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PurposeThe inhibition of thrombin has proven to be an efficacious therapeutic approach for managing cardiovascular disease (CVD), with widespread implementation in clinical settings. Oral ingestion of peptides and protein drugs is influenced by gastrointestinal digestive enzymes. We aimed to evaluate the thrombin inhibitory properties of hirudo hydrolysates (HHS) produced by pepsin and propose a comprehensive approach to screen and evaluate thrombin inhibitors.MethodsWe evaluated the in vitro inhibitory properties of the hirudo extract, both before and after hydrolysis with pepsin, toward thrombin. We screened for the most potent thrombin inhibitory peptide (TIP) using nano liquid chromatography-tandem mass spectrometry (Nano LC-MS/MS) coupled with in silico analysis. Next, we employed the thrombin inhibition activity IC50 to investigate the interaction between TIP and thrombin, and conducted in vitro evaluations of its anticoagulant effects (APTT, TT, PT), as well as its ability to inhibit platelet aggregation. Furthermore, we utilized UV-Vis spectroscopy to explore structural changes in thrombin upon binding with TIP and employed molecular dynamics simulations to delve deeper into the potential atomic-level interaction modes between thrombin and TIP.ResultsThe retention rate of thrombin inhibition for HHS was found to be between 60% and 75%. A total of 90 peptides from the HHS were identified using LC-MS/MS combined with de novo sequencing. Asn-Asp-Leu-Trp-Asp-Gln-Gly-Leu-Val-Ser-Gln-Asp-Leu (NDLWDQGLVSQDL, P1) was identified as the most potent thrombin inhibitory peptide after in silico screening (molecular docking and ADMET). Then, the in vitro study revealed that P1 had a high inhibitory effect on thrombin (IC50: 2,425.5 ± 109.7 μM). P1 exhibited a dose-dependent prolongation of the thrombin time (TT) and a reduction in platelet aggregation rate. Both UV-Vis spectroscopy and molecular dynamics simulations demonstrated that P1 binds effectively to thrombin.ConclusionOverall, the results suggested that HHS provides new insights for searching and evaluating potential antithrombotic compounds. The obtained P1 can be structurally optimized for in-depth evaluation in animal and cellular experiments.

BackgroundAging is marked by the gradual deterioration of cells, tissues, and organs and is a major risk factor for many chronic diseases. Considering the complex mechanisms of aging, traditional Chinese medicine (TCM) could offer distinct advantages. However, due to the complexity and variability of metabolites in TCM, the comprehensive screening of metabolites associated with pharmacology remains a significant issue.MethodsA reliable and integrated identification method based on UPLC-Q Exactive-Orbitrap HRMS was established to identify the chemical profiles of Huan Shao Dan (HSD). Then, based on the theory of sequential metabolism, the metabolic sites of HSD in vivo were further investigated. Finally, a deep learning model and a bioactivity assessment assay were applied to screen potential anti-aging metabolites.ResultsThis study identified 366 metabolites in HSD. Based on the results of sequential metabolism, 135 metabolites were then absorbed into plasma. A total of 178 peaks were identified from the sample after incubation with artificial gastric juice. In addition, 102 and 91 peaks were identified from the fecal and urine samples, respectively. Finally, based on the results of the deep learning model and bioactivity assay, ginsenoside Rg1, Rg2, and Rc, pseudoginsenoside F11, and jionoside B1 were selected as potential anti-aging metabolites.ConclusionThis study provides a valuable reference for future research on the material basis of HSD by describing the chemical profiles both in vivo and in vitro. Moreover, the proposed screening approach may serve as a rapid tool for identifying potential anti-aging metabolites in TCM.

BackgroundPulmonary fibrosis (PF) emerges as a significant pulmonary sequelae in the convalescent phase of coronavirus disease 2019 (COVID-19), with current strategies neither specifically preventive nor therapeutic. Licoricesaponin G2 (LG2) displays a spectrum of natural activities, including antibacterial, anti-inflammatory, and antioxidant properties, and has been effectively used in treating various respiratory conditions. However, the potential protective effects of LG2 against PF remain underexplored.MethodsNetwork analysis and molecular docking were conducted in combination to identify the core targets and pathways through which LG2 acts against PF. In the model of bleomycin (BLM)-induced C57 mice and transforming growth factor-β1 (TGF-β1)-induced A549 and MRC5 cells, techniques such as western blot (WB), quantitative Real-Time PCR (qPCR), Immunohistochemistry (IHC), Immunofluorescence (IF), and Transwell migration assays were utilized to analyze the expression of Epithelial-mesenchymal transition (EMT) and inflammation proteins. Based on the analysis above, we identified targets and potential mechanisms underlying LG2’s effects against PF.ResultsNetwork analysis has suggested that the mechanism by which LG2 combats PF may involve the TNF-α pathway. Molecular docking studies have demonstrated a high binding affinity of LG2 to TNF-α and MMP9. Observations from the study indicated that LG2 may mitigate PF by modulating EMT and extracellular matrix (ECM) remodeling. It is proposed that the therapeutic effect is likely arises from the inhibition of inflammatory expression through regulation of the TNF-α pathway.ConclusionLG2 mitigates PF by suppressing TNF-α signaling pathway activation, modulating EMT, and remodeling the ECM. These results provide compelling evidence supporting the use of LG2 as a potential natural therapeutic agent for PF in clinical trials.

