The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.

Targeting the p53-MDM2 pathway to reactivate tumor p53 is a chemotherapeutic approach. However, the involvement of this pathway in CD8+ T cell-mediated antitumor immunity is unknown. Here, we report that mice with MDM2 deficiency in T cells exhibit accelerated tumor progression and a decrease in tumor-infiltrating CD8+ T cell survival and function. Mechanistically, MDM2 competes with c-Cbl for STAT5 binding, reduces c-Cbl-mediated STAT5 degradation and enhances STAT5 stability in tumor-infiltrating CD8+ T cells. Targeting the p53-MDM2 interaction with a pharmacological agent, APG-115, augmented MDM2 in T cells, thereby stabilizing STAT5, boosting T cell immunity and synergizing with cancer immunotherapy. Unexpectedly, these effects of APG-115 were dependent on p53 and MDM2 in T cells. Clinically, MDM2 abundance correlated with T cell function and interferon-γ signature in patients with cancer. Thus, the p53-MDM2 pathway controls T cell immunity, and targeting this pathway may treat patients with cancer regardless of tumor p53 status.

Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.

CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy.

Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.

Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding.

TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS's nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization. This is coupled with binding of a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) to p53-RS, but not the p53 form with mutations of four serines/threonines previously shown to be crucial for PIN1 binding. As a result, p53-RS interacts with c-Myc and enhances c-Myc-dependent rDNA transcription key for ribosomal biogenesis. These results unveil a CDK4-PIN1-p53-RS-c-Myc pathway as a novel mechanism for the GOF of p53-RS in HCC.

A Meta-Analysis to Revisit the Property-Aggregation Relationships of Carbon Nanomaterials: Experimental Observations versus Predictions of the DLVO Theory.

Contradicting relationships between physicochemical properties of nanomaterials (e.g., size and ζ-potential) and their aggregation behavior have been constantly reported in previous literature, and such contradictions deviate from the predictions of the classic Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. To resolve such controversies, in this work, we employed a meta-analytic approach to synthesize the data from 46 individual studies reporting the critical coagulation concentration (CCC) of two carbon nanomaterials, namely, graphene oxide (GO) and carbon nanotube (CNT). The correlations between CCC and material physicochemical properties (i.e., size, ζ-potential, and surface functionalities) were examined and compared to the theoretical predictions. Results showed that the CCC of electrostatically stabilized carbon nanomaterials increased with decreasing nanomaterial size when their hydrodynamic sizes were smaller than ca. 200 nm. This is qualitatively consistent with the prediction of the DLVO theory but with a smaller threshold size than the predicted 2 µm. Above the threshold size, the material ζ-potential can be correlated to CCC for nanomaterials with moderate/low surface charge, in agreement with the DLVO theory. The correlation was not observed for highly charged nanomaterials because of their underestimated surface potential by the ζ-potential. Furthermore, a correlation between the C/O ratio and CCC was observed, where a lower C/O ratio resulted in a higher CCC. Overall, our findings rationalized the inconsistency between experimental observation and theoretical prediction and provided essential insights into the aggregation behavior of nanomaterials in water, which could facilitate their rational design.

Alteration of Thyroid Hormones in Mouse Models of Alzheimer's Disease and Aging.

INTRODUCTION: Aging is characterized by the deterioration of a wide range of functions in tissues and organs, and Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. Hypothyroidism occurs when there is insufficient production of thyroid hormones (THs) by the thyroid. The relationship between hypothyroidism and aging as well as AD is controversial at present. METHODS: We established an animal model of AD (FAD4T) with mutations in the APP and PSEN1 genes, and we performed a thyroid function test and RNA sequencing (RNA-Seq) of the thyroid from FAD4T and naturally aging mice. We also studied gene perturbation correlation in the FAD4T mouse thyroid, bone marrow, and brain by further single-cell RNA sequencing (scRNA-seq) data of the bone marrow and brain. RESULTS: In this study, we found alterations in THs in both AD and aging mice. RNA-seq data showed significant upregulation of T-cell infiltration- and cell proliferation-related genes in FAD4T mouse thyroid. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that upregulated genes were enriched in the functional gene modules of activation of immune cells. Downregulated energy metabolism-related genes were prominent in aging thyroids, which reflected the reduction in THs. GSEA showed a similar enrichment tendency in both mouse thyroids, suggesting their analogous inflammation state. In addition, the regulation of leukocyte activation and migration was a common signature between the thyroid, brain, and bone marrow of FAD4T mice. CONCLUSIONS: Our findings identified immune cell infiltration of the thyroid as the potential underlying mechanism of the alteration of THs in AD and aging.

