maintain a stable HF stage for better prognosis. Trial registration ChiCTR2400086622, 08/07/2024.

Background and objective: Stress urinary incontinence (SUI) in women is a common condition that affects middle-aged and elderly women. Currently, there are still many limitations in the epidemiological research on SUI. This study aims to address the gap in the prevalence of female SUI in mainland China and provide theoretical support for the prevention and treatment of SUI. Methods: A comprehensive literature search was conducted on the prevalence of female SUI in mainland China, systematically searching Chinese and English databases including PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Weipu Database as of April 1, 2024. Detailed criteria for screening and exclusion were established. The prevalence of SUI in the selected studies was synthesized using Stata MP (version 15) software, and a multisubgroup analysis, a sensitivity analysis, and publication bias detection of the prevalence of SUI were also performed using the software. Additionally, ArcGIS software (version 10.8) and Geoda software (version 1.2) were utilized to explore the geographical distribution characteristics of the prevalence of female SUI in mainland China. Key findings and limitations: A total of 688 articles were screened, and finally 85 articles were included. The overall rate of female SUI in mainland China was 24.5% (95% confidence interval: 22.5–26.5%). The heterogeneity of the study is statistically significant (I2 = 99.0%, p

Abstract The various mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose a substantial challenge in mitigating the viral infectivity. The identification of novel host factors influencing SARS-CoV-2 replication holds potential for discovering new targets for broad-spectrum antiviral drugs that can combat future viral mutations. In this study, potential host factors regulated by SARS-CoV-2 infection were screened through different high-throughput sequencing techniques and further identified in cells. Subsequent analysis and experiments showed that the reduction of m6A modification level on ACTN4 (Alpha-actinin-4) mRNA leads to a decrease in mRNA stability and translation efficiency, ultimately inhibiting ACTN4 expression. In addition, ACTN4 was demonstrated to target nsp12 for binding and characterized as a competitor for SARS-CoV-2 RNA and the RNA-dependent RNA polymerase complex, thereby impeding viral replication. Furthermore, two ACTN4 agonists, YS-49 and demethyl-coclaurine, were found to dose-dependently inhibit SARS-CoV-2 infection in both Huh7 cells and K18-hACE2 transgenic mice. Collectively, this study unveils the pivotal role of ACTN4 in SARS-CoV-2 infection, offering novel insights into the intricate interplay between the virus and host cells, and reveals two potential candidates for future anti-SARS-CoV-2 drug development.

ObjectivesThis study aimed to investigate the relationship between albumin-corrected anion gap (ACAG) and lumbar spine bone mineral density (BMD) in a diverse population, assessing how variations in ACAG levels correlate with changes in lumbar spine BMD and the potential implications for osteoporosis risk.MethodsA cross-sectional analysis was conducted involving 3,057 participants (1,555 males and 1,502 females). Participants were stratified into quartiles based on baseline ACAG levels. Demographic and clinical characteristics were analyzed, including age, sex, education level, body mass index (BMI), and prevalence of diabetes and hypertension. The association between ACAG and lumbar spine BMD was evaluated using multiple regression models, and a generalized additive model was employed to identify potential nonlinear relationships.ResultsThe analysis revealed a significant negative correlation between ACAG and lumbar spine BMD (P < 0.001). For each 1-unit increase in ACAG, BMD decreased with β coefficients of −0.004 to −0.005 across various models. Quartile analysis indicated that participants in the highest ACAG quartile (≥19.55) experienced the most substantial reductions in BMD (β coefficients ranging from −0.034 to −0.036, P < 0.001). Furthermore, a U-shaped relationship was identified, with a turning point at an ACAG value of 22.15, indicating that lower ACAG levels were associated with decreased BMD, while higher levels showed a positive effect. Subgroup analyses by sex demonstrated consistent findings, with significant associations in both males and females.ConclusionThe findings underscore a significant association between elevated ACAG levels and reduced lumbar spine BMD, suggesting that ACAG may serve as a valuable biomarker for assessing osteoporosis risk. The identified nonlinear relationship further emphasizes the complexity of metabolic influences on bone health. These results warrant further investigation into the mechanisms underlying ACAG’s impact on bone density and its potential role in osteoporosis prevention strategies.

The treatment landscape of non-small cell lung cancer (NSCLC) has shifted significantly from empirical, histology-driven, and clinician-directed cytotoxic regimens to a stratified approach predicated on molecular profiling of tumor genetics and immune biomarkers, by the former can indicate targeted therapy that bull’s eye hits the arrow, while the latter can hint the benefit amplitude of immune checkpoint inhibitors (ICBs). While third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the cornerstone of frontline therapy for patients harboring classic sensitive EGFR mutations, all tumors ultimately develop acquired resistance to these approaches, which can be categorized into three primary mechanism subclasses. The first subclass involves the acquisition of target mutations that lead to changes in the kinase domain, thereby hindering drug binding. The second mechanism, known as bypass resistance, entails tumor clones utilizing alternative signaling pathways for proliferation. Lastly, the third acquired mechanism pertains to histological transformation, such as the emergence of small cell lung cancer (SCLC) clones. The transformation of pathological types has brought great confusion to the clinical diagnosis and treatment process. We report a case of advanced lung adenocarcinoma with EGFR-sensitive mutation that transformed into small cell lung cancer after EGFR-TKIs treatment. Subsequent treatment revealed the presence of both adenocarcinoma and small cell carcinoma through needle biopsies at various metastatic sites. Based on the pathological, the patient received combination therapy with anlotinib at different times and achieved a long survival time.

Osteoporosis results from a disruption in skeletal homeostasis caused by an imbalance between bone resorption and bone formation. Conventional treatments, such as pharmaceutical drugs and hormone replacement therapy, often yield suboptimal results and are frequently associated with side effects. Recently, biomaterial-based approaches have gained attention as promising alternatives for managing osteoporosis. This review summarizes the current advancements in 3D-printed biomaterials designed for osteoporosis treatment. The benefits of biomaterial-based approaches compared to traditional systemic drug therapies are discussed. These 3D-printed materials can be broadly categorized based on their functionalities, including promoting osteogenesis, reducing inflammation, exhibiting antioxidant properties, and inhibiting osteoclast activity. 3D printing has the advantages of speed, precision, personalization, etc. It is able to satisfy the requirements of irregular geometry, differentiated composition, and multilayered structure of articular osteochondral scaffolds with boundary layer structure. The limitations of existing biomaterials are critically analyzed and future directions for biomaterial-based therapies are considered.

