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Objective·To investigate the safety and feasibility of early goal-directed mobilization in the recovery of gastrointestinal function after pancreaticoduodenectomy.Methods·The non-contemporaneous controlled studies were conducted. Subjects who underwent pancreaticoduodenectomy were included. From Sep 2022 to May 2023, forty patients were selected as the control group, and forty patients were selected from June 2023 to February 2024 as the experimental group. The general clinical data of the two groups were collected. The control group was treated with the nursing routine after pancreaticoduodenectomy, and there were no specific requirements for the time and goal of early activity. The experimental group had daily activity goals established for early mobilization, which were performed by the patients and their families, while the rest of their care was identical to that of the control group. The main index of effectiveness evaluation was the time of first flatus and first defecation, and the secondary indexes included the time of first getting out of bed, the time of oral drinking, the time of the gastric tube removal, and the postoperative levels of K+, Na+, and Cl- on the 3rd day of the postoperative period. Safety evaluations included chyle leak, postoperative pancreatic fistula, biliary leak and delayed gastric emptying, postoperative hemorrhage, unplanned reoperation, unplanned extubation, falls and death.Results·There was no statistically significant difference in the general clinical data of the patients in the 2 groups. After the implementation of early goal-directed mobilization, the time of first flatus was advanced from (3.95±1.68) d to (2.88±0.91) d (t=-3.560, P=0.001), and the time of first defecation was advanced from (4.90±1.61) d to (3.80±1.30) d (t=-3.352, P=0.001). The time of first getting out of bed was advanced from (5.18±1.77) d to (2.30±0.88) d (t=-9.205, P

Abstract Objectives To develop and validate a quantitative model for predicting serosal invasion based on multi-parameters in preoperative dual-energy CT (DECT). Materials and methods A total of 342 LAGC patients who underwent gastrectomy and DECT from six centers were divided into one training cohort (TC), and two validation cohorts (VCs). Dual-phase enhanced DECT-derived iodine concentration (IC), water concentration, and monochromatic attenuation of lesions, along with clinical information, were measured and collected. The independent predictors among these characteristics for serosal invasion were screened with Spearman correlation analysis and logistic regression (LR) analysis. A quantitative model was developed based on LR classifier with fivefold cross-validation for predicting the serosal invasion in LAGC. We comprehensively tested the model and investigated its value in survival analysis. Results A quantitative model was established using IC, 70 keV, 100 keV monochromatic attenuations in the venous phase, and CT-reported T4a, which were independent predictors of serosal invasion. The proposed model had the area-under-the-curve (AUC) values of 0.889 for TC and 0.860 and 0.837 for VCs. Subgroup analysis showed that the model could well discriminate T3 from T4a groups, and T2 from T4a groups in all cohorts (all p

Abstract This study investigated the effects of heat shock protein 22 (HSP22) against doxorubicin (DOX)-induced kidney injury. Mice were randomly assigned to four groups: CON, ad-HSP22, DOX, and ad-HSP22 + DOX. Adeno-associated virus carrying the HSP22 gene (ad-HSP22) was administered via tail vein injection for four weeks, followed by intraperitoneal simulation with DOX (20 mg/kg) for another five days. Upon euthanasia, ELISA, histological staining (H&E, IHC, DHE, and TUNEL), and western blot analyses were employed to assess relevant markers. Serum biomarkers of kidney injury, SCr, and BUN, were upregulated after DOX administration but normalized with HSP22 overexpression. Pathological changes induced by DOX were also reversed by HSP22 overexpression in H&E, IHC, DHE, and TUNEL stains. DOX-induced upregulation of NOX-2 and NOX-4 and downregulation of SOD-1 and SOD-2 were reversed by HSP22 overexpression. Similarly, DOX-induced increases in Bax and decrease in Bcl-2 were attenuated by HSP22 overexpression. The study further demonstrated that the Nrf2/HO-1 signaling pathway was activated by HSP22 overexpression. In vitro experiments corroborated the findings from in vivo experiments. In conclusion, HSP22 alleviates DOX-induced kidney injury by suppressing oxidative stress and apoptosis, primarily through the activation of the Nrf2/HO-1 signaling pathway. These results suggest HSP22 as a potential therapeutic target for DOX-induced kidney injury.

Abstract Circular RNAs (circRNAs) are a type of regulatory RNA that feature covalently closed single-stranded loops. Evidence suggested that circRNAs play important roles in the progression and development of various cancers. However, the impact of circRNA on autophagy-mediated progression of colorectal cancer (CRC) remains unclear. The objective of this project was to investigate the influence of circSEC24B on autophagy and its underlying mechanisms in CRC. To validate the presence and circular structure of circSEC24B in CRC cells and tissues, PCR and Sanger sequencing techniques were employed. Drug resistance and invasive phenotype of CRC cells were evaluated using CCK8, transwell, and Edu assays. Gain- and loss-of-function experiments were conducted to assess the effects of circSEC24B and its protein partner on the growth, invasion, and metastasis of CRC cells in vitro and in vivo. Interactions between circSEC24B, OTUB1, and SRPX2 were analyzed through immunofluorescence, RNA-pulldown, and RIP assays. Mass spectrometry analysis was used to identify potential binding proteins of circRNA in CRC cells. Vectors were constructed to investigate the specific structural domain of the deubiquitinating enzyme OTUB1 that binds to circSEC24B. Results showed that circSEC24B expression was increased in CRC tissues and cell lines, and it enhanced CRC cell proliferation and autophagy levels. Mechanistically, circSEC24B promoted CRC cell proliferation by regulating the protein stability of SRPX2. Specifically, circSEC24B acted as a scaffold, facilitating the binding of OTUB1 to SRPX2 and thereby enhancing its protein stability. Additionally, evidence suggested that OTUB1 regulated SRPX2 expression through an acetylation-dependent mechanism. In conclusion, this study demonstrated that circSEC24B activated autophagy and induced chemoresistance in CRC by promoting the deubiquitination of SRPX2, mediated by the deubiquitinating enzyme OTUB1.

Metal injection molding of aluminium alloy (MIM-Al) attracts attention, owing to the lightweight, corrosion resistance and good thermal conductivity. However, it is hard to fabricate high-quality MIM-Al due to the hard-to-sinter powder and poor mechanical properties. Here, we report a facile compression molding process for fabricating high-density 7075Al alloy parts using polyformaldehyde (POM)-based feedstock. Pressureless sintering with a high nitrogen flow rate was adopted to promote sintering densification process. The wetting behavior, rheological properties, and morphology of the feedstock were characterized, showcasing the shear-thinning behavior and suitable viscosity for POM-PP-SA binder. Through controlling the compact pressure, mold temperature and holding time, green gear part with good shape retention and dense microstructure was achieved. Influence of process factors and sintering temperature on the microstructure and mechanical properties of 7075Al alloy are investigated. Remarkably, the aluminum alloy components sintered at 610 °C exhibited excellent performance, with a relative density reaching 97.6 % and a tensile strength of 214.8 MPa. This achievement provides a foundation for the industrial application of complex-shaped aluminum alloy components through the compression molding process.

Abstract Regulated cell death (RCD) plays a crucial role in the immune microenvironment, development, and progression of hepatocellular carcinoma (HCC). However, reliable immune-related cell death signatures have not been explored. In this study, we collected 12 RCD modes (e.g., apoptosis, ferroptosis, and cuproptosis), including 1078 regulators, to identify immune-related cell death genes based on HCC immune subgroups. Using a developed competitive machine learning framework, nine genes were screened to construct the immune-related cell death index (IRCDI), which is available for online application. Multi-omics data, along with clinical features, were analyzed to explore the HCC malignant heterogeneity. To validate the efficacy of this model, more than 18 independent cohorts, including survival and diverse treatment cohorts and datasets, were utilized. These findings were further validated using in-house samples and molecular biological experiments. Overall, the IRCDI may have a wide application in individual therapeutic decision-making and improving outcomes for HCC patients.

Immunotherapy, represented by immune checkpoint inhibitors, may lead to immune-related adverse events (irAEs) while demonstrating favorable efficacy in patients with malignant tumors. Many domestic and international guidelines or consensus have been established to assist clinicians in effectively managing the majority of irAEs. However, further exploration about irAEs is required regarding the definition and determination, temporal patterns, individual variances, utilization of hormones and immunosuppressants, correlation between irAEs and therapeutic outcomes, immune reactivation, and special populations. The identification and management of severe, refractory, and multiple irAEs necessitate additional solutions. This paper aims to clarify 10 prominent issues concerning irAEs individually and provide assistance for clinicians.

