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Abstract Background Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment. Methods This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy. Results CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival. Conclusions These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.

Abstract Younger premenopausal women are more prone to developing ovarian metastases (OM) of gastric cancer (GC) than metastases of other organs; however, the molecular mechanisms remain unclear. Here we perform single-cell RNA sequencing on 45 tumor samples from 18 GC patients with OM. Interestingly, fibroblasts in OM of GC express high levels of estrogen receptor (ER) and midkine (MDK), interacting with tumor cells through activating ER-MDK-LRP1 (low-density lipoprotein receptor-related protein 1) signaling axis. Functional experiments demonstrate that estrogen stimulation induces MDK secretion by ovarian fibroblasts, and binding of MDK to LRP1 increases GC cell migration and invasion. Furthermore, in vivo, estrogen stimulation remarkably augments ovarian engraftment and metastasis of LRP1+ GC cells. Collectively, our findings reveal that ER+ ovarian fibroblasts secrete MDK under estrogen influence, driving OM of GC via the MDK-LRP1 axis. Our study holds the potential to catalyze innovative therapeutic strategies aimed at intercepting and managing OM in GC.

Understanding the spatial interaction among residents, cooling service, and heat risk area in complex urban areas is conducive to developing targeted management. However, traditional urban thermal environment assessments typically relied on simple linear integration of associated indicators, often neglecting the spatial interaction effect. To explore the spatial interaction among the three elements, this study proposes an accessibility-based urban thermal environment assessment framework. Using Zhengzhou, a rapidly urbanizing city, as an example, remotely sensed images from three periods (2010, 2015 and 2020) were applied to extract urban green space (UGS) and hot island area (HIA). An improved two-step floating catchment area (2SFCA) method and bivariate local Moran’s I were employed to explore whether residents’ clustering locations are more likely to access cooling service or to be exposed to heat risk. The results demonstrate that the UGS in the city has been expanding, whereas the HIA shrank within the inner city in 2015 and then increased in 2020. Even though the urban thermal environment may have improved in the last decade, the spatial interaction among the residents, cooling service and heat risk area could be exacerbated. Spatial autocorrelation shows an increase in locations that are disadvantageous for resident congregation. Even when sufficient cooling services were provided, residents in these areas could still be exposed to high heat risk. The developed urban thermal environment framework provides a novel insight into the residents’ heat risk exposure and cooling service accessibility, and the findings could assist urban planners in targeting the improvement of extra heat exposure risk locations.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. Research on the tumor microenvironment (TME) of PDAC has propelled the development of immunotherapeutic and targeted therapeutic strategies with a promising future. The emergence of single-cell sequencing and mass spectrometry technologies, coupled with spatial omics, has collectively revealed the heterogeneity of the TME from a multiomics perspective, outlined the development trajectories of cell lineages, and revealed important functions of previously underrated myeloid cells and tumor stroma cells. Concurrently, these findings necessitated more refined annotations of biological functions at the cell cluster or single-cell level. Precise identification of all cell clusters is urgently needed to determine whether they have been investigated adequately and to identify target cell clusters with antitumor potential, design compatible treatment strategies, and determine treatment resistance. Here, we summarize recent research on the PDAC TME at the single-cell multiomics level, with an unbiased focus on the functions and potential classification bases of every cellular component within the TME, and look forward to the prospects of integrating single-cell multiomics data and retrospectively reusing bulk sequencing data, hoping to provide new insights into the PDAC TME.

Abstract Background Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. Methods We collected a prospective study cohort of 110 stage I–II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. Results Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942–0.982) in the study cohort, 0.972 (95% CI: 0.953–0.992) in the first validation cohort and 0.937 (95% CI: 0.890–0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. Conclusions We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. Trial registration This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

AimThe objective of this study was to gain insight into the nature of cognitive fatigue and to identify future trends of objective assessment techniques in this field.MethodsOne thousand and eighty-five articles were retrieved from the Web of Science Core Collection database. R version 4.3.1, VOSviewer 1.6.20, CiteSpace 6.2.R4, and Microsoft Excel 2019 were used to perform the analysis.ResultsA total of 704 institutes from 56 countries participated in the relevant research, while the People’s Republic of China contributed 126 articles and was the leading country. The most productive institute was the University of Gothenburg. Johansson Birgitta from the University of Gothenburg has posted the most articles (n = 13). The PLOS ONE published most papers (n = 38). The Neurosciences covered the most citations (n = 1,094). A total of 3,116 keywords were extracted and those with high frequency were mental fatigue, performance, quality-of-life, etc. Keywords mapping analysis indicated that cognitive fatigue caused by continuous work and traumatic brain injury, as well as its rehabilitation, have become the current research trend. The most co-cited literature was published in Sports Medicine. The strongest citation burst was related to electroencephalogram (EEG) event-related potential and spectral power analysis.ConclusionPublication information of related literature on the objective assessment of cognitive fatigue from 2007 to 2024 was summarized, including country and institute of origin, authors, and published journal, offering the current hotspots and novel directions in this field.

PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC50s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.

Background and aim: Yueju Pill (YJ) not only has good antidepressant effect but also can effectively treat digestive system diseases. However,it remains unclear whether the mechanism of antidepressant action of YJ is related to the peripheral digestive system. The purpose of this study was to elucidate the antidepressant mechanism of YJ on ghrelin level based on gastric mTOR/S6K signal pathway and sensitized hippocampal Ghrelin/GHS-R system in CUMS mice. Experimental procedure: The depression model was induced by chronic unpredictable mild stress (CUMS) and social isolation. The antidepressant effect of YJ was observed by behavioral experiment and hemodynamic experiments. Ghrelin levels in in hippocampus and blood were measured by Elisa kit, and the mRNA of ghrelin in mice stomach was measured by Real-time Quantitative PCR (RT-qPCR). The activation level of gastric mTOR/S6K signal pathway was detected by Western Blot (WB). Rapamycin (Rapa) and L-Leucine (L-Leu) were used to verify the effects of YJ on the synthesis and release of ghrelin. The activity of GHS-R in hippocampus was observed by immunofluorescence. Hippocampal neuronal damage was evaluated by HE staining and Nissl staining. The level of central neurotransmitter was measured by liquid chromatograph mass spectrometer (LC-MS). Results and conclusion: YJ ameliorates CUMS-induced depressive-like behavior by inhibiting the gastric mTOR/S6K signaling pathway and increasing GHR expression in the mouse stomach. However, these effects of YJ could be resisted by L-Leu (a mTOR receptor agonist). Further studies have shown that YJ can sensitize the Ghrelin/GHS-R system in the hippocampus, with significant neuroprotective effects, and is also involved in regulating the levels of key neurotransmitters (5-hydroxytryptamine, Dopamine and γ-aminobutyric acid) in depressive-like states.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