Enhanced Arsenate Immobilization by Kaolinite via Heterogeneous Pathways during Ferrous Iron Oxidation.

Clay minerals are ubiquitous in subsurface environments and have long been recognized as having a limited or negligible impact on the fate of arsenic (As) due to their negatively charged surfaces. Here, we demonstrate the significant role of kaolinite (Kln), a pervasive clay mineral, in enhancing As(V) immobilization during ferrous iron (Fe(II)) oxidation at near-neutral pH. Our results showed that Fe(II) oxidation alone was not capable of immobilizing As(V) at relatively low Fe/As molar ratios (≤2) due to the generation of Fe(III)-As(V) nanocolloids that could still migrate easily as truly dissolved As did. In the presence of kaolinite, dissolved As(V) was significantly immobilized on the kaolinite surfaces via forming Kln-Fe(III)-As(V) ternary precipitates, which had large sizes (at micrometer levels) to reduce the As mobility. The kaolinite-induced heterogeneous pathways for As(V) immobilization involved Fe(II) adsorption, heterogeneous oxidation of adsorbed Fe(II), and finally heterogeneous nucleation/precipitation of Fe(III)-As(V) phases on the edge surfaces of kaolinite. The surface precipitates were mixtures of amorphous basic Fe(III)-arsenate and As-rich hydrous ferric oxide. Our findings provide new insights into the role of clay minerals in As transformation, which is significant for the fate of As in natural and engineered systems.

High-energy-density zinc ion capacitors based on 3D porous free-standing defect-reduced graphene oxide hydrogel cathodes.

Zinc ion capacitors (ZICs) have shown potential for breaking the energy density ceiling of traditional supercapacitors (SCs) via appropriate device design. Nevertheless, a significant challenge remains in advancing ZIC positive electrode materials with excellent conductivity, high specific capacitance, and reliable cycle stability. A highly attractive option for carbon-based electrode materials is reduced graphene oxide (RGO) due to its vast specific surface area, prominent porosity, and 3D cross-linked frame. However, the tight stacking of RGO sheets driven by van der Waals forces can restrict active sites, decrease specific capacitance, and elevate electrochemical impedance. To overcome these challenges, 3D defective RGO (DRGO) hydrogels were prepared by a metal Co cocatalytic gasification reaction. This method produced mesoporous defects on the surface of RGO hydrogels via a low-temperature hydrothermal self-assembly strategy. The surface of the layer has a wide and uniform distribution, which can offer abundant redox active sites, rich ion transfer channels, and fast reaction kinetics. In this work, 3D DRGO//Zn exhibited a wide operating window (0-1.8 V), high specific capacitance (189.39 F g-1 at 1 A g-1), outstanding energy density (85.23 W h kg-1 at 960.31 W kg-1; 52.36 W h kg-1 at 17454.87 W kg-1), and persistent cycling life (98.86% initial capacitance retention after 10 000 cycles at 10 A g-1). This study emphasizes the device design of ZIC and promising prospects of using 3D DRGO hydrogel as a feasible positive electrode for ZIC.

Impaired gut barrier integrity and reduced colonic expression of free fatty acid receptors in patients with Parkinson's disease.