Abstract Reading difficulty (RD) is associated with phonological deficits; however, it remains unknown whether the phonological deficits are different in children and adults with RD as reflected in foreign speech perception and production. In the current study, using functional Near-infrared spectroscopy (fNIRS), we found less difference between Chinese adults and Chinese children in the RD groups than the control groups in the activation of the right inferior frontal gyrus (IFG) and the dorsolateral prefrontal cortex (DLPFC) during Spanish speech perception, suggesting slowed development in these regions associated with RD. Furthermore, using multivariate pattern analysis (MVPA), we found that activation patterns in the left middle temporal gyrus (MTG), premotor, supplementary motor area (SMA), and IFG could serve as reliable markers of RD. We provide both behavioral and neurological evidence for impaired speech perception and production in RD readers which can serve as markers of RD.

Abstract For patients presenting with prostate imaging reporting and data system (PI-RADS) 3/4 findings on magnetic resonance imaging (MRI) examinations, the standard recommendation typically involves undergoing a biopsy for pathological assessment to ascertain the nature of the lesion. This course of action, though essential for accurate diagnosis, invariably amplifies the psychological distress experienced by patients and introduces a host of potential complications associated with the biopsy procedure. However, [18F]DCFPyL PET/CT imaging emerges as a promising alternative, demonstrating considerable diagnostic efficacy in discerning benign prostate lesions from malignant ones. This study aims to explore the diagnostic value of [18F]DCFPyL PET/CT imaging for prostate cancer in patients with PI-RADS 3/4 lesions, assisting in clinical decision-making to avoid unnecessary biopsies. 30 patients diagnosed with PI-RADS 3/4 lesions through mpMRI underwent [18F]DCFPyL PET/CT imaging, with final biopsy pathology results as the “reference standard”. Diagnostic performance was assessed through receiver operating characteristic (ROC) analysis, evaluating the diagnostic efficacy of molecular imaging PSMA (miPSMA) visual analysis and semi-quantitative analysis in [18F]DCFPyL PET/CT imaging. Lesions were assigned miPSMA scores according to the prostate cancer molecular imaging standardized evaluation criteria. Among the 30 patients, 13 were pathologically confirmed to have prostate cancer. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of visual analysis in [18F]DCFPyL PET/CT imaging for diagnosing PI-RADS 3/4 lesions were 61.5%, 88.2%, 80.0%, 75.0%, and 76.5%, respectively. Using SUVmax 4.17 as the optimal threshold, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for diagnosis were 92.3%, 88.2%, 85.7%, 93.8%, and 90.0%, respectively. The area under the ROC curve (AUC) for semi-quantitative analysis was 0.94, significantly higher than visual analysis at 0.80. [18F]DCFPyL PET/CT imaging accurately diagnosed benign lesions in 15 (50%) of the PI-RADS 3/4 patients. For patients with PI-RADS 4 lesions, the positive predictive value of [18F]DCFPyL PET/CT imaging reached 100%. [18F]DCFPyL PET/CT imaging provides potential preoperative prediction of lesion nature in mpMRI PI-RADS 3/4 patients, which may aid in treatment decision-making and reducing unnecessary biopsies.

Rock discontinuity information plays a key role in engineering activities. In severely fragmented and discontinuous samples, the identification accuracy of rock discontinuities can be improved with the help of geologic knowledge with identified spatial features and geoscience interaction mechanisms. Therefore, we proposed a new method – a knowledge-based intelligent recognition method for rock discontinuities that used point cloud data – to correct inaccurate identification by considering the spatial relationships of rock discontinuities. This paper integrated the geologic knowledge bases in rock discontinuity information extraction rules and combined the generative rule inference model with the region growing method for intelligent extraction. In the case study, we developed four typical rule sets as examples based on the constructed rule system to group rock discontinuities and subsume the fractured rock discontinuities. Results show that this new method is effective in identifying and classifying rock discontinuities of complex areas with a greater reduction in manual intervention.

Objective·To establish the early symptom network of adult intensive care unit (ICU) patients after transfer (post-ICU patients), identify the core symptoms and bridge symptoms, compare the symptom networks of two subgroups, i.e. mixed ICU and coronary care unit (CCU), and analyze the occurrence of symptoms.Methods·From December 2022 to August 2023, a total of 328 adult patients transferred to wards from mixed ICU and CCU of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine were selected by convenience sampling. The general situation and clinical data questionnaire, and symptom questionnaires (including Hospital Anxiety and Depression Scale, Fatigue Severity Scale, Richards-Campbell Sleep Questionnaire, and Pain Numeric Rating Scale) were used. Based on Spearman correlation analysis and GLASSO algorithm, contemporaneous symptom network was built, and centrality indices and differences between subgroup symptom networks were computed. The edge accuracy and the stability of centrality indices of the network were tested.Results·A total of 302 valid questionnaires were collected, and the effective rate was 92.1%. The results of the centrality indices computations showed that in the early symptom network of post-ICU patients, the highest strength was “feel cheerful” (rS=1.145), the highest closeness was “enjoy something” (rC=1.851×10-3), and the highest expected influence was “（fatigue） interferes with physical function” (rE=1.143). The top three highest bridge strengths of symptoms were “worrying thoughts” (rb=10.392), “enjoy something” (rb=10.359), and pain (rb=10.221). There were no significant differences in network structure (M=0.289) and overall connection strength (GSmixed ICU=13.876, GSCCU=13.838; S=0.039) of the early symptom networks between mixed ICU and CCU patients after being transferred to wards. When comparing the centrality indices, apart from the strength and expected influence of five symptoms showing statistically significant differences (all P

Abstract Various noncollinear spin textures and magnetic phases have been predicted in twisted two-dimensional CrI3 due to competing ferromagnetic (FM) and antiferromagnetic (AFM) interlayer exchange from moiré stacking—with potential spintronic applications even when the underlying material possesses a negligible Dzyaloshinskii–Moriya or dipole–dipole interaction. Recent measurements have shown evidence of coexisting FM and AFM layer order in small-twist-angle CrI3 bilayers and double bilayers. Yet, the nature of the magnetic textures remains unresolved and possibilities for their manipulation and electrical readout are unexplored. Here, we use tunneling magnetoresistance to investigate the collective spin states of twisted double-bilayer CrI3 under both out-of-plane and in-plane magnetic fields together with detailed micromagnetic simulations of domain dynamics based on magnetic circular dichroism. Our results capture hysteretic and anisotropic field evolutions of the magnetic states and we further uncover two distinct non-volatile spin textures (out-of-plane and in-plane domains) at ≈1° twist angle, with a different global tunneling resistance that can be switched by magnetic field.

Abstract The membrane-delimited receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2 (ACE2), which is expressed in the intestine, collaborates with broad neutral amino acid transporter 1 (B0AT1). Tryptophan (Trp) is transported into intestinal epithelial cells by ACE2 and B0AT1. However, whether ACE2 and its binding protein B0AT1 are involved in Trp-mediated alleviation of intestinal injury is largely unknown. Here, we used weaned piglets and IPEC-J2 cells as models and found that ACE2/B0AT1 alleviated lipopolysaccharide (LPS)-induced diarrhea and promoted intestinal barrier recovery via transport of Trp. The levels of the aryl hydrocarbon receptor (AhR) and mechanistic target of rapamycin (mTOR) pathways were altered by ACE2. Dietary Trp supplementation in LPS-treated weaned piglets revealed that Trp alleviated diarrhea by promoting ACE2/B0AT1 expression, and examination of intestinal morphology revealed that the damage to the intestinal barrier was repaired. Our study demonstrated that ACE2 accompanied by B0AT1 mediated the alleviation of diarrhea by Trp through intestinal barrier repair via the mTOR pathway.

