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Abstract Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the colon and are thought to be protective against gastrointestinal disease. SCFAs such as acetate, propionate and butyrate are important metabolites in the maintenance of intestinal homeostasis and have been shown to be beneficial in colorectal cancer (CRC). SCFAs are responsible for maintaining a normal intestinal barrier and exhibit numerous immunomodulatory functions. In this review article, we will discuss the metabolism and mechanism of action of SCFAs and their effects on the CRC, with particular emphasis on dietary fiber treatment and the clinical research progress.

Abstract Introduction Several observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis. Methods In the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI). Results Based on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 − 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 − 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 − 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 − 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 − 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 − 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 − 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 − 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 − 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 − 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 − 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 − 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection. Conclusions Our findings do not support a genetic association between HPV infection and lung cancer.

Abstract Although computerized cognitive training (CCT) is an effective digital intervention for cognitive impairment, its dose-response relationship is understudied. This retrospective cohort study explores the association between training dose and cognitive improvement to find the optimal CCT dose. From 2017 to 2022, 8,709 participants with subjective cognitive decline, mild cognitive impairment, and mild dementia were analyzed. CCT exposure varied in daily dose and frequency, with cognitive improvement measured weekly using Cognitive Index. A mixed-effects model revealed significant Cognitive Index increases across most dose groups before reaching the optimal dose. For participants under 60 years, the optimal dose was 25 to

Abstract Background The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. Methods In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. Results Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Mechanistically, MSI2 directly binds to the translation regulatory region of NLK mRNA at positions 79–87 nt, enhancing its transcriptional activity and exerting post-transcriptional regulatory roles. The analysis of molecular docking showed the close relationship between MSI2 and NLK in pancreatic cancer patients. Conclusions Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.

Abstract Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.

BackgroundHypertensive disorders of pregnancy (HDP) are associated with an increased risk of stroke later in life in multiparous women. However, causality of these associations remains unclear. This study employed 2-sample univariate and multivariate Mendelian randomization (MR) to assess the causal connection between HDP and stroke.MethodsGenetic variants for HDP and two subtypes were identified from recent large-scale genome-wide association studies and the FinnGen consortium. Stroke summary data were obtained from the MEGASTROKE consortium. The primary analytical approach for univariate MR was the inverse variance weighting method. Sensitivity analyses incorporated methods such as MR-Egger regression, weighted median, and maximum likelihood to ascertain the robustness of the results. Additionally, multivariable MR analyses were conducted to account for potential associative effects of hypertension and type 2 diabetes.ResultsGenetically predicted HDP was associated with a high risk of large artery atherosclerosis (odds ratio [OR]=1.50, 95% confidence interval [CI]: 1.17–1.91, P=1.13×10-3) and small vessel stroke (OR=1.29, 95% CI: 1.20–1.50, P=1.52×10-3). HDP may also correlate with ischemic stroke (OR=1.13, 95% CI: 1.04–1.23, P=4.99×10-3) and stroke (OR=1.11, 95% CI: 1.03–1.20, P=8.85×10-3). An elevated risk of small vessel stroke (OR=1.20, 95% CI: 1.01–1.43, P=3.74×10-2) and large artery atherosclerosis (OR=1.22, 95% CI: 1.01–1.47, P=4.07×10-2) may be related with genetically predicted susceptibility to gestational hypertension. Genetically predicted susceptibility to preeclampsia or eclampsia may be associated with an increased risk of stroke (OR = 1.10, 95% CI: 1.02–1.19, P = 1.16×10-2) and ischemic stroke (OR = 1.10, 95% CI: 1.02–1.20, P = 1.84×10-2). Type 2 diabetes mellitus and hypertension were identified as significant factors contributing to the association between HDP and stroke.ConclusionsThis study provides genetic evidence supporting an association between HDP and increased stroke risk bolstering HDP as a cerebrovascular risk factor.

Abstract Objective To analyze the effect of mast cells (MCs) in neurogenic inflammation and the neuroimmune response of trigeminal ganglia (TG) due to pulpitis and detect the regulatory effect of curcumin (Cur) on neuroimmune responses induced by pulpitis. Methodology Immunohistochemistry, toluidine blue staining (TB), and other methods were used to detect the dynamic changes of MCs, as well as tryptase expression changes and protease activated receptor 2 (PAR2) and calcitonin gene-related peptide (CGRP) levels in the neuroimmune response induced by pulpitis. After administering Cur by intraperitoneal injection, the expression levels of Toll-like receptor 4 (TLR4), CGRP, glial fibrillary acidic protein (GFAP), fractalkine (CX3CL1), Tumor necrosis factor (TNF-α), and other factors were examined in the TG of pulpitis-induced rats. Results After pulpitis induction, the expression of CGRP-positive neurons and GFAP-positive soluble guanylate cyclase (SGC) in the TG significantly increased. A large number of MCs underwent degranulation. MCs were scattered between the CGRP-positive nerve fibers. MCs showing a typical degranulated state within the TG significantly increased and tryptase-positive MCs surrounded the TG nerve fibers and neurons. After treatment with Cur, the inflammatory response in the periodontal bone induced by pulpitis decreased and promoted early tissue repair. The expression of TNF-α significantly decreased as did degranulation of MCs. In contrast, the expression of CGRP, TLR4-positive neurons, activated SGCs, and PAR2-positive TG neurons significantly decreased. MCs could participate in the neuroimmune response induced by pulpitis by the tryptase signaling pathway. Conclusion Importantly, Cur inhibited the degranulation of MCs, downregulated the expression of tryptase and PAR2 in the TG, and attenuated the activation response of osteoclasts in the apical periodontium.

Abstract Extracellular vesicles (EVs) have emerged as a promising tool for clinical liquid biopsy. However, the identification of EVs derived from blood samples is hindered by the presence of abundant plasma proteins, which impairs the downstream biochemical analysis of EV‐associated proteins and nucleic acids. Here, we employed optimized asymmetric flow field‐flow fractionation (AF4) combined with density cushion ultracentrifugation (UC) to obtain high‐purity and intact EVs with very low lipoprotein contamination from human plasma and serum. Further proteomic analysis revealed more than 1000 EV‐associated proteins, a large proportion of which has not been previously reported. Specifically, we found that cell‐line‐derived EV markers are incompatible with the identification of plasma‐EVs and proposed that the proteins MYCT1, TSPAN14, MPIG6B and MYADM, as well as the traditional EV markers CD63 and CD147, are plasma‐EV markers. Benefiting from the high‐purity of EVs, we conducted comprehensive miRNA profiling of plasma EVs and nanosized particles (NPs), as well as compared plasma‐ and serum‐derived EVs, which provides a valuable resource for the EV research community. Overall, our findings provide a comprehensive assessment of human blood EVs as a basis for clinical biopsy applications.