Due to the influence of storm surges, hard coastal protection structures may exacerbate beach erosion, hence beach nourishment methods are considered in coastal protection and restoration efforts. An experiment is conducted in a wave flume to compare the advantages and disadvantages of three types of beach nourishment methods (berm nourishment, profile nourishment, and bar nourishment) under non-storm and storm wave conditions. The experiment analyzes wave height distribution, beach morphology changes, net sediment transport, shoreline recession, beach width increase, and beach volume changes. The findings indicate that the implementation of bar nourishment strategies facilitates the pre-breaking of storm waves, thereby mitigating the disruption caused by wave breaking on water flow dynamics. Moreover, the application of berm and profile nourishment methods proves to be highly effective in expanding the width of the beach and bolstering its stability. However, it is worth noting that bar nourishment exhibits limited efficacy in terms of restoring beach berms and mitigating coastal erosion within the same duration of wave action. The study presents two equations incorporating hydrodynamic parameters to predict the erosion or accretion status of beaches, and compares the predicted results with experimental data, thereby refining the criteria and making the formulas more applicable to beach nourishment projects. These findings provide valuable insights into the strengths and weaknesses of different beach nourishment methods, which will contribute to the implementation of nourishment projects.

BackgroundPostdoctoral researchers are critical to scholarly advancements, and promoting postdoctoral career growth is an endogenous path to help postdocs break through the “encircled city of scientific research”. However, further research is needed to fully explore the mechanisms that connect workplace support to postdoctoral career growth.MethodsDrawing from the Conservation of Resources theory, this study proposes a chain mediation model that demonstrates how workplace support enhances career growth by connecting psychological capital with work-life balance. To understand the motivation and career growth of postdocs in China, we conducted two questionnaires in 2021 and 2023 with the support of relevant stations.ResultsAnalyzing 367 questionnaires from Chinese postdocs, our research indicates that workplace support has a positive impact on career growth. Additionally, both psychological capital and work-life balance are key factors that contribute to career growth, serving as separate mediators and as part of a chain of mediators.DiscussionThis study validates the appropriateness of the Conservation of Resources theory in the study of the influence mechanism of postdoctoral career growth and proposes targeted strategies for academic institutions to improve support systems, promoting more effective career development pathways.

IntroductionAlthough the composition and succession of microbial communities in soy sauce fermentation have been well-characterized, the understanding of phage communities in soy sauce remains limited.MethodsThis study determined the diversity, taxonomic composition, and predicted function of phage communities and the phage-host interactions in two types of raw soy sauce (Cantonese-type fermentation, NJ; Japanese-type fermentation, PJ) using shotgun metagenomics.Results and discussionThese two raw soy sauces showed differences in phage composition (121 viral operational taxonomic units (vOTUs) in NJ and 387 vOTUs in PJ), with a higher abundance of the family Siphoviridae (58.50%) in the NJ phage community and a higher abundance of Myoviridae (33.01%) in PJ. Auxiliary metabolic functional annotation analyses showed that phages in the raw soy sauces mostly encoded genes with unknown functions (accounting for 66.33% of COG profiles), but the NJ sample contained genes mostly annotated to conventional functions related to carbohydrate metabolism (0.74%) and lipid metabolism (0.84%), while the PJ sample presented a higher level of amino acid metabolism functions (0.12%). Thirty auxiliary metabolism genes (AMGs) were identified in phage genomes, which were associated with carbohydrate utilization, cysteine and methionine metabolism, and aspartic acid biosynthesis for the host. To identify phage-host interactions, 30 host genomes (affiliated with 22 genera) were also recruited from the metagenomic dataset. The phage-host interaction analysis revealed a wide range of phage hosts, for which a total of 57 phage contigs were associated with 17 host genomes, with Shewanella fodinae and Weissella cibaria infected by the most phages. This study provides a comprehensive understanding of the phage community composition, auxiliary metabolic functions, and interactions with hosts in two different types of raw soy sauce.