The gut microbiota is implicated in the pathogenesis of hyperuricemia (HUA) and gout. However, it remains unclear whether probiotics residing in the host gut, such as Lactobacillus, can prevent HUA development. Herein, we isolated Lactobacillus plantarum SQ001 from the cecum of HUA geese and conducted in vitro assays on uric acid (UA) and nucleoside co-culture. Metabolomics and genome-wide analyses, revealed that this strain may promote nucleoside uptake and hydrolysis through its nucleoside hydrolase gene. The functional role of iunH gene was confirmed via heterologous expression and gene knockout studies. Oral administration of L. plantarum SQ001 resulted in increased abundance of Lactobacillus species and reduced serum UA levels. Furthermore, it downregulated hepatic xanthine oxidase, a key enzyme involved in UA synthesis, as well as renal reabsorption protein GLUT9, while enhancing the expression of renal excretion protein ABCG2. Our findings suggest that L. plantarum has potential to ameliorate gut microbial dysbiosis with HUA, thereby offering insights into its potential application as a probiotic therapy for individuals with HUA or gout.

BackgroundMonoclonal antibodies against programmed cell death protein-1 (PD-1)/programmed death-ligand-1 (PD-L1) have emerged as critical tools in cancer treatment. However, concerns regarding their potential cutaneous and mucosal toxicity, along with severe complications, have drawn clinical attention. Further research is warranted to investigate the adverse reactions and treatment strategies associated with PD-1 monoclonal antibodies.MethodsWe present a detailed case report of a laryngeal cancer patient who developed toxic epidermal necrolysis (TEN) after treatment with PD-1 monoclonal antibody. We analyzed the etiology, diagnosis, and treatment approaches by integrating clinical manifestations, pathological examinations, and literature research.ResultsAfter PD-1 monoclonal antibody therapy, the patient exhibited systemic rash, bullae, and epidermal detachment, which subsequently involved the tracheal and bronchial mucosa, resulting in dyspnea. The patient recovered after treatments with steroids, macrolides, immunoglobulins, and etanercept, along with repeated removal of scabs via bronchoscopy. Literature reviewing suggests a potential association between PD-1 monoclonal antibodies and the pathogenesis of Steven Johnson’s Syndrome (SJS) and Toxic epidermal necrolysis (TEN), possibly due to immune dysregulation. Treatment consists of immediate discontinuation of suspicious drugs, essential supportive therapy, and systemic corticosteroid administration, with the addition of immunosuppressants and/or immunoglobulins needed.ConclusionThe mucocutaneous toxicity induced by PD-1 monoclonal antibodies is not limited to the surface of the skin but also in deep mucosal layers, potentially leading to life-threatening complications. Therefore, when using PD-1 monoclonal antibodies, clinicians should closely monitor adverse events and apply appropriate treatments as soon as possible to prevent severe complications.

BackgroundThe incidence of gastric cancer is concomitantly rising with gastric cardia cancer worldwide. While the improvement of gastric cancer surgical techniques is glowing, this study assesses the impact of the upper margin length and tumor size on the survival rate for gastric cardia cancer patients who underwent total laparoscopic total gastrectomy(TLTG) or laparoscopic assisted total gastrectomy(LATG).Materials and methodsA total of 63 patients with gastric cardia cancer who underwent laparoscopic total gastrectomy were retro-prospectively collected from January 2021 to May 2023. While assessing the impact of upper margin length and tumor size on the survival rate, esophagojejunostomy using a linear stapler has been compared to a circular stapler.ResultsThe sixty-three patients met inclusion criteria; 32 (51%) underwent LATG and 31 (49%) underwent TLTG. Their mean age was 65 years (range, 45–77). The blood loss means in LATG and TLTG was 74.69 and 50.16 ml, respectively (p = 0.005), and surgery duration was higher in LATG than LATG with respective means of 247 min and 222.42 min. (p = 0.006). However, the tumor size means (p = 0.5), and upper margin length means (p = 0.052) were not significantly different in the LATG and TLTG groups, respectively. The number of resected and assessed lymph node was adequate in the LATG and TLTG groups. The current study still does not find an independent related risk from the upper margin length and tumor size to the survival rate according to the multiple regression analysis (p = 0.080).ConclusionThe upper margin length and tumor size do not have a relationship with the survival rate of the compared esophagojejunostomy (EJS) methods. The EJS using a linear stapler requires a shorter surgery duration and less blood loss than EJS using a circular stapler.

BackgroundA definite diagnosis goes undiscovered for a percentage of children with undiagnosed disorders, with significant medical, psychological, and social effects. Other than specialized clinical centers, exceptional molecular studies, common procedures, and devoted activities at the national and international levels, children with complex undiagnosed disorders require innovative approaches.MethodsIn March 2016, Children’s hospital of Fudan university represented the Children’s Undiagnosed Diseases Program (UDP). The purpose of this study is to describe the project findings and underline the critical significance of multidisciplinary teamwork in China’s undiagnosed rare illnesses program. We investigated the 758 cases in our UDP system retrospectively. Demographic information, laboratory test results, and genetic information were gathered.ResultsBetween January 2017 and December 2021, 758 cases were examined. Males made up 436 (57.5%) of the total. Over half of the patients were children under the age of five. The average patient course time preceding admission to UDP was 6.0 months (95% CI 10.512.6). These patients visited an average of 1.8 clinics during their diagnostic journey. Except for 69 individuals (90.9%), all had more than one presenting symptom in various organs: 460 (60.7%) had neurology difficulties, 151 (19.9%) had endocrine problems, and 141 (18.6%) had immunology problems. UDP has a diagnosis rate of 61.3%. Genetic testing was performed on 469 of the 758 patients, for a genetic diagnosis rate of 15.8%. The UDP method has a sensitivity of 94.5%, a specificity of 86.4%, a positive predictive value of 92.8%, and an negative predictive value of 89.5%.ConclusionOur UDP targets an unmet need, namely the diagnosis of patients with complicated, multisystem illnesses. Using a multidisciplinary team model approach, this UDP pilot study achieved a reasonable diagnosis success rate, increasing the possibility of more diagnoses and new scientific discoveries of difficult and rare diseases.

This is an article in the field of ceramics and composites. In order to improve the impermeability and microstructure of the impermeable wall materials, four kinds of calcium-based bentonite modified and filling material with different dosages were prepared under the action of alkali excitation reaction. The modified and filling material samples in the curing process were tested by flexible wall penetration (FWPT), nuclear magnetic resonance (NMR) scanning and electron microscope scanning (SEM). The results show that the permeability coefficient of filling material samples decreases first and then increases with the increase of bentonite content, and reaches a minimum value when the content of bentonite is 4%. The relaxation time (T2) distribution curves of the filled material specimens after curing from 1 to 28 d were all bimodal, with more than 80% of the peaks representing small pores, and the percentage of the peaks representing large pores decreasing with the increase of curing time. According to SEM images, it can be seen that a certain amount of calcium bentonite can promote the occurrence of hydration reaction, and the porosity of the material is significantly reduced. At 4% phosphate slag, the cementitious filler has the best compactness and better impermeability and strength. Accordingly, it can be determined that the better dosage of phosphate slag modified cementitious filler is 4%.

Abstract Hyperuricemia (HUA) is a metabolic syndrome caused by abnormal purine metabolism. Although recent studies have noted a relationship between the gut microbiota and gout, whether the microbiota could ameliorate HUA-associated systemic purine metabolism remains unclear. In this study, we constructed a novel model of HUA in geese and investigated the mechanism by which Lactobacillus rhamnosus GG (LGG) could have beneficial effects on HUA. The administration of antibiotics and fecal microbiota transplantation (FMT) experiments were used in this HUA goose model. The effects of LGG and its metabolites on HUA were evaluated in vivo and in vitro. Heterogeneous expression and gene knockout of LGG revealed the mechanism of LGG. Multi-omics analysis revealed that the Lactobacillus genus is associated with changes in purine metabolism in HUA. This study showed that LGG and its metabolites could alleviate HUA through the gut-liver-kidney axis. Whole-genome analysis, heterogeneous expression, and gene knockout of LGG enzymes ABC-type multidrug transport system (ABCT), inosine-uridine nucleoside N-ribohydrolase (iunH), and xanthine permease (pbuX) demonstrated the function of nucleoside degradation in LGG. Multi-omics and a correlation analysis in HUA patients and this goose model revealed that a serum proline deficiency, as well as changes in Collinsella and Lactobacillus, may be associated with the occurrence of HUA. Our findings demonstrated the potential of a goose model of diet-induced HUA, and LGG and proline could be promising therapies for HUA.