Objective: Drug-induced liver injury (DILI), a type of acute inflammation, has sparked significant concern owing to its unpredictability and severity. Psoraleae Fructus (PF), an edible Chinese herb widely used in traditional Chinese medicine (TCM), causes liver injury. Therefore, the elucidation of the mechanism underlying PF-induced liver injury and the search for more effective means of detoxification using herbal compatibility has become an urgent issue. This study evaluated the hepatoprotective effects of Paeoniae Radix Alba (PRA), a hepatoprotective Chinese medicine, on PF-induced liver injury and explored the underlying mechanisms. Methods: A rat model of lipopolysaccharide (LPS)-induced immune stress was established to evaluate the hepatotoxicity of PF and the detoxifying effect of PRA. Subsequently, inflammatory pathways were identified using network pharmacology. Finally, the molecular mechanism by which PRA alleviates PF-induced liver injury was validated using an inflammasome activation model in bone marrow-derived macrophages (BMDMs). Results: In vivo, hepatocytes in rats treated with LPS + PF exhibited massive inflammatory infiltration and apoptosis, and the expression of liver injury indicators and inflammatory factors was significantly upregulated, which was reversed by PRA pretreatment. Network pharmacology showed that PRA alleviated PF-induced liver injury and was associated with the NOD-like receptor signaling pathway. Moreover, PF directly induced inflammasome activation in LPS-primed BMDMs which in turn induced caspase-1 activation and the secretion of downstream effector cytokines such as IL-1β. PRA pretreatment inhibited PF-induced activation of the NLRP3 inflammasome by mitigating the accumulation of mitochondrial reactive oxygen species (mtROS). Conclusions: The present study demonstrates that PRA alleviated PF induced-liver injury by inhibiting NLRP3 inflammasome activation. The results of this study are expected to inform the prevention and control of PF-induced hepatotoxicity in clinical practice.

Melioidosis is a potentially severe disease caused by the gram-negative soil-dwelling bacterium called Burkholderia pseudomallei. The true breadth of the distribution of this tropical pathogen is starting to emerge with environmental and clinical isolates frequently characterized in new countries and regions. Even so, isolates, clinical cases, and genetic data from the continent of Africa remain scant. We previously confirmed the presence of B. pseudomallei in the environment of Ghana, unmasking a new area of endemicity for this pathogen. Here, we describe the genetic characteristics of isolates obtained from that environmental survey. Twenty-one isolates were subjected to whole genome sequencing and found to represent three discrete sequence types (ST), one of which was novel, and designated ST2058. Phylogenetic analysis places this novel isolate within a B. pseudomallei clade that includes genomes derived from the Americas, although it is closely related to a sub-clade that includes isolates from Africa. Importantly, phenotypic characterization demonstrates common features including API 20NE profiles and B. pseudomallei CPS to support existing diagnostics, and susceptibility to standard of care antibiotics often used in the clinical management of melioidosis. These findings add to our knowledge about the presence and distribution of B. pseudomallei in Africa and represent the first published genomes out of Ghana.

Rice blast, a prevalent and highly destructive rice disease that significantly impacts rice yield, is caused by the rice blast fungus. In the present study, a strain named MTC-8, identified as Bacillus mojavensis, was demonstrated has strong antagonistic activity against the rice blast fungus, Rhizoctonia solani, Ustilaginoidea virens, and Bipolaria maydis. The potential biocontrol agents were identified using ultra-performance liquid chromatography—tandem mass spectrometry (UPLC-MS/MS) analysis and chromatography. Further investigations elucidated the inhibitory mechanism of the isolated compound and demonstrated its ability to suppress spore germination, alter hyphal morphology, disrupt cell membrane integrity, and induce defense-related gene expression in rice. MTC-8 promoted plant growth and may lead to the development of a biocontrol agent that meets agricultural standards. Overall, the Bacillus mojavensis MTC-8 strain exerted beneficial effects on plant growth, immunity and disease resistance against rice blast fungus. In this study, we isolated and purified a bioactive substance from fermentation broth, and the results provide a foundation for the development and application of biopesticides. Elucidation of the inhibitory mechanism against rice blast fungus provides theoretical support for the identification of molecular targets. The successful development of a biocontrol agent lays the groundwork for its practical application in agriculture.

Spinocerebellar ataxia is a phenotypically and genetically heterogeneous group of autosomal dominant-inherited degenerative disorders. The gene mutation spectrum includes dynamic expansions, point mutations, duplications, insertions, and deletions of varying lengths. Dynamic expansion is the most common form of mutation. Mutations often result in indistinguishable clinical phenotypes, thus requiring validation using multiple genetic testing techniques. Depending on the type of mutation, the pathogenesis may involve proteotoxicity, RNA toxicity, or protein loss-of-function. All of which may disrupt a range of cellular processes, such as impaired protein quality control pathways, ion channel dysfunction, mitochondrial dysfunction, transcriptional dysregulation, DNA damage, loss of nuclear integrity, and ultimately, impairment of neuronal function and integrity which causes diseases. Many disease-modifying therapies, such as gene editing technology, RNA interference, antisense oligonucleotides, stem cell technology, and pharmacological therapies are currently under clinical trials. However, the development of curative approaches for genetic diseases remains a global challenge, beset by technical, ethical, and other challenges. Therefore, the study of the pathogenesis of spinocerebellar ataxia is of great importance for the sustained development of disease-modifying molecular therapies.

For the problem of manufacturing system residual life prognosis with insufficient small sample data and unbalanced distribution, this paper proposes a model for equipment health status analysis and life prognosis based on improved ant colony optimization K-Means (ACO-K-Means) and multi-classification Self-Adding SVM (MCS-SVM). First, based on the fuzzy data set, the data is classified for the first time according to the traditional SVM, and the initial classification results are obtained. Second, the improved K-Means algorithm based on the ant colony algorithm is used to cluster the data set after the initial classification, to obtain more health status labels in different states.The noise scale coefficient is established, and the data set distribution is optimized by introducing the unbalanced scale standard and the adaptive addition rule, to enrich the sample capacity of the scarce label under the influence of noise. On this basis, the SVMset is introduced according to the number of clusters to achieve multi-classification of the data set. Finally, by using the state data of the hydraulic pump of Caterpillar, the simulation results show that the two improved algorithms can accurately analyze the health state and lifetime prognosis of equipment under small noise samples and unbalanced data.

Abstract Natural ester insulating oil is widely used in transformers due to its good fire resistance and biodegradability. It is mainly composed of triglycerides, and there are some differences in fatty acid composition and content among natural esters. Therefore, the fault diagnosis methods based on dissolved gas analysis are different. Three kinds of natural ester insulating oils are used to study the dissolved gas in oil under typical electrical and thermal faults of power transformers. Thermal faults from 200°C to 800°C and electrical faults with different discharge energies, which include partial discharge, breakdown discharge, and arc discharge, are simulated. The characteristic gases and their variation trends of natural esters under thermal and electrical faults are obtained through the experimental results. The gas generation characteristics of the three natural ester insulating oils under typical electrical and thermal faults are almost similar, but the relative percentages of characteristic gases have certain differences. Natural ester insulating oil with a higher unsaturation degree tends to produce more H2 and less C2H4. Finally, the fault diagnosis methods are used to determine the fault gas data, and the Duval pentagon is modified and improved according to the gas generation characteristics of natural esters.