The northern part of the Jurassic Sichuan Basin has long been thought of as a foreland basin in relation to the post-collisional compression along the northern margin of the Yangtze block. However, the exact coupling mechanism between mountain building and basin formation remains unclear. Here, we integrate stratigraphic correlation, basin subsidence analysis and flexural simulation to quantitatively assess the extent to which the fold-thrust belts have controlled basin subsidence. Flexural backstripping of the stratigraphic record, spanning from 201 to 149 Ma, along two cross sections that are perpendicular to the Micangshan fold-thrust belt and the Dabashan fold-thrust belt, respectively, reveals a limited flexural control of mountain loading on basin subsidence. Owing to the short-wavelength nature of plate flexure, the basin-adjacent thrust belts exerted dominant control on basin subsidence only along its margin, with the width of the foredeeps not exceeding ca. 120 km, failing to drive subsidence in the forebulge and backbulge regions. Flexural modeling results suggest that crustal thickening was relatively weak during the Early to Middle Jurassic. This was followed by a more rapid and intense phase of crustal growth in the Late Jurassic, possibly extending into the earliest Early Cretaceous. Compared to the Micangshan region, the Dabashan region has experienced more intense compression during the Late Jurassic. Additionally, our results reveal spatial variations in plate rigidity along the northern margin of the Yangtze block, with greater plate stiffness in the Dabashan region. The presence of residual subsidence, an anomalous long-wavelength subsidence component corrected for both basin-adjacent thrust loading and associated sediment loading, highlights the necessity for an additional driving mechanism for basin subsidence. This residual subsidence was likely dynamic subsidence induced by the flat subduction of the Paleo-Pacific plate (the Izanagi plate) beneath East Asia as the flat slab progressively migrated inland.

BackgroundIn recent years, both society and employers have put forward higher requirements for the comprehensive quality of college students in the new era. Based on the conservation of resources theory and life-cycle approach, this study aimed to examine the relationship between the Big Five personality traits, the psychological capital, and the key competencies among college students and analyzed the mediating role of the psychological capital in this link.MethodsA total of 1,132 Chinese undergraduates (67.40% girls; 48.67% from key universities) participated. Participants completed self-report questionnaires that evaluated the five key characteristics of personality, psychological capital, and key competencies.ResultsThere were extremely significant university-type differences in key competencies of college students. And the mediating role of psychological capital in the link between Big Five personality traits and key competencies was validated according to PROCESS model 4. Psychological capital serves as a partial mediator in the relationships between neuroticism and critical thinking, openness and creativity, conscientiousness and creativity, openness and communication, conscientiousness and communication, extraversion and collaboration, as well as openness and collaboration. The proportion of mediating effects for the above models was 5.97, 10.89, 11.82, 12.24, 11.98, 12.39, and 22.72%, respectively.DiscussionThe findings provide a better understanding of the key competencies of college students from the perspectives of the Big Five personality traits and psychological capital and suggest a greater emphasis to focusing on personality and improving psychological capital.

Background: Respiratory diseases are common and frequent diseases. Due to the high pathogenicity and side effects of respiratory diseases, the discovery of new strategies for drug treatment is a hot area of research. Scutellaria baicalensis Georgi (SBG) has been used as a medicinal herb in China for over 2000 years. Baicalin (BA) is a flavonoid active ingredient extracted from SBG that BA has been found to exert various pharmacological effects against respiratory diseases. However, there is no comprehensive review of the mechanism of the effects of BA in treating respiratory diseases. This review aims to summarize the current pharmacokinetics of BA, baicalin-loaded nano-delivery system, and its molecular mechanisms and therapeutical effects for treating respiratory diseases.Method: This review reviewed databases such as PubMed, NCBI, and Web of Science from their inception to 13 December 2022, in which literature was related to “baicalin”, “Scutellaria baicalensis Georgi”, “COVID-19”, “acute lung injury”, “pulmonary arterial hypertension”, “asthma”, “chronic obstructive pulmonary disease”, “pulmonary fibrosis”, “lung cancer”, “pharmacokinetics”, “liposomes”, “nano-emulsions”, “micelles”, “phospholipid complexes”, “solid dispersions”, “inclusion complexes”, and other terms.Result: The pharmacokinetics of BA involves mainly gastrointestinal hydrolysis, the enteroglycoside cycle, multiple metabolic pathways, and excretion in bile and urine. Due to the poor bioavailability and solubility of BA, liposomes, nano-emulsions, micelles, phospholipid complexes, solid dispersions, and inclusion complexes of BA have been developed to improve its bioavailability, lung targeting, and solubility. BA exerts potent effects mainly by mediating upstream oxidative stress, inflammation, apoptosis, and immune response pathways. It regulates are the NF-κB, PI3K/AKT, TGF-β/Smad, Nrf2/HO-1, and ERK/GSK3β pathways.Conclusion: This review presents comprehensive information on BA about pharmacokinetics, baicalin-loaded nano-delivery system, and its therapeutic effects and potential pharmacological mechanisms in respiratory diseases. The available studies suggest that BA has excellent possible treatment of respiratory diseases and is worthy of further investigation and development.