Breast cancer (BC) is a complex and heterogeneous disease including different biological subtypes. This results in molecular and phenotypic heterogeneity within the BC. Stratification of tumors contributed to achieving better outcome in terms of response to therapy and overall survival. Little is known about the features of clonal heterogeneity in different lesion in BC patient. We reported a case of a 52-year-old woman who was diagnosed with luminal B (HER2−) BC and accepted chemotherapy. She achieved partial response based on RECIST 1.1 criteria. However, progressive disease (PD) was then identified with multiple subtypes including luminal B and triple-negative breast cancer (TNBC). Next-generation sequencing (NGS) technologies showed that the different regions of diseased tissue were originated from same clonal genes. We also demonstrated the clonal heterogeneity and gene characterization between lesions of luminal B and TNBC. The patient archived complete remission (CR) with a clear beneficial outcome from immunotherapy treatment. In addition, tumour mutational burden (TMB) and DNA damage repair (DDR) pathway were considered as potential biomarkers for better prediction of tumor immunotherapy efficacy.

Background: Acute myeloid leukemia (AML) with t(8;21) manifests as a diverse hematological malignancy. Although it was categorized into a favorable subtype, 30–40% of patients experience relapse. The objective of this research was to devise a nomogram for the accurate anticipation of both overall survival (OS) and cancer-specific survival (CSS) in t(8;21) AML.Methods: From the Surveillance, Epidemiology, and End Results (SEER) database, individuals diagnosed with t(8;21) AML from 2000 to 2018 were selected. Prognostic factors for t(8;21) AML were identified using Cox regression analysis and Akaike Information Criterion (AIC), forming the basis for constructing prognostic nomograms.Results: Key variables, including first primary tumor, age group, race, and chemotherapy, were identified and integrated into the nomogram. The C-index values for the nomograms predicting OS and CSS were 0.753 (validation: 0.765) and 0.764 (validation: 0.757), respectively. Ultimately, based on nomogram scores, patients were stratified into high-risk and low-risk groups, revealing significant disparities in both OS and CSS between these groups (P

Conventional practices in earth construction, such as cement stabilization and the energy-intensive firing of bricks, contribute significantly to carbon emissions due to the processes involved in cement production and kiln operation. Additionally, concerns over the low strength of earth-based materials have limited their broader applications. This research addresses these challenges by implementing ultra-high pressures (200 MPa and 400 MPa) and bio-binders (animal glue and xanthan gum) to enhance earth materials for construction. Unstabilized earth mixture and normal pressure case (20 MPa) are also included in this study for comparison. A custom-designed mold and a specialized production process are developed to fabricate cylindrical earth samples for testing. After undergoing three hours of consolidation and 28 days of curing, unconfined compressive strengths are measured. Scanning electron microscopy is used to investigate the influence of ultra-high pressures and bio-binders on the microstructures of compressed earth blocks. The experimental results demonstrate that animal-glue- and xanthan-gum-stabilized samples under ultra-high pressure achieve compressive strengths comparable to traditional fired bricks, while unstabilized samples exhibit the strength of cement-stabilized rammed earth. This research demonstrates that ultra-compression combined with bio-binder stabilization presents a viable strategy for reducing the carbon footprint of earth construction while significantly enhancing the mechanical properties.

ABSTRACT Streptococcus suis type 2 (SS2) is a zoonotic pathogen capable of eliciting meningitis, presenting significant challenges to both the swine industry and public health. Suilysin (Sly), one of SS2 most potent virulence determinants, releases a surfeit of inflammatory agents following red blood cell lysis. Notably, while current research on Sly role in SS2-induced meningitis predominantly centers on its interaction with the blood-brain barrier (BBB), the repercussions of Sly hemolytic products on BBB function have largely been sidestepped. In this vein, our study delves into the ramifications of Sly-induced hemolysis on BBB integrity. We discern that Sly hemolytic derivatives exacerbate the permeability of Sly-induced in vitro BBB models. Within these Sly hemolytic products, Interleukin-33 (IL-33) disrupts the expression and distribution of Claudin-5 in brain microvascular endothelial cells, facilitating the release of Interleukin-6 (IL-6) and Interleukin-8 (IL-8), thereby amplifying BBB permeability. Preliminary mechanistic insights suggest that IL-33-driven expression of IL-6 and IL-8 is orchestrated by the p38-mitogen-activated protein kinase signaling, whereas matrix metalloproteinase 9 mediates IL-33-induced suppression of Claudin-5. To validate these in vitro findings, an SS2-infected mouse model was established, and upon intravenous administration of growth stimulation expressed gene 2 (ST2) antibodies, in vivo results further underscored the pivotal role of the IL-33/ST2 axis during SS2 cerebral invasion. In summation, this study pioneerly illuminates the involvement of Sly hemolytic products in SS2-mediated BBB compromise and spotlights the instrumental role and primary mechanism of IL-33 therein. These insights enrich our comprehension of SS2 meningitis pathogenesis, laying pivotal groundwork for therapeutic advancements against SS2-induced meningitis.IMPORTANCEThe treatment of meningitis caused by Streptococcus suis type 2 (SS2) has always been a clinical challenge. Elucidating the molecular mechanisms by which SS2 breaches the blood-brain barrier (BBB) is crucial for the development of meningitis therapeutics. Suilysin (Sly) is one of the most important virulence factors of SS2, which can quickly lyse red blood cells and release large amounts of damage-associated molecular patterns, such as hemoglobin, IL-33, cyclophilin A, and so on. However, the impact of these hemolytic products on the function of BBB is unknown and ignored. This study is the first to investigate the effect of Sly hemolytic products on BBB function. The data are crucial for the study of the pathogenesis of SS2 meningitis and can provide an important reference for the development of meningitis therapeutics.

BackgroundSarcopenia is linked to an unfavorable prognosis in individuals with rheumatoid arthritis (RA). Early identification and treatment of sarcopenia are clinically significant. This study aimed to create and validate a nomogram for predicting sarcopenia risk in RA patients, providing clinicians with a reliable tool for the early identification of high-risk patients.MethodsPatients with RA diagnosed between August 2022 and January 2024 were included and randomized into training and validation sets in a 7:3 ratio. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis and multifactorial logistic regression analysis were used to screen the risk variables for RA-associated muscle loss and to create an RA sarcopenia risk score. The predictive performance and clinical utility of the risk model were evaluated by plotting the receiver operating characteristic curve and calculating the area under the curve (AUC), along with the calibration curve and clinical decision curve (DCA).ResultsA total of 480 patients with RA were included in the study (90% female, with the largest number in the 45–59 age group, about 50%). In this study, four variables (body mass index, disease duration, hemoglobin, and grip strength) were included to construct a nomogram for predicting RA sarcopenia. The training and validation set AUCs were 0.915 (95% CI: 0.8795–0.9498) and 0.907 (95% CI: 0.8552–0.9597), respectively, proving that the predictive model was well discriminated. The calibration curve showed that the predicted values of the model were basically in line with the actual values, demonstrating good calibration. The DCA indicated that almost the entire range of patients with RA can benefit from this novel prediction model, suggesting good clinical utility.ConclusionThis study developed and validated a nomogram prediction model to predict the risk of sarcopenia in RA patients. The model can assist clinicians in enhancing their ability to screen for RA sarcopenia, assess patient prognosis, make early decisions, and improve the quality of life for RA patients.