China’s shale gas has undergone nearly 20 years of exploration; unconventional oil and gas geological evaluation theories and research methods have been greatly enriched, but how to quickly, conveniently, and accurately identify the sweet spots of shale gas is still puzzling many researchers. This study focuses on the black shale of the Wufeng–Longmaxi Formation in the southeastern edge of the Sichuan Basin; lithofacies classification, the relationship between lithofacies and depositional environments, and the correlation between lithofacies and shale gas–bearing capacity are discussed. At last, we have established the lithofacies classification criteria; the Wufeng–Longmaxi Formation deposited eight types of lithofacies, which the paleoenvironment during deposition evolved gradually from anaerobic environment to oxygen-poor and oxygen-rich environment. The black high-carbon and high-silicon shale lithofacies and the black carbon-rich and silicon-rich shale lithofacies are rich in organic matter, and they were deposited in high primary productivity, low terrigenous detritus input, and euxinic environment. The black medium-carbon medium-silica shale lithofacies and the black medium-carbon and high-silica shale lithofacies contain organic matter, which are deposited in medium primary productivity, middle terrigenous detritus input, and oxygen-poor and low hydrodynamic environment. The gray–black low-carbon low-silicon clay-rich shale lithofacies, the gray low-carbon and high-silicon shale lithofacies, and the gray–white low-carbon and silicon-rich shale lithofacies are poor in organic matter, which are deposited in a transitional environment of low primary productivity and oxygen poor–oxygen rich. In the analysis of the relationship between organic matter–rich black shale facies and sedimentary environment, it is shown that the enrichment of organic matter is positively correlated with the oxidation–reduction discrimination indicators Ni/Co, U/Th ratio of ancient oceans, and the evaluation indicators Babio and Ba/Al ratios of primary productivity. Only under the favorable sedimentary geochemical conditions and good preservation conditions can deposit lithofacies sections (zones). Based on the optimization of shale gas dessert section and the drilling of horizontal wells, the optimization of favorable black shale lithofacies types and the classification of shale gas dessert section are the key to shale gas exploration. The shale gas–bearing capacity is closely related to lithofacies. Black carbon-rich silicon-rich shale lithofacies and black high-carbon high-silicon shale lithofacies have the best gas-bearing capacity and are favorable lithofacies.

Background: The concept “one airway, one disease” for childhood rhinitis and asthma has been challenged in recent years. This study aimed to evaluate associations of environmental exposures with alone and co-morbid symptoms of rhinitis and asthma and identify critical risk factor. Methods: 5828 children aged 3–6 years in Shanghai were surveyed in 2019. Rhinitis and wheezing symptoms in the past 12 months were collected using questionnaire. 11 outdoor environment exposure factors were assessed by high-resolution spatial-temporal model based on residences. Logistic regression and random forest were applied to evaluate and rank the association of environmental exposure with rhinitis and wheezing symptoms. Results: The proportions of children with rhinitis alone, wheezing & rhinitis, and wheezing alone were 37.2 %, 4.6 %, and 2.6 %, respectively. Regression modeling of two exposure factors adjusted for each other showed that PM1, PM2.5 and nighttime light(NTL) remained the robust significant associations with rhinitis alone, whereas NO2 had the robust significant association with wheezing & rhinitis and wheezing alone. Random forest ranking analysis further corroborated the most significant environmental exposure for rhinitis alone was PM1, and for wheezing symptoms (both wheezing & rhinitis and wheezing alone) was NO2. Significant additive and multiplicative interactions were examined between indoor dampness and PM1 exposure on rhinitis alone. Conclusion: Children’s current rhinitis alone was more susceptible to ambient PM1 and PM2.5, while asthmatic wheezing symptom, either with or without rhinitis, was more susceptible to NO2. Co-exposure to indoor dampness and PM1 exposure had synergistic effects on rhinitis alone.

BackgroundDanshen [Salvia miltiorrhiza Bunge (Lamiaceae; Salviae miltiorrhizae radix et rhizoma)] class injections (DSCIs) are widely used in the treatment of coronary heart disease (CHD). However, there are various types of DSCIs available on the market, and it remains uncertain which DSCI has the best clinical efficacy, as well as which one is most effective in regulating inflammatory markers and oxidative stress indicators. The aim of this network meta-analysis (NMA) is to compare the therapeutic effects of different DSCIs to identify the optimal DSCI for the treatment of CHD.MethodsThe databases searched to identify randomized controlled trials (RCTs) of DSCIs for CHD included the China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), Chinese Biomedical Literature Database (CBM), PubMed, Web of Science, and Cochrane Library. The search period spanned from the inception of each database up to June 2024. NMA was conducted using RevMan 5.3 and Stata 16.0 software.ResultsA total of 106 studies including 14,979 patients, involving 10,931 patients, with 5,640 in the experimental group and 5,291 in the control group. And ten DSCIs were extracted, namely: Danhong injection (DH), Danshen injection (DS), Danshenchuanxiongqin injection (DSCXQ), Dansenduofensuanyan injection (DSDFSY), Danshenfen injection (DSFZ), Fufang Danshen injection (FFDS), Guanxinning injection (GXN), Sodium Tanshinone IIA Sulfonate injection (STS), Xiangdan injection (XD), Shenxiongputaotang injection (SXPTT). The results of NMA showed that, XD injection significantly enhances clinical efficacy; STS is more effective in reducing hs-CRP levels; DSDFSY shows better efficacy in decreasing IL-1 and increasing NO levels; DSCXQ has a greater advantage in reducing IL-6 levels; GXN is more effective in regulating SOD levels; and DH is better at reducing MDA levels.ConclusionThe combined treatment of DSCIs and WM more significant efficacy in patients with CHD compared to WM treatment alone, including clinical efficacy evaluation, inflammatory markers, and oxidative stress markers. Overall, DSDFSY and DSCXQ show better performance in clinical efficacy evaluation and regulation of inflammatory markers, while DH exhibits a more stable effect in regulating oxidative stress. However, larger sample sizes and high-quality RCTs are still necessary to further compare the various DSCIs.Systematic Review Registration[PROSPERO], identifier [CRD42024548928].