With the improvement of consumers' requirements for pork quality, the method of crossbreeding with excellent local pig breeds to improve meat quality is popular. Saba pig has high reproduction rate, good meat quality and high utilization rate of roughage, but its excellent characteristics have not been fully developed and utilized. To promote the development and utilization of Saba pigs and production of high-quality pork, the meat quality traits and glycolysis potential of Duroc × (Landrace × Yorkshire) (DLY), Berkshire × (Duroc × Saba) (BDS), and Duroc × (Berkshire × Saba) (DBS) three-way crossbred pigs were compared. The results showed that DLY had the highest live weight, carcass weight, lean meat percentage, drip loss, glycolysis potential, muscle diameter, and relative mRNA expression levels of type IIb muscle fibers as well as the lowest ultimate pH (p < 0.05). The lightness value of DBS was the highest (p < 0.05). Among the three crossbred pigs, myristic, arachidic, palmitoleic, and eicosenoic acids were the highest in BDS. These results indicated that the carcass traits of local crossbred pigs were worse than those of DLY pigs, but meat quality was markedly higher, with BDS showing the best meat quality.

Dysfunction of the mucus layer allows commensal and pathogenic microorganisms to reach the intestinal epithelium, thereby leading to infection and inflammation. This barrier is synthesized and secreted by host goblet cells. Many factors that influence the function of goblet cells (GCs) have been studied. However, how the microenvironment surrounding GCs influences the mucus layer and microbiota of the colon is unclear. To explore the effect of GC Piezo1 on the mucus layer and microbiota in the colon, we generated an intestinal epithelial Piezo1 conditional knockout mouse model. The fecal-associated microbiota (FAM) and mucosa-associated microbiota (MAM) of the two groups were characterized based on amplicon sequencing of the 16S rRNA gene. Our results showed that GC Piezo1-/- mice developed decreased GC numbers, thinner mucus layer, and increased inflammatory cytokines (e.g., CXCL1, CXCL2, IL-6) on the 7th day. In addition, decreased Spdef and increased DOCK4 were discovered in KO mice. Meanwhile, the diversity and richness were increased in MAM and decreased in FAM in the GC Piezo1-/- group compared with the GC Piezo1+/+ group. We also observed increased abundances of Firmicutes and decreased abundances of Verrucomicrobiota and Actinobacteriota in the MAM of the GC Piezo1-/- group. Additionally, BugBase predicts that potentially pathogenic bacteria may have increased in the inner mucus layer, which is consistent with the higher abundance of Helicobacter hepaticus, Lactobacillus johnsonii, Escherichia-Shigella and Oscillospiraceae in MAM. These results further support the hypothesis that the role of Piezo1 in GCs is important for maintaining the function of the mucus layer and intestinal microbiota balance in the mouse colon.

PurposeThis study sought to identify the changes and potential association between sleep characteristics and short-term memory, and mood states among volunteers at different altitudes and times.MethodA total of 26 healthy volunteers were recruited from the PLA General Hospital, and we conducted a longitudinal prospective survey for over 1 year from November 2019 to April 2021. First, we collected demographic data, sleep parameters by overnight polysomnography (PSG), short-term memory by digit span test, and mood states by completing a questionnaire with a brief profile of mood states among participants in the plain (53 m). Then, we continuously followed them up to collect data in the 3rd month at an altitude of 1,650 m (on the 3rd month of the 1-year survey period), the 3rd month at an altitude of 4,000 m (on the 6th month of the 1-year survey period), and the 9th month at an altitude of 4,000 m (on the 12th month of the 1-year survey period). Multiple linear regression analysis was used to construct models between sleep parameters and short-term memory, and mood states.ResultsThe prevalence of sleep apnea syndrome (SAS) significantly increased with rising elevation (P < 0.01). The apnea-hypopnea index (AHI), the mean apnea time (MAT), the longest apnea time (LAT), and the duration of time with SaO2 < 90% (TSA90) were increased (P < 0.05), and the mean pulse oxygen saturation (MSpO2), the lowest pulse oxygen saturation (LSpO2), and heart rate were significantly decreased with increasing altitude (P < 0.05). Digit span scores were decreased with increasing altitude (P < 0.001). A negative mood was more severe and a positive mood increasingly faded with rising elevation (P < 0.001). Additionally, linear correlation analysis showed that higher AHI, LAT, and MAT were strongly associated with a greater decline in short-term memory (in the 3rd and 9th month at an altitude of 4,000 m, respectively: rs = −0.897, −0.901; rs = −0.691, −0.749; rs = −0.732, −0.794, P < 0.001), and also were strongly associated with more severe negative mood (in the 3rd month at altitudes of 1,650 m and 4,000 m, respectively: rs = 0.655, 0.715, 0.724; rs = 0.771, 0.638, 0.737, P < 0.000625). Multiple linear regression pointed out that AHI was a significant predictor of negative mood among people at different altitudes (in the 3rd month at an altitude of 1,650 m: TMD = 33.161 + 6.495*AHI; in the 3rd month at an altitude of 4,000 m: TMD = 74.247 + 1.589*AHI, P < 0.05).ConclusionSAS developed easily in high altitudes, most often in CSA (central sleep apnea, CSA). The sleep, short-term memory, and negative mood were significantly more damaged with elevation in volunteers. Sleep parameters were closely associated with short-term memory and mood states in volunteers at high altitudes; the higher the sleep parameters (AHI, LAT, and MAT) scores, the more significant the mood disorders and the more obvious impairment of short-term memory. AHI was a critical predictor of the negative mood of volunteers at different altitudes. This study provides evidence that could help with the prevention and control of sleep disorder, cognitive disorder, and negative mood among populations with high altitudes.