Abstract Background Neoadjuvant immunochemotherapy (NICT) plus esophagectomy has emerged as a promising treatment option for locally advanced esophageal squamous cell carcinoma (LA-ESCC). Pathologic complete response (pCR) is a key indicator associated with great efficacy and overall survival (OS). However, there are insufficient indicators for the reliable assessment of pCR. Methods 192 patients with LA-ESCC treated with NICT from December 2019 to October 2023 were recruited. According to pCR status, patients were categorized into pCR group (22.92%) and non-pCR group (77.08%). Radiological features of pretreatment and preoperative CT images were extracted. Logistic and COX regressions were trained to predict pathological response and prognosis, respectively. Results Four of the selected radiological features were combined to construct an ESCC preoperative imaging score (ECPI-Score). Logistic models revealed independent associations of ECPI-Score and vascular sign with pCR, with AUC of 0.918 in the training set and 0.862 in the validation set, respectively. After grouping by ECPI-Score, a higher proportion of pCR was observed among the high-ECPI group and negative vascular sign. Kaplan Meier analysis demonstrated that recurrence-free survival (RFS) with negative vascular sign was significantly better than those with positive (P = 0.038), but not for OS (P = 0.310). Conclusions This study demonstrates dynamic radiological features are independent predictors of pCR for LA-ESCC treated with NICT. It will guide clinicians to make accurate treatment plans.

Abstract Background Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. Methods In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. Results Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. Conclusions Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. Trial registration ClinicalTrials.gov (NCT 04401800).

Background Neoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking.Methods Formalin-fixed and paraffin-embedded pre-neoadjuvant chemoimmunotherapy biopsy samples from locally advanced ESCC patients were collected. Cohort 1 composed of 66 locally advanced ESCC patients from a prospective clinical trial (NCT04506138) received two cycles of camrelizumab in combination with nab-paclitaxel and carboplatin every 3 weeks. Cohort 2 included 48 patients receiving various types of immune checkpoint inhibitors with (nab-)paclitaxel and platinum-based chemotherapy as neoadjuvant therapy. Cohort 3 consisted of 27 ESCC patients receiving neoadjuvant treatment of toripalimab with chemotherapy and was used as the external validation dataset. Targeted RNA sequencing, immunohistochemistry for programmed death ligand 1 (PD-L1), and multiplex immunofluorescence (mIF) imaging were performed.Results Integration of targeted RNA sequencing, PD-L1 immunohistochemistry, and mIF revealed a significant immune-suppressive microenvironment with higher neutrophil infiltration, enriched TGF-β, and cell cycle pathways in non-pathological complete response (non-pCR) patients. NK, activated CD4+ T cell infiltration, interferon-gamma, antigen processing and presentation, and other immune response signatures were significantly associated with pCR. Based on discovered tumor microenvironmental characteristics and their closely related genes were screened. Consequently, a seven-gene neoadjuvant chemoimmunotherapy risk prediction signature (NCIRPs) model, was constructed. In addition to cohort 1, this model alone or with PD-L1-combined positive score (CPS) demonstrated a higher prediction accuracy of pathological response than PD-L1 CPS or other routinely used immune signatures, such as IFN-γ, in cohorts 2 and 3. Neither prognostic association nor correlation with response to chemoradiotherapy was observed in The Cancer Genome Atlas Program ESCC dataset or in ESCC patients in the neoadjuvant chemoradiotherapy cohort (cohort 4).Conclusion The NCIRPs model that was developed and validated using treatment-naïve endoscopic samples from the largest ESCC neoadjuvant chemoimmunotherapy dataset represents a robust and clinically meaningful approach to select a putative responder for neoadjuvant chemoimmunotherapy in locally advanced ESCC patients.

BackgroundUnilateral biportal endoscopic discectomy (UBED) is a widely accepted minimally invasive surgery for the treatment of lumbar degenerative diseases. However, some patients continue to have persistent low back pain (LBP) symptoms in the short and long term after surgery, which may be related to improper postoperative nursing and rehabilitation of patients. Further research is needed to determine whether continuous nursing can improve the symptoms of patients after UBED.MethodsThis study retrospectively enrolled 282 lumbar disc herniation (LDH) patients who underwent UBED in our hospital from January 2019 to January 2022. The patients were divided into two groups according to whether they accepted the continuous nursing program: 147 patients in the traditional nursing group and 135 patients in the continuous nursing group. Demographic characteristics, radiological parameters, and follow-up data of the patients were collected. Finally, the risk factors of LBP after UBED were analyzed.ResultsThe visual analog scale (VAS) score of LBP in the continuous nursing group was 0.97 ± 1.159 at 3 months and 0.61 ± 0.954 at 12 months after operation, and VAS of leg pain was 0.23 ± 0.421 at 12 months after operation, which were better than those in the traditional nursing group (1.51 ± 1.313, 1.10 ± 1.076, 0.68 ± 0.788, respectively, p

Immune inflammation is one of the main factors in the pathogenesis of depression. It is an effective and active way to find more safe and effective anti-inflammatory depressant drugs from plant drugs. The purpose of this study is to explore the potential of marine plant Sargassum pallidum (Turn).C.Ag. (Haihaozi, HHZ) in the prevention and treatment of depression and to explain the related mechanism. Phytochemical analysis showed that alkaloids, terpenes, and organic acids are the main constituents. In vitro and in vivo activity studies showed the anti-neuroinflammatory and antidepressant effect of Sargassum pallidum, furthermore, confirmed that 7-Hydroxycoumarin, Scoparone, and Kaurenoic Acid are important plant metabolites in Sargasum pallidum for anti-neuroinflammation. Mechanism exploration showed that inhibition of ERK1/2/p38 inflammatory signaling pathway contributing to the antidepressant effect of Sargassum pallidum in reducing intestinal inflammatory levels. This study confirmed the value of Sargassum pallidum and its rich plant metabolites in anti-inflammatory depression, providing a new choice for the follow-up research and development of antidepressant drugs.