Summary: Background: Ovarian cancer has the highest mortality rate among gynaecological malignancies and is initially screened using ultrasound. Owing to the high complexity of ultrasound images of ovarian masses and the anatomical characteristics of the deep pelvic cavity, subjective assessment requires extensive experience and skill. Therefore, detecting the ovaries and ovarian masses and diagnose ovarian cancer are challenging. In the present study, we aimed to develop an automated deep learning framework, the Ovarian Multi-Task Attention Network (OvaMTA), for ovary and ovarian mass detection, segmentation, and classification, as well as further diagnosis of ovarian masses based on ultrasound screening. Methods: Between June 2020 and May 2022, the OvaMTA model was trained, validated and tested on a training and validation cohort including 6938 images and an internal testing cohort including 1584 images which were recruited from 21 hospitals involving women who underwent ultrasound examinations for ovarian masses. Subsequently, we recruited two external test cohorts from another two hospitals. We obtained 1896 images between February 2024 and April 2024 as image-based external test dataset, and further obtained 159 videos for the video-based external test dataset between April 2024 and May 2024. We developed an artificial intelligence (AI) system (termed OvaMTA) to diagnose ovarian masses using ultrasound screening. It includes two models: an entire image-based segmentation model, OvaMTA-Seg, for ovary detection and a diagnosis model, OvaMTA-Diagnosis, for predicting the pathological type of ovarian mass using image patches cropped by OvaMTA-Seg. The performance of the system was evaluated in one internal and two external validation cohorts, and compared with doctors’ assessments in real-world testing. We recruited eight physicians to assess the real-world data. The value of the system in assisting doctors with diagnosis was also evaluated. Findings: In terms of segmentation, OvaMTA-Seg achieved an average Dice score of 0.887 on the internal test set and 0.819 on the image-based external test set. OvaMTA-Seg also performed well in ovarian mass detection from test images, including healthy ovaries and masses (internal test area under the curve [AUC]: 0.970; external test AUC: 0.877). In terms of classification diagnosis prediction, OvaMTA-Diagnosis demonstrated high performance on image-based internal (AUC: 0.941) and external test sets (AUC: 0.941). In video-based external testing, OvaMTA recognised 159 videos with ovarian masses with AUC of 0.911, and is comparable to the performance of senior radiologists (ACC: 86.2 vs. 88.1, p = 0.50; SEN: 81.8 vs. 88.6, p = 0.16; SPE: 89.2 vs. 87.6, p = 0.68). There was a significant improvement in junior and intermediate radiologists who were assisted by AI compared to those who were not assisted by AI (ACC: 80.8 vs. 75.3, p = 0.00015; SEN: 79.5 vs. 74.6, p = 0.029; SPE: 81.7 vs. 75.8, p = 0.0032). General practitioners assisted by AI achieved an average performance of radiologists (ACC: 82.7 vs. 81.8, p = 0.80; SEN: 84.8 vs. 82.6, p = 0.72; SPE: 81.2 vs. 81.2, p > 0.99). Interpretation: The OvaMTA system based on ultrasound imaging is a simple and practical auxiliary tool for screening for ovarian cancer, with a diagnostic performance comparable to that of senior radiologists. This provides a potential tool for screening ovarian cancer. Funding: This work was supported by the National Natural Science Foundation of China (Grant Nos. 12090020, 82071929, and 12090025) and the R&D project of the Pazhou Lab (Huangpu) (Grant No. 2023K0605).

To visualize and quantify these exchanges among primary stakeholders in megaprojects, this study introduces network stakeholder value network as the core methodology. Starting with a qualitative organizational safety behavior model encompassing 8 stakeholders and 61 value flows, it's built based on 3 organizational safety behavior categories. Moreover, questionnaire data from 356 experts quantifies the model, and the design structure matrix identifies 13845 safety value paths, including 4827 cycles. Analysis delves into critical cycles, stakeholders, flows, and organizational safety behavior types to refine safety strategies. The findings, based on Chinese megaprojects, suggest that contractors and governments must lead safety awareness efforts, with safety compliance paramount for all parties. The study's contributions are threefold: firstly, it broadens the scope to encompass organizational safety behavior; secondly, it introduces a novel approach to visualize and quantify safety value flows; and thirdly, it considers multiple types of value exchanges, underscores their significance in promoting safety value, and offers practical recommendations to strengthen construction safety performance.

Abstract Purpose To develop and validate a nomogram based on 3D-PDU parameters and clinical characteristics to predict LNM and LVSI in early-stage cervical cancer preoperatively. Materials and methods A total of first diagnosis 138 patients with cervical cancer who had undergone 3D-PDU examination before radical hysterectomy plus lymph dissection between 2014 and 2019 were enrolled for this study. Multivariate logistic regression analyses were performed to analyze the 3D-PDU parameters and selected clinicopathologic features and develop a nomogram to predict the probability of LNM and LVSI in the early stage. ROC curve was used to evaluate model differentiation, calibration curve and Hosmer-Lemeshow test were used to evaluate calibration, and DCA was used to evaluate clinical practicability. Results Menopause status, FIGO stage and VI were independent predictors of LNM. BMI and maximum tumor diameter were independent predictors of LVSI. The predicted AUC of the LNM and LSVI models were 0.845 (95%CI,0.765–0.926) and 0.714 (95%CI,0.615–0.813). Calibration curve and H-L test (LNM groups P = 0.478; LVSI P = 0.783) all showed that the predicted value of the model had a good fit with the actual observed value, and DCA indicated that the model had a good clinical net benefit. Conclusion The proposed nomogram based on 3D-PDU parameters and clinical characteristics has been proposed to predict LNM and LVSI with high accuracy, demonstrating for the first time the potential of non-invasive prediction. The probability derived from this nomogram may have the potential to provide valuable guidance for physicians to develop clinical individualized treatment plans of FIGO patients with early cervical cancer.

Backgrounds: The functional recovery after peripheral nerve injury remains unsatisfactory. This study aims to perform a comprehensive evaluation of the efficacy of Fasudil Hydrochloride at treating the sciatic nerve transection injury in rats and the mechanism involved. Materials and methods: In animal experiments, 75 Sprague Dawley rats that underwent transection and repair of the right sciatic nerve were divided into a control, Fasudil, and Fas + LY group, receiving daily intraperitoneal injection of saline, Fasudil Hydrochloride (10 mg/kg), and Fasudil Hydrochloride plus LY294002 (5 mg/kg), respectively. At day 3 after surgery, the expression of ROCK2, p-PI3K, and p-AKT in L4-5 DRG and the lumbosacral enlargement was determined using Western blotting. At day 7 and 14, axon density in the distal stump was evaluated with immunostaining using the anti-Neurofilament-200 antibody. At day 30, retrograde tracing by injecting Fluoro-gold in the distal stump was performed. Three months after surgery, remyelination was analyzed with immostaining using the anti-MPZ antibody and the transmission electron microscope; Moreover, Motion-Evoked Potential, and recovery of sensorimotor functions was evaluated with a neuromonitor, Footprint, Hot Plate and Von Frey Filaments, respectively. Moveover, the Gastrocnemius muscles were weighed, and then underwent H＆E staining, and staining of the neuromuscular junction using α-Bungarotoxin to evaluate the extent of atrophy and degeneration of the endplates in the Gastrocnemius. In vitro, spinal motor neurons (SMNs) and dorsal root ganglia (DRG) were cultured to examine the impact of Fasudil Hydrochloride and LY294002 on the axon outgrowth. Results: Three days after injury, the expression of ROCK2 increased significantly (P＜0.01), and Fasudil application significantly increased the expression of p-PI3K and p-AKT in L4-6 DRG and the lumbosacral enlargement (P

Since the approval of gemtuzumab ozogamicin, an antibody–drug conjugate (ADC) targeting CD33 in 2000, 13 ADC drugs have been approved by the FDA. Although these drugs have clearly improved the survival of patients with various types of advanced cancers, their significant toxicity has compromised their therapeutic benefits. The adverse reactions of ADC drugs are complex and include on-target and off-target toxicities, where the payload drug is a determining factor. Antibody and linker may also affect the degree of toxicity. Combination therapy becomes an important strategy in anticancer treatment because of its increased efficiency, but treatment-related adverse reactions also increase accordingly. This review comprehensively analyzes the toxicity mechanisms of current ADC drugs and proposes various optimization strategies, including but not limited to optimizing linker molecules, upgrading antibody design, and changing drug administration strategies, to improve the overall safety profile of ADC drugs.

