Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation.

BACKGROUND: Cardiac hypertrophy and its associated remodeling are among the leading causes of heart failure. Lysine crotonylation is a recently discovered posttranslational modification whose role in cardiac hypertrophy remains largely unknown. NAE1 (NEDD8-activating enzyme E1 regulatory subunit) is mainly involved in the neddylation modification of protein targets. However, the function of crotonylated NAE1 has not been defined. This study aims to elucidate the effects and mechanisms of NAE1 crotonylation on cardiac hypertrophy. METHODS: Crotonylation levels were detected in both human and mouse subjects with cardiac hypertrophy through immunoprecipitation and Western blot assays. TMT-labeled quantitative lysine crotonylome analysis was performed to identify the crotonylated proteins in a mouse cardiac hypertrophic model induced by transverse aortic constriction. We generated NAE1 knock-in mice carrying a crotonylation-defective lysine to arginine K238R (lysine to arginine mutation at site 238) mutation (NAE1 K238R) and NAE1 knock-in mice expressing a crotonylation-mimicking lysine to glutamine K238Q (lysine to glutamine mutation at site 238) mutation (NAE1 K238Q) to assess the functional role of crotonylation of NAE1 at K238 in pathological cardiac hypertrophy. Furthermore, we combined coimmunoprecipitation, mass spectrometry, and dot blot analysis that was followed by multiple molecular biological methodologies to identify the target GSN (gelsolin) and corresponding molecular events contributing to the function of NAE1 K238 crotonylation. RESULTS: The crotonylation level of NAE1 was increased in mice and patients with cardiac hypertrophy. Quantitative crotonylomics analysis revealed that K238 was the main crotonylation site of NAE1. Loss of K238 crotonylation in NAE1 K238R knock-in mice attenuated cardiac hypertrophy and restored the heart function, while hypercrotonylation mimic in NAE1 K238Q knock-in mice significantly enhanced transverse aortic constriction-induced pathological hypertrophic response, leading to impaired cardiac structure and function. The recombinant adenoviral vector carrying NAE1 K238R mutant attenuated, while the K238Q mutant aggravated Ang II (angiotensin II)-induced hypertrophy. Mechanistically, we identified GSN as a direct target of NAE1. K238 crotonylation of NAE1 promoted GSN neddylation and, thus, enhanced its protein stability and expression. NAE1 crotonylation-dependent increase of GSN promoted actin-severing activity, which resulted in adverse cytoskeletal remodeling and progression of pathological hypertrophy. CONCLUSIONS: Our findings provide new insights into the previously unrecognized role of crotonylation on nonhistone proteins during cardiac hypertrophy. We found that K238 crotonylation of NAE1 plays an essential role in mediating cardiac hypertrophy through GSN neddylation, which provides potential novel therapeutic targets for pathological hypertrophy and cardiac remodeling.

The development of resilience research in critical infrastructure systems: A bibliometric perspective.

Critical infrastructure systems (CISs) are the cornerstone of modern cities. Substantial economic losses and social impacts are caused once natural disasters or man-made disruptions attack the CISs. As a "resilient city" has become an essential theme of communities' sustainable development, research on resilience and its practice in industries boost the CISs' capacity to respond and adapt to changing environments. From the Web of Science (WOS) Core Collection, this study screened 1,247 scientific articles related to resilience in CISs and conducted a bibliometric analysis to investigate the evolution and future potential in this field. Topic visualized networks were constructed for CIS resilience using CiteSpace, a dedicated tool for visualizing and analyzing trends and patterns in scientific literature. The results demonstrate collaborative research networks among countries, institutions, main scholar/group networks, and leading journals publishing CIS resilience work. This study also explained how the research interest evolved over the last 20 years and found the current frontiers pointing to "power systems resilience" and "supply chain resilience." The reasons were discussed subsequently from the perspectives of the influence that natural hazards (based on the EM-DAT data) and government policies have upon CISs' resilience work.

Longxuetongluo Capsule alleviate ischemia/reperfusion induced cardiomyocyte apoptosis through modulating oxidative stress and mitochondrial dysfunction.