Abstract Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKI) acquired resistance was an inevitably events in NSCLC treatment. Aims Intending to overcome the acquired resistance of EGFR‐TKI. Materials & Methods A clinical trial was, we enrolled 12 patients who were slowly progressing on first‐generation EGFR‐TKI, and added apatinib when the patients got slow progression. Results Seven patients were included in the efficacy analysis. The median PFS2 of apatinib combined with EGFR‐TKI was 8.2 months (95% CI, 7.3 m‐NA), and the total PFS reached 20.9 months (95% CI, 17.3 m‐NA) when plus PFS1. All the adverse events were manageable. The median PFS was significantly longer for circulating tumor DNA (ctDNA)‐cleared patients (8.4 months; 95% CI, 8.2‐NA) than for those ctDNA not cleared (7.1 months; 95% CI, 6.9‐NA) (p = 0.0082). Discussion The addition of apatinib did improve the duration of first‐generation EGFR‐TKI use, and the duration was better than the first‐line use of third‐generation EGFR‐TKI. Conclusion The addition of apatinib when the patients got slow progression after initial EGFR‐TKI therapy may be a good treatment option and the side effects are controllable. It is possible to monitor treatment efficacy using ctDNA.

Being one of the pivotal adipocytokines, adiponectin binds to various receptors and exerts diverse biological functions, encompassing anti-fibrosis, anti-atherosclerosis, anti-ischemia-reperfusion, regulation of inflammation, and modulation of glucose and lipid metabolism. Alterations in adiponectin levels are observed in patients afflicted with diverse cardiovascular diseases. This paper comprehensively reviews the impact of adiponectin on the pathogenesis and progression of cardiovascular diseases, elucidating the underlying cellular and molecular mechanisms along with the associated cell signaling pathways. Furthermore, it deliberates on the diagnostic and predictive efficacy of adiponectin as a protein marker for cardiovascular diseases. Additionally, it outlines methods for manipulating adiponectin levels in vivo. A thorough understanding of these interconnections can potentially inform clinical strategies for the prevention and management of cardiovascular diseases.

Soil salinization is a global constraint that significantly hampers agricultural production, with cotton being an important cash crop that is not immune to its detrimental effects. The rhizosphere microbiome plays a critical role in plant health and growth, which assists plants in resisting adverse abiotic stresses including soil salinization. This study explores the impact of soil salinization on cotton, including its effects on growth, yield, soil physical and chemical properties, as well as soil bacterial community structures. The results of β-diversity analysis showed that there were significant differences in bacterial communities in saline-alkali soil at different growth stages of cotton. Besides, the more severity of soil salinization, the more abundance of Proteobacteria, Bacteroidota enriched in rhizosphere bacterial composition where the abundance of Acidobacteriota exhibited the opposite trend. And the co-occurrence network analysis showed that soil salinization affected the complexity of soil bacterial co-occurrence network. These findings provide valuable insights into the mechanisms by which soil salinization affects soil microorganisms in cotton rhizosphere soil and offer guidance for improving soil salinization using beneficial microorganisms.

BackgroundIt has been suggested in several observational studies that migraines are associated with the gut microbiota. It remains unclear, however, how the gut microbiota and migraines are causally related.MethodsWe performed a bidirectional two-sample mendelian randomization study. Genome-wide association study (GWAS) summary statistics for the gut microbiota were obtained from the MiBioGen consortium (n = 18,340) and the Dutch Microbiota Project (n = 7,738). Pooled GWAS data for plasma metabolites were obtained from four different human metabolomics studies. GWAS summary data for migraine (cases = 48,975; controls = 450,381) were sourced from the International Headache Genetics Consortium. We used inverse-variance weighting as the primary analysis. Multiple sensitivity analyses were performed to ensure the robustness of the estimated results. We also conducted reverse mendelian randomization when a causal relationship between exposure and migraine was found.ResultsLachnospiraceaeUCG001 (OR = 1.12, 95% CI: 1.05–1.20) was a risk factor for migraine. Blautia (OR = 0.93, 95% CI: 0.88–0.99), Eubacterium (nodatum group; OR = 0.94, 95% CI: 0.90–0.98), and Bacteroides fragilis (OR = 0.97, 95% CI: 0.94–1.00) may have a suggestive association with a lower migraine risk. Functional pathways of methionine synthesis (OR = 0.89, 95% CI: 0.83–0.95) associated with microbiota abundance and plasma hydrocinnamate (OR = 0.85, 95% CI: 0.73–1.00), which are downstream metabolites of Blautia and Bacteroides fragilis, respectively, may also be associated with lower migraine risk. No causal association between migraine and the gut microbiota or metabolites was found in reverse mendelian randomization analysis. Both significant horizontal pleiotropy and significant heterogeneity were not clearly identified.ConclusionThis Mendelian randomization analysis showed that LachnospiraceaeUCG001 was associated with an increased risk of migraine, while some bacteria in the gut microbiota may reduce migraine risk. These findings provide a reference for a deeper comprehension of the role of the gut–brain axis in migraine as well as possible targets for treatment interventions.

BackgroundCell transplants as a treatment for Parkinson’s disease have been studied for decades, and stem cells may be the most promising cell sources for this treatment. We aimed to investigate whether stem cell transplantation contributes to the cure for Parkinson’s disease and the factors that may influence the efficacy for this therapy.MethodsPubMed, Embase, Cochrane Library, Web of Science, SinoMed, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and ChinaInfo were thoroughly searched to find controlled trials or randomized controlled trials performing stem cell transplantation in patients with Parkinson’s disease. The pooled effects were analyzed to evaluate the weighted mean difference (WMD) with 95% confidence intervals.ResultsNine articles were identified including 129 individuals. Stem cell transplantation was an effective treatment for Parkinson’s disease (WMD = −14.86; 95% CI: −16.62 to −13.10; p

The key to effective mechanical reinforcement in polymer nancomposites lies within the stress transfer mechanisms and the distribution of the nanofillers within a polymer matrix. In this work, the micromechanics of Ti3C2Tx MXene-reinforced poly(vinyl alcohol) (PVA) nanocomposites have been studied in detail. Ti3C2Tx MXene/PVA nanocomposites were prepared by solution blending. The spatial orientation of Ti3C2Tx MXene in the nanocomposites was characterized by polarized Raman spectroscopy and the orientation factor was correlated to the effective Young's modulus of the flakes through well-established micromechanical theories. The mechanical properties of the nanocomposites were evaluated by tensile testing. A 27% increase in Young's modulus and a 24% improvement in tensile strength were achieved by addition of only 0.6 wt% Ti3C2Tx. Efficient stress transfer from the polymer matrix to Ti3C2Tx MXene in bulk nanocomposites has been observed through strain-induced Raman band shifts for the first time. The effective Young's modulus of the MXene nanoplatelets was calculated to be in the order of 300 GPa, in good agreement with the values derived from the application of micromechanical models.

An accurate diagnosis of consciousness disorder after brain injury is the basis for further treatment. The previous evaluation of consciousness disorder after brain injury is mainly based on behavior scales and imaging examination, which is limited to subjective factors and external interference and difficult to detect and evaluate in real time. The development of objective and efficient evaluation methods of consciousness disorder after brain injury is currently a hot spot in clinical research. Neurophysiological monitoring is safe, objective, simple to operate, and can be detected continuously timely. It can be used as an evaluation method for consciousness disorder after brain injury. In this paper, we summarize the application paradigms and analysis methods of evoked potential and EEG in the clinical evaluation of consciousness disorder after brain injury in recent years, in order to provide new technical ideas for improving the clinical diagnosis and treatment of consciousness disorder after brain injury.