Abstract Purpose This study aimed to investigate clinical diagnostic values of mSEPT9 combined with NLR, PLR and LMR in CRC. Methods 329 subjects composed of 120 CRC patients, 105 polyps patients and 104 healthy participants were prospectively recruited. Clinicopathologic features were collected and analyzed. Plasma samples were collected for mSEPT9, NLR, PLR and LMR test. The sensitivity, specificity and AUC of each biomarker separately or in combination were estimated by the ROC curve. Results The levels of NLR, PLR and the PDR of mSEPT9 in CRC patients were significantly higher than those in non-CRC subjects, while LMR was the opposite. The PDR of mSEPT9 in CRC patients was significantly correlated with age, tumor size, tumor stage and M stage. ROC curve analysis demonstrated moderate diagnostic values of mSEPT9, NLR, PLR and LMR in CRC patients with AUC of 0.78 (Se = 0.68, and Sp = 0.89), 0.78 (Se = 0.68, and Sp = 0.83), 0.80 (Se = 0.68, and Sp = 0.81), and 0.77 (Se = 0.72, and Sp = 0.73), respectively. Moreover, combination of these four biomarkers dramatically enhanced the diagnostic accuracy of CRC (AUC = 0.92, Se = 0.90, and Sp = 0.87), especially for CRC patients with large tumors (AUC = 0.95) or distal metastasis (AUC = 0.95). Conclusion mSEPT9, NLR, PLR and LMR showed the potential to be reliable biomarkers for the diagnosis of CRC. And the combined application of these biomarkers further improved the diagnostic accuracy of CRC significantly.

Abstract Background In China, the national cervical cancer screening protocol involves initial testing for high-risk human papillomavirus (hrHPV), followed by cytology for hrHPV-positive cases. This study evaluates the effectiveness of PAX1 methylation (PAX1 m ) analysis in identifying precancerous or cancerous lesions in cervical samples from Chinese women positive for non-16/18 hrHPV strains. Methods Between February 2022 and March 2023, 281 cervical samples from non-16/18 hrHPV-positive women underwent cytological examination and PAX1 m analysis. The study assessed the statistical relationship between PAX1 m levels and the presence of cervical lesions, comparing the diagnostic performance of PAX1 m to conventional cytology. Results A significant association was found between PAX1 methylation levels and the risk of CIN2 + and CIN3 + lesions, with 47 instances of CIN2 + detected. Odds ratios (ORs) for moderate and high PAX1 m levels were 8.86 (95% CI: 2.24–42.17) and 166.32 (95% CI: 47.09-784.97), respectively. The area under the ROC curve for PAX1 m in identifying CIN2 + lesions was 0.948 (95% CI: 0.895–0.99). PAX1 m demonstrated similar sensitivity and negative predictive value (NPV) to cytology but reduced the colposcopy referral rate from 47.7% with cytology alone to 25.6% with PAX1 m , showing superior specificity and positive predictive value across age groups. Conclusions PAX1 methylation is a strong indicator of CIN2 + and CIN3 + risk, offering diagnostic performance comparable to cytology with the added benefit of reduced unnecessary colposcopy referrals. These findings support the use of PAX1 m analysis as a reliable tool for triaging non-16/18 hrHPV-positive women in outpatient settings.

Abstract Mycobacterium tuberculosis (Mtb) employs multiple mechanisms, such as phagocytosis and autophagy, to evade innate immune clearance and establish infection. In the present study, we identified the ESX-1 secretion-associated protein EspL, which promotes Mtb survival by inhibiting phagosome maturation and autophagy initiation. EspL knockout decreased Mtb intracellular survival, while EspL overexpression increased bacterial survival by interfering with phagocytosis and autophagy. EspL interacts with ULK1 and promotes its phosphorylation at Ser757, leading to the inhibition of autophagy initiation. Additionally, overexpression of EspL reduced antigen presentation and T-cell responses both in vitro and in vivo. Our findings revealed that EspL interferes with autophagy and antigen presentation by suppressing ULK1 activation. These insights provide a novel understanding of Mtb pathogenicity.

Background: Previous studies found that urinary phthalates (PAEs) metabolites may be associated with increased serum uric acid concentration and hyperuricemia risk. However, no population-based study has investigated the underlying biological mechanisms. Methods: This nationwide cross-sectional study analyzed the data from the National Health and Nutrition Examination Survey (NHANES) 2003–2018. Urinary PAEs metabolites were measured and 8 PAEs metabolites (MCPP, MECPP, MEHHP, MEOHP, MBzP, MiBP, MBP, and MEP) were incorporated into the analysis. Serum uric acid was determined and hyperuricemia cases were identified. Multi-variable generalized linear model, exposure-response (E-R) function and weighted quantile sum (WQS) regression were utilized to investigate the relationships of PAEs metabolites with serum uric acid concentration and hyperuricemia risk. Systemic immune inflammation (SII) was assessed using the SII index and its mediation effects were explored using causal mediation effect model. Results: Data from 10,633 US adults in the NHANES 2003–2018 was analyzed. Except for MEP, individual PAEs metabolite and total PAEs metabolites were associated with increased serum uric acid concentration and hyperuricemia risk. E-R function of PAEs metabolites with serum uric acid concentration and the risk of hyperuricemia showed significantly positive associations with most curves in a nearly linear relationship. WQS regression showed that the mixture of PAEs metabolites was related to elevated serum uric acid and hyperuricemia risk, and MBzP was identified as the most contributing PAEs metabolite. The causal mediation effect model found that SII significantly mediated the relationships of PAEs metabolites with serum uric acid and hyperuricemia risk. Conclusion: Individual and mixture of urinary PAEs metabolites were associated with increased serum uric acid concentration and the risk of hyperuricemia. MBzP exhibited the highest contribution to the overall effects. SII alteration may be an important biological mechanism underlining the impact of PAEs metabolites on serum uric acid concentration and hyperuricemia risk.

Puncture biopsy is an important clinical technique to obtain diseased tissue for pathological diagnosis, where imaging guidance is critical. In this paper, we describe a metal reflector-enhanced microwave-induced thermoacoustic imaging (TAI) approach capable of guiding puncture biopsy for detection of breast cancer and joint diseases. Numerical experimentations simulating puncture guidance in breast cancer and knee gout models were first conducted using (CST STUDIO SUITE) (CST) software, and then ex-vivo experiments were performed followed by qualitative observations and semi-quantitative analysis. The results of both the simulations and ex-vivo experiments showed that our reflector-enhanced TAI could image the puncture needle in high resolution with a large depth of [Formula: see text][Formula: see text]cm.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and lethal disease. Gasdermins are primarily associated with necrosis via membrane permeabilization and pyroptosis, a lytic pro‐inflammatory type of cell death. In this study, GSDMC upregulation during PDAC progression is reported. GSDMC directly induces genes related to stemness, EMT, and immune evasion. Targeting Gsdmc in murine PDAC models reprograms the immunosuppressive tumor microenvironment, rescuing the recruitment of anti‐tumor immune cells through CXCL9. This not only results in diminished tumor initiation, growth and metastasis, but also enhances the response to KRASG12D inhibition and PD‐1 checkpoint blockade, respectively. Mechanistically, it is discovered that ADAM17 cleaves GSDMC, releasing nuclear fragments binding to promoter regions of stemness, metastasis, and immune evasion‐related genes. Pharmacological inhibition of GSDMC cleavage or prevention of its nuclear translocation is equally effective in suppressing GSDMC's downstream targets and inhibiting PDAC progression. The findings establish GSDMC as a potential therapeutic target for enhancing treatment response in this deadly disease.