BACKGROUND: Chinese dragon's blood, the red resin of Dracaena cochinchinensis (Lour.) S. C. Chen., is widely used to treat cardiovascular and cerebrovascular diseases in China. Longxuetongluo Capsule (LTC) is a total phenolic compound extracted from Chinese dragon's blood, currently used in treating ischemic stroke. Myocardial injury can be aggravated after reperfusion of ischemic myocardium, which is called myocardial ischemia-reperfusion injury (MIRI), and the mechanism of MIRI is complex. However, the exact effect and mechanism of LTC on MIRI are still unclear. We explore the effect of LTC on alleviating MIRI based on mitochondrial dysfunction and oxidative stress. AIM OF THE STUDY: To explore the cardioprotective mechanism of LTC against MIRI. MATERIALS AND METHODS: A rat MIRI model was constructed through ligation of the left anterior descending coronary artery, and LTC was given continuously for 28 days before surgery. The H9c2 cardiomyocyte injury model was induced by oxygen-glucose deprivation/reperfusion (OGD/R), and LTC was given 24 h before OGD. Myocardial ischemia areas were detected with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cardiac histopathological changes were detected with hematoxylin-eosin (HE) staining. And biochemical indexes were detected with serum biochemical kit. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining and flow cytometry were used to detect apoptosis. Fluorescent probes were used to observe reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), Ca2+and other indexes. MitoTracker staining and immunofluorescence were used to observe the morphology of mitochondria and translocation of dynamin-related protein 1 (Drp1). Finally, immunohistochemistry and Western blotting were used to examine the expression of proteins related to apoptosis, mitochondrial fission and fusion and oxidative stress. RESULTS: LTC could ameliorate cardiac pathological changes, decrease myocardial infarct area and the content or level of relevant serum cardiac enzymes, indicating that LTC could alleviate MIRI. Meanwhile, LTC could inhibit cardiomyocyte apoptosis via regulating apoptosis-related protein expression, and it could restore mitochondrial morphology, maintain ΔΨm, inhibit mitochondrial ROS generation and Ca2+ accumulation, increase the expression of mitochondrial fusion protein 2 (Mfn2), decrease the level of phosphorylation dynamin-related protein 1 (p-Drp1), and regulate ATP synthesis, thereby significantly ameliorating mitochondrial dysfunction. Moreover, LTC significantly reduced the expression of NADPH oxidase 2 (NOX2), NADPH oxidase 4 (NOX4) and neutrophil cytosolic factor 2 (NOXA2/p67phox), and reduced ROS production. CONCLUSION: The study demonstrated that LTC could inhibit MIRI induced cardiomyocyte apoptosis by inhibiting ROS generation and mitochondrial dysfunction, and these fundings suggested that LTC can be used to alleviate MIRI, which provides a potential therapeutic approach for future treatment of MIRI.

Recent advances in computational prediction of molecular properties in food chemistry.

The combination of food chemistry and computational simulation has brought many impacts to food research, moving from experimental chemistry to computer chemistry. This paper will systematically review in detail the important role played by computational simulations in the development of the molecular structure of food, mainly from the atomic, molecular, and multicomponent dimension. It will also discuss how different computational chemistry models can be constructed and analyzed to obtain reliable conclusions. From the calculation principle to case analysis, this paper focuses on the selection and application of quantum mechanics, molecular mechanics and coarse-grained molecular dynamics in food chemistry research. Finally, experiments and computations of food chemistry are compared and summarized to obtain the best balance between them. The above review and outlook will provide an important reference for the intersection of food chemistry and computational chemistry, and is expected to provide innovative thinking for structural research in food chemistry.

A scientometrics analysis and visualization of refractory gastroesophageal reflux disease.