Abstract Background Headache disorders are widely prevalent and pose a considerable economic burden on individuals and society. Globally, misdiagnosis and inadequate treatment of primary headache disorders remain significant challenges, impeding the effective management of such conditions. Despite advancements in headache management over the last decade, a need for comprehensive evaluations of the status of primary headache disorders in China regarding diagnosis and preventative treatments persists. Methods In the present study, we analyzed the established queries in the Survey of Fibromyalgia Comorbidity with Headache (SEARCH), focusing on previous diagnoses and preventative treatment regimens for primary headache disorders. This cross-sectional study encompassed adults diagnosed with primary headache disorders who sought treatment at 23 hospitals across China between September 2020 to May 2021. Results The study comprised 2,868 participants who were systematically examined. Migraine and tension-type headaches (TTH) constituted a majority of the primary headache disorders, accounting for 74.1% (2,124/2,868) and 23.3% (668/2,868) of the participants, respectively. Medication overuse headache (MOH) affected 8.1% (231/2,868) of individuals with primary headache disorders. Over half of the individuals with primary headache disorders (56.6%, 1,624/2,868) remained undiagnosed. The previously correct diagnosis rates for migraine, TTH, TACs, and MOH were 27.3% (580/2,124), 8.1% (54/668), 23.2% (13/56), and 3.5% (8/231), respectively. The misdiagnosis of “Nervous headache” was found to be the most prevalent among individuals with migraine (9.9%, 211/2,124), TTH (10.0%, 67/668), trigeminal autonomic cephalalgias (TACs) (17.9%, 10/56), and other primary headache disorders (10.0%, 2/20) respectively. Only a minor proportion of individuals with migraine (16.5%, 77/468) and TTH (4.7%, 2/43) had received preventive medication before participating in the study. Conclusions While there has been progress made in the rate of correct diagnosis of primary headache disorders in China compared to a decade ago, the prevalence of misdiagnosis and inadequate treatment of primary headaches remains a veritable issue. As such, focused efforts are essential to augment the diagnosis and preventive treatment measures related to primary headache disorders in the future.

Abstract Obesity/overweight and lipid metabolism disorders have become increased risk factors for lung cancer. Fatty acid translocase CD36 promotes cellular uptake of fatty acids. Whether and how CD36 facilitates lung adenocarcinoma (LUAD) growth in high-fat environment is unknown. Here, we demonstrated that palmitic acid (PA) or high-fat diet (HFD) promoted LUAD cell proliferation and metastasis in a CD36-dependent manner. Mechanistically, CD36 translocated from cytoplasm to cell membrane and interacted with Src kinase upon PA stimulation in human LUAD cells. Akt and ERK, downstream of Src, were then activated to mediate LUAD cell proliferation and metastasis. Furthermore, PA treatment promoted CD36 sarcolemmal translocation, where it activated Rac1 and upregulated MMP-9 through Src-Akt/ERK pathway, resulting in redistribution of cortactin, N-WASP and Arp2/3, and finally led to occurrence of finger-like protrusions of actin on cell surface to enhance cell metastasis. Compared with normal-chew diet (NCD) mice, the HFD group exhibited higher level of blood free fatty acid (FFA) and cholesterol (TC), developed larger xenograft LUAD tumors and enhanced tumor cell metastatic potential, which were accompanied by obvious sarcolemmal actin remodeling and were blocked by simultaneous CD36 knockdown in LUAD cells. Consistently, xenografted and tail vein-injected scramble-RNA-A549 cells but not CD36-shRNA-A549 in HFD mice formed metastatic LUAD tumors on the lung. CD36 inhibitor SSO significantly inhibited LUAD cell metastasis to the lung. Collectively, CD36 initiates Src signaling to promote LUAD cell proliferation and actin remodeling-involved metastasis under high-fat environment. Our study provides the new insights that CD36 is a valid target for LUAD therapy.

Abstract Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the mouth, characterised by rapid progression and poor prognosis. Hence, an urgent need exists for the development of predictive targets for early diagnosis, prognosis determination, and clinical therapy. Dysregulation of lymphoid enhancer-binding factor 1 (LEF1), an important transcription factor involved in the Wnt-β-catenin pathway, contributes to the poor prognosis of OSCC. Herein, we aimed to explore the correlation between LEF1 and histone lysine demethylase 4 A (KDM4A). Results show that the KDM4A complex is recruited by LEF1 and specifically binds the LATS2 promoter region, thereby inhibiting its expression, and consequently promoting cell proliferation and impeding apoptosis in OSCC. We also established NOD/SCID mouse xenograft models using CAL-27 cells to conduct an in vivo analysis of the roles of LEF1 and KDM4A in tumour growth, and our findings show that cells stably suppressing LEF1 or KDM4A have markedly decreased tumour-initiating capacity. Overall, the results of this study demonstrate that LEF1 plays a pivotal role in OSCC development and has potential to serve as a target for early diagnosis and treatment of OSCC.

Abstract Synovial sarcoma is a highly malignant tumor that accounts for 10% of all soft tissue sarcomas. Primary pulmonary synovial sarcoma (PPSS) is extremely rare, and its prognosis is poor. A diagnosis is usually established after other primary lung malignancies or metastatic extrathoracic sarcomas have been excluded. Therefore, it is often misdiagnosed. In this study, we report the case of a 38‐year‐old woman who was misdiagnosed as having pleural mesothelioma and finally endured surgery to remove the tumor. The tumor showed SYT‐SSX fusion transcripts and was diagnosed as PPSS after combining histopathological and immunohistochemical analyses. Finally, we determined some biomarkers through whole‐exome sequencing (WES) to improve the diagnosis and treatment strategies.

The impact of intraocular scatter and higher order aberrations (HOAs) on ocular optical quality was investigated. An optical eye model was constructed using the measured ocular aberrations, corneal surfaces, axial length, and scatter fraction, and the impact of HOAs and scatter on modulation transfer functions (MTFs) was studied based on the newly established optical eye model. For uniform intraocular scatter, the monochromatic and polychromatic MTF decreased as the HOAs or scatter fractions increased independently at each spatial frequency, which implied that both were essential for visual quality. In addition, the scatter effect on MTF was more significant for the eye with less HOA. The combined deterioration effect of these two factors on the MTF was less than their summation, suggesting a potential compensatory mechanism between HOAs and scatter.