Aggressive periodontitis (AgP) is characterized by rapid and progressive destruction of the periodontal tissues and eventual tooth loss. Genetic risk contributions have been explored and rare mutations in NOD2 were reported. Sequencing analysis of the coding regions of NOD2 was conducted using individuals of African ancestry, to identify the pathogenic protein-altering variants in individuals with AgP using: 1) In Silico tools and clinical variant classification system; 2) IF staining to understand the expression pattern, and 3) In vitro cell based assay to understand the variant protein function. We discovered a novel nonsense NOD2 variant (c.835G>T; p.Glu279Ter) ; a truncating protein variant that is clinically pathogenic, and the gene-product lacks domains regulating inflammatory responses. Murine studies suggest that this gene contributes to tooth development. In vitro analysis suggests a dominant-negative effect of the variant. NOD2 gene is expressed in the immune cells and periodontal tissues and regulates the inflammatory response within this tissue. This truncating variant found in one African family, which results in a dominant-negative effect, could explain the exacerbated immune response to pathogens in the pathogenesis of this periodontal disease.

Abstract Background Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear. Methods Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase‐Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitation‒quantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient‐derived xenograft models were constructed to validate the effects of the drug combinations. Results As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)‐mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac‐mediated recruitment of the BRD4‐p‐P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5‐fluorouracil or regorafenib) in CRC xenograft‐bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p‐P65/NLRP3 and is a prognostic factor for CRC patients. Conclusion Collectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD‐mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy. Highlights Silencing of NLRP3 limits the GSDMD‐dependent pyroptosis in colorectal cancer. HDAC2‐mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p‐P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.

Fluorine-19 (19F) is a nucleus of great importance in the field of Nuclear Magnetic Resonance (NMR) spectroscopy due to its high receptivity and wide chemical shift dispersion. 19F NMR plays crucial roles in both organic synthesis and biomedicine. Herein, a machine learning-based comprehensive 19F NMR chemical shift prediction model was established based on the experimental 19F NMR dataset from the book by Dolbier and the open NMR database nmrshiftdb2. Fluorine radical SMILES (Fr-SMILES) that reflected the fluorine chemical equivalence, was designed as the representation of fluorine in the molecule. Model trained with the graph convolution network (GCN) algorithm gave a low mean absolute error (MAE) of 3.636 ppm on the testing set. This model exhibits broad applicability and can effectively predict 19F NMR shifts for a wide range of organic fluorine molecules. We believe that the current work will provide a powerful tool for not only predicting 19F NMR shifts but also aiding in the analysis and identification of these shifts in diverse organic fluorine compounds. An online prediction platform was constructed based on the current model, which can be found at https://fluobase.cstspace.cn/fnmr.

Background: This study aimed to show a 3-year trajectory of physical performance among Chinese elderly in Beijing communities and explore the associations between new adverse events during the 3-year follow-up period and decreased physical performance. Methods: A longitudinal observational study included baseline data and transitional information of physical performance from 456 community elders (mean age 67.3 ± 4.9 years, female 43.2 %) at a 3-year follow-up. The Mini-Mental State Examination (MMSE) and the Short Physical Performance Battery (SPPB) were used to measure cognition and physical performance, respectively. The number of chronic diseases, cognitive impairment, malnutrition, depression, knee pain, falls, and frailty were the principal independent variables in multivariate logistic regression analysis. Results: The proportion of the elderly with poor physical performance (26.97 %) increased to 42.11 % and the proportion of those with good physical performance (44.96 %) dropped to 30.48 % after the three-year follow-up. As for physical performance transitions, 39.47 % of the elderly progressed to a worsening physical status. After adjustment for covariates, only new onset cognitive impairment (OR: 5.17; 95%CI: 2.01–14.54; P = 0.001) was associated with physical performance deterioration. Conclusion: Cognitive impairment is an independent risk factor for decreased physical performance in elderly people. Active interventions targeted at cognitive impairment could help promote healthy aging.

Objective: To detect levofloxacin (LFX) and moxifloxacin (MFX) resistance among rifampicin-resistant tuberculosis (RR-TB) isolates, and predict the resistance level based on specific mutations in gyrA and gyrB genes. Methods: A total of 686 RR-TB isolates were collected from Chinese Drug Resistance Surveillance Program from 2013 to 2020. The minimum inhibitory concentrations (MICs) of 12 anti-TB drugs were acquired using the broth microdilution method, followed by whole genome sequencing (WGS) analysis. Results: Among the 686 RR isolates, the most prevalent resistance was to isoniazid (80.5 %) and ethambutol (28.4 %), followed by LFX (26.1 %) and MFX (21.9 %). The resistance rate of LFX (26.1%–99.4 %) was higher than that of MFX (21.9%–83.3 %) across various drug resistance patterns. Of the 180 fluoroquinolones (FQs) resistant isolates, 168 (93.3 %) had mutations in quinolone-resistant determining regions (QRDRs) with 21 mutation types, and Asp94Gly (32.7 %, 55/168) was the predominant mutation. Isolates with mutations in Asp94Asn and Asp94Gly were associated with high levels of resistance to LFX and MFX. Using broth microdilution method as gold standard, the sensitivities of WGS for LFX and MFX were 93.3 % and 98.0 %, and the specificities were 98.6 % and 95.0 %, respectively. Conclusion: The resistance rate of LFX was higher than that of MFX among various drug resistance patterns in RR-TB isolates. The gyrA Asp94Gly was the predominant mutation type underlying FQs resistance. However, no significant difference was observed between mutation patterns in gyrA gene and resistance level of FQs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.