BACKGROUND: Altered gut metabolites, especially short-chain fatty acids (SCFAs), in feces and plasma are observed in patients with Parkinson's disease (PD). OBJECTIVE: We aimed to investigate the colonic expression of two SCFA receptors, free fatty acid receptor (FFAR)2 and FFAR3, and gut barrier integrity in patients with PD and correlations with clinical severity. METHODS: In this retrospective study, colonic biopsy specimens were collected from 37 PD patients and 34 unaffected controls. Of this cohort, 31 participants (14 PD, 17 controls) underwent a series of colon biopsies. Colonic expression of FFAR2, FFAR3, and the tight junction marker ZO-1 were assayed by immunofluorescence staining. The You Only Look Once (version 8, YOLOv8) algorithm was used for automated detection and segmentation of immunostaining signal. PD motor function was assessed with the Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale (UPDRS), and constipation was assessed using Rome-IV criteria. RESULTS: Compared with controls, PD patients had significantly lower colonic expression of ZO-1 (p < 0.01) and FFAR2 (p = 0.01). On serial biopsy, colonic expression of FFAR2 and FFAR3 was reduced in the pre-motor stage before PD diagnosis (both p < 0.01). MDS-UPDRS motor scores did not correlate with colonic marker levels. Constipation severity negatively correlated with colonic ZO-1 levels (r = -0.49, p = 0.02). CONCLUSIONS: Colonic expression of ZO-1 and FFAR2 is lower in PD patients compared with unaffected controls, and FFAR2 and FFAR3 levels decline in the pre-motor stage of PD. Our findings implicate a leaky gut phenomenon in PD and reinforce that gut metabolites may contribute to the process of PD.

Effect of virtual reality training to enhance laparoscopic assistance skills.

BACKGROUND: While laparoscopic assistance is often entrusted to less experienced individuals, such as residents, medical students, and operating room nurses, it is important to note that they typically receive little to no formal laparoscopic training. This deficiency can lead to poor visibility during minimally invasive surgery, thus increasing the risk of errors. Moreover, operating room nurses and medical students are currently not included as key users in structured laparoscopic training programs. OBJECTIVES: The aim of this study is to evaluate the laparoscopic skills of OR nurses, clinical medical postgraduate students, and residents before and after undergoing virtual reality training. Additionally, it aimed to compare the differences in the laparoscopic skills among different groups (OR nurses/Students/Residents) both before and after virtual reality training. METHODS: Operating room nurses, clinical medical postgraduate students and residents from a tertiary Grade A hospital in China in March 2022 were selected as participants. All participants were required to complete a laparoscopic simulation training course in 6 consecutive weeks. One task from each of the four training modules was selected as an evaluation indicator. A before-and-after self-control study was used to compare the basic laparoscopic skills of participants, and laparoscopic skill competency was compared between the groups of operating room nurses, clinical medical postgraduate students, and residents. RESULTS: Twenty-seven operating room nurses, 31 clinical medical postgraduate students, and 16 residents were included. The training course scores for the navigation training module, task training module, coordination training module, and surgical skills training module between different groups (operating room nurses/clinical medical postgraduate/residents) before laparoscopic simulation training was statistically significant (p < 0.05). After laparoscopic simulation training, there was no statistically significant difference in the training course scores between the different groups. The surgical level scores before and after the training course were compared between the operating room nurses, clinical medical postgraduate students, and residents and showed significant increases (p < 0.05). CONCLUSION: Our findings show a significant improvement in laparoscopic skills following virtual surgery simulation training across all participant groups. The integration of virtual surgery simulation technology in surgical training holds promise for bridging the gap in laparoscopic skill development among health care professionals.

Melatonin increased antioxidant capacity to ameliorate growth retardation and intestinal epithelial barrier dysfunction in diquat-challenged piglets.

BACKGROUND: Diquat is a common environmental pollutant, which can cause oxidative stress in humans and animals. Diquat exposure causes growth retardation and intestinal damage. Therefore, this study was performed to investigate the effects of melatonin on diquat-challenged piglets. RESULTS: Dietary supplementation with 2 mg kg-1 melatonin significantly increased the average daily gain and feed conversion rate in piglets. Melatonin increased antioxidant capacity, and improved intestinal epithelial barrier function of duodenum and jejunum in piglets. Moreover, melatonin was found to regulated the expression of immune and antioxidant-related genes. Melatonin also alleviated diquat-induced growth retardation and anorexia in diquat-challenged piglets. It also increased antioxidant capacity, and ameliorated diquat-induced intestinal epithelial barrier injury. Melatonin also regulated the expression of MnSOD and immuner-elated genes in intestinal. CONCLUSION: Dietary supplementation with 2 mg kg-1 melatonin increased antioxidant capacity to ameliorate diquat-induced oxidative stress, alleviate intestinal epithelial barrier injury, and increase growth performance in weaned piglets. © 2023 Society of Chemical Industry.