Background: Refractory gastroesophageal reflux disease (refractory GERD) is a heterogeneous disease characterized by unresponsiveness or poor efficacy to proton-pump inhibitors (PPIs). This chronic disorder substantially weakens patients' mental wellbeing and quality of life, increasing the financial burden on society. Multiple articles have been reported in this area. However, literature involving scientometric analysis of refractory GERD is absent. Therefore, it is necessary to understand the evolution of research themes and the main hotspots of refractory GERD through bibliometric methods. Methods: All documents related to refractory GERD based on the WOS Core Collection from January 2000 to November 2023 were selected for analysis. Citespace V 6.1 R6, VOSviewer V 1.6.20, and Scimago Graphica V 1.0.38 were used to perform bibliometric analysis. Results: We collected a total of 241 research articles from 36 countries and 322 institutions, contributed by over 1,000 authors. Over the last 20 years, the number of articles in this field has increased year by year, and since 2011, the number of publications has increased dramatically, with 85.89% of the papers. These countries are led by the United States and Japan. GUT had the highest number of citations and DIGESTION had the highest number of publications. Research on standardized diagnosis and management, mechanisms, novel monitoring methods, and innovative drugs and procedures for refractory GERD are the main topics and hotspots in this field. This study also found that neuroimmune interaction is closely related to refractory GERD, which may be a new direction for future mechanism research. Conclusion: Our study is the first bibliometric analysis of the global literature on refractory GERD. This research provides valuable insights for researchers, enabling them to quickly understand the research frontier and hot topics of this field.

Emergence of a novel pathogenic porcine G1P[7] rotavirus in China.

Among group A rotaviruses (RVAs), the G1 genotype is the main genotype causing diarrhea in children, but it has rarely been reported in pigs. During our epidemiological investigation, we detected G1P[7] rotavirus infection in piglets across several provinces in China and then isolated a porcine G1P[7] rotavirus strain (CN1P7). Sequencing revealed that the virus constellation was G1-P[7]-I5-R1-C1-M1-A8-N1-T1-E1-H1. Phylogenetic analyses revealed that CN1P7 most likely emerged due to genetic reassortment among porcine, human, giant panda and dog rotavirus strains. In vivo experiments were conducted on two-day-old piglets, which revealed that the CN1P7 strain was pathogenic to piglets. The virus was shed through the digestive tract and respiratory tract. In addition to the intestine, the CN1P7 strain displayed extraintestinal tropisms in piglets. Histopathological analysis revealed that the lung and small intestine were the targets of CN1P7. This study is the first to explore the molecular and pathogenic characterization of a pig-origin G1P[7] rotavirus.

Association of serum 25-hydroxyvitamin D3 levels with carotid artery intima-media thickness and carotid atherosclerotic plaques in smokers.

OBJECTIVE: This study explores the association of serum 25-hydroxyvitamin D3 (25(OH)D3) levels with carotid artery intima-media thickness (CIMT), and the presence of carotid atherosclerotic plaques in individuals with a history of smoking. METHODS: A total of 469 patients suspected of having carotid atherosclerosis, aged 52 to 73 years with an average age of 65.26 ±â€¯4.37 years, were recruited from the author's hospital from January 2023 to October 2023. All patients had a smoking history of nearly 5 years. Based on their serum 25(OH)D3 levels, they were divided into two groups: the normal group (serum level 30-50 ng/mL, n = 300) and the deficiency group (<30 ng/mL, n = 169). General details of the two patient groups were collected. Carotid artery ultrasound was employed to assess pulse wave velocity (PWV), carotid artery compliance coefficient (CC), and CIMT. Blood chemistry analysis measured serum lipid metabolism indicators including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HD-LC). The relationship between CIMT and each variable was analyzed through Pearson correlation, and logistic regression was used to identify risk factors influencing carotid artery plaque development. RESULTS: General patient information between the two groups showed no significant differences (P > 0.05). Patients in the 25(OH)D3 deficiency group exhibited elevated left and right PWV and CC compared to the 25(OH)D3 normal group (P < 0.05). The deficiency group exhibited larger CIMT and plaque area compared to the normal group (P < 0.05). Additionally, the deficiency group demonstrated higher levels of TC, LDL-C, and HD-LC compared to the normal group (P < 0.05). A moderate positive correlation was found between TC, LDL-C, and CIMT (P < 0.05), while a strong positive correlation existed between 25(OH)D3 and CIMT (P < 0.05). In smokers, the formation of carotid artery plaque was associated with factors such as patient age, CIMT, serum LDL-C, and 25(OH)D3 levels (P < 0.05). As age, CIMT, LDL-C levels increased, and 25(OH)D3 levels decreased, the risk of carotid plaques in smokers increased (P < 0.05). CONCLUSIONS: Smokers with lower 25(OH)D3 levels exhibit higher CIMT and more prominent carotid atherosclerotic plaques, indicating increased arterial stiffness and elevated cardiovascular risk. These findings demonstrate crucial implications that insufficient levels of vitamin D may potentially contribute to a higher risk of atherosclerosis among smokers.