Abstract Neoplastic cells need to adapt their gene expression pattern to survive in an ever-changing or unfavorable tumor microenvironment. Protein synthesis (or mRNA translation), an essential part of gene expression, is dysregulated in cancer. The emergence of distinct translatomic technologies has revolutionized oncological studies to elucidate translational regulatory mechanisms. Ribosome profiling can provide adequate information on diverse aspects of translation by aiding in quantitatively analyzing the intensity of translating ribosome-protected fragments. Here, we review the primary currently used translatomics techniques and highlight their advantages and disadvantages as tools for translatomics studies. Subsequently, we clarified the areas in which ribosome profiling could be applied to better understand translational control. Finally, we summarized the latest advances in cancer studies using ribosome profiling to highlight the extensive application of this powerful and promising translatomic tool.

Granulocytic myeloid-derived suppressor cells (G-MDSCs) are one of the main subgroups of MDSCs, which are widely enriched in most cancers. It can inhibit the killing function of T-lymphocyte through the expression of arginase-1 (Arg-1) and reactive oxygen species (ROS), reshape the tumor immune microenvironment, and promote the occurrence and development of tumors. In recent years, more and more studies have found that G-MDSCs are significantly correlated with the prognosis and immunotherapy efficacy of patients with non-small cell lung cancer, and the use of drugs specifically targeting the recruitment, differentiation and function of G-MDSCs can effectively inhibit tumor progression. This article reviews the immunosuppressive effect of G-MDSCs in non-small cell lung cancer and the progress of related pathway targeting drugs.

Abstract Purpose Hypoxia is one of the most frequent adverse events under deep sedation in the semiprone position. We hypothesized that supraglottic jet oxygenation and ventilation (SJOV) via Wei nasal jet tube (WNJ) can reduce the incidence of hypoxia in patients under deep sedation during endoscopic retrograde cholangiopancreatography (ERCP). Methods A total of 171 patients were divided into three groups: N group, supplementary oxygen via a nasopharyngeal airway (4–6 L/min); W group, supplementary oxygen via WNJ (4–6 L/min); WS group, SJOV via WNJ. The primary outcome was the incidence of adverse events, including sedation-related adverse events [SRAEs, hypoxemia (SpO2 = 75–89% lasted less than 60 s); severe hypoxemia (SpO2

Summary: Nuclear factor kappa B (NF-κB) plays a pivotal role in the development of pancreatic cancer, and its phosphorylation has previously been linked to the regulation of NUAK2. However, the regulatory connection between NF-κB and NUAK2, as well as NUAK2’s role in pancreatic cancer, remains unclear. In this study, we observed that inhibiting NUAK2 impeded the proliferation, migration, and invasion of pancreatic cancer cells while triggering apoptosis. NUAK2 overexpression partially resisted apoptosis and reversed the inhibitory effects of the NF-κB inhibitor. NF-κB transcriptionally regulated NUAK2 transcription by binding to the promoter region of NUAK2. Mechanistically, NUAK2 knockdown remarkably reduced the expression levels of p-SMAD2/3 and SMAD2/3, resulting in decreased nuclear translocation of SMAD4. In SMAD4-negative cells, NUAK2 knockdown impacted FAK signaling by downregulating SMAD2/3. Moreover, NUAK2 knockdown heightened the sensitivity of pancreatic cancer cells to gemcitabine, suggesting that NUAK2 inhibitors could be a promising strategy for pancreatic cancer treatment.

Abstract Electrical control of magnetism in single-molecule magnets with peculiar quantum magnetic behaviours has promise for applications in molecular electronics and quantum computing. Nevertheless, such kind of magnetoelectric effects have not been achieved in such materials. Herein, we report the successful realization of significant magnetoelectric effects by introducing ferroelectricity into a dysprosium-based single-molecule magnet through spatial cooperation between flexible organic ligands and halide ions. The stair-shaped magnetization hysteresis loop, alternating current susceptibility, and magnetic relaxation can be directly modulated by applying a moderate electric field. Conversely, the electric polarization can be modulated by applying a small magnetic field. In addition, a resonant magnetodielectric effect is clearly observed, which enables detection of quantum tunnelling of magnetization by a simple electrical measurement. The integration of ferroelectricity into single-molecule magnets not only broadens the family of single-molecule magnets but also makes electrical detection and modulation of the quantum tunnelling of magnetization a reality.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR are effective in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients, but drug resistance is inevitable. With the application and expansion of individualized and combined therapy, more and more studies have shown that combined administration of Metformin effectively solves the problem of acquired drug resistance to EGFR-TKIs in clinical treatment and prolongs the survival of patients with NSCLC. EGFR-TKIs combined with Metformin is expected to be the treatment method of choice for NSCLC patients with EGFR-TKIs resistance. This paper intends to summarize the research progress of EGFR-TKIs combined with Metformin in the treatment of EGFR-TKIs acquired resistance in NSCLC, in order to provide a new idea for the treatment of NSCLC patients with acquired resistance to EGFR-TKIs.

Abstract Background Open spina bifida is an uncommon malformation in animals, and there is a lack of imaging, clinical, and pathological characterisation of this condition in dogs. Objective Open spina bifida is rarely observed in animals due to high levels of perinatal mortality and frequent euthanasia. To the best of our knowledge, we present the first case of spina bifida in a dog was diagnosed in‐utero and then followed post‐partum. Methods A 3‐year‐old Poodle was presented with twin pregnancy. Radiographic and ultrasonographic findings were suggestive of vertebral malformation and open spina bifida with myelomeningocele in one foetus. Conservative treatment was given but the puppy died 3 days after birth. Thereafter, anatomical and histopathological analysis of several organs was performed to characterise the disease. Results When the twins were born, one puppy had a linear dorsal midline cutaneous defect extending from the level of vertebrae L2–L6. R Radiographic examination showed several congenital vertebral malformations involving the thoracic segment, lumbar segment, sacrum and scapula. Histopathological examinations confirmed the presence of open spina bifida and identified additional abnormalities in several internal organs. Conclusions This case presents a complete characterisation of open spina bifida, before birth and after death, using imaging and histopathology techniques.