Abstract With the rapid emergence of antibiotic‐resistant pathogens, nanomaterial‐assisted catalytic sterilization has been well developed to combat pathogenic bacteria by elevating the level of reactive oxygen species including hydroxyl radical (·OH). Although promising, the ultra‐short lifetime and limited diffusion distance of ·OH severely limit their practical antibacterial usage. Herein, the rational design and preparation of novel virus‐like copper silicate hollow spheres (CSHSs) are reported, as well as their applications as robust artificial bacteriophages for localized bacterial capture and enhanced catalytic sterilization in the treatment of oral infectious diseases. During the whole process of capture and killing, CSHSs can efficiently capture bacteria via shortening the distance between bacteria and CSHSs, produce massive ·OH around bacteria, and further iinducing the admirable effect of bacterial inhibition. By using mucosal infection and periodontitis as typical oral infectious diseases, it is easily found that the bacterial populations around lesions in animals after antibacterial treatment fall sharply, as well as the well‐developed nanosystem can decrease the inflammatory reaction and promote the hard or soft tissue repair. Together, the high Fenton‐like catalytic activity, strong bacterial affinity, excellent antibacterial activity, and overall safety of the nanoplatform promise its great therapeutic potential for further catalytic bacterial disinfection.

Objectives: Neuregulin 1 (NRG1) is a risk gene for schizophrenia and involved in neurodevelopment and synaptic plasticity. Polymorphisms in NRG1 may affect psychotic symptoms in schizophrenia. This study investigated the effects of the single nucleotide polymorphism (SNP) rs6982890 on peripheral plasma NRG1 immunoreactivity, clinical symptoms and cognitive functions in schizophrenia patients. Material and methods: We recruited subjects from the Han population of northern China from 2010 to 2022. We first genotyped and analyzed 6 NRG1 SNPS in 1304 patients with schizophrenia and 871 healthy controls. Then, 91 patients with schizophrenia and 40 healthy controls were selected to detect the peripheral plasma NRG1 immunoreactivity by ELISA. Among them, 84 patients were divided into rs6982890 genotypes to analyze the correlation between NRG1 immunoreactivity and clinical symptoms. Results: Rs6982890 allelic frequencies were statistically significant between patients and controls. Baseline peripheral plasma NRG1 immunoreactivity in patients were significantly lower than controls. NRG1 immunoreactivity in patients were significantly increased after 8 weeks of antipsychotic treatment and significantly correlated with clinical symptoms and cognitive function. Genotyping of patients with SNP rs6982890 indicated NRG1 immunoreactivity in CC genotype increased significantly after treatment, while CT genotype had no significant change. Baseline NRG1 immunoreactivity with the CT genotype were significantly higher than CC genotype. Conclusions: NRG1 SNP rs6982890 is significantly associated with schizophrenia in the Han population of northern China, and it may affect the effect of antipsychotic drug treatment by regulating the peripheral plasma NRG1 immunoreactivity.

CRISPR technology has revolutionized fungal genetic engineering by accelerating the pace and expanding the feasible scope of experiments in this field. Among various CRISPR-Cas systems, Cas9 and Cas12a are widely used in genetic and metabolic engineering. In filamentous fungi, both Cas9 and Cas12a have been utilized as CRISPR nucleases. In this work we first compared efficacies and types of genetic edits for CRISPR-Cas9 and -Cas12a systems at the polyketide synthase (albA) gene locus in Aspergillus niger. By employing a tRNA-based gRNA polycistronic cassette, both Cas9 and Cas12a have demonstrated equally remarkable editing efficacy. Cas12a showed potential superiority over Cas9 protein when one gRNA was used for targeting, achieving an editing efficiency of 86.5% compared to 31.7% for Cas9. Moreover, when employing two gRNAs for targeting, both systems achieved up to 100% editing efficiency for single gene editing. In addition, the CRISPR-Cas9 system has been reported to induce large genomic deletions in various species. However, its use for engineering large chromosomal segments deletions in filamentous fungi still requires optimization. Here, we engineered Cas9 and -Cas12a-induced large genomic fragment deletions by targeting various genomic regions of A. niger ranging from 3.5 kb to 40 kb. Our findings demonstrate that targeted engineering of large chromosomal segments can be achieved, with deletions of up to 69.1% efficiency. Furthermore, by targeting a secondary metabolite gene cluster, we show that fragments over 100 kb can be efficiently and specifically deleted using the CRISPR-Cas9 or -Cas12a system. Overall, in this paper, we present an efficient multi-gRNA genome editing system utilizing Cas9 or Cas12a that enables highly efficient targeted editing of genes and large chromosomal regions in A. niger.

Purpose To predict bone marrow metastasis in neuroblastoma using contrast-enhanced computed tomography (CECT) radiomics features and explainable machine learning. Methods This cohort study retrospectively included a total of 345 neuroblastoma patients who underwent testing for bone marrow metastatic status. Tumor lesions on CECT images were delineated by two radiologists, and 1409 radiomics features were extracted. Correlation analysis, Least Absolute Shrinkage and Selection Operator regression, and one-way analysis of variance were used to identify radiomics features associated with bone marrow metastasis. A predictive model for bone marrow metastasis was then developed using the support vector machine algorithm based on the selected radiomics features. The performance of the radiomics model was evaluated using the area under the curve (AUC), 95% confidence interval (CI), accuracy, sensitivity, and specificity. Results The radiomics model included 16 features, with a predominant focus on texture features (12/16, 75%). In the training set, the model demonstrated an AUC of 0.891 (95% CI: 0.848-0.933), an accuracy of 0.831 (95% CI: 0.829-0.832), a sensitivity of 0.893 (95% CI: 0.840-0.946), and a specificity of 0.757 (95% CI: 0.677-0.837). In the test set, the AUC, accuracy, sensitivity, and specificity were 0.807 (95% CI: 0.720-0.893), 0.767 (95% CI: 0.764-0.770), 0.696 (95% CI: 0.576-0.817), and 0.851 (95% CI: 0.749-0.953), respectively. Conclusion Radiomics features extracted from CECT images are associated with the presence of bone marrow metastasis in neuroblastoma, providing potential new imaging biomarkers for predicting bone marrow metastasis in this disease.