Microorganisms play essential roles in flavor formation during soy sauce fermentation. Different soy sauce fermentation types significantly affect flavor formation. However, comparisons of microbial communities and metabolites between different fermentation types have been little studied. Here, we investigated variation in microbial communities, metabolite profiles, and metabolic pathways during Japanese-type (JP) and Cantonese-type (CP) fermentation. Free amino acids and volatile compound profiles varied significantly between fermentation types, with JP samples containing higher contents of esters (39.84%; p

ObjectivesTo analyze the characteristics of oral microbiota in plateau and plain youth and the possible function of the microbiome.Materials and methodsA total of 120 healthy young males (80 on the plateau, 40 on the plain) completed this cross-sectional study. Oral microflora samples were collected from all participants. The bacterial 16S rDNA was amplified using PCR and sequenced using Illumina MiSeq high-throughput sequencing. The data were analyzed to determine the microbial distribution and community structure of the oral microflora from the two groups. Metastats was used to test differences in relative species abundance between the groups. The correlation between the abundance of specific bacteria and blood indicators was also analyzed.ResultsAs demonstrated by alpha and beta diversity, the plateau group had lower microbial richness and a less even distribution of oral microbiota than the plain group. All predominant phyla and genera were qualitatively similar between the two groups, but their relative abundances differed. The relative abundance of bacteria in the phylum Firmicutes was significantly higher in the plateau group than in the plain group. At the genus level, Streptococcus spp. and Gemella spp. were also more abundant in the plateau group. The functional prediction indicated vigorous microbial metabolism in the oral bacterial community. We also found that the relative abundance of Streptococcus spp., the dominant genus, was positively correlated with triglyceride levels in the plateau group.ConclusionsWith increasing altitude, the diversity of oral microbiota and the relative proportion of predominant bacteria were altered. The distribution and related function of Streptococcus spp. were prominent in plateau samples. This comprehensive study of the relationship between oral microecology and elevation provides a point of reference for studying the human body’s adaptability or inadaptability to high altitude.

Novel metaphors in literary texts (hereinafter referred to as literary metaphors) seem to be more creative and open-ended in meaning than metaphors in non-literary texts (non-literary metaphors). However, some disagreement still exists on how literary metaphors differ from non-literary metaphors. Therefore, this study explored the neural mechanisms of literary metaphors extracted from modern Chinese poetry by using the methods of Event-Related Potentials (ERPs) and Event-Related Spectral Perturbations (ERSPs), as compared with non-literary conventional metaphors and literal expressions outside literary texts. Forty-eight subjects were recruited to make the semantic relatedness judgment after reading the prime-target pairs in three linguistic conditions. According to the ERPs results, the earliest differences were presented during the time window of P200 component (170–260 ms) in the frontal and central areas, with the amplitude of P200 for literary metaphors more positive than the other two conditions, reflecting the early allocation of attention and the early conscious experience of the experimental stimuli. Meanwhile, significant differences were presented during the time window of N400 effect (430–530 ms), with the waveform of literary metaphors more negative than others in the frontal and central topography of scalp distributions, suggesting more efforts in retrieving conceptual knowledge for literary metaphors. The ERSPs analysis revealed that the frequency bands of delta and theta were both involved in the cognitive process of literary metaphor comprehension, with delta band distributed in the frontal and central scalp and theta band in parietal and occipital electrodes. Increases in the two power bands during different time windows provided extra evidences that the processing of literary metaphors required more attention and effort than non-literary metaphors and literal expressions in the semantic related tasks, suggesting that the cognitive process of literary metaphors was distinguished by different EEG spectral patterns.

Graphical AbstractUro-A, which is a metabolite of intestinal flora and mainly produced from pomegranates and some nuts, suppresses osteoclast formation and bone resorption by activating autophagy. Uro-A upregulated the expression of Beclin 1 and LC3 and modulated bone homeostasis 4 in BMMs, thus resulting in decreased osteoclast-related markers and bone loss.