Abstract Introduction Serum neurofilament light chain (sNfL) is an emerging biomarker of neuronal damage in several neurological disorders. Its association with cognitive function in the general US population aged 60 years and above is unknown. The aim of this study was to investigate the correlation between sNfL and cognitive function in the general US population aged 60 and above. Methods The data were obtained from the 2013–2014 National Health and Nutrition Examination Survey (NHANES), which include 506 individuals aged 60 or older who met our search criteria. In our study, sNfL levels were divided into two groups based on dichotomization (19.0 pg/mL). After adjusting for multiple covariates, it was found that the high sNfL group (≥ 19.0 pg/mL) had lower cognitive performance than the low sNfL group (

Abstract Background Blended learning is increasingly being adopted, and yet a gap remains in the related literature pertaining to its skill performance, learning engagement and inner experience in undergraduate surgical nursing skills course. Objectives To investigate the changes in skills performance and learning engagement in the application of blended learning, and what it actually brings to nursing students. Design The study uses a historical control, two-armed, mixed and quasi-experimental design. Methods The blended learning version of the course was offered to the 2019 class of 334 nursing undergraduates. Quantitative and qualitative data were collected after the course to obtain a comprehensive understanding of the course effects compared with the 304 nursing undergraduates of grade 2017 who adapted traditional learning. Quantitative data were analyzed by descriptive and inferential statistics using IBM SPSS 26.0, and qualitative data were encoded using Nvivo11.0. Results There were significant differences in skill performance and learning engagement between the class of 2017 and 2019 (p

Headspace solid-phase microextraction (HS-SPME) and gas chromatography-mass spectrometry (GC-MS) combined with multivariate statistical analysis were used to explore the differences in the volatile components of three kinds of black tea, including Keemun black tea, GABA black tea, and Yunnan black tea. GC-MS results showed that a total of 78 volatile components were identified, including hydrocarbons, terpenes, alcohols, esters, ketones, aldehydes, heterocyclic compounds, and phenols. The total volatile substances of three kinds of black tea were similar in quantity, but their content was quite different, and the common volatile components mainly include linalool, geraniol, nonanal, methyl salicylate, linalool oxide, etc. The results of multivariate statistical analysis showed that GABA black tea, Yunnan black tea, and Keemun black tea could be distinguished according to the volatile components. Partial least squares discriminant analysis screened 12 differential volatile components, including neryl acetate, methyl salicylate, isoborneol, linalool, citral, etc. Neryl acetate and citral had the highest content in Keemun black tea, which helped to form the floral and fruity aroma type of Keemun black tea. Isoborneol and linalool had the highest content in Yunnan black tea. The content of linalool and methyl salicylate was high in GABA black tea, which was conducive to the formation of the fresh and tender floral and fruity aroma of GABA black tea. The results of this study can lay a theoretical foundation for scientifically and objectively evaluating the aroma characteristics of GABA black tea, clarifying the difference in aroma quality between Keemun black tea, GABA black tea, and Yunnan black tea, and constructing the flavor quality identification map of different types of black tea.

To investigate the impact of electrode structure on Electrical Stimulation Therapy (EST) for chronic wound healing, this study designed three variants of flexible microelectrodes (FMs) with Ag-Cu coverings (ACCs), each exhibiting distinct geometrical configurations: hexagonal, cross-shaped, and serpentine. These were integrated with PPY/PDA/PANI (3/6) (full name: polypyrrole/polydopamine/polyaniline 3/6). Hydrogel dressing comprehensive animal studies, coupled with detailed electrical and mechanical modeling and simulations, were conducted to assess their performance. Results indicated that the serpentine-shaped FM outperformed its counterparts in terms of flexibility and safety, exhibiting minimal thermal effects and a reduced risk of burns. Notably, FMs with metal coverings under 3% demonstrated promising potential for optoelectronic self-powering capabilities. Additionally, simulation data highlighted the significant influence of hydrogel non-uniformity on the distribution of electrical properties across the skin surface, providing critical insights for optimizing EST protocols when employing hydrogel dressings.

Diabetes has become one of the most prevalent global epidemics, significantly impacting both the economy and the health of individuals. Diabetes is associated with numerous complications, such as obesity; hyperglycemia; hypercholesterolemia; dyslipidemia; metabolic endotoxemia; intestinal barrier damage; insulin-secretion defects; increased oxidative stress; and low-grade, systemic, and chronic inflammation. Diabetes cannot be completely cured; therefore, current research has focused on developing various methods to control diabetes. A promising strategy is the use of probiotics for diabetes intervention. Probiotics are a class of live, non-toxic microorganisms that can colonize the human intestine and help improve the balance of intestinal microbiota. In this review, we summarize the current clinical studies on using probiotics to control diabetes in humans, along with mechanistic studies conducted in animal models. The primary mechanism by which probiotics regulate diabetes is improved intestinal barrier integrity, alleviated oxidative stress, enhanced immune response, increased short-chain fatty acid production, etc. Therefore, probiotic supplementation holds great potential for the prevention and management of diabetes.

In this study, molecular dynamics (MD) simulations were employed to elucidate the processes and underlying mechanisms that govern the adsorption and accumulation of gas (represented by N2) at the hydrophobic solid–liquid interface, using the GROMACS program with an AMBER force field. Our findings indicate that, regardless of surface roughness, the presence of water molecules is a prerequisite for the adsorption and aggregation of N2 molecules on solid surfaces. N2 molecules dissolved in water can cluster even without a solid substrate. In the gas–solid–liquid system, the exclusion of water molecules at the hydrophobic solid–liquid interface and the adsorption of N2 molecules do not occur simultaneously. A loosely arranged layer of water molecules is initially formed on the hydrophobic solid surface. The two-stage process of N2 molecule adsorption and accumulation at the hydrophobic solid/liquid interface involves initial adsorption to the solid surface, displacing water molecules, followed by N2 accumulation via self-interaction after saturating the substrate’s surface. The process and underlying mechanisms of gas adsorption and accumulation at hydrophobic solid/liquid interfaces elucidated in this study offer a molecular-level understanding of nano-gas layer formation.