Abstract Background Although headache disorders are common, the current diagnostic approach is unsatisfactory. Previously, we designed a guideline-based clinical decision support system (CDSS 1.0) for diagnosing headache disorders. However, the system requires doctors to enter electronic information, which may limit widespread use. Methods In this study, we developed the updated CDSS 2.0, which handles clinical information acquisition via human–computer conversations conducted on personal mobile devices in an outpatient setting. We tested CDSS 2.0 at headache clinics in 16 hospitals in 14 provinces of China. Results Of the 653 patients recruited, 18.68% (122/652) were suspected by specialists to have secondary headaches. According to “red-flag” responses, all these participants were warned of potential secondary risks by CDSS 2.0. For the remaining 531 patients, we compared the diagnostic accuracy of assessments made using only electronic data firstly. In Comparison A, the system correctly recognized 115/129 (89.15%) cases of migraine without aura (MO), 32/32 (100%) cases of migraine with aura (MA), 10/10 (100%) cases of chronic migraine (CM), 77/95 (81.05%) cases of probable migraine (PM), 11/11 (100%) cases of infrequent episodic tension-type headache (iETTH), 36/45 (80.00%) cases of frequent episodic tension-type headache (fETTH), 23/25 (92.00%) cases of chronic tension-type headache (CTTH), 53/60 (88.33%) cases of probable tension-type headache (PTTH), 8/9 (88.89%) cases of cluster headache (CH), 5/5 (100%) cases of new daily persistent headache (NDPH), and 28/29 (96.55%) cases of medication overuse headache (MOH). In Comparison B, after combining outpatient medical records, the correct recognition rates of MO (76.03%), MA (96.15%), CM (90%), PM (75.29%), iETTH (88.89%), fETTH (72.73%), CTTH (95.65%), PTTH (79.66%), CH (77.78%), NDPH (80%), and MOH (84.85%) were still satisfactory. A patient satisfaction survey indicated that the conversational questionnaire was very well accepted, with high levels of satisfaction reported by 852 patients. Conclusions The CDSS 2.0 achieved high diagnostic accuracy for most primary and some secondary headaches. Human–computer conversation data were well integrated into the diagnostic process, and the system was well accepted by patients. The follow-up process and doctor–client interactions will be future areas of research for the development of CDSS for headaches.

The effect of COVID-19 vaccines in reducing hospitalization risks was studied using the Long Short-Term Memory (LSTM) model. We first devised a dynamic environment using an LSTM that characterizes the impact of COVID-19 vaccine administrations on COVID-19 infections in the real-world setting from May 2021 to April 2023. Then, we generated hypothetical subjects with various vaccination profiles (e.g., all subjects received or not received the booster vaccine, or all subjects had followed the vaccine policy) and predicted their counterfactual outcomes based on the LSTM to make inferences on the vaccine effectiveness and estimate the population-averaged risk of infection if there was full compliance for the vaccine policy. Our findings confirm that booster doses significantly reduced the risk of COVID-19 hospitalization while bivalent booster had similar or slightly better effectiveness than the monovalent booster. Additionally, our analysis highlights the importance of adhering to vaccine policies in effectively reducing the risk of hospitalizations. Our study contributes to understanding the dynamics of vaccine efficacy and supports informed decision-making in public health strategies.

AbstractBackground In order to better understand the interplay between ferroptosis and autophagy, enhance the interpretation of the crosstalk between these two forms of regulated cell death, develop the effective pharmacological mechanisms for cancer treatment, discover novel biomarkers for better diagnostic, and envisage the future hotspots of the research on ferroptosis and autophagy, we harnessed bibliometric tools to study the articles published from 2012 to 2022 on the relationship between ferroptosis and autophagy.Methods Web of Science Core Collection (WOSCC) database was used to conduct a comprehensive search and analysis of articles in this field from January 1, 2012, to September 1, 2022. The Citespace 6.1.R2 software and VOS viewer 6.1.8 software were utilized to analyze the overall structure of the network, network clusters, links between clusters, key nodes or pivot points, and pathways.Results A total of 756 articles associated with the crosstalk between ferroptosis and autophagy were published in 512 journals by 4183 authors in 980 organizations from 55 countries or regions. The distribution of countries and organizations was demonstrated using CiteSpace and VOS viewer. The top three countries with the most articles were China (n = 511), United States (n = 166), and Germany (n = 37). The most productive institutions were Guangzhou Medical University and Central South University (n = 42), but their centralities were relatively low, which values were respective 0.04 and 0.03. Kang and Tang published the most articles related to ferroptosis and autophagy (n = 49), followed by Jiao Liu (n = 22), Guido Kroemer (n = 20), and Daniel Klionsky (n = 12). Published studies on ferroptosis and asthma have the most cited counts. The top three keywords with the highest frequencies were autophagy (n = 283), cell death (n = 243), and oxidative stress (n = 165).Conclusion Our results provide insights into the development of recognition related to the crosstalk between ferroptosis and autophagy, and the current molecular crosslinked mechanisms in the context of common signal transduction pathways or affecting cellular environment to induce the adaptive stress response and to activate the particular form of regulated cell death (RCD), and the development of cancer treatment based on novel targets and signaling regulatory networks provided by ferroptosis and autophagy.

AbstractIcariin (ICA) played an important role in the treatment of inflammatory bone defects. However, pharmacokinetic studies have shown that its poor bioavailability limited its application. In this context, we isolated bovine milk-derived sEV and prepared sEV-ICA to improve the osteogenic effect of ICA. In this study, we successfully constructed sEV-ICA. sEV-ICA was found to have significantly higher osteogenic efficiency than ICA in cell culture and cranial bone defect models. Mechanistically, bioinformatics analysis predicted that signal transducers and activators of transcription 5 (STAT5a) may bind to the GJA1 promoter, while luciferase activity assays and chromatin immunoprecipitation (ChIP) experiments confirmed that STAT5a directly binded to the GJA1 promoter to promote osteogenesis. We proved that compared with ICA, sEV-ICA showed a better effect of promoting bone repair in vivo and in vitro. In addition, sEV-ICA could promote osteogenesis by promoting the combination of STAT5a and GJA1 promoter. In summary, as a complex drug delivery system, sEV-ICA constituted a rapid and effective method for the treatment of bone defects and could improve the osteogenic activity of ICA.

Abstract Background A wide spectrum of changes occurs in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunction is one of the significant factors associated with age. Adiponectin (APN), an essential adipokine in glucose and lipid metabolism, is involved in the aging; however, its role in brain aging has not been adequately explored. Here, we aimed to explore the relationship between APN deficiency and brain aging using multiple biochemical and pharmacological methods to probe APN in humans, KO mice, primary microglia, and BV2 cells. Results We found that declining APN levels in aged human subjects correlated with dysregulated cytokine levels, while APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN-deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. In BV2 cells, the APN receptor agonist AdipoRon alleviated the mitochondrial deficits and aging markers induced by rotenone or antimycin A. HDAC1 antagonism by Compound 60 (Cpd 60) improved mitochondrial dysfunction and age-related inflammation, as validated in D-galactose-treated APN KO mice. Conclusion These findings indicate that APN is a critical regulator of brain aging by preventing neuroinflammation associated with mitochondrial impairment via HDAC1 signaling.

In view of the problem that the exchange effectiveness is calculated according to a fixed value or only considering the influence of outdoor air parameters when analyzing the suitability of total heat recovery for plate heat recovery equipment in air-conditioned spaces without humidity control, the indoor humidity calculation model and moisture balance equation were established in this research to predict relative indoor humidity. Moreover, the relationship between total heat recovery, effective heat recovery, and the reduction in outdoor air heating load was analyzed using a psychrometric chart of the outdoor air treatment process. Referring to the standard for weather data of building energy efficiency in the Ningbo region, 6 typical days were taken as the calculation conditions. The moisture balance differential equation was solved using MATLAB software to obtain numerical solutions for the hourly indoor air humidity ratio, relative humidity, exchange effectiveness, and effective heat recovery when adopting an air-to-air total heat exchanger in an air-conditioned room of an office, classroom, or commercial building in the winter. The results indicate that, under the calculation conditions, the relative indoor humidity of commercial buildings is relatively high, making it unsuitable for a total heat exchanger. The relative humidity of indoor air in offices and classrooms can be maintained above 30%, and the total exchange effectiveness of a total heat exchanger is between 45% and 100%. The effective total heat recovery was calculated as sensible heat recovery under most calculation conditions.