Koji making is a pre-fermentation stage in soy sauce manufacturing that impacts final product quality. Previous studies have provided valuable insights into the microbial species present in koji. However, changes in microbial community functional potential during koji-making are not well-known, nor are the associations among microbial populations and flavoring characteristics. In the present study, we investigated the succession of microbial communities, microbial community functional potential, metabolite profiles, and associations among microbial community members/functions with metabolites during koji making using shotgun metagenomic and metabolomic analyses. Firmicutes, Proteobacteria, and Ascomycota were identified as the most abundant microbial phyla in early koji making (0–12 h). Aspergillus (fungi) and Weissella (bacteria) exhibited marked abundance increases (0.98–38.45% and 0.31–30.41%, respectively) after 48 h of fermentation. Metabolite analysis revealed that aspartic acid, lysine, methyl acetate, isovaleraldehyde, and isoamyl alcohol concentrations increased ∼7-, 9-, 5-, 49-, and 10-fold after 48 h of fermentation. Metagenomic profiling demonstrated that koji communities were dominated by genes related to carbohydrate metabolism and amino acid metabolism, but functional profiles exhibited marked shifts after 24 h of fermentation. The abundances of genes within the categories of carbohydrate and amino acid metabolism all increased during koji making, except for pyruvate metabolism, glycolysis/gluconeogenesis, and the citrate cycle. Correlational analyses indicated that Aspergillus, Lactococcus, Enterococcus, Corynebacterium, and Kocuria abundances were positively correlated with 15 amino acid concentrations (all p < 0.05), while Weissella abundances were positively correlated with concentrations of volatile flavor compounds, including eight amino acids, phenylacetaldehyde, acetic acid, 2,3-butanediol, ethyl acetate, and ethanol (p < 0.05). These results provide valuable information for understanding the microbial-associated mechanisms of flavor formation during koji making.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are activated under pathological conditions, such as cancer, or mature myeloid cells that are converted immune-suppressive cells via tumor-derived exosomes, and potently support the tumor processes at different levels. Currently, multiple studies have demonstrated that MDSCs induce immune checkpoint blockade (ICB) therapy resistance through their contribution to the immunosuppressive network in the tumor microenvironment. In addition, non-immunosuppressive mechanisms of MDSCs such as promotion of angiogenesis and induction of cancer stem cells also exert a powerful role in tumor progression. Thus, MDSCs are potential therapeutic targets to enhance the antitumor efficacy of ICB therapy in cases of multiple cancers. This review focuses on the tumor-promoting mechanism of MDSCs and provides an overview of current strategies that target MDSCs with the objective of enhancing the antitumor efficacy of ICB therapy.

Cholangiocarcinoma (CCA) is a malignant hepatic tumor with a poor prognosis, which needs early diagnosis urgently. The gut microbiota has been shown to play a crucial role in the progression of liver cancer. Here, we explored a gut microbiota model covering genera Burkholderia-Caballeronia-Paraburkholderia, Faecalibacterium, and Ruminococcus_1 (B-F-R) for CCA early diagnosis. A case-control study was conducted to enroll 53 CCA patients, 47 cholelithiasis patients, and 40 healthy controls. The feces samples and clinical information of participants were collected in the same period. The gut microbiota and its diversity of individuals were accessed with 16S rDNA sequencing, and the gut microbiota profile was evaluated according to microbiota diversity. Finally, four enriched genera in the CCA group (genera Bacteroides, Muribaculaceae_unclassified, Muribaculum, and Alistipes) and eight enriched genera in the cholelithiasis group (genera Bifidobacterium, Streptococcus, Agathobacter, Ruminococcus_gnavus_group, Faecalibacterium, Subdoligranulum, Collinsella, Escherichia-Shigella) constitute an overall different microbial community composition (P = 0.001). The B-F-R genera model with better diagnostic value than carbohydrate antigen 19-9 (CA19-9) was identified by random forest and Statistical Analysis of Metagenomic Profiles (STAMP) to distinguish CCA patients from healthy controls [area under the curve (AUC) = 0.973, 95% CI = 0.932–1.0]. Moreover, the correlative analysis found that genera Burkholderia-Caballeronia-Paraburkholderia were positively correlated with body mass index (BMI). The significantly different microbiomes between cholelithiasis and CCA were found via principal coordinates analysis (PCoA) and linear discriminant analysis effect size (LEfSe), and Venn diagram and LEfSe were utilized to identify four genera by comparing microbial compositions among patients with malignant obstructive jaundice (MOJ-Y) or not (MOJ-N). In brief, our findings suggest that gut microbiota vary from benign and malignant hepatobiliary diseases to healthy people and provide evidence supporting gut microbiota to be a non-invasive biomarker for the early diagnosis of CCA.