Abstract Background Gastric cancer is a highly heterogeneous disease, which makes it challenging to develop effective targeted therapies. Although the potassium voltage‐gated channel subfamily D (KCND) channels, particularly KCND2 (also known as Kv4.2), have found evidence of involvement in the occurrence and development of various cancers, there are still some limitations in our understanding of KCND2's roles in gastric cancer. Methods We analyzed the correlation between KCND2 expression and clinical features as well as immune infiltration using the Cancer Genome Atlas (TCGA) database. Functional assays of KCND2 were conducted using Cell counting Kit‐8 (CCK8), clone formation assay and cell cycle analysis. Additionally, immunofluorescence, flow cytometry and quantitative real‐time polymerase chain reaction (qRT‐PCR) techniques were used to investigate tumor proliferation and immune cell infiltration at different levels of KCND2 expression in vivo. Results KCND2 was markedly elevated in gastric cancer and its expression appeared to link to different grades, T stages, and N stages. In addition, KCND2 was an independent predictor of prognosis, and its elevated levels in TCGA database revealed a more unfavorable prognosis for patients with gastric cancer. KCND2 strengthened the viability at the cellular level by boosting the proliferation of gastric cancer cells and reducing their death rate. Additionally, it also highlights that KCND2 the abilities of proliferating of gastric cancer cells by stimulating NF‐κB both in cell and animal levels. In addition, the findings provided proof that in animal levels, KCND2 might regulate the immune system by associating with promoting M2 macrophages, which are known to play critical roles in cancer progression. Mechanistically, KCND2 was found to lead to the infiltration of M2 macrophages through activation of NF‐κB, ultimately promoting the advancement of gastric cancer. Conclusion Overall, these findings suggest that KCND2 is likely to be available as an underlying therapeutic target for gastric cancer.

Abstract Respiratory syncytial virus (RSV) is a nonsegmented, negative strand RNA virus that has caused severe lower respiratory tract infections of high mortality rates in infants and the elderly, yet no effective vaccine or antiviral therapy is available. The RSV genome encodes the nucleoprotein (N) that forms helical assembly to encapsulate and protect the RNA genome from degradation, and to serve as a template for transcription and replication. Previous crystal structure revealed a decameric ring architecture of N in complex with the cellular RNA (N-RNA) of 70 nucleotides (70-nt), whereas cryo-ET reconstruction revealed a low-resolution left-handed filament, in which the crystal monomer structure was docked with the helical symmetry applied to simulate a nucleocapsid-like assembly of RSV. However, the molecular details of RSV nucleocapsid assembly remain unknown, which continue to limit our complete understanding of the critical interactions involved in the nucleocapsid and antiviral development that may target this essential process during the viral life cycle. Here we resolve the near-atomic cryo-EM structure of RSV N-RNA that represents roughly one turn of the helical assembly that unveils critical interaction interfaces of RSV nucleocapsid and may facilitate development of RSV antiviral therapy.

Abstract A promising approach to the next generation of low-power, functional, and energy-efficient electronics relies on novel materials with coupled magnetic and electric degrees of freedom. In particular, stripy antiferromagnets often exhibit broken crystal and magnetic symmetries, which may bring about the magnetoelectric (ME) effect and enable the manipulation of intriguing properties and functionalities by electrical means. The demand for expanding the boundaries of data storage and processing technologies has led to the development of spintronics toward two-dimensional (2D) platforms. This work reports the ME effect in the 2D stripy antiferromagnetic insulator CrOCl down to a single layer. By measuring the tunneling resistance of CrOCl on the parameter space of temperature, magnetic field, and applied voltage, we verified the ME coupling down to the 2D limit and probed its mechanism. Utilizing the multi-stable states and ME coupling at magnetic phase transitions, we realize multi-state data storage in the tunneling devices. Our work not only advances the fundamental understanding of spin-charge coupling, but also demonstrates the great potential of 2D antiferromagnetic materials to deliver devices and circuits beyond the traditional binary operations.

Alternative splicing is an essential regulatory mechanism for development and pathogenesis. Through alternative splicing one gene can encode multiple isoforms and be translated into proteins with different functions. Therefore, this diversity is an important dimension to understand the molecular mechanism governing embryo development. Isoform expression in preimplantation embryos has been extensively investigated, leading to the discovery of new isoforms. However, the dynamics of isoform switching of different types of transcripts throughout the development remains unexplored. Here, using single-cell direct isoform sequencing in over 100 single blastomeres from the mouse oocyte to blastocyst stage, we quantified isoform expression and found that 3-prime partial transcripts lacking stop codons are highly accumulated in oocytes and zygotes. These transcripts are not transcription by-products and might play a role in maternal to zygote transition (MZT) process. Long-read sequencing also enabled us to determine the expression of transposable elements (TEs) at specific loci. In this way, we identified 3,894 TE loci that exhibited dynamic changes along the preimplantation development, likely regulating the expression of adjacent genes. Our work provides novel insights into the transcriptional regulation of early embryo development.

Abstract Nanotransfer printing of colloidal nanoparticles is a promising technique for the fabrication of functional materials and devices. However, patterning nonplanar nanostructures pose a challenge due to weak adhesion from the extremely small nanostructure‐substrate contact area. Here, the study proposes a thermal‐assisted nonplanar nanostructure transfer printing (NP‐NTP) strategy for multiscale patterning of polystyrene (PS) nanospheres. The printing efficiency is significantly improved from ≈3.1% at low temperatures to ≈97.2% under the glass transition temperature of PS. Additionally, the arrangement of PS nanospheres transitioned from disorder to long‐range order. The mechanism of printing efficiency enhancement is the drastic drop of Young's modulus of nanospheres, giving rise to an increased contact area, self‐adhesive effect, and inter‐particle necking. To demonstrate the versatility of the NP‐NTP strategy, it is combined with the intaglio transfer printing technique, and multiple patterns are created at both micro and macro scales at a 4‐inch scale with a resolution of ≈2757 pixels per inch (PPI). Furthermore, a multi‐modal anti‐counterfeiting concept based on structural patterns at hierarchical length scales is proposed, providing a new paradigm of imparting multiscale nanostructure patterning into macroscale functional devices.