Background: Sepsis, a severe infectious disease, carries a high mortality rate. Early detection and prompt treatment are crucial for reducing mortality and improving prognosis. The aim of this research is to develop a clinical prediction model using machine learning algorithms, leveraging complete blood cell (CBC) parameters, to detect sepsis at an early stage. Methods: The study involved 572 patients admitted to West China Hospital of Sichuan University between July 2020 and September 2021. Among them, 215 were diagnosed with sepsis, while 357 had local infections. Demographic information was collected, and 57 CBC parameters were analyzed to identify potential predictors using techniques such as the Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest (RF), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost). The prediction model was built using Logistic Regression and evaluated for diagnostic specificity, discrimination, and clinical applicability including metrics such as the area under the curve (AUC), calibration curve, clinical impact curve, and clinical decision curve. Additionally, the model's diagnostic performance was assessed on a separate validation cohort. Shapley's additive explanations (SHAP), and breakdown (BD) profiles were used to explain the contribution of each variable in predicting the outcome. Results: Among all the machine learning methods' prediction models, the LASSO-based model (λ = min) demonstrated the highest diagnostic performance in both the discovery cohort (AUC = 0.9446, P

Abstract Activating autologous stem cells after the implantation of biomaterials is an important process to initiate bone regeneration. Although several studies have demonstrated the mechanism of biomaterial‐mediated bone regeneration, a comprehensive single‐cell level transcriptomic map revealing the influence of biomaterials on regulating the temporal and spatial expression patterns of mesenchymal stem cells (MSCs) is still lacking. Herein, the osteoimmune microenvironment is depicted around the classical collagen/nanohydroxyapatite‐based bone repair materials via combining analysis of single‐cell RNA sequencing and spatial transcriptomics. A group of functional MSCs with high expression of matrix Gla protein (Mgp) is identified, which may serve as a pioneer subpopulation involved in bone repair. Remarkably, these Mgp high‐expressing MSCs (MgphiMSCs) exhibit efficient osteogenic differentiation potential and orchestrate the osteoimmune microenvironment around implanted biomaterials, rewiring the polarization and osteoclastic differentiation of macrophages through the Mdk/Lrp1 ligand–receptor pair. The inhibition of Mdk/Lrp1 activates the pro‐inflammatory programs of macrophages and osteoclastogenesis. Meanwhile, multiple immune‐cell subsets also exhibit close crosstalk between MgphiMSCs via the secreted phosphoprotein 1 (SPP1) signaling pathway. These cellular profiles and interactions characterized in this study can broaden the understanding of the functional MSC subpopulations at the early stage of biomaterial‐mediated bone regeneration and provide the basis for materials‐designed strategies that target osteoimmune modulation.

Abstract In this work, 2D ferromagnetic M3GeTe2 (MGT, M = Ni/Fe) nanosheets with rich atomic Te vacancies (2D‐MGTv) are demonstrated as efficient OER electrocatalyst via a general mechanical exfoliation strategy. X‐ray absorption spectra (XAS) and scanning transmission electron microscope (STEM) results validate the dominant presence of metal‐O moieties and rich Te vacancies, respectively. The formed Te vacancies are active for the adsorption of OH* and O* species while the metal‐O moieties promote the O* and OOH* adsorption, contributing synergistically to the faster oxygen evolution kinetics. Consequently, 2D‐Ni3GeTe2v exhibits superior OER activity with only 370 mV overpotential to reach the current density of 100 mA cm−2 and turnover frequency (TOF) value of 101.6 s−1 at the overpotential of 200 mV in alkaline media. Furthermore, a 2D‐Ni3GeTe2v‐based anion‐exchange membrane (AEM) water electrolysis cell (1 cm2) delivers a current density of 1.02 and 1.32 A cm−2 at the voltage of 3 V feeding with 0.1 and 1 m KOH solution, respectively. The demonstrated metal‐O coordination with abundant atomic vacancies for ferromagnetic M3GeTe2 and the easily extended preparation strategy would enlighten the rational design and fabrication of other ferromagnetic materials for wider electrocatalytic applications.

Background Examine how Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) can be used to manage patient safety and improve the standard of care for patients.Methods In order to improve key medical training in areas like surgical safety management, blood transfusion closed-loop management, drug safety management and identity recognition, we apply the TeamSTEPPS teaching methodology. We then examine the effects of this implementation on changes in pertinent indicators.Results Our hospital’s perioperative death rate dropped to 0.019%, unscheduled reoperations dropped to 0.11%, and defined daily doses fell to 24.85. Antibiotic usage among hospitalised patients declined to 40.59%, while the percentage of antibacterial medicine prescriptions for outpatient patients decreased to 13.26%. Identity recognition requirements were implemented at a rate of 94.5%, and the low-risk group’s death rate dropped to 0.01%. Critical transfusion episodes were less common, with an incidence of 0.01%. The physician’s TeamSTEPPS Teamwork Perceptions Questionnaire and Teamwork Attitudes Questionnaire scores dramatically improved following the TeamSTEPPS team instruction course.Conclusion An evidence-based team collaboration training programme called TeamSTEPPS combines clinical practice with team collaboration skills to enhance team performance in the healthcare industry and raise standards for medical quality, safety, and effectiveness.

Abstract Cyclic dimeric guanosine monophosphate (c-di-GMP) serves as a bacterial second messenger that modulates various processes including biofilm formation, motility, and host-microbe symbiosis. Numerous studies have conducted comprehensive analysis of c-di-GMP. However, the mechanisms by which certain environmental signals such as iron control intracellular c-di-GMP levels are unclear. Here, we show that iron regulates c-di-GMP levels in Pseudomonas aeruginosa by modulating the interaction between an iron-sensing protein, IsmP, and a diguanylate cyclase, ImcA. Binding of iron to the CHASE4 domain of IsmP inhibits the IsmP-ImcA interaction, which leads to increased c-di-GMP synthesis by ImcA, thus promoting biofilm formation and reducing bacterial motility. Structural characterization of the apo-CHASE4 domain and its binding to iron allows us to pinpoint residues defining its specificity. In addition, the cryo-electron microscopy structure of ImcA in complex with a c-di-GMP analog (GMPCPP) suggests a unique conformation in which the compound binds to the catalytic pockets and to the membrane-proximal side located at the cytoplasm. Thus, our results indicate that a CHASE4 domain directly senses iron and modulates the crosstalk between c-di-GMP metabolic enzymes.

Abstract Doxorubicin (DOX) is an effective anti-tumor drug accompanied with many side effects, especially heart injury. To explore what effects of sophocarpine (SOP) on DOX-induced heart injury, this study conducted in vivo experiment and in vitro experiment, and the C57BL/6J mice and the H9C2 cells were used. The experimental methods used included echocardiography, enzyme-linked immunosorbent assay (ELISA), dihydroethidium (DHE) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, western blotting and so on. Echocardiography showed that SOP alleviated DOX-induced cardiac dysfunction, as evidenced by the improvements of left ventricle ejection fraction and left ventricle fractional shortening. DOX caused upregulations of creatine kinase (CK), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), while SOP reduced these indices. The relevant stainings showed that SOP reversed the increases of total superoxide level induced by DOX. DOX also contribute to a higher level of MDA and lower levels of SOD and GSH, but these changes were suppressed by SOP. DOX increased the pro-oxidative protein level of NOX-4 while decreased the anti-oxidative protein level of SOD-2, but SOP reversed these effects. In addition, this study further discovered that SOP inhibited the decreases of Nrf2 and HO-1 levels induced by DOX. The TUNEL staining revealed that SOP reduced the high degree of apoptosis induced by DOX. Besides, pro-apoptosis proteins like Bax, cleaved-caspase-3 and cytochrome-c upregulated while anti-apoptosis protein like Bcl-2 downregulated when challenged by DOX, but them were suppressed by SOP. These findings suggested that SOP could alleviate DOX-induced heart injury by suppressing oxidative stress and apoptosis, with molecular mechanism activating of the Nrf2/HO-1 signaling pathway.

In this paper, we propose an analytical stochastic dynamic programming (SDP) algorithm to address the optimal management problem of price-maker community energy storage. As a price-maker, energy storage smooths price differences, thus decreasing energy arbitrage value. However, this price-smoothing effect can result in significant external welfare changes by reducing consumer costs and producer revenues, which is not negligible for the community with energy storage systems. As such, we formulate community storage management as an SDP that aims to maximize both energy arbitrage and community welfare. To incorporate market interaction into the SDP format, we propose a framework that derives partial but sufficient market information to approximate impact of storage operations on market prices. Then we present an analytical SDP algorithm that does not require state discretization. Apart from computational efficiency, another advantage of the analytical algorithm is to guide energy storage to charge/discharge by directly comparing its current marginal value with expected future marginal value. Case studies indicate community-owned energy storage that maximizes both arbitrage and welfare value gains more benefits than storage that maximizes only arbitrage. The proposed algorithm ensures optimality and largely reduces the computational complexity of the standard SDP.