Chronic Wound Caused by Lymphorrhea after Skin Abscess Drainage on Lower Extremity: A Case Report.

ABSTRACT: Surgical operations such as lymph node dissection may inadvertently damage the lymphatic system and lead to lymphorrhea. Excessive lymphatic exudation can cause a chronic wound. However, for surgery that does not involve the lymphatic system, lymphorrhea is a rare postoperative complication. This case report describes a 38-year-old patient who presented with lymphatic cutaneous leakage after incision and drainage of a skin abscess on the lower extremity. Persistent lymphorrhea increased the amount of wound exudation, which affected wound healing. After treatment of the lymphorrhea, the lower extremity wound healed completely within 4 weeks and did not result in lymphedema. Ligation of lymphatic vessels is a simple and easily performed treatment method for lymphatic leakage.

GGC repeat expansions in NOTCH2NLC cause uN2CpolyG cerebral amyloid angiopathy.

The expansion of GGC repeats within NOTCH2NLC leads to the translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). This study aims to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy (CAA)-related cerebral microbleeds (CMBs). A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analyzed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use, and MRI features between NIID patients with and without CMBs. We further performed hematoxylin and eosin (H&E), Perl's, Congo red, and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients. A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes, and approximately 20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs suffered a higher incidence of previous ischemic and hemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy. H&E staining showed blood vessel leakage and hemosiderin-laden macrophage clusters, and Prussian blue staining revealed brain tissue iron deposition. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labeled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy. In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a novel perspective, providing initial clinical, neuroimaging, and pathological evidence suggesting that uN2CpolyG may contribute to a distinct type of CAA.

Design of a liposome casein hydrogel as an efficient front-end homeostatic anthocyanin loading system.

Proteins have been studied and applied to improve the stability of anthocyanins (ACNs), but the changes in the pH microenvironment during the preparation of steady-state systems are often ignored, and more attention is given to the stability of the system after preparation. In this study, we propose the "anthocyanin front-end homeostasis strategy", which involves designing a system can protect anthocyanins under acidic conditions so that more anthocyanin prototypes can be loaded inside the protein. Anthocyanins are encapsulated in liposomes (Lip) at pH 3.0 and combined with casein methacrylate (CSMA) to form Anthocyanin-loaded liposomes/CSMA hydrogel (Lip@ACNs/CSMA), with good physical properties and good blood compatibility. The system increased the hydrogen peroxide scavenging capacity by 1.16 mg Vc equiv./mg ACNs and the cellular antioxidant activity by 17.55 µM quercetin/100 mg ACNs, the photo and thermal storage stability increased by 36.50 % and 30.71 %, the digestive rate increased by 17.50 %, and the biological availability increased by 0.0049 mg/mL. This study designed a liposome casein hydrogel as an efficient front-end homeostatic anthocyanin loading system and provided a new approach for improving the stability of anthocyanins.

Organo-cation catalyzed enantioselective α-hydroxylation of pyridinone-fused lactones: asymmetric synthesis of SN-38 and irinotecan.

A catalytic asymmetric α-hydroxylation of pyridinone-fused lactones, containing the core structure of camptothecin, is described. Development of a novel spiropyrrolidine amide (SPA) derived triazolium bromide organo-cation catalyst is crucial for a highly enantioselective oxidation, which also accommodates a wide array of lactones with various substituents. The resulting tricyclic tertiary alcohol with an oxa-quaternary carbon center can be further applied in the synthesis of SN-38 and irinotecan, two anti-cancer drugs derived from camptothecin.

Study on the intervention effect of HCH integrated SMG health management model on community high-risk group of cardiovascular disease.