As a typical 2-dimensional material, molybdenum disulfide (MoS2) has atomic thickness in longitudinal size, showing unique optical and electrical properties. MoS2 has become a research hotspot in the field of photodetection. The properties of MoS2 devices are highly dependent on their material characteristics, device structures, and fabrication techniques. Therefore, their photoresponse characteristics may be determined by multiple physical effects, which contribute to the development of MoS2-based broadband photodetectors. Here, we present an experimental study on the broadband MoS2 photodetector ranging from 410 to 1,550 nm, obviously wider than that of conventionally reported MoS2 photodetectors. Our results indicate that the performance of the MoS2 device is dependent on the fabrication procedures. Under the optimal process, the maximum responsivity is 33.75 A W−1 and the corresponding specific detectivity is 6.1 × 1011 cm Hz1/2 W−1 at 480-nm illumination. Through a series of electrical and optoelectronic experimental analysis, the working mechanisms of multiband photoresponse of the MoS2 device are clarified.

Cell-cultured meat, which is obtained by adsorbing cells on the three-dimensional scaffold, is considered a potential solution to animal welfare issues. Edible and safe cell-cultured meat scaffolds are a key part of its research. Soy protein isolate (SPI) hydrogel has a three-dimensional network structure and has been studied for L929 cell culture because of its non-toxicity and biocompatibility. However, the toughness and mechanical properties of SPI hydrogel are not enough to bear the requirements of cell cultivation. In this paper, sodium alginate (SA) was added to SPI hydrogel, and the interpenetrating network (IPN) technology was used to construct SPI-SA IPN hydrogel by transglutaminase and Ca2+ double crosslinking method. SPI-SA IPN hydrogel has excellent mechanical properties, structural stability and biodegradable performance than SPI hydrogel. The bio-compatibility and degradability of L929 and C2C12 cells on SPI-SA IPN hydrogel were studied by cytotoxicity, trypan blue and living/dead cell staining, and the growth law of the hydrogel as a scaffold for cell culture was analyzed. The results showed that L929/C2C12 cells can proliferate normally and adhere in hydrogel and have good bio-compatibility. L929 cells with size about 20–50 µm have better adhesion and growth abilities on SPI-SA IPN hydrogel than C2C12 cells with 100–300 µm. Therefore, the SPI-SA IPN hydrogel is non-toxic and supports the growth of cells in the pores of the material. This study provides a reference for the application of SPI-SA IPN hydrogels in vitro cell growth.

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death worldwide. Clinical research results have provided more treatment opportunities for CRC patients, showing that an optimal combination of existing drugs and new drugs is needed to mitigate the burden of this disease. In this review, we have summarized recent advances in drug clinical research for CRC in 2022, including chemotherapy, targeted therapy, and immunotherapy, to find opportunities for substantial improvements in drug discovery and clinical development methods.

In this study, a commercial sodium butyrate protected by a new buffer salt solution (NSB) was tested to determine whether it can be used as an antibiotic alternative in broiler production. A total of 192 1-day-old broilers were randomly allocated to three dietary treatments: soybean meal diet (CON), antibiotic diet (ANT, basal diet + 100 mg/kg aureomycin), and NSB (basal diet + 800 mg/kg NSB). The growth performance, serum anti-inflammatory cytokines, intestinal morphology, gut barrier function, antioxidative parameters, SCFAs’ content, and cecal microbiota were analyzed. The result showed that NSB significantly improved ADFI and ADG (p < 0.01), and decreased FCR (p < 0.01). Serum anti-inflammatory cytokine IL-10 was up-regulated (p < 0.01), and pro-inflammatory TNF-α was down-regulated (p < 0.05) by NSB supplementation. H&E results showed that VH and the VH/CD ratio significantly increased (p < 0.05) in the jejunum and ileum in the NSB group. Furthermore, ZO-1 (p < 0.01), claudin-1 (p < 0.01), and occludin (p < 0.05) in the jejunum and claudin-1 (p < 0.01) and mucin-2 (p < 0.05) in the ileum were significantly up-regulated in the NSB group. Additionally, SOD (p < 0.05) and the T-AOC/MDA ratio (p < 0.01) in the jejunum and SOD in the ileum were significantly increased (p < 0.05) in the NSB group. The MDA level also significantly increased (p < 0.01) in the ANT group in the jejunum. Propionic acid (p < 0.05) and butyric acid (p < 0.01) content significantly increased in the NSB group in the jejunum and ileum segments. The 16S rRNA sequencing results showed no significant difference (p > 0.05) in alpha and beta diversity among the groups. LEFSe analysis also indicated that Peptostreptococcaceae, Colidextribacter, Firmicutes, Oscillospira, and Erysipelatoclostridiaceae, which promote SCFA production (p < 0.05), were identified as dominant taxon-enriched bacterial genera in the NSB group. The Spearman correlation analysis revealed that Colidextribacter with ADFI, ADG, VH, claudin-1 (p < 0.05), and unclassified_f__Peptostreptococcaceae with ADFI, IL-10, and ZO-1 were positively correlated (p < 0.05). Furthermore, ADFI and ADG with IL-10, claudin-1, SOD, T-AOC, and butyric acid (p < 0.05), and similarly, ADG with VH (p < 0.05), showed a positive correlation. In conclusion, NSB enhanced the growth performance by improving jejunum and ileum morphology, and serum anti-inflammatory cytokines, and by regulating the intestinal barrier function and antioxidant capacity, SCFAs’ content, and cecum microbiota, showing its potential use as an alternative to antibiotics in poultry nutrition.

Hepatocyte lipid accumulation in type 2 diabetes mellitus (T2DM) promotes the development of metabolic dysfunction-associated steatosis liver disease (MASLD), whereas no specific drug treatment is available. Pinocembrin assists in the treatment of many diseases, however, little is known about its protective effect on hepatic lipid metabolism disorders induced by T2DM. In this study, the ameliorative effects of pinocembrin on T2DM-induced hepatocyte lipid accumulation were investigated by in vitro experiments combined with a comprehensive analysis strategy of network pharmacology and molecular docking. High glucose and free fatty acid co-cultured HepG2 cell line was used. The results indicated that pinocembrin reduced lipid deposition by modulating the release of Cyclooxygenase-2 (COX-2)-mediated inflammatory factors and improving insulin resistance (IR) in HepG2 cells. Overall, the findings of this study suggested that pinocembrin ameliorated lipid accumulation and IR in vitro, and thus may be a potential therapeutic agent for the treatment of T2DM-induced hepatic steatosis.