The study of screening active constituents from traditional Chinese medicine (TCM) is important for explicating the mechanism of action of TCM and further evaluating the safety and efficacy effectively. However, detecting and identifying the active constituents from complicated biological samples still remain a challenge. Here, a practical, quick, and novel integrated strategy from in vitro, in situ, in vivo to in silico for rapidly screening the active constituents was developed. Firstly, the chemical profile of TCM in vitro was identified using UPLC-Q Exactive-Orbitrap HRMS. Secondly, the in situ intestinal perfusion with venous sampling (IPVS) method was used to investigate the intestinal absorption components. Thirdly, after intragastric administration of the TCM extract, the in vivo absorbed prototype components were detected and identified. Finally, the target network pharmacology approach was applied to explore the potential targets and possible mechanisms of the absorbed components from TCM. The reliability and availability of this approach was demonstrated using Tongfengding capsule (TFDC) as an example of herbal medicine. A total of 141 compounds were detected and identified in TFDC, and among them, 64 components were absorbed into the plasma. Then, a total of 35 absorbed bioactive components and 50 related targets shared commonly by compounds and gout were integrated via target network pharmacology analysis. Ultimately, the effects of the absorbed components on metabolism pathways were verified by experiments. These results demonstrated that this original method may provide a practical tool for screening bioactive compounds from TCM treating particular diseases. Furthermore, it also can clarify the potential mechanism of action of TCM and rationalize the application of TFDC as an effective herbal therapy for gout.

Due to remarkable reduction of sediment supply, the vulnerability of Yellow River deltaic system increased and ecological impacts occurred to some extent. To have a comprehensive and quantitative understanding of the morphological evolution of deltas, surficial sediments of tidal flat along the abandoned southern Yellow River sub-delta and two adjacent coastal units were systematically collected and evaluated by grain-size analysis in the study. The results reveal that surficial sediments of the abandoned southern Yellow River sub-delta have been coarsening significantly since the 1980s, as characterized by a decrease in both the mud content and the clay/mud ratio. In particular, the transition from cohesive to non-cohesive sediment was completed between 2007 and 2013. With a sharp decrease in sediment flux from the Yellow River estuary, the flood currents from the submarine coastal slope carry few fine particles into the tidal zone, whereas the ebb currents with reverse direction remove some fine particles from the tidal flat. This is a major cause of sediment coarsening in the tidal flat. As sediment coarsening, the coastline of the abandoned southern Yellow River sub-delta has remained stable. The significant change in the grain size of the tidal flat surficial sediments may have a profound impact on the future coastal geomorphic evolution.

Screening functional food ingredients (FFI) from medicinal and edible plants (MEP) has still remained a great challenge due to the complexity of MEP and its obscure function mechanisms. Herein, an integrated strategy based on sequential metabolites identification approach, network pharmacology, molecular docking, and surface plasmon resonance (SPR) analysis was proposed for quickly identifying the active constituents in MEP. First, the sequential biotransformation process of MEP, including intestinal absorption and metabolism, and hepatic metabolism, was investigated by oral gavage, and intestinal perfusion with venous sampling method. Then the blood samples were analyzed by UPLC-Q Exactive Orbitrap HRMS. Second, the network pharmacology approach was used to explore the potential targets and possible mechanisms of the in vivo metabolites of MEP. Third, molecular docking and SPR approaches were used to verify the specific interactions between protein targets and representative ingredients. The proposed integrated strategy was successfully used to explore the heptoprotective components and the underlying molecular mechanism of Paeoniae Radix Alba (PRA). A total of 44 compounds were identified in blood samples, including 17 porotypes and 27 metabolites. The associated metabolic pathways were oxidation, methylation, sulfation, and glucuronidation. After further screening, 31 bioactive candidates and 377 related targets were obtained. In addition, the bioactive components contained in PRA may have therapeutic potentials for non-alcoholic fatty liver disease (NAFLD). The above results demonstrated the proposed strategy may provide a feasible tool for screening FFI and elaborating the complex function mechanisms of MEP.

Sufu is a traditional fermented soybean food produced in China. However, the microbial compositions and metabolites of different types of sufu have not been studied in detail. Accordingly, in this study, we evaluated the differences in bacterial communities and metabolites between commercial red sufu (RS) and white sufu (WS). Principal coordinate analysis and the unweighted pair group method with arithmetic means analysis of 16S rRNA genes revealed that the bacterial community structures of RS and WS differed dramatically. At the phylum level, the relative abundances of Firmicutes and Proteobacteria were significantly different between RS and WS (P < 0.01). Moreover, the abundances of Lactococcus and Tetragenococcus genera were significantly different between RS and WS (P < 0.01). Among metabolites, most free amino acids, few of volatile flavor compounds, and some organic acids showed significant differences between RS and WS (P < 0.05). Additionally, correlations between microbiota and metabolites were determined. Aggregated boosted tree analysis showed that formic acid had the highest relative influence (20.27%) on bacterial community diversity (Chao 1), following by arginine (5.38%), propanol (4.57%), oxalic acid (4.46%), and hexanol (4.43%). Moreover, Streptococcaceae and Moraxellaceae had the highest relative influence on the concentration of formic acid (12.84% and 8.75%, respectively). The profiles obtained in this study improve our understanding of the relationships between bacterial flora and metabolites in different types of sufu. These findings may help us interpret the roles of bacterial communities in the flavor and characteristics of sufu.