Biochar Promotes Arsenopyrite Weathering in Simulated Alkaline Soils: Electrochemical Mechanism and Environmental Implications.

Oxidation dissolution of arsenopyrite (FeAsS) is one of the important sources of arsenic contamination in soil and groundwater. Biochar, a commonly used soil amendment and environmental remediation agent, is widespread in ecosystems, where it participates in and influences the redox-active geochemical processes of sulfide minerals associated with arsenic and iron. This study investigated the critical role of biochar on the oxidation process of arsenopyrite in simulated alkaline soil solutions by a combination of electrochemical techniques, immersion tests, and solid characterizations. Polarization curves indicated that the elevated temperature (5-45 °C) and biochar concentration (0-1.2 g·L-1) accelerated arsenopyrite oxidation. This is further confirmed by electrochemical impedance spectroscopy, which showed that biochar substantially reduced the charge transfer resistance in the double layer, resulting in smaller activation energy (Ea = 37.38-29.56 kJ·mol-1) and activation enthalpy (ΔH* = 34.91-27.09 kJ·mol-1). These observations are likely attributed to the abundance of aromatic and quinoid groups in biochar, which could reduce Fe(III) and As(V) as well as adsorb or complex with Fe(III). This hinders the formation of passivation films consisting of iron arsenate and iron (oxyhydr)oxide. Further observation found that the presence of biochar exacerbates acidic drainage and arsenic contamination in areas containing arsenopyrite. This study highlighted the possible negative impact of biochar on soil and water, suggesting that the different physicochemical properties of biochar produced from different feedstock and under different pyrolysis conditions should be taken into account before large-scale applications to prevent potential risks to ecology and agriculture.

A Ti3C2Tx@PANI core-shell heterostructure assembled into a 3D porous hydrogel as a free-standing electrode for high-energy supercapacitors.

Although Ti3C2Tx MXenes have attracted attention in electrochemical energy storage devices due to their excellent electronic conductivity, controllable layer structure, and huge redox active surface area, the application of Ti3C2Tx as supercapacitor (SC) electrode materials is severely limited by the ineffective chemical ion transport kinetics caused by self-restacking. In order to increase the interlayer spacing of Ti3C2Tx, the intercalation method is hailed as an effective process. Herein, polyaniline (PANI) nanorods as intercalators were synthesized by the polymerization of an aniline (ANI) monomer chemisorbed onto Ti3C2Tx wrinkled nanosheets, and the formation of a Ti3C2Tx@PANI heterostructure is conducive to the large interlayer voids. Then, the heterostructure was integrated into a three-dimensional (3D) porous cross-linked framework via a simple graphene oxide (GO)-assisted self-convergence hydrothermal strategy with low temperatures. Due to the synergistic effect among each component and 3D porous interconnected structure, the hierarchical Ti3C2Tx@PANI-reduced graphene oxide (RGO) heterostructure hydrogel possesses the advantages of excellent electrical conductivity, high specific capacitance, repressive aggregation, and large electrochemical active area. Heterostructure hydrogel electrodes (without binders) display excellent electrochemical performance with a specific capacitance as high as 301.0 F g-1 at 1 A g-1, 90.74% capacitance retention over 10 000 cycles, and a maximum energy density of 44.6 W h kg-1 at a power density of 504.7 W kg-1. Our study provides a fresh strategy for constructing a 3D Ti3C2Tx-based framework applicable to other MXenes in the design of hybrid structures for maximizing their potential applications in energy storage.

Association of clinical characteristics and recurrence of conventional colorectal adenomas with patient age: a single-center study.