Deploying 5G in new and diverse use cases, such as Industry 4.0 and factory automation, requires 5G systems to harmonize with the communication technologies used in these industries. To this end, 3GPP Release 16 and Release 17 have made significant progress in integrating 5G systems with the IEEE 802.1 working group specifications on Time-Sensitive Networking (TSN). This paper explains a method and architecture for supporting TSN over a wireless channel in a 5G network that adds the TSN synchronization function in a Small Cell gNB implementing the TSN Translator function (SC-TT). This TSN-capable small cell provides TSN over the wireless network to synchronize UEs with the Grand Master (GM) using the physical layer signal of the 5G radio frame and the transmission of the GM reference time to provide high-precision synchronization. This paper explores the pivotal role of a Slot Indicator Signal in enhancing synchronization precision, ensuring that the UE-GM synchronization occurs within an exceptionally narrow timeframe as small as 10 ns.

Abstract Background PD-1/PD-L1 play a crucial role as immune checkpoint inhibitors in various types of cancer. Although our previous study revealed that NPM1 was a novel transcriptional regulator of PD-L1 and stimulated the transcription of PD-L1, the underlying regulatory mechanism remains incompletely characterized. Methods Various human cancer cell lines were used to validate the role of NPM1 in regulating the transcription of PD-L1. The acetyltransferase NAT10 was identified as a facilitator of NPM1 acetylation by coimmunoprecipitation and mass spectrometry. The potential application of combined NAT10 inhibitor and anti-CTLA4 treatment was evaluated by an animal model. Results We demonstrated that NPM1 enhanced the transcription of PD-L1 in various types of cancer, and the acetylation of NPM1 played a vital role in this process. In particular, NAT10 facilitated the acetylation of NPM1, leading to enhanced transcription and increased expression of PD-L1. Moreover, our findings demonstrated that Remodelin, a compound that inhibits NAT10, effectively reduced NPM1 acetylation, leading to a subsequent decrease in PD-L1 expression. In vivo experiments indicated that Remodelin combined with anti-CTLA-4 therapy had a superior therapeutic effect compared with either treatment alone. Ultimately, we verified that the expression of NAT10 exhibited a positive correlation with the expression of PD-L1 in various types of tumors, serving as an indicator of unfavorable prognosis. Conclusion This study suggests that the NAT10/NPM1 axis is a promising therapeutic target in malignant tumors.

Highlights Sn-based MAX/MXene hybrids with abundant Sn vacancies, Sn@Ti2CT X /Ti2SnC–V, fabricated by controlled etching method, are demonstrated to be an excellent electrocatalyst for N2 electroreduction. An economic “NH3 farm” has been developed based on Sn@Ti2CT X /Ti2SnC–V electrode, demonstrated by a commercial electrochemical photovoltaic cell, which may open a novel avenue for solar energy-driven synthesis of ammonia directly from air and water. The potential of the “NH3 farm” was demonstrated by a systematic technical economic analysis.

Abstract Ferroptosis is a new type of iron-dependent programmed cell death induced by lipid peroxidation. However, the underlying mechanisms and function in tumor therapy still remain undisclosed especially in post-transcription regulation. Here, we found that targeting AKT significantly induced GPX4 dependent ferroptosis and suppressed colorectal cancer growth both in vitro and in vivo. During this process, demethylase FTO was downregulated, which increased the m6A methylation level of GPX4, subsequently recognized by YTHDF2 and degraded. Prediction results showed that there are three potential methylated sites (193/647/766), and 193 site was identified as the right one, which was demethylated by FTO and read by YTHDF2. In parallel, AKT inhibition caused the accumulation of ROS which had a negative feedback on GPX4 expression. In addition, protective autophagy was initiated by MK2206 stimulation, while blocking autophagy further increased ferroptosis and markedly enhanced the anti-tumor activity of MK2206. In a word, inhibiting AKT activated ferroptosis through FTO/YTHDF2/GPX4 axis to suppress colon cancer progression, which raised FTO/GPX4 as potential biomarkers and targets in colorectal cancer therapy.

Volume-phase holographic gratings are suitable for use in greenhouse gas detection imaging spectrometers, enabling the detection instruments to achieve high spectral resolution, high signal-to-noise ratios, and high operational efficiency. However, when utilized in the infrared wavelength band with high dispersion requirements, gratings struggle to meet the demands for low polarization sensitivity due to changes in diffraction performance caused by phase delays in the incidence of light waves with distinct polarization states, and current methods for designing bulk-phase holographic gratings require a large number of calculations that complicate the balance of diffraction properties. To overcome this problem, a design method for transmissive bulk-phase holographic gratings is proposed in this study. The proposed method combines two diffraction theories (namely, Kogelnik coupled-wave theory and rigorous coupled-wave theory) and establishes a parameter optimization sequence based on the influence of design parameters on diffraction characteristics. Kogelnik coupled-wave theory is employed to establish the initial Bragg angle range, ensuring that the diffraction efficiency and phase delay of the grating thickness curve meet the requirements for incident light waves in various polarization states. Utilizing rigorous coupled-wave theory, we optimize grating settings based on criteria such as a center wavelength diffraction efficiency greater than 95%, polarization sensitivity less than 10%, maximum bandwidth, and spectral diffraction efficiency exceeding 80%. The ideal grating parameters are ultimately determined, and the manufacturing tolerances for various grating parameters are analyzed. The design results show that the grating stripe frequency is 1067 lines per millimeter, and the diffraction efficiencies of TE and TM waves are 96% and 99.89%, respectively. The diffraction efficiency of unpolarized light is more than 88% over the whole spectral range with an average efficiency of 94.49%, an effective bandwidth of 32 nm, and a polarization sensitivity of less than 7%. These characteristics meet the performance requirements for dispersive elements based on greenhouse gas detection, the spectral resolution of the detection instrument is up to 0.1 nm, and the signal-to-noise ratio and working efficiency are improved by increasing the transmittance of the instrument.

Dihydroquercetin (DHQ) is commonly used as a dietary additive, but its activity in improving brain injury with metabolic syndrome (MS) remains known. In present study, the MS rat model was induced using 10 % fructose water. The apoptosis rate of primary brain cells was detected. The HIF-1α/AKT/NR2B signalling pathway, levels of KEAP1/NRF2, HO-1 and NQO-1 were detected. In vitro experiments were performed using H2O2-stimulated PC-12 cells. The effect of DHQ on rates of cell survival and apoptosis were detected. After silencing HIF-1α, we further elucidate the mechanism of action of DHQ. The results indicated that DHQ reduced the hyperactivity and inhibited oxidative stress via increasing the levels of HIF-1α/AKT/NR2B signalling pathway, whereas regulated KEAP1/NRF2 pathway. In vitro experiments showed that the HIF-1α plays an important role in this process. Overall, DHQ may improve impaired brain function in rats with metabolic syndrome by regulating the HIF-1α/AKT/NR2B signalling pathway.

IntroductionIn the process of comprehension, linguistic negation induces inhibition of negated scenarios. Numerous studies have highlighted the role of the right Inferior Frontal Gyrus (rIFG) - a key component of the inhibitory network - in negation processing. Social avoidance can be linguistically portrayed using attitudinal verbs such as “exclude” vs. “include”, which inherently carry negative connotations. Consequently, we hypothesize that the interplay between explicit negation and the implicit negativity of avoidance verbs can be modulated via transcranial direct current stimulation (tDCS) targeting the rIFG.MethodsIn our study, sixty-four participants read approach/avoidance sentences, which were either affirmative or negative, such as “Anne included (did not include) meat in her diet” vs. “Anne excluded (did not exclude) meat in her diet”. This reading task followed a 20-minute tDCS session. The sentences were sequentially displayed, and at 1500 ms post-sentence, a verb was shown – either the one previously mentioned or its semantic alternative counterpart (e.g., included vs. excluded).ResultsFindings revealed that anodal stimulation intensifies the inhibitory impact of negation during sentence comprehension. Under anodal conditions, negative sentences led to extended reading times for the mentioned verbs compared to their affirmative counterparts, suggesting an increased inhibitory effect on the verb. Furthermore, in avoidance sentences, anodal stimulation resulted in reduced reading times for alternative verbs (e.g. “included”) in negative sentences compared to alternative verbs (e.g. “excluded”) in negated approach sentences.DiscussionAs “avoidance” is semantically equivalent to “non-approach”, the inhibitory effect of negation is primarily applied to the implicit negation: NOT EXCLUDED = NOT→NOT (INCLUDED), which consequently activates the representation of the alternative verb making it more available. We further discuss these findings in light of the rIFG’s pivotal role in processing attitudinal verbs and linguistic negation. This discussion is framed within the overarching context of the two-step model of negation processing, highlighting its significance in the realm of social communication.