Ultrasound induced cavitation effects can dramatically affect physicochemical performance in photocatalysis as a result of enhanced mass transfer and the formation of highly active radicals under localized high temperature and pressure. The use of ultrasound facilitates a systematic control of photo-generated carrier properties within a nanostructured framework. Considerable research efforts have been directed at developing methodologies for the design of nanostructures with a high degree of precision. We provide a comprehensive overview of rational strategies in the sonochemical synthesis of photocatalysts and address the viability of controlling catalyst structural features. Research progress in sono-photocatalysis and piezo-photocatalysis is assessed, focusing on the integration of cavitation phenomena and artificial nanostructures in terms of practical application. Moreover, we evaluate current technologies used in quantitative analysis as a means of understanding the underlying mechanisms and evaluating catalyst properties predictably and reproducibly. Finally, we provide some insight into the possibilities, limitations and perspectives in this field.

Autophagy is a critical protein and organelle quality control system, which regulates cellular homeostasis and survival. Growing pieces of evidence suggest that autophagic dysfunction is strongly associated with many human diseases, including neurological diseases and cancer. Among various autophagic regulators, microphthalmia (MiT)/TFE transcription factors, including transcription factor EB (TFEB), have been shown to act as the master regulators of autophagosome and lysosome biogenesis in both physiological and pathological conditions. According to the previous studies, chlorpromazine (CPZ), an FDA-approved antipsychotic drug, affects autophagy in diverse cell lines, but the underlying mechanism remains elusive. In our present study, we find that CPZ treatment induces TFEB nuclear translocation through Rag GTPases, the upstream regulators of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Meanwhile, CPZ treatment also blocks autophagosome–lysosome fusion. Notably, we find a significant accumulation of immature autophagosome vesicles in CPZ-treated cells, which may impede cellular homeostasis due to the dysfunction of the autophagy–lysosome pathway. Interestingly and importantly, our data suggest that the expression of the active form of Rag GTPase heterodimers helps in reducing the accumulation of autophagosomes in CPZ-treated cells, further suggesting a major contribution of the Rag GTPase–mTORC1–TFEB signaling axis in CPZ-induced autophagic impairment.

Summary: The immunogenomic features of tumor-adjacent lungs (TALs) in stage I lung squamous cell carcinoma (LUSC) are not clear. Multiomics analyses of tumor tissues and paired TALs from 59 stage I LUSC patients were performed. Compared to tumors, TALs exhibited a better-preserved immune contexture indicated by upregulation of immune pathways, increased immune infiltration, and higher expression of immune effector molecules. Notably, TALs had no mutations in PTEN and KEAP1, a lower incidence of human leukocyte antigen (HLA) loss and higher expression of HLA class I genes, major histocompatibility complex (MHC) I chaperones, and interferon (IFN)-γ-associated genes. Digital spatial profiling validated the generally higher immune infiltration in TALs and revealed a higher level of immune heterogeneity in LUSC tumors. Importantly, patients with higher immune infiltration in TALs had significantly longer survival, while high immune heterogeneity was associated with inferior patient survival. Our work can be considered in the selection of patients for adjuvant therapy, especially immunotherapy.

Summary: The spliceosomal snRNP cores, each comprised of a snRNA and a seven-membered Sm ring (D1/D2/F/E/G/D3/B), are assembled by twelve chaperoning proteins in human. However, only six assembly-assisting proteins, ICln and the SMN complex (SMN/Gemin2/Gemin6-8), have been found in Schizosaccharomyces pombe (Sp). Here, we used recombinant proteins to reconstitute the chaperone machinery and investigated the roles of these proteins systematically. We found that, like the human system, the assembly in S. pombe requires ICln and the SMN complex sequentially. However, there are several significant differences. For instance, h_F/E/G forms heterohexamers and heterotrimers, while Sp_F/E/G only forms heterohexamers; h_Gemin2 alone can bind D1/D2/F/E/G, but Sp_Gemin2 cannot. Moreover, we found that Sp_Gemin2 is essential using genetic approaches. These mechanistic studies reveal that these six proteins are necessary and sufficient for Sm core assembly at the molecular level, and enrich our understanding of the chaperone systems in species variation and evolution.

Objective:. The genomic landscapes of metastatic colorectal cancer (mCRC) have been extensively studied; however, the genetic mechanisms underlying the locoregional recurrence (LR) of CRC remain unclear. The objective of our study was to investigate genomic evolution during LR in CRC using high-throughput sequencing. Methods:. Twenty-three CRC patients with matched primary and LR tissues were recruited from Nanfang Hospital and Zhejiang Cancer Hospital between January 2011 and December 2018. The last date of follow-up was March 2020. Tissue samples were analyzed by whole-exome sequencing and the genomic profiles were depicted by single nucleotide variation, mutational signature, copy number variation, clonal architecture, and other features. The evolutionary process was speculated with comparison of the genetic variations between primary and LR lesions. The disseminating clusters from primary to LR lesions were identified by variant allele frequency dynamics. Furthermore, the early-recurrent biomarker was explored by comparing the indel signature between early- and late-recurrent patients. The study was approved by the Institutional Review Board of Nanfang Hospital of Southern Medical University (approval No. 2020010) on September 11, 2020. Results:. The results highlighted distinct origins of LR between patients with high microsatellite instability and microsatellite stability. LR lesions evolved independently in patients with high microsatellite instability, while LR lesions were highly clonally related to the primary lesions in patients with microsatellite stability. Late-acquired variations in LR lesions encompassed a wide range of driver genes involved in histone methylation, DNA replication, T cell activation, PDCD1 gain, and LMNA loss. Furthermore, clonal analysis of the disseminating cells identified a dominant polyclonal seeding pattern during LR. The indel signature ID4 was associated with significantly shorter disease-free survival in patients with relapsed CRC according to a public dataset. Conclusion:. These findings pose a challenge for the development of new approaches targeting the interactions of multiple clones in the establishment of LR and in terms of optimizing the clinical management of susceptible patients.