Objective: This study aimed to evaluate the integration of the Hospital-Community-Home (HCH) model with the Self-Mutual-Group (SMG) health management model for high-risk populations with cardiovascular disease in the Yuhua community of Shijiazhuang city. The study focused on implementing care interventions (HCH, SMG) with a specific emphasis on SMG to promote beneficial views/behaviors, enhance self-efficacy/agency, and address detrimental determinants of health, ultimately leading to durable changes and healthier lifestyles. Comparing the HCH model with the combined SMG model helps to comprehensively assess the strengths and weaknesses of different health management approaches. This comparison contributes to theoretical innovation and practical development in the field of health management, as well as improving patients' health outcomes and quality of life. Methods: This study employed a quasi-experimental design. Using stratified sampling, individuals who underwent health examinations in Community A and Community B from Shijiazhuang city between May 2023 and August 2023 were randomly selected. After informing the participants about the study and obtaining informed consent via telephone, high-risk patients with cardiovascular disease were screened based on their medical examination reports. Data on lifestyle behaviors, self-efficacy, medical responses, quality of life, and readmission rates were collected and compared before and after the intervention. Results: A total of 526 eligible participants were included, with 241 in the control group and 285 in the study group. After the intervention, there was no significant change in the proportions of smokers, alcohol consumers, and individuals engaging in leisure exercises in the control group. However, in the study group, the proportions of smokers and alcohol consumers significantly decreased, while the proportion of individuals engaging in leisure exercises significantly increased. After the intervention, both the study group and the control group showed significant increases in scores on the General Self-Efficacy Scale-Schwarzer (GSES) and the Seattle Angina Questionnaire (SAQ), with the study group scoring significantly higher than the control group. Avoidance and surrender scores significantly increased after the intervention, with the study group scoring significantly lower than the control group. Confrontation scores significantly increased after the intervention, with the study group scoring significantly higher than the control group. During the follow-up period, the study group had a significantly lower readmission rate than the control group. Conclusion: The integration of HCH with SMG health management model can significantly improve lifestyle behaviors, optimize medical responses, enhance self-efficacy and quality of life, and significantly reduce readmission rates among high-risk populations with cardiovascular disease.

FABP3 Induces Mitochondrial Autophagy to Promote Neuronal Cell Apoptosis in Brain Ischemia-Reperfusion Injury.

This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.

The research landscape of ferroptosis in neurodegenerative disease: a bibliometric analysis.

Background: Ferroptosis, a newly proposed concept of programmed cell death, has garnered significant attention in research across different diseases in the last decade. Despite thorough citation analyses in neuroscience, there is a scarcity of information on ferroptosis research specifically related to neurodegenerative diseases. Method: The Web of Science Core Collection database retrieved relevant articles and reviews. Data on publications, countries, institutions, authors, journals, citations, and keywords in the included studies were systematically analyzed using Microsoft Excel 2019 and CiteSpace 6.2.R7 software. Result: A comprehensive analysis and visualization of 563 research papers on ferroptosis in neurodegenerative diseases from 2014 to 2023 revealed emerging research hotspots and trends. The number of annual publications in this field of study has displayed a pattern of stabilization in the early years of the decade, followed by a notable increase in the later years and peaking in 2023 with 196 publications. Regarding publication volume and total citations, notable research contributions were observed from countries, institutions, and authors in North America, Western Europe, and China. Current research endeavors primarily focus on understanding the intervention mechanisms of neurodegenerative diseases through the ferroptosis pathway and exploring and identifying potential therapeutic targets. Conclusion: The study highlights key areas of interest and emerging trends in ferroptosis research on neurodegenerative diseases, offering valuable insights for further exploration and potential directions for diagnosing and treating such conditions.

An Embedded Electromyogram Signal Acquisition Device.

In this study, we design an embedded surface EMG acquisition device to conveniently collect human surface EMG signals, pursue more intelligent human-computer interactions in exoskeleton robots, and enable exoskeleton robots to synchronize with or even respond to user actions in advance. The device has the characteristics of low cost, miniaturization, and strong compatibility, and it can acquire eight-channel surface EMG signals in real time while retaining the possibility of expanding the channel. This paper introduces the design and function of the embedded EMG acquisition device in detail, which includes the use of wired transmission to adapt to complex electromagnetic environments, light signals to indicate signal strength, and an embedded processing chip to reduce signal noise and perform filtering. The test results show that the device can effectively collect the original EMG signal, which provides a scheme for improving the level of human-computer interactions and enhancing the robustness and intelligence of exoskeleton equipment. The development of this device provides a new possibility for the intellectualization of exoskeleton systems and reductions in their cost.