OBJECTIVES: We performed a clinical study comparing early-onset and late-onset conventional colorectal adenomas (CCRAs) since little is known about the differences in their characteristics. METHODS: Pearson's chi-square test and the Kruskal‒Wallis test were used to compare basic information. MCAR tests and multiple imputation were performed to complete missing values. Multivariate logistic analysis and propensity score matching were used to identify the risk factors for recurrence. RESULTS: We included 2793 patients (688 with early-onset CCRAs and 2105 with late-onset CCRAs) from January 2017 to December 2021. Patients with early-onset CCRAs had higher levels of Hb, ALB, and triglycerides but lower HDL levels and N/L ratios. Moreover, we found that more early-onset CCRAs were in the left colon than late-onset CCRAs, and the size of early-onset CCRAs was larger. Early-onset CCRAs tended to lack pedicles compared to late-onset CCRAs. Additionally, the ratio of EMR and APC in early-onset CCRAs was higher than that in late-onset CCRAs, and the ratio of ESD and surgery for late-onset CCRAs was higher. We found that age ≥ 50 years, abnormal vessels, drinking alcohol, and DB and ALB levels may be risk factors for recurrence, while the LDL level may be a protective factor. Finally, analysis of cumulative recurrence rates after PSM showed that patients with late-onset CCRAs exhibited higher recurrence rates (P < 0.05). CONCLUSION: Compared with late-onset CCRAs, early-onset CCRAs were associated with higher triglyceride levels, lower HDL levels, and larger tumor volumes. Age ≥ 50 years, abnormal vessels, alcohol consumption, and DB and ALB levels were independent risk factors for recurrence of CCRAs.

Mannan oligosaccharides selenium ameliorates intestinal mucosal barrier, and regulate intestinal microbiota to prevent Enterotoxigenic Escherichia coli -induced diarrhea in weaned piglets.

Enterotoxigenic Escherichia coli (ETEC) is a common diarrheal pathogen in humans and animals. To prevent and treat ETEC induced diarrhea, we synthesized mannan oligosaccharide selenium (MOSS) and studied its beneficial effect on ETEC-induced diarrhea. A total of 32 healthy weaned piglets (6.69 ± 0.01 kg) were randomly divided into four groups: NC group (Basal diet), MOSS group (0.4 mg/kg MOSS supplemented diet), MOET group (0.4 mg/kg MOSS supplemented diet + ETEC treatment), ETEC group (ETEC treatment). NC and ETEC group fed with basal diet, MOSS and MOET group fed with the MOSS supplemented diet. On the 8th and 15th day of the experiment, MOET and ETEC group were gavaged with ETEC, and NC and MOSS group were gavaged with stroke-physiological saline solution. Our data showed that dietary MOSS supplementation increased average daily gain (ADG) and average daily feed intake (ADFI) and significantly decreased diarrhea index and frequency in ETEC-treated piglets. MOSS did not affect the α diversity and ß diversity of ileal microbial community, but it significantly decreased the proportion of lipopolysaccharide biosynthesis in ileal microbial community. MOSS supplementation regulated colonic microbiota community composition, which significantly increased carbohydrate metabolism, and inhibited lipopolysaccharide biosynthesis pathway in colonic microbial community. Moreover, MOSS significantly decreased inflammatory stress, and oxidative stress in ETEC treated piglets. Furthermore, dietary MOSS supplementation significantly decreased intestinal barrier permeability, and alleviated ETEC induced intestinal mucosa barrier irritation. In conclusion, our study showed that dietary MOSS supplementation ameliorated intestinal mucosa barrier, and regulated intestinal microbiota to prevent ETEC induced diarrhea in weaned piglets.

The nanocomposites of modified attapulgite with vitamin E and mannan oligosaccharide regulated the intestinal epithelial barrier and improved intestinal microbiota composition to prevent diarrhea in weaned piglets.