Introduction: Medication-overuse headache (MOH) is a secondary chronic headache disorder that occurs in individuals with a pre-existing primary headache disorder, particularly migraine disorder. Obesity is often combined with chronic daily headaches and is considered a risk factor for the transformation of episodic headaches into chronic headaches. However, the association between obesity and MOH among individuals with migraine has rarely been studied. The present study explored the association between body mass index (BMI) and MOH in people living with migraine. Methods: This cross-sectional study is a secondary analysis of data from the Survey of Fibromyalgia Comorbidity with Headache study. Migraine and MOH were diagnosed using the criteria of the International Classification of Headache Disorders, 3rd edition. BMI (kg/m2) is calculated by dividing the weight (kg) by the square of the height (m). Multivariable logistic regression analysis was used to evaluate the association between BMI and MOH. Results: A total of 2,251 individuals with migraine were included, of whom 8.7% (195/2,251) had a concomitant MOH. Multivariable logistic regression analysis, adjusted for age, sex, education level, headache duration, pain intensity, headache family history, chronic migraine, depression, anxiety, insomnia, and fibromyalgia, demonstrated there was an association between BMI (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01–1.11; P = 0.031) and MOH. The results remained when the BMI was transformed into a category. Compared to individuals with Q2 (18.5 kg/m2 ≤ BMI ≤ 23.9 kg/m2), those with Q4 (BMI ≥ 28 kg/m2) had an adjusted OR for MOH of 1.81 (95% CI, 1.04-3.17; P = 0.037). In the subgroup analyses, BMI was associated with MOH among aged more than 50 years (OR, 1.13; 95%, 1.03-1.24), less than high school (OR, 1.08; 95%, 1.01-1.15), without depression (OR, 1.06; 95%, 1.01-1.12), and without anxiety (OR, 1.06; 95%, 1.01-1.12). An association between BMI and MOH was found in a sensitivity analysis that BMI was classified into four categories according to the World Health Organization guidelines. Conclusion: In this cross-sectional study, BMI was associated with MOH in Chinese individuals with migraine.

Background: Citrus yellow vein-clearing virus (CYVCV) is a Mandarivirus that causes great economic losses in lemon production. CYVCV infection is associated with obvious yellow vein-clearing disease symptoms and is directly regulated by plant hormone responses. Methods: To understand how lemon plants respond to CYVCV infection, we performed transcriptomic and phytohormone metabolomics. Results: A total of 936 differentially expressed genes were identified, and 773 were downregulated. Salicylic acid and auxin levels increased after CYVCV infection, and phytohormone regulatory systems were also explored. Jasmonic acid and auxin levels decreased after the CYVCV challenge, and jasmonic acid and auxin signaling pathway components were mostly downregulated. The differentially expressed genes (DEGs) involved in the immune response to viral infection, including those related to cell wall integrity, lectin, microtubules, and mildew resistance locus O (MLO), may also provide new candidate targets for CYVCV control. Conclusions: Our findings provide new insights into the molecular changes underlying the pathogenesis of CYVCV in lemon plants.

Per- and poly-fluoroalkyl substances (PFAS), such as GenX, are a class of highly stable synthetic compounds that have recently become the focus of environmental remediation endeavors due to their toxicity. While considerable strides have been made in PFAS remediation, the diversity of these compounds, and the costs associated with approaches such as ion exchange resins and advanced oxidation technologies, remain challenging for widespread application. In addition, little is known about the potential binding and impacts of GenX on human proteins. To address these issues, we applied phage display and screened short peptides that bind specifically to GenX, with the ultimate goal of identifying human proteins that bind with GenX. In this study we identified the amino acids that contribute to the binding and measured the binding affinities of the two discovered peptides with NMR. A human protein, ankyrin-repeat-domain-containing protein 36B, with matching sequences of one of the peptides, was identified, and the binding positions were predicted by docking and molecular dynamics simulation. This study created a platform to screen peptides that bind with toxic chemical compounds, which ultimately helped us identify biologically relevant molecules that could be inhibited by the GenX, and also provided information that will contribute to future bioengineered GenX-binding device design.

Abstract Immune checkpoint blockades are the most promising therapy in lung adenocarcinoma (LUAD). However, the response rate remains limited, underscoring the urgent need for effective sensitizers. Interleukin 4 induced 1 (IL4I1) is reported to have immunoinhibitory and tumor‐promoting effects in several cancers. However, the targetable value of IL4I1 in sensitizing the immunotherapy is not clear, and there is a lack of effective small molecules that specifically target IL4I1. Here, we show that silencing IL4I1 significantly remodels the immune microenvironment via inhibiting aryl hydrocarbon receptor (AHR) signaling, thereby enhancing the efficacy of anti‐PD‐1 antibody in LUAD, which suggests that IL4I1 is a potential drug target for the combination immunotherapy. We then identify thymol as the first small molecule targeting IL4I1 transcription through a drug screening. Thymol inhibits the IL4I1 expression and blocks AHR signaling in LUAD cells. Thymol treatment restores the antitumor immune response and suppresses the progression of LUAD in an orthotopic mouse model. Strikingly, the combination treatment of thymol with anti‐PD‐1 antibody shows significant tumor regression in LUAD mice. Thus, we demonstrate that thymol is an effective small molecule to sensitize the PD‐1 blockade in LUAD via targeting IL4I1, which provides a novel strategy for the immunotherapy of LUAD.

ObjectiveEpstein-Barr virus (EBV) is a virus that is ubiquitous in humans. To investigate the association between EBV infection and lung cancer risk to reveal whether it is involved in the development and development of lung cancer. Although there has been discussion of EBV and lung cancer in the past. Through this study, we hope to deepen our understanding of the causes of lung cancer and provide new clues and targets for the prevention, early diagnosis and treatment of lung cancer. This study is also beneficial to the development of medical science and public health. First of all, the research results are expected to be incorporated into lung cancer prevention and treatment strategies and policies, so as to provide better treatment decisions for lung cancer patients and improve the survival rate and quality of life of patients. At the same time, communicating the research results to the public can help raise awareness of lung cancer risk factors. By encouraging healthy lifestyles and screening measures, the public can reduce their risk of lung cancer. In addition, this study also provides an important foundation for subsequent academic research and scientific exploration. It provides valuable information and inspiration for in-depth understanding of lung cancer and other related fields. Overall, this study makes an important contribution to both medical science and public health.MethodBy September 26, 2022, an online database was used to conduct a literature search in English. Random effects models were employed to estimate the prevalence of EBV with 95% confidence intervals (CIs). Additionally, the pooled odds ratio (OR) and 95%CI were calculated from case-control studies to determine the association between EBV and lung cancer.ResultsIn this study of 886 patients with lung cancer, the overall prevalence of EBV infection was found to be 44.36% (95%CI: 4.08-16.9). Fourteen studies were included in the analysis, all of which used a case-control design and involved comparisons of tumors with adjacent or non-adjacent normal and non-cancerous controls. There was a significant difference in the prevalence of EBV infection in lung cancer tissues between China and other regions, with an odds ratio (OR) of 9.36 (95% confidence interval: 4.00-21.94, P