Investigating the relationship between postoperative radiotherapy and intestinal flora in rectal cancer patients: a study on efficacy and radiation enteritis.

Objective: This study aimed to investigate the impact of radiation therapy and radiation enteritis on intestinal flora, providing insights for treatment and prevention. Methods: Fecal samples were collected from 16 patients undergoing pelvic radiotherapy at Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital). Samples were collected before and after radiotherapy (27-30Gy), and analyzed using DNA sequencing and biostatistical methods. Results: Patients with radiation enteritis showed increased α-diversity and ß-diversity of intestinal flora compared to those without radiation enteritis. Differences in flora composition were observed, with higher abundance of secondary pathways such as amino acid metabolism, carbohydrate metabolism, cofactors and vitamins metabolism, and lipid metabolism. Conclusion: The study revealed that patients developing radiation enteritis during pelvic radiation therapy had increased diversity and abundance of intestinal flora compared to those who did not develop radiation enteritis. Additionally, patients without radiation enteritis showed significantly higher diversity and abundance of intestinal flora post-radiation compared to pre-radiation.

Implications of intestinal microecology and immune function alterations for immunotherapy outcomes in advanced unresectable lung adenocarcinoma.

OBJECTIVE: This investigation aims to explore alterations in intestinal microecology and immune function among patients with advanced, unresectable lung adenocarcinoma undergoing different outcomes from immunotherapy. METHODS: A cohort of 30 patients diagnosed with advanced unresectable lung adenocarcinoma received sintilimab immunotherapy as a monotherapy. Post four treatment cycles, efficacy was assessed, leading to the segregation of patients into two distinct cohorts: those responsive to treatment and those nonresponsive. Analysis involved observing variations in the abundance, distribution, and composition of fecal intestinal microorganisms pretreatment and posttreatment via 16S rRNA gene sequencing. RESULTS: In this study involving 30 advanced lung adenocarcinoma patients, significant observations were made regarding the impact of immunotherapy on immune function and the gut microbiome composition. Patients were divided into treatment and control groups, revealing that immunotherapy led to a significant increase in CD4+ T cells and a decrease in CD8+ T cells among the treatment-responsive individuals, indicating an enhanced immune response. Furthermore, an in-depth analysis of the gut microbiome showed an increase in diversity and abundance of beneficial bacteria such as Faecalibacterium and Subdoligranulum in the treatment group. These findings highlight the dual effect of immunotherapy on modulating immune function and altering gut microbiome diversity, suggesting its potential therapeutic benefits in improving the health status of patients with advanced lung adenocarcinoma. CONCLUSION: The structuring of gut flora plays a pivotal role in augmenting the efficacy of anti-tumor immunotherapy, underscoring the interplay between intestinal microecology and immune response in cancer treatment outcomes.

Value of neutrophil-to-lymphocyte ratio in neuronal intranuclear inclusion disease.

Background and objectives: The neutrophil-to-lymphocyte ratio (NLR) is a widely recognized marker of inflammation in peripheral blood. However, its specific role in neuronal intranuclear inclusion disease (NIID) has not been reported. This study aims to investigate the relationship between NIID and NLR. Methods: A multicenter database was collected, including 157 NIID patients from seven hospitals (The Affiliated Hospital of Xuzhou Medical University, Yantai Yuhuangding Hospital, Tengzhou Central People's Hospital,The Affiliated Brain Hospital of Nanjing Medical University, Liaocheng People's Hospital,The Second Hospital of Shandong University, Inner Mongolia People's Hospital, Xuanwu Hospital Capital Medical University,The First Affiliated Hospital of USTC), along with 157 age- and gender-matched healthy control subjects. White blood cell counts (including neutrophils, lymphocytes, monocytes, eosinophils, and basophils) were obtained, and the NLR was calculated. Additionally, cognitive impairment was assessed using clinical evaluation scores. Results: NIID patients exhibited significantly higher NLR values compared to the healthy control group (p < 0.001). The plasma NLR levels in NIID patients showed a weak positive correlation with disease duration (r = 0.219, p = 0.016). However, no significant correlations were found between NLR and age of onset or cognitive impairment (p > 0.05). Conclusion: There is a significant association between NLR and NIID, suggesting a potential role of peripheral blood inflammation in the pathogenesis of NIID.