ABSTRACT: Ammonia (NH3) is a toxic gas that in intensive poultry houses, damages the poultry health and induces various diseases. This study investigated the effects of NH3 exposure (0, 15, 30, and 45 ppm) on growth performance, serum biochemical indexes, antioxidative indicators, tracheal and lung impairments in Pekin ducks. A total of 288 one-day-old Pekin male ducks were randomly allocated to 4 groups with 6 replicates and slaughtered after the 21-d test period. Our results showed that 45 ppm NH3 significantly reduced the average daily feed intake (ADFI) of Pekin ducks. Ammonia exposure significantly reduced liver, lung, kidney, and heart indexes, and lowered the relative weight of the ileum. With the increasing of in-house NH3, serum NH3 and uric acid (UA) concentrations of ducks were significantly increased, as well as liver malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPX-Px) contents. High NH3 also induced trachea and lung injury, thereby increasing levels of tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) in the lung, and decreasing the mRNA expressions of zonula occludens 1 (ZO-1) and claudin 3 (CLDN3) in the lung. In conclusion, in-house NH3 decrease the growth performance in ducks, induce trachea and lung injuries and meanwhile increase the compensatory antioxidant activity for host protection.

Introduction:Head and neck cancer is one of the most common tumors worldwide. However, drug resistance in its treatment has become a major factor limiting the efficacy. This study aims to comprehensively understand the current status of research in this field.Methods:The study analyzes papers related to therapeutic resistance in head and neck cancer published between 2000 and 2023 in the Web of Science Core Collection To achieve the research objectives, we searched the WoSCC for research and review papers on therapeutic resistance in head and neck cancer from 2000 to 2023, screened the English literature, and analyzed the research hotspots, academic collaborations, and trends in detail using tools such as Citespace, SCImago Graphica, and VOS viewer.Results:This study summarizes 787 head and neck cancer treatment resistance publications from WoSCC. The analysis showed that China and the United States are the major contributors in this field, and Grandis Jennifer R and Yang Jai-Sing are the key scholars. Keyword analysis showed that “cisplatin resistance” is a continuing focus of attention, while “Metastasis” and “Ferroptosis” may be emerging research hotspots. Literature clustering analysis pointed out that “Ferroptosis”, “Immunotherapy” and “ERK signaling” were the recent hotspots that received extensive attention and citations. Finally, we discuss the current status and challenges in drug-resistant therapies for head and neck cancer.Conclusion:This study is the first comprehensive bibliometric analysis of drug resistance in head and neck cancer. Reveals current trends and helps researchers grasp cutting-edge hotspots in the field.

Purpose: Helicobacter pylori (H. pylori) is a significant risk factor for development of gastric cancer (GC), one of the deadliest malignancies in the world. However, the mechanism by which H. pylori induces gastric oncogenesis remains unclear. Here, we investigated the function of IL-6 in gastric oncogenesis and macrophage-epithelial cell interactions. Methods: We analyzed publicly available datasets to investigate the expression of IL-6 and infiltration of M2 macrophages in GC tissues, and determine the inter-cellular communication in the context of IL-6. Human gastric epithelial and macrophage cell lines (GES-1 and THP-1-derived macrophages, respectively) were used in mono- and co-culture experiments to investigate autocrine-and paracrine induction of IL-6 expression in response to H. pylori or IL-6 stimulation. Results: We found that IL-6 is highly expressed in GC and modulates survival. M2 macrophage infiltration is predominant in GC and drives an IL-6 mediated communication with gastric epithelium cells. In vitro, IL-6 triggers its own expression in GES-1 and THP-1-derived macrophages cells. In addition, these cell lines are able to upregulate each other's IL-6 levels in an autocrine fashion, which is enhanced by H. pylori stimulation. Conclusion: This study indicates that IL-6 in the tumor microenvironment is essential for intercellular communication. We show that H. pylori enhances an IL-6-driven autocrine and paracrine positive feedback loop between macrophages and gastric epithelial cells, which may contribute to gastric carcinogenesis.

Background: EGFR and ERBB2 exon 20 insertion (Ex20ins) account for a small fraction of patients with EGFR mutations. The efficacy of immune checkpoint inhibitors (ICIs) for these patients was still controversial. Methods: This retrospective study enrolled lung cancer patients harboring either EGFR or ERBB2 Ex20ins mutations. All the patients were treated with platinum-based chemotherapy plus ICIs, or platinum-based chemotherapy. The demographic features and clinical outcome of each patient were reviewed and analyzed. Results: When treated with immunochemotherapy, patients with EGFR/ERBB2 Ex20ins mutations (n = 31) had poor PFS compared with those without EGFR mutations (n = 141, 5.0 mon and 11.2 mon, p < 0.001). When compared with those with EGFR classic mutations who received immunotherapy as the salvage therapy (n = 24), these patients with EGFR/ERBB2 Ex20ins mutations had similar PFS (5.0 mon and 4.1 mon, p = 0.625), ORR (37.5% vs. 48.4%), and DCR (70.8% vs. 77.4%). In the patients with EGFR/ERBB2 Ex20ins mutations, the PFS of those treated with chemotherapy (n = 54) and those treated with immunochemotherapy (n = 31) was 6.5 mon vs. 5.0 mon (p = 0.066). In the EGFR Ex20ins subgroup, the PFS of addition of bevacizumab to chemotherapy (n = 20) and chemotherapy alone (n = 16) was 8.8 mon and 5.2 mon, respectively (p = 0.082) or immunochemotherapy (n = 15, 8.8 mon and 5.0 mon, p = 0.097). Similarly, in the ERBB2 subgroup, the combination of bevacizumab and chemotherapy achieved a numerically longer PFS over chemotherapy alone (9.1 mon and 4.5 mon, p = 0.253), but there was no statistical significance. Conclusions: This study showed that platinum-based chemotherapy plus ICIs had limited efficiency compared to platinum-based chemotherapy for patients with EGFR/ERBB2 Ex20ins. Chemotherapy plus bevacizumab may be a potential scheme for these patients.

Abstract A two-stage computational framework is proposed to optimize the radiated noise and weight of a large mining planetary gear reducer under the rated conditions, based on a combination of response surface methodology and multi-objective optimization. The well-established transient dynamic analysis model of a large mining planetary gear reducer, which is used to analyze the mechanical strength and acoustic characteristics of the gear reducer. A unified experimental design is developed to obtain the response surface of the gearbox radiated noise and the mass of the gearbox housing. After obtaining the multi-objective optimization function, the multi-objective optimization problem for a lightweight and low-noise gearbox is performed using non-dominated sorting from the Genetic Algorithm II (NSGA-II). The research results demonstrates the effectiveness of the proposed optimization method in reducing vibrating amplitude and weight of the gearbox. This is crucial for minimizing energy consumption and enhancing the overall performance of the system. Additionally, the optimized gearbox design not only saves energy but also contributes to the reduction of carbon emissions, making it environmentally friendly.

Abstract With the rapid development of integrated energy system (IES), it has become a trend to form multiple integrated energy systems (MIESs) in a certain region. However, there is a lack of coordination and cooperation among MIESs. This paper proposes an optimal operation model of MIESs with four cost objectives, which focuses on energy interaction among MIESs. As a non‐linear and large optimization problem, it is difficult for conventional mathematical methods to solve. Hence, this paper proposes a hybrid Taguchi‐compact salp swarm algorithm (TCSSA). The compact technique can save the operation memory of model. Taguchi method can improve the convergence speed and solution accuracy of model. The proposed algorithm is tested on 28 benchmark functions and applied to optimal operation of MIESs. Results demonstrate that: (1) compared with other famous algorithms, TCSSA can provide more efficient execution and better solutions. (2) The optimal operation of MIESs based on TCSSA can achieve the complementary of energy advantages, which effectively reduces the total cost of MIESs (up to 9.67%).