Summary: Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are dysregulated in many pervasive diseases. Recently, we discovered that ERK1/2 is oxidized by signal-generated hydrogen peroxide in various cell types. Since the putative sites of oxidation lie within or near ERK1/2’s ligand-binding surfaces, we investigated how oxidation of ERK2 regulates interactions with the model substrates Sub-D and Sub-F. These studies revealed that ERK2 undergoes sulfenylation at C159 on its D-recruitment site surface and that this modification modulates ERK2 activity differentially between substrates. Integrated biochemical, computational, and mutational analyses suggest a plausible mechanism for peroxide-dependent changes in ERK2-substrate interactions. Interestingly, oxidation decreased ERK2’s affinity for some D-site ligands while increasing its affinity for others. Finally, oxidation by signal-generated peroxide enhanced ERK1/2’s ability to phosphorylate ribosomal S6 kinase A1 (RSK1) in HeLa cells. Together, these studies lay the foundation for examining crosstalk between redox- and phosphorylation-dependent signaling at the level of kinase-substrate selection.

Aims: Cultural ecosystem services are important component of ecosystem services which play increasingly important roles in enhancing human well-being. Hangzhou Xixi National Wetland Park (hereafter referred to as Xixi Wetland), the first National Wetland Park of China located in Hangzhou City of the Yangtze River Delta urban agglomerations, plays a fundamental, leading and exemplary role in the ecological construction of urban wetland ecosystems. This paper aims to reveal spatio-temporal characteristics of its cultural ecosystem services and their relations to landscape factors. Methods: First, the sets of photographs which were uploaded by tourists in 2019 from the two-step website, were used as the data source. Then, we established the corresponding index framework and evaluation model of cultural ecosystem services basing on previous case studies. The social media photo analysis method was used to collect information about the captured images. By means of the ArcGIS software, we visualized the spatial distribution hotspots of different aspects of cultural ecosystem services in Xixi Wetland, and their differences in tourists' perceptions were obtained. Principal component analysis was used to analyze the correlation between cultural ecosystem services and landscape factors. Results: The result showed that most of social media photos were shared to present aesthetic values along with recreation and ecotourism and infrastructure appreciation. Besides, for the landscape elements appearing in the photographs, biological landscape had the highest frequency (40.8%, n = 2667). We found that different types of cultural ecosystem services have different kernel density distributions and perception levels, and also affected by seasonal scales. Besides, there were significant positive spatial correlations between different items of cultural ecosystem services. Among which, the strongest correlations were observed between aesthetic and infrastructure appreciation. In addition, there were spatial correlations between cultural ecosystem services and landscape factors. Conclusions: We concluded that the spatial distribution of cultural ecosystem services in Xixi Wetland presents different patterns under the influence of landscape heterogeneity and seasonal time dimension. There was a correlation between different types of cultural ecosystem services and most landscape factors, indicating that tourists have certain preferences when they perceive cultural ecosystem services.

Though necessary and advantageous in many fields, the high coherence of lasers is detrimental to their performance in certain applications, including illumination, imaging, and projection. This is due to the formation of coherence artifacts, commonly known as speckles, resulting from the interference of randomly scattering spatially coherent photons. It is possible to resolve this issue by increasing the number of mutually incoherent modes emitted from the laser. In vertical-cavity surface-emitting lasers (VCSELs), this can be performed by designing them to have chaotic cavities. This paves the way toward their use in simultaneous illumination and communication scenarios. Herein, we show that chaotic-cavity broad-area VCSELs can achieve significantly broader modulation bandwidths (up to 5 GHz) and higher data rates (up to 12.6 GB/s) compared to other low-coherence light sources, with a lower speckle contrast. We further report a novel technique for lowering the speckle contrast by carefully designing the AC signal used for communication. We show that the apparent spatial coherence is dramatically decreased by inserting a short chirp signal between symbols. Using this method with a chaotic-cavity VCSEL, the number of apparent modes can be up to 450, compared to 88 modes measured from a conventional broad-area VCSEL (a fivefold increase). In light of the recent advances in visible-light VCSELs, this work shows the potential of low-coherence surface-emitting lasers (LCSELs) in simultaneous illumination and optical wireless communication systems since they combine the high speed of lasers with the excellent illumination properties of light-emitting diodes.

IntroductionCognitive dysfunction has frequently been found in patients with migraine. The so-called contingent negative variation (CNV) and EEG power spectral densities may be the best choices to explore the underlining pathophysiology, such as cortical inhibition and habituation.MethodsThirty migraine patients without aura and healthy controls matched for sex, age, and education were recruited separately for CNV recording. The amplitudes, latencies, and squares of different CNV components, such as oCNV, iCNV, tCNV, and PINV, were selected and analyzed. Behavioral data, such as manual reaction time (RT), were analyzed. We used the Person correlation coefficient R to analyze different ERP components in relation to clinical characteristics. A multiple regression analysis was conducted for the migraine group. Spectral analysis of EEG data from all channels using the fast Fourier transform (FFT).ResultsThe migraine group had longer A-latency, C-latency, and iCNV-latency than the control group. The migraine group had higher iCNV-amplitude, oCNV-amplitude, and tCNV-amplitude than the control group, especially those located in the occipital area. The iCNV-square, oCNV-square, tCNV-square, or PINV-square in the migraine group was significantly larger than the control group. Different correlations were found between clinical characteristics and ERP components. The delta or theta activity in the migraine group was statistically lower than in the control group.DiscussionOur study has revealed that migraine attacks may influence responsivity, pre-activation, habituation, and cortical inhibition not only on the behavioral level but also on the electrophysiological level. Abnormal changes in cortical habituation and inhibition can be interpreted as CNV components. Additionally, analyses have revealed correlations between CNV components and various factors, including age, the clinical course of the condition, attack frequency, pain intensity, and duration. Thus, repetitive migraine attacks can lead to a reduction in cortical inhibition and subsequent impairment in executive function.

Bone regeneration is a dynamic process that involves angiogenesis and the balance of osteogenesis and osteoclastogenesis. In bone tissue engineering, the transplantation of mesenchymal stem cells (MSCs) is a promising approach to restore bone homeostasis. MSCs, particularly their small extracellular vesicles (sEVs), exert therapeutic effects due to their paracrine capability. Increasing evidence indicates that microRNAs (miRNAs) delivered by sEVs from MSCs (MSCs-sEVs) can alter gene expression in recipient cells and enhance bone regeneration. As an ideal delivery vehicle of miRNAs, MSCs-sEVs combine the high bioavailability and stability of sEVs with osteogenic ability of miRNAs, which can effectively overcome the challenge of low delivery efficiency in miRNA therapy. In this review, we focus on the recent advancements in the use of miRNAs delivered by MSCs-sEVs for bone regeneration and disorders. Additionally, we summarize the changes in miRNA expression in osteogenic-related MSCs-sEVs under different microenvironments.