BACKGROUND: Overuse of antibiotics contributes to bacterial resistance in animals. Therefore, it is necessary to find a new way to ensure animal health and promote animal growth. This experiment was conducted to investigate the effect of mannan oligosaccharide (MOS)/vitamin E (VE)/attapulgite (APT) nanocomposites (SLK1, SLK3, SLK5) on growth performance and intestinal health in weaned piglets. Each 1 kg of SLK1, SLK3 or SLK5 contains 50 g of vitamin E, and each had a different MOS concentration [SLK1 (50 g kg -1 MOS), SLK3 (100 g kg -1 MOS), SLK5 (150 g kg -1 MOS)]. In total, 135 piglets were randomly divided into five groups (normal control group, traditional antibiotic substitutes group, SLK1 group, SLK3 group and SLK5 group), and growth performance, diarrhea index, intestinal epithelial barrier function and intestinal microbial composition were measured. RESULTS: SLK1 and SLK5 significantly decreased diarrhea frequency in weaned piglets (p < 0.05). Furthermore, SLK5 significantly increased survival rate of weaned piglets compared to the traditional antibiotic substitutes group (p < 0.05). SLK5 also increased villus height of ileum, and increased goblet number of the jejunum (p < 0.05). 16S rRNA sequencing showed that SLK5 significantly regulated intestinal colonic microbiota composition (p < 0.05). Specifically, SLK5 significantly increased the abundance of Phascolarctobacterium succinatutens in the cecum and increased the abundance of Lactobacillus and Bifidobacterium in the colon (p < 0.05). In addition, dietary supplementation with 1 kg T-1 SLK5 also significantly increased the propionate content in the colon, which is significantly correlated with Phascolarctobacterium (p < 0.05). CONCLUSION: Dietary supplementation with 1 kg T-1 SLK5 improved intestinal epithelial barrier function, and regulated intestinal microbiota composition to prevent diarrhea in weaned piglets. © 2023 Society of Chemical Industry.

Construction of nursing-sensitive quality indicators for the care of patients with prone position ventilation using the Delphi method.

BACKGROUND: Prone position ventilation (PPV) has gradually become an adjuvant treatment to improve oxygenation in patients with acute respiratory distress syndrome. Scientific and comprehensive evaluation of the quality of nursing care for patients with PPV is of great significance to ensure the effectiveness of treatment and patient safety. However, there are no established objective indicators for evaluating the quality of nursing care for patients with PPV. This study intended to identify a set of scientific, systematic and clinically applicable nursing-sensitive quality indicators for the care of patients with PPV. METHODS: Based on the Donabedian structure-process-result theory model, the quality evaluation indicators of nursing care for patients with PPV were preliminarily constructed based on an evidence-based perspective, and two rounds of Delphi surveys were conducted with the purpose of collecting opinions from a panel of independent experts. RESULTS: The questionnaire recovery rates of the two rounds of correspondence were 100.00% and 95.00%, the recovery rates of expert opinions were 80.00% and 26.32%, the expert authority coefficient values were 0.89, and the Kendall coordination coefficient W values were 0.110 and 0.133, respectively. The final nursing-sensitive quality indicators for the care of patients with PPV included 3 first-level indicators, 9 s-level indicators and 29 third-level indicators. CONCLUSION: The constructed nursing-sensitive quality indicators for the care of patients with PPV involve quality supervision during the whole process of PPV from three dimensions: structure, process and results. These indicators have strong operability, reliability, practicability and scientificity and can provide a reference for the quality evaluation and monitoring of nursing care for patients with PPV. IMPLICATIONS FOR NURSING MANAGEMENT: The quality indicators of nursing care for patients with PPV constructed in this research are scientific and reliable, and the content of the quality indicators can better reflect the technical characteristics of special nursing. Nursing managers are encouraged to use these quality indicators to evaluate the quality of clinical nursing care and improve safety for patients with PPV.

[Clinical Effect of Surgical Reconstruction of Extracranial Vertebral Artery].

Objective To evaluate the effect of surgical reconstruction of extracranial vertebral artery and to summarize the experience. Methods The clinical data of 15 patients undergoing surgical reconstruction of extracranial vertebral artery from September 2018 to June 2022 were collected.The operation methods,operation duration,intraoperative blood loss,operation complications,and relief of symptoms were retrospectively analyzed. Results Eleven patients underwent vertebral artery (V1 segment) to common carotid artery transposition,two patients underwent endarterectomy of V1 segment,two patients underwent V3 segment to external carotid artery bypass or transposition.The operation duration,intraoperative blood loss,and blocking time of common carotid artery varied within 120-340 min,50-300 ml,and 12-25 min,with the medians of 240 min,100 ml,and 16 min,respectively.There was no cardiac accident,cerebral hyperperfusion syndrome,cerebral hemorrhage or lymphatic leakage during the perioperative period.One patient suffered from cerebral infarction and three patients suffered from incomplete Horner's syndrome after the operation.During the follow-up (4-45 months,median of 26 months),there was no anastomotic stenosis,new cerebral infarction or cerebral ischemia. Conclusion Surgical reconstruction of extracranial vertebral artery is safe and effective,and individualized reconstruction strategy should be adopted according to different conditions.

Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF-α Pathway.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is a common risk gene for Parkinson's disease (PD) and inflammatory bowel disorders. However, the penetrance of the most prevalent LRRK2 mutation, G2019S, is <50%. Factors other than genetic mutations are needed in PD process. OBJECTIVES: To examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD. METHODS: A mild and chronic dextran sodium sulfate (DSS)-induced colitis mice model harboring LRRK2 G2019S mutation was established. The colitis severity, immune responses, locomotor function, dopaminergic neuron, and microglia integrity were compared between littermate controls, transgenic LRRK2 wild type (WT), and LRRK2 G2019S mice. RESULTS: The LRRK2 G2019S mice are more vulnerable to DSS-induced colitis than littermate controls or LRRK2 WT animals with increased intestinal expressions of pattern-recognition receptors, including toll-like receptors (TLRs), nuclear factor (NF)-κB activation, and pro-inflammatory cytokines secretion, especially tumor necrosis factor (TNF)-α. Notably, the colonic expression of α-synuclein was significantly increased in LRRK2 G2019S colitis mice. We subsequently observed more aggravated locomotor defect, microglia activation, and dopaminergic neuron loss in LRRK2 G2019S colitis mice than control animals. Treatment with anti-TNF-α monoclonal antibody, adalimumab, abrogated both gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in LRRK2 G2019S colitis mice. Finally, we validated increased colonic expressions of LRRK2, TLRs, and NF-κB pathway proteins and elevated plasma TNF-α level in PD patients compared to controls, especially in those with LRRK2 risk variants. CONCLUSIONS: Our findings demonstrate that chronic colitis promotes parkinsonism in genetically susceptible mice and TNF-α plays a detrimental role in the gut-brain axis of PD. © 2021 International Parkinson and Movement Disorder Society.

Deep Learning Assisted Diagnosis of Musculoskeletal Tumors Based on Contrast-Enhanced Magnetic Resonance Imaging.

BACKGROUND: Misdiagnosis of malignant musculoskeletal tumors may lead to the delay of intervention, resulting in amputation or death. PURPOSE: To improve the diagnostic efficacy of musculoskeletal tumors by developing deep learning (DL) models based on contrast-enhanced magnetic resonance imaging and to quantify the improvement in diagnostic performance obtained by using these models. STUDY TYPE: Retrospective. POPULATION: Three hundreds and four musculoskeletal tumors, including 212 malignant and 92 benign lesions, were randomized into the training (n = 180), validation (n = 62) and testing cohort (n = 62). FIELD STRENGTH/SEQUENCE: A 3 T/T1 -weighted (T1 -w), T2 -weighted (T2 -w), diffusion-weighted imaging (DWI), and contrast-enhanced T1-weighted (CET1 -w) images. ASSESSMENT: Three DL models based, respectively, on the sagittal, coronal, and axial MR images were constructed to predict the malignancy of tumors. Blinded to the prediction results, a group of specialists made independent initial diagnoses for each patient by reading all image sequences. One month after the initial diagnoses, the same group of doctors made another round of diagnoses knowing the malignancy of each tumor predicted by the three models. The reference standard was the pathological diagnosis of malignancy. STATISTICAL TESTS: Sensitivity, specificity, and accuracy (all with 95% confidential intervals [CI]) corresponding to each diagnostic test were computed. Chi-square tests were used to assess the differences in those parameters with and without DL models. A P value < 0.05 was considered statistically significant. RESULTS: The developed models significantly improved the diagnostic sensitivities of two oncologists by 0.15 (95% CI: 0.06-0.24) and 0.36 (95% CI: 0.24-0.28), one radiologist by 0.12 (95% CI: 0.04-0.20), and three of the four orthopedists, respectively, by 0.12 (95% CI: 0.04-0.20), 0.29 (95% CI: 0.18-0.40), and 0.23 (95% CI: 0.13-0.33), without impairing any of their diagnostic specificities (all P > 0.128). DATA CONCLUSION: The DL models developed can significantly improve the performance of doctors with different training and experience in diagnosing musculoskeletal tumors. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.