Predictors and outcomes of withholding and withdrawal of life-sustaining treatments in intensive care units in Singapore: a multicentre observational study.

BACKGROUND: Clinical practice guidelines on limitation of life-sustaining treatments (LST) in the intensive care unit (ICU), in the form of withholding or withdrawal of LST, state that there is no ethical difference between the two. Such statements are not uniformly accepted worldwide, and there are few studies on LST limitation in Asia. This study aimed to evaluate the predictors and outcomes of withholding and withdrawal of LST in Singapore, focusing on the similarities and differences between the two approaches. METHODS: This was a multicentre observational study of patients admitted to 21 adult ICUs across 9 public hospitals in Singapore over an average of three months per year from 2014 to 2019. The primary outcome measures were withholding and withdrawal of LST (cardiopulmonary resuscitation, invasive mechanical ventilation, and vasopressors/inotropes). The secondary outcome measure was hospital mortality. Multivariable generalised mixed model analysis was used to identify independent predictors for withdrawal and withholding of LST and if LST limitation predicts hospital mortality. RESULTS: There were 8907 patients and 9723 admissions. Of the former, 80.8% had no limitation of LST, 13.0% had LST withheld, and 6.2% had LST withdrawn. Common independent predictors for withholding and withdrawal were increasing age, absence of chronic kidney dialysis, greater dependence in activities of daily living, cardiopulmonary resuscitation before ICU admission, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, and higher level of care in the first 24 h of ICU admission. Additional predictors for withholding included being of Chinese race, the religions of Hinduism and Islam, malignancy, and chronic liver failure. The additional predictor for withdrawal was lower hospital paying class (with greater government subsidy for hospital bills). Hospital mortality in patients without LST limitation, with LST withholding, and with LST withdrawal was 10.6%, 82.1%, and 91.8%, respectively (p < 0.001). Withholding (odds ratio 13.822, 95% confidence interval 9.987-19.132) and withdrawal (odds ratio 38.319, 95% confidence interval 24.351-60.298) were both found to be independent predictors of hospital mortality on multivariable analysis. CONCLUSIONS: Differences in the independent predictors of withholding and withdrawal of LST exist. Even after accounting for baseline characteristics, both withholding and withdrawal of LST independently predict hospital mortality. Later mortality in patients who had LST withdrawn compared to withholding suggests that the decision to withdraw may be at the point when medical futility is recognised.

Rotavirus infection inhibits SLA-I expression on the cell surface by degrading ß2 M via ERAD-proteasome pathway.

Group A Rotavirus (RVA) is a major cause of diarrhea in infants and piglets. ß2-microglobulin (ß2 M), encoded by the B2M gene, serves as a crucial subunit of the major histocompatibility complex class I (MHC-I) molecules. ß2 M is indispensable for the transport of MHC-I to the cell membrane. MHC-I, also known as swine leukocyte antigen class I (SLA-I) in pigs, presents viral antigens to the cell surface. In this study, RVA infection down-regulated ß2 M expression in both porcine intestinal epithelial cells-J2 (IPEC-J2) and MA-104 cells. RVA infection did not down-regulate the mRNA level of the B2M gene, indicating that the down-regulation of ß2 M occurred on the protein level. Mechanismly, RVA infection triggered ß2 M aggregation in the endoplasmic reticulum (ER) and enhanced the Lys48 (K48)-linked ubiquitination of ß2 M, leading to the degradation of ß2 M through ERAD-proteasome pathway. Furthermore, we found that RVA infection significantly impeded the level of SLA-I on the surface, and the overexpression of ß2 M could recover its expression. In this study, our study demonstrated that RVA infection degrades ß2 M via ERAD-proteasome pathway, consequently hampering SLA-I expression on the cell surface. This study would enhance the understanding of the mechanism of how RVA infection induces immune escape.