Zein is widely used in loading and delivery of food functional components due to its unique self-assembly properties. However, due to the strong hydrophobicity, the interface stability of the pure Zein-based Pickering emulsion is difficult to meet the needs of practical applications, and the construction of a composite system with appropriate polysaccharides is an effective strategy to improve the stability of its emulsion. On account of this, composite particles (NZPs) using Zein and Nicandra physaloides gum (NPG) with different protein-polysaccharide compounding ratios were prepared in this work by complex coacervation method. The physicochemical properties, structure and emulsion properties of NZPs were characterized. The results showed that the surface wettability of NZPs increased with the increasing addition of NPG, and meanwhile the formed composite particles became smaller with better dispersity, caused by the specific electrostatic force between protein and polysaccharide. The endogenous fluorescence spectrum of NZPs showed that the peak intensity of the corresponding characteristic peaks was proportional to the content of Zein and NPG, respectively, and the introduction of NPG affected the microenvironment polarity of tyrosine residues in Zein molecules. The shift of the absorption peak in Fourier transform infrared spectroscopy (FT-IR) indicated the enhanced hydrogen bond interaction and the generation of new peaks indicated the formation of new chemical bonds in NZPs. The storage modulus (G') of NZPs-based Pickering emulsions was higher than the loss modulus (G"). When the compounding ratio was 1:1 (Zein:NPG), both G' and G" of emulsions reached the maximum, obtaining the optimum emulsion system structure. The creaming index (CI) results showed that the stability of NZPs-based Pickering emulsions was generally higher than that of the pure Zein or NPG emulsions under different pH and heating treatments. This study provides a theoretical reference for the development of new Zein-polysaccharide composite system and its highly efficient and stable Pickering emulsions.

Objective This study aimed to investigate the effects of dietary supplementation of a fatty acid-balanced oil, instead of soybean oil, on reproductive performance, nutrient digestibility, blood indexes, milk composition in lactating sows, and fecal microbial composition in piglets. Methods Twenty-four sows (Landrace×Yorkshire, mean parity 4.96) were randomly allotted to two treatments with twelve pens per treatment and one sow per pen based on their backfat thickness and parity. The experiment began on day 107 of gestation and continued until weaning on day 21 of lactation, lasting for 28 days. The control group (CG) was fed a basal diet supplemented with 2% soybean oil and the experimental group (EG) was fed the basal diet supplemented with 2% fatty acid-balanced oil. Results The fatty acid-balanced oil supplementation increased (p

Corn straw-based board has great potential for the protection of forest resources, waste recycling, and sustainable economic development. However, corn stalk-based board has poor mechanical properties due to its short fiber length and poor water resistance because of the presence of numerous hydrophilic hydroxyl functional groups in its structure. Natural mycelium originating from waste Pleurotus ostreatus substrate is a hydrophobic bio-adhesive. In the present study, formaldehyde-free corn stalk/P. ostreatus substrate bio-composites were prepared using the hot-pressing technique without the addition of any chemical adhesive. The mechanical properties and water resistance of the prepared bio-composites were excellent. The highest internal bonding strength (IBS) of 2.16 MPa and the minimum thickness swelling (TS) of 18.3% were observed, which are beyond the national standards for particleboard in China. These bio-composites were prepared using a simple, green, and convenient manufacturing method to promote their popularization and application. The method may, therefore, be used as a novel technical measure to resolve the problem of overuse of forestry resources and waste disposal.

Abstract Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

Immune checkpoint inhibitors (ICIs) are monoclonal antibody antagonists, which can block cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1/ligand-1 (PD-1/PD-L1) pathways, and other molecules exploited by tumor cells to evade T cell-mediated immune response. ICIs have transformed the treatment landscape for various cancers due to their amazing efficacy. Many anti-tumor therapies, including targeted therapy, radiotherapy, and chemotherapy, combine ICIs to make the treatment more effective. However, the off-target immune activation caused by ICIs may lead to a broad spectrum of immune-related adverse events (irAEs) affecting multiple organ systems. Among irAEs, cardiotoxicity induced by ICIs, uncommon but fatal, has greatly offset survival benefits from ICIs, which is heartbreaking for both patients and clinicians. Consequently, such cardiotoxicity requires special vigilance, and it has become a common challenge both for patients and clinicians. This article reviewed the clinical manifestations and influence of cardiotoxicity from the view of patients and clinicians, elaborated on the underlying mechanisms in conjunction with animal studies, and then attempted to propose management strategies from a cardio-immuno-oncology multidisciplinary perspective.

The application of light-responsive nanomaterials (LRNs) in bone tissue engineering shows broad prospects, especially in promoting bone healing and regeneration. With a deeper understanding of the mechanisms of bone defects and healing disorders, LRNs are receiving increasing attention due to their non-invasive, controllable, and efficient properties. These materials can regulate cellular biological reactions and promote bone cell adhesion, proliferation, and differentiation by absorbing specific wavelengths of light and converting them into physical and chemical signals. In addition, the unique surface morphology and biocompatibility of LRNs enable them to effectively load drugs in bone tissue engineering, achieve precise release, and optimize the bone regeneration process. Through photothermal and photodynamic therapy, these materials also possess antibacterial properties and can play an important role in the repair of infectious bone defects. Although LRNs have shown significant advantages in bone tissue regeneration, a series of challenges still need to be overcome to achieve their widespread and effective clinical applications. This article summarizes the basic principles, classification, and potential applications of LRNs in bone tissue regeneration, aiming to provide reference for future research and clinical applications.

The aim of this study was to investigate the combination effects of α-glycerol monolaurate (GML) and glyceryl tributyrate (TB) on growth performance, nutrient digestibility, gut microbiota, and immune function in weaned piglets. A total of 120 weaned piglets with an average body weight (BW) of 6.88 kg were randomly allocated to one of the three dietary treatments: (1) CON: a basal diet; (2) 0.1%: a basal diet with 0.1% MSCFA (GML/TB = 1:1); (3) 0.2%: a basal diet with 0.2% MSCFA (GML/TB = 1:1). The experiment lasted 28 days. There were no differences on average daily growth (ADG), average daily feed intake (ADFI), and feed conversion ratio (FCR). Supplementation with 0.1% MSCFA increased apparent total tract digestibility (ATTD) of crude protein (CP) and gross energy (GE, p < 0.05) on d 14 and increased GE (p < 0.05) on d 28 compared with the CON group. The ATTD of dry matter (DM), organic matter (OM) and crude protein (CP) of piglets supplemented with 0.1% MSCFA was higher (p < 0.05). Compared with the CON group, supplementation with 0.1% MSCFA increased immunoglobulin M (IgM) concentration, decreased interleukin-6 (IL-6) content (p < 0.05) on d 14 and decreased malonaldehyde (MDA), interleukin-1beta (IL-1β), IL-6 concentrations (p < 0.05) on d 28. Supplementation with 0.1% MSCFA increased total antioxidant capacity (T-AOC) concentration (p < 0.05), decreased GSH-Px, MDA content (p < 0.05) in jejunum compared with the CON group. Moreover, supplementation with MSCFA increased the activity of duodenal lipase (p < 0.05) and the abundance of firmicutes and decreased the abundance of proteobacteria compared with the CON group. Overall, supplementation with MSCFA can improve nutrient digestibility, enhance immunity and antioxidant capacity, and improve the intestinal health of piglets. The combined use of MSCFA is a nutrition regulation strategy worthy of further exploration in modern animal husbandry.