Abstract Background Ochratoxin A (OTA) is a mycotoxin widely present in raw food and feed materials and is mainly produced by Aspergillus ochraceus and Penicillium verrucosum. Our previous study showed that OTA principally induces liver inflammation by causing intestinal flora disorder, especially Bacteroides plebeius (B. plebeius) overgrowth. However, whether OTA or B. plebeius alteration leads to abnormal tryptophan-related metabolism in the intestine and liver is largely unknown. This study aimed to elucidate the metabolic changes in the intestine and liver induced by OTA and the tryptophan-related metabolic pathway in the liver. Materials and methods A total of 30 healthy 1-day-old male Cherry Valley ducks were randomly divided into 2 groups. The control group was given 0.1 mol/L NaHCO3 solution, and the OTA group was given 235 μg/kg body weight OTA for 14 consecutive days. Tryptophan metabolites were determined by intestinal chyme metabolomics and liver tryptophan-targeted metabolomics. AMPK-related signaling pathway factors were analyzed by Western blotting and mRNA expression. Results Metabolomic analysis of the intestinal chyme showed that OTA treatment resulted in a decrease in intestinal nicotinuric acid levels, the downstream product of tryptophan metabolism, which were significantly negatively correlated with B. plebeius abundance. In contrast, OTA induced a significant increase in indole-3-acetamide levels, which were positively correlated with B. plebeius abundance. Simultaneously, OTA decreased the levels of ATP, NAD+ and dipeptidase in the liver. Liver tryptophan metabolomics analysis showed that OTA inhibited the kynurenine metabolic pathway and reduced the levels of kynurenine, anthranilic acid and nicotinic acid. Moreover, OTA increased the phosphorylation of AMPK protein and decreased the phosphorylation of mTOR protein. Conclusion OTA decreased the level of nicotinuric acid in the intestinal tract, which was negatively correlated with B. plebeius abundance. The abnormal metabolism of tryptophan led to a deficiency of NAD+ and ATP in the liver, which in turn activated the AMPK signaling pathway. Our results provide new insights into the toxic mechanism of OTA, and tryptophan metabolism might be a target for prevention and treatment. Graphical Abstract

Abstract Broiler ascites syndrome (AS) is one of the main diseases threatening the health of broilers. It is well documented that myocardial hypertrophy and failure is one of the key mechanisms of broiler ascites syndrome. Therefore, prevention of cardiac hypertrophy and failure would be one goal to reduce broiler ascites syndrome incidence. Myocardial hypertrophy and failure are closely related to endoplasmic reticulum stress (ERS) in cardiac myocytes, and the endoplasmic reticulum stress signaling system (ATF6-DR5) is one of the important pathways of myocardial apoptosis. Excessive hypertrophy will affect the heart muscle’s normal contraction and diastole function, and the heart will turn from compensated to decompensate thus causing myocardial injury. Myocardial apoptosis is a core component of the pathological changes of this myocardial injury. Nano-selenium is a kind of red elemental selenium nanoparticle. Due to its excellent physical, chemical and biological properties, it has attracted extensive academic attention in recent years. It has been proven to have excellent antioxidant, antibacterial, antitumor, antihypertrophic, and antiapoptotic abilities. Herein, nano-selenium (1 µmol/L) can inhibit hydrogen peroxide (H2O2)-induced oxidative stress in broiler primary cardiomyocytes, and at the same time reduce cardiomyocyte apoptosis. In vivo, nano-selenium can reduce broiler myocardial injury-related enzyme indicators (AST, CK and LDH), and alleviate myocardial injury. It can also activate the antioxidant enzyme system (SOD, GSH-Px and CAT) and reduce MDA, and make the recovery of T-AOC ability in the organization. Meanwhile, nano-selenium can down-regulate the genes and proteins expression of ATF-6, GRP-78, CHOP and caspase 12 in the ERS-related signaling pathway, and inhibit that of downstream-related caspase 3, Bax and caspase 9, and increase that of the downstream anti-apoptotic Bcl-2, thereby maintaining the homeostasis of the endoplasmic reticulum and alleviating cardiomyocyte apoptosis. It can be seen that nano-selenium can protect the damaged myocardium in the broiler ascites caused by high-salt drinking by regulating the ATF6-DR5 signaling pathway. This study was performed in chickens and cardiomyocyte cells and attempted to demonstrate that selenium nanoparticles can protect the damaged myocardium in broiler ascites. This paper provides a new idea for preventing and treating broiler ascites syndrome.

Abstract Background Renal fibrosis with Renin–angiotensin–aldosterone system (RAAS) activation and oxidative stress are one of the major complications in hypertension. 2-phenylacetamide (PA), a major active component of Lepidium apetalum Willd. (L.A), has numerous pharmacological effects. Its analogues have the effect of anti-renal fibrosis and alleviating renal injury. This study aims to explore the underlying mechanism of PA for regulating the renal fibrosis in SHR based on the MAPK pathway mediated RAAS and oxidative stress. Methods The SHR rats were used as the hypertension model, and the WKY rats were used as the control group. The blood pressure (BP), urine volume were detected every week. After PA treatment for 4 weeks, the levels of RAAS, inflammation and cytokines were measured by Enzyme-Linked Immunosorbnent Assay (ELISA). Hematoxylin–Eosin staining (HE), Masson and Immunohistochemistry (IHC) were used to observe the renal pathology, collagen deposition and fibrosis. Western blot was used to examine the MAPK pathway in renal. Finally, the SB203580 (p38 MAPK inhibitor) antagonism assay in the high NaCl-induced NRK52e cells was used, together with In-Cell Western (ICW), Flow Cytometry (FCM), High Content Screening (HCS) and ELISA to confirm the potential pharmacological mechanism. Results PA reduced the BP, RAAS, inflammation and cytokines, promoted the urine, and relieved renal pathological injury and collagen deposition, repaired renal fibrosis, decreased the expression of NADPH Oxidase 4 (NOX4), transforming growth factor-β (TGF-β), SMAD3 and MAPK signaling pathway in SHR rats. Meanwhile,,the role of PA could be blocked by p38 antagonist SB203580 effectively in the high NaCl-induced NRK52e cells. Moreover, molecular docking indicated that PA occupied the ligand binding sites of p38 MAPK. Conclusion PA inhibited renal fibrosis via MAPK signalling pathway mediated RAAS and oxidative stress in SHR Rats.

BackgroundArticular cartilage and cartilage matrix degradation are key pathological changes occurring in the early stage of knee osteoarthritis (KOA). However, currently, there are limited strategies for early prevention and treatment of KOA. Duhuo Jisheng Decoction (DHJSD) is a formula quoted in Bei Ji Qian jin Yao Fang, which was compiled by Sun Simiao in the Tang Dynasty of China. As a complementary therapy, it is widely used to treat early-stage KOA in China; however, its mechanism has not been completely elucidated.ObjectiveThis study investigated the potential role of DHJSD in preventing cartilage degradation and the underlying mechanism.MethodsA rat model of KOA model was established via the Hulth method. Subsequently, 25 rats were randomized into sham (saline), model control (saline), high-DHJSD (1.9g/mL of DHJSD), medium-DHJSD (1.2g/mL of DHJSD), and low-DHJSD groups (0.6g/mL of DHJSD). After 4 weeks of treatment, all rats were sacrificed and the severity of the cartilage degeneration was evaluated by a series of histological methods. The autophagosome was observed using transmission electron microscopy, and the related functional proteins were detected by the western blotting and real-time polymerase chain reaction. Next, the mechanism by which DHJSD improves knee cartilage degeneration was further clarified the in vitro by gene silencing technology combined with a series of functional experiments. The proteins levels of PTEN, Akt, p-Akt, mTOR, and p-mTOR, as well as the marker proteins of autophagy and apoptosis were determined. Zinc levels in chondrocytes were determined using inductively coupled plasma mass spectrometry.ResultsHistopathological staining revealed that DHJSD had a protective effect on the cartilage. DHJSD increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in chondrocytes. Moreover, it reduced the phosphorylation levels of Akt and mTOR and the levels of zinc, MMP-13, Bax, and Bcl-2. Following PTEN silencing, this DHJSD-mediated reduction in Akt and mTOR phosphorylation and Bax, Bcl-2, and zinc levels were further decreased; in addition, DHJSD-mediated increase in LC3 and Beclin-1 levels was decreased.ConclusionDHJSD inhibits the Akt/mTOR signaling pathway by targeting PTEN to promote autophagy in chondrocytes, which may help reduce MMP-13 production by regulating zinc levels in chondrocytes.