Summary: Smoking carcinogen nicotine-derived nitrosamine ketone (NNK) is the most potent contributor to lung adenocarcinoma (LUAD) development, but the mechanism has not been fully elucidated. Here, we reported that fatty acid translocase CD36 was significantly overexpressed in both human LUAD tissues and NNK-induced A/J mice LUAD tumors. The overexpressed CD36 was positively correlated with Src kinase activation, smoking status, metastasis, and worse overall survival of patients with smoking history. Upon NNK binding with α7 nicotinic acetylcholine receptor (α7nAChR), sarcolemmal CD36 was increased and it interacted with surface α7nAChR and cytosol Src simultaneously, which in turn activated Src and downstream pro-carcinogenic kinase ERK1/2 and Akt, and finally caused LUAD cells to form subcutaneous and pulmonary metastatic tumors. This process could be blocked by CD36 knockdown and CD36 irreversible inhibitor SSO. Furthermore, the effect of NNK was inhibited obviously in CD36−/− A/J mice. Thus, targeting CD36 may provide a breakthrough therapy of LUAD.

With the development of the combination of medicine and engineering and the improvement of clinical rehabilitation demand, intelligent upper limb rehabilitation robots can provide stroke patients with high intensity and repetition of active rehabilitation training to restore the upper limb motor function and achieve the remodeling of damaged brain nerves. However, many upper limb rehabilitation robot systems are still in the stage of laboratory development or clinical verification. This paper summarizes the latest research results of upper limb rehabilitation robots at home and abroad, compares the advantages and disadvantages of different types of robots, looks forward to the development trend of upper limb rehabilitation robots, and provides ideas for further promoting clinical transformation.

Context Swertia mussotii Franch. (Gentianaceae) is a source of the traditional Tibetan medicine, ZangYinChen, and is used to treat chronic hepatitis and many types of jaundice.Objective This study explored the therapeutic effects and mechanism of S. mussotii on non-alcoholic fatty liver disease in diet-induced hypercholesterolaemia.Materials and methods After a week of adaptive feeding, 32 Sprague-Dawley rats were divided into four groups: (1) Control, (2) Control-S, (3) Model, and (4) Model-S. During the 12 experimental weeks, we established the Model using a high-fat diet. Control-S and Model-S were given 1.0 g/kg S. mussotii water extract via gavage starting in the fifth week until the end of experiment.Results When compared with Model rats, the S. mussotii water extract led to a reduction in high-density lipoproteins (43.9%) and albumin (13.9%) and a decrease in total cholesterol (54.0%), triglyceride (45.6%), low-density lipoproteins (8.6%), aspartate aminotransferase (11.0%), alanine aminotransferase (15.5%), alkaline phosphatase (19.1%), total protein (6.4%), and glucose (20.8%) in serum. A reduction in three cytokines (IL-1β, IL-6, and TNFα) was detected. Histopathological examination showed that liver steatosis was significantly relieved in S. mussotii-treated high-fat diet rats. S. mussotii also caused a downregulation in the expression of TLR4 (43.2%), MyD88 (33.3%), and a decrease in phosphorylation of NF-κB.Discussion and conclusions Our findings indicate that S. mussotii may act as a potential anti-inflammation drug via inhibition of the TLR4/MyD88/NF-κB pathway. Further in vivo and in vitro studies are needed to validate its potential in clinical medicine.

In recent years, the corona virus disease 2019 (COVID-19) pandemic has had a huge impact on the global medical, political and economic fields. Since the beginning of the COVID-19 epidemic, our understanding of the impact of COVID-19 has grown exponentially. Recently, the COVID-19 epidemic has changed rapidly in China, and there has been controversy over how to carry out surgical operations for patients with lung neoplastic lesions. Some studies have shown that lung cancer patients undergoing surgery are more likely to experience respiratory failure and perioperative death after contracting COVID-19 than the general population, however, delays in cancer treatment are also associated with increased mortality among these patients. In particular, the novel coronavirus Omikron variant has a higher transmissibility and may escape the immunity obtained through the previous novel coronavirus infection and vaccination. In order to minimize the risk of novel coronavirus infection in surgical patients, it is necessary to develop new treatment guidelines, expert consensus and preventive measures. However, the current rapid change of the epidemic situation has led to insufficient time and evidence to develop guidelines and consensus. Therefore, thoracic surgeons need to evaluate specific patient populations at higher risk of severe complications before surgery and weigh the benefit of surgical treatment against the risk of novel coronavirus infection. We try to give some recommendations on lung surgery during the current domestic epidemic situation based on the guidelines and consensus of oncology and thoracic surgery organizations in different regions on lung surgery.

Abstract Purpose The aim of this study was to determine the expression of lipid metabolism-related proteins in rheumatic heart valve disease (RHVD). Methods This retrospective study involved a total of 20 cases of moderate or severe rheumatic mitral valve stenosis and 4 cases of mitral regurgitation due to secondary causes from September 2018 to September 2021. The patients enrolled included 12 males and 12 females who underwent surgical excision of the mitral valve at the cardiac surgery department of Hainan General Hospital. The samples of mitral valve were collected during surgery treatment as the study group, and mitral valves collected from patients with ischemic heart disease were allocated into the control group. Hematoxylin–eosin (HE), oil red staining and immunohistochemical (IHC) staining were conducted to compare the expression of lipid metabolism-related proteins (ATP-binding cassette transporter A1 and acyl-coenzyme A: cholesterol acyltransferase-1), and real-time polymerase chain reaction (RT–PCR) was applied to compare the mRNA levels of ABCA1, ACAT1, and the inflammatory cytokines TNF-α, IL-10, and MCP-1. Results In general, the rheumatic mitral valve showed leaflet thickening along with border adhesions and visible yellow fats. Oil red O staining also revealed the abovementioned results as well as fat cells. Both ABCA1 and ACAT1 were expressed in the rheumatic mitral valve via IHC, whereas only ACAT1 showed a faint level of expression in the ischemic mitral valve with no expression of ABCA1. In addition, compared with the ischemic mitral valve, RT-PCT showed increased mRNA expression levels of ABCA1, ACAT1, and the inflammatory cytokines TNF-α, IL-10, and MCP-1 (P

Abstract Background Phosphoinositide 3-kinase (PI3K) is located within cells, and is involved in regulating cell survival, proliferation, apoptosis and angiogenesis. The purpose of this study was to investigate the role of PI3K in the process of bone destruction in apical periodontitis, and provide reference data for the treatment of this disease. Methods The relative mRNA expression of PI3K, Acp5 and NFATc1 in the normal human periodontal ligament and in chronic apical periodontitis were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). A mouse model of apical periodontitis was established by root canal exposure to the oral cavity, and HE staining was used to observe the progress of apical periodontitis. Immunohistochemical staining was used to detect the expression of PI3K and AKT in different stages of apical periodontitis, while enzymatic histochemical staining was used for detection of osteoclasts. An Escherichia coli lipopolysaccharide (LPS)-mediated inflammatory environment was also established at the osteoclast and osteoblast level, and osteoclasts or osteoblasts were treated with the PI3K inhibitor LY294002 to examine the role of PI3K in bone resorption. Results The expression of PI3K, Acp5 and NFATc1 genes in chronic apical periodontitis sample groups was significantly increased relative to healthy periodontal ligament tissue (P

A combination of repeated systemic infusion and local transplantation of hiPSC-MSCs could enhance regenerative therapies for cardiovascular disease.