Over the last decade, epidermal growth factor receptor (EGFR)-targeted therapies have transformed the treatment landscape for patients with advanced solid tumors. Despite these advances, resistance to anti-EGFR therapies is still a significant clinical challenge. While cell-autonomous mechanisms of resistance are well-documented, they do not fully elucidate the complexity of drug resistance. Cancer-associated fibroblasts (CAFs), key mediators within the tumor microenvironment (TME), have emerged as pivotal players in cancer progression and chemoresistance. Recent evidence implicates CAFs in resistance to anti-EGFR therapies, suggesting they may undermine treatment efficacy. This review synthesizes current data, highlighting the critical role of CAFs in resistance pathogenesis and summarizing recent therapeutic strategies targeting CAFs. We underscore the challenges and advocate for the exploration of CAFs as a potential dual-targeted approach.

Accurately predicting freeway accident severity is crucial for accident prevention, road safety, and emergency rescue services in intelligent freeway systems. However, current research lacks the required precision, hindering the effective implementation of freeway rescue. In this paper, we efficiently address this challenge by categorizing influencing factors into two levels: human and non-human, further subdivided into 6 and 36 categories, respectively. Furthermore, based on the above factors, an efficient and accurate Freeway Accident Severity Prediction (FASP) method is developed by using the two-level fuzzy comprehensive evaluation. The factor and evaluation sets are determined by calculating the fuzzy evaluation matrix of a single factor. The weight matrix is calculated through the entropy method to compute the final evaluation matrix. Based on the maximum membership principle, the severity of the freeway accident is predicted. Finally, based on the experiments conducted with the traffic accident datasets in China and the US, it is shown that FASP is able to accurately predict the severity of freeway traffic accidents with thorough considerations and low computational cost. It is noted that FASP is the first attempt to achieve freeway accident severity prediction using the two-level fuzzy comprehensive evaluation method to the best of our knowledge.

BackgroundClear cell renal cell carcinoma (ccRCC) is a metabolic disorder characterized by abnormal lipid accumulation in the cytoplasm. Lipid metabolism-related genes may have important clinical significance for prognosis prediction and individualized treatment.MethodsWe collected bulk and single-cell transcriptomic data of ccRCC and normal samples to identify key lipid metabolism-related prognostic signatures. qPCR was used to confirm the expression of signatures in cancer cell lines. Based on the identified signatures, we developed a lipid metabolism risk score (LMRS) as a risk index. We explored the potential application value of prognostic signatures and LMRS in precise treatment from multiple perspectives.ResultsThrough comprehensive analysis, we identified five lipid metabolism-related prognostic signatures (ACADM, ACAT1, ECHS1, HPGD, DGKZ). We developed a risk index LMRS, which was significantly associated with poor prognosis in patients. There was a significant correlation between LMRS and the infiltration levels of multiple immune cells. Patients with high LMRS may be more likely to respond to immunotherapy. The different LMRS groups were suitable for different anticancer drug treatment regimens.ConclusionPrognostic signatures and LMRS we developed may be applied to the risk assessment of ccRCC patients, which may have potential guiding significance in the diagnosis and precise treatment of ccRCC patients.

Abstract Background The combination of dual‐targeted human epidermal growth factor receptor 2 (HER2) therapy and chemotherapy is the standard first‐line regimen for recurrent/metastatic breast cancer (mBC). However, the toxicity of such combination therapy can lead to some patients being unable to tolerate adverse events or bear treatment costs. As a novel irreversible pan‐ErbB receptor TKI (pyrotinib), can the dual oral administration of pyrotinib plus capetabine (PyroC) provide first‐line survival benefits and serve as a more affordable treatment option? Methods This real‐world retrospective study included patients diagnosed with HER2‐positive mBC who received PyroC as a first‐line treatment at West China Hospital between May 2018 and July 2023. The survival data and toxicity profiles were reported in this study. Results A total of 64 patients received PyroC as first‐line therapy. The median progression‐free survival (PFS) was 19.6 months (95% CI 15.0–27.2), while overall survival (OS) has not yet been reached. Kaplan–Meier analysis indicated that age (≥60, p = 0.03) and metastasis sites (p = 0.004) were related to poor efficacy of PyroC, while there was no relationship between effectiveness and menstrual status, hormone receptor (HR) status or previous treatment with anti‐HER2 therapy. Furthermore, the objective response rate (ORR) and disease control rate (DCR) were 79.7% and 98.4%, respectively. Of the patients, 78.1% reported treatment‐related adverse events (TRAEs). The predominant adverse events were diarrhea (n = 46, 71.9%) and hand‐foot syndrome (n = 10, 15.6%). Conclusion The dual oral administration regimen (PyroC) has a promising ORR or PFS in HER2‐positive mBC patients, with an acceptable safety profile and convenience.

Abstract While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0–3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R2 = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p

As one of the main active ingredients of garlic, garlic polysaccharide has many biological activities, such as enhancing immunity, antibacterial, antiviral, antioxidant, hepatoprotective, hypolipidemic, hypoglycemic, etc., and has a broad application prospect. The extraction methods of garlic polysaccharides are most common by hot water method, enzyme method and ultrasound-assisted method. It is found by structural determination that garlic polysaccharide is a heteropolysaccharide composed of fructose, glucose, galactose, mannose, galacturonic acid, etc. Chemical modifications such as acetylation, selenization and phosphorylation can increase the antioxidant and other biological activities of garlic polysaccharide. This paper systematically summarizes the current research status of garlic polysaccharides from the perspectives of extraction, structure determination, chemical modification and bioactivity of garlic polysaccharides, and in the future, attention should be paid to the conformational relationship between polysaccharide structure and bioactivity, and the efficacy mechanism of garlic polysaccharides should be explored in depth, with a view to providing theoretical references for the development and utilization of garlic polysaccharides as functional products.

Abstract Early diagnosis and pharmacological treatment of central nervous system (CNS) diseases has been a long-standing challenge for clinical research due to the presence of the blood–brain barrier. Specific proteins and RNAs in brain-derived extracellular vesicles (EVs) usually reflect the corresponding state of brain disease, and therefore, EVs can be used as diagnostic biomarkers for CNS diseases. In addition, EVs can be engineered and fused to target cells for delivery of cargo, demonstrating the great potential of EVs as a nanocarrier platform. We review the progress of EVs as markers and drug carriers in the diagnosis and treatment of neurological diseases. The main areas include visual imaging, biomarker diagnosis and drug loading therapy for different types of CNS diseases. It is hoped that increased knowledge of EVs will facilitate their clinical translation in CNS diseases.

Abstract Eukaryotic five-methylcytosine (m5C) is an important regulator of viral RNA splicing, stability, and translation. However, its role in HBV replication remains largely unknown. In this study, functional m5C sites are identified in hepatitis B virus (HBV) mRNA. The m5C modification at nt 1291 is not only indispensable for Aly/REF export factor (ALYREF) recognition to promote viral mRNA export and HBx translation but also for the inhibition of RIG-I binding to suppress interferon-β (IFN-β) production. Moreover, NOP2/Sun RNA methyltransferase 2 (NSUN2) catalyzes the addition of m5C to HBV mRNA and is transcriptionally downregulated by the viral protein HBx, which suppresses the binding of EGR1 to the NSUN2 promoter. Additionally, NSUN2 expression correlates with m5C modification of type I IFN mRNA in host cells, thus, positively regulating IFN expression. Hence, the delicate regulation of NSUN2 expression induces m5C modification of HBV mRNA while decreasing the levels of m5C in host IFN mRNA, making it a vital component of the HBV life cycle. These findings provide new molecular insights into the mechanism of HBV-mediated IFN inhibition and may inform the development of new IFN-α based therapies.

Introduction: Clodronate-Liposomes (Clod-Lipo) injection after hematopoietic stem cell transplantation (HSCT) has been shown to be detrimental to hematopoietic reconstitution after transplantation, and our previous study showed that Clod-Lipo injection after HSCT increased adipocytes in the bone marrow cavity of mice after HSCT, but the reason for the large increase in adipocytes has not been clearly explained. The aim of this study was to investigate the source and mechanism of bone marrow cavity adipocytes after HSCT injection of Clod-Lipo. Methods: BALB/c mice received 7.5 Gy of total body irradiation followed by infusion of 5x106 bone marrow mononuclear cells from C57BL/6 via the tail vein. Clod-Lipo were injected through the tail vein on the first day after HSCT and every 5 days for the rest of the day. BALB/c mice were then divided into three groups: BMT, BMT + Clodronate-Liposomes (BMT + Clod-Lipo), and BMT + PBS-Liposomes (BMT + PBS-Lipo). Bone marrow pathological changes were detected by H&E staining, Western blot was used to detect the expression of NLRP3 and Caspase-1 in mouse bone marrow cells, and RT-qPCR was used to detect the expression levels of the key transcription factors peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT/enhancer binding protein (C/EBPα) mRNA in bone marrow cells. Mouse mesenchymal stem cells (MSC) cultured in vitro were identified by flow cytometry, and adipocyte induction assays were performed using Clod-Lipo action for 24 h, Oil red staining was used to identify adipogenesis. Western blot was performed to detect NLRP3 and caspase-1 expression in MSC after Clod-Lipo action. Caspase-1 was blocked with Ac-YVAD-cmk (Ac-YV), followed by adipogenesis assay after 24 h of Clod-Lipo action to observe the change in the amount of adipogenesis. Results: Compared with the other two groups, a significant increase in adipocytes was found in the Clod-Lipo group by HE staining, and increased expression of NLRP3 and Caspase-1 in mouse bone marrow cells was found by western Blot. By culturing MSC in vitro and performing adipogenesis assay after 24 h of Clod-Lipo action, it was found that adipogenesis was increased in the Clod-Lipo group, while the expression of NLRP3 and Caspase-1 was increased in MSCs, and adipogenesis assay was performed after 2 h of action using Caspase-1 inhibitor, and it was found that adipocytes was reduced. Conclusions: The results of this study suggest that MSC are biased towards adipocyte generation in response to Clod-Lipo, a process that may be associated with activation of the NLRP3/caspase-1 pathway.

Indoor microorganisms impact asthma and allergic rhinitis (AR), but the associated microbial taxa often vary extensively due to climate and geographical variations. To provide more consistent environmental assessments, new perspectives on microbial exposure for asthma and AR are needed. Home dust from 97 cases (32 asthma alone, 37 AR alone, 28 comorbidity) and 52 age- and gender-matched controls in Shanghai, China, were analyzed using high-throughput shotgun metagenomic sequencing and liquid chromatography-mass spectrometry. Homes of healthy children were enriched with environmental microbes, including Paracoccus, Pseudomonas, and Psychrobacter, and metabolites like keto acids, indoles, pyridines, and flavonoids (astragalin, hesperidin) (False Discovery Rate

To effectively mitigate the effects of atmospheric turbulence in free space optical (FSO) communication, we propose a parallel carrier frequency offset estimation (FOE) scheme based on time-tagged QPSK partitioning (TTQP). This scheme can be applied to spatial diversity polarization multiplexing (PM) coherent FSO communication systems. Specifically, the TTQP scheme performs QPSK partitioning by time-tagging signal points, accurately recording the time intervals between signals, and significantly reducing implementation complexity through a modified Mth power algorithm. The simulation results for the PM 16-quadrature amplitude modulation (QAM) validate the effectiveness of the proposed scheme. Compared to traditional QPSK partitioning algorithms, the TTQP algorithm achieves high accuracy, low complexity, and multi-format versatility in high-speed coherent FSO communication.

Abstract Current techniques for visualizing and quantifying cellular forces have limitations in live cell imaging, throughput, and multi-scale analysis, which impede progress in cell force research and its practical applications. We developed a photonic crystal cellular force microscopy (PCCFM) to image vertical cell forces over a wide field of view (1.3 mm ⨯ 1.0 mm, a 10 ⨯ objective image) at high speed (about 20 frames per second) without references. The photonic crystal hydrogel substrate (PCS) converts micro-nano deformations into perceivable color changes, enabling in situ visualization and quantification of tiny vertical cell forces with high throughput. It enabled long-term, cross-scale monitoring from subcellular focal adhesions to tissue-level cell sheets and aggregates.

Abstract Background RPLP2, an integral part of ribosomal stalk, plays an important role in the tumorigenesis of various cancers. However, its specific effect on HCC remains elusive. Methods TCGA, GTEx, HCCDB, HPA, UALCAN, MethSurv, TISIDB, K–M plotter, FerrDb, RNAactDrug, STRING, Cytoscape and R studio were conducted for bioinformatics analysis. RPLP2 expression level in HCC was verified by IHC and western blot. IHC was used to demonstrate the immune cell infiltration. Functional experiments including CCK8, transwell and colony formation assays, and nude mice xenograft model were performed for in vitro and in vivo validation. Western blot, IHC, CCK8 assay and detection of GSH and lipid ROS were adopted to determine the effect of RPLP2 on the ferroptosis of HCC cells. Results Here, we demonstrate that elevated level of RPLP2 is strongly associated with advanced clinicopathologic features, and predicts poor prognosis of HCC patients. Additionally, DNA methylation level of RPLP2 decreases in HCC, and significantly correlates with patients outcome. Moreover, high RPLP2 expression level is linked closely to the unfavorable immune infiltration. Most importantly, RPLP2 positively associates with ferroptosis suppressor GPX4, and inhibition of RPLP2 could lead to the acceleration of ferroptosis to suppress tumor progression of HCC. Last, drug sensitivity analysis predicts many drugs that potentially target RPLP2. Conclusion Together, our study reveals previous unrecognized role of RPLP2 in HCC, and provides new regulatory mechanism of ferroptosis, indicating RPLP2 may be a novel therapeutic target for HCC.