Ovarian cancer (OC) is the gynecological malignancy with the poorest prognosis. Surgery and chemotherapy are the primary therapies for OC; however, patients often experience recurrence. Given the intimate interaction between OC cells and the tumor microenvironment (TME), it is imperative to devise treatments that target both tumor cells and TME components. Recently, follicle-stimulating hormone (FSH) levels in the blood have been shown to correlate with poorer prognosis in individuals with OC. Ovarian carcinoma cells express FSH receptors (FSHRs). Thus, FSH is an important target in the development of novel therapeutic agents. Here, we review the effects of FSH on normal physiology, including the reproductive, skeletal, cardiac, and fat metabolic systems. Importantly, this review outlines the role and mechanism of the FSH/FSHR axis in the proliferation, survival, and metastasis of OC, providing theoretical support for the targeted FSHR treatment of OC. Current progress in targeting FSHR for OC, including the recent application of nanotechnology and immunotherapy, is presented. Finally, we discuss prospects and future directions of targeted FSHR therapy in OC.

BackgroundThe estimated glucose disposal rate (eGDR), triglyceride glucose (TyG), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, and metabolic score for insulin resistance (METS-IR) are dependent indicators of insulin resistance (IR). We aimed to evaluate the association between these indicators and the current or feature incidence of cardiovascular disease (CVD) in middle-aged and elderly individuals. This study tests the hypothesis that IR indices positively or negatively correlate with CVD, and that the potential predictive performance of the IR indices was not the same.MethodsMiddle-aged and elderly individuals from the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS) with complete data on eGDR, TyG, TG/HDL-C, and METS-IR at baseline were obtained. The association between the four indices and CVD was evaluated using multivariate logistic regression analysis. In addition, an adjusted restricted cubic spline (RCS) was applied. Finally, the potential predictive performance of the IR indices was assessed using receiver operating characteristic (ROC) curves.ResultsWe included 7,220 participants (mean age: 61.9 ± 10.7 years; 54.0% male) from the NHANES cohort and 6,426 participants (mean age: 57.9 ± 8.4 years; 45.2% male) from the CHARLS cohort in the study. Multivariate logistic regression analysis indicated that a decreasing eGDR significantly increased the incidence of CVD both presently and in the future. Similarly, a higher TyG level and METS-IR were significantly associated with a higher incidence of CVD at both timeframes. However, the TG/HDL-C ratio was not significantly associated with CVD, heart disease, or stroke. No significant interactions were observed between the continuous or quartile variables of eGDR, TyG, TG/HDL-C, or METS-IR, and the incidence of various endpoints across most subgroups. The ROC curve indicated the superior predictive performance of the IR indices. Furthermore, the eGDR was superior to other IR indices for the prediction of CVD both at present and in the future in middle-aged and elderly individuals.ConclusionAs continuous variables, eGDR, TyG, and METS-IR were significantly associated with the incidence of CVD, both currently and in the future, among middle-aged and elderly individuals. Notably, incorporating eGDR, TyG, or METS-IR and the basic model significantly increased the predictive value for CVD. Among these indices, the eGDR index stands out as the most promising parameter for predicting CVD, both at present and in the future.

IntroductionBoth the incidence and mortality rates associated with methicillin-resistant Staphylococcus aureus (MRSA) have progressively increased worldwide. A nucleic acid testing system was developed in response, enabling swift and precise detection of Staphylococcus aureus (S. aureus) and its MRSA infection status. This facilitates improved prevention and control of MRSA infections.MethodsIn this work, we introduce a novel assay platform developed by integrating Pyrococcus furiosus Argonaute (PfAgo) with recombinase polymerase amplification (RPA), which was designed for the simultaneous detection of the nuc and mecA genes in MRSA.ResultsThis innovative approach enables visual MRSA detection within 55 mins, boasting a detection limit of 102 copies/μL. Characterized by its high specificity, the platform accurately identifies MRSA infections without cross-reactivity to other clinical pathogens, highlighting its unique capability for S. aureus infection diagnostics amidst bacterial diversity. Validation of this method was performed on 40 clinical isolates, demonstrating a 95.0% accuracy rate in comparison to the established Vitek2-COMPACT system.DiscussionThe RPA-PfAgo platform has emerged as a superior diagnostic tool, offering enhanced sensitivity, specificity, and identification efficacy for MRSA detection. Our findings underscore the potential of this platform to significantly improve the diagnosis and management of MRSA infection.

ObjectivesImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice.MethodsBased on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality.ResultsThe NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs.ConclusionThese findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.

BackgroundA high risk of developing mild cognitive impairment (MCI) is faced by elderly patients with type 2 diabetes mellitus (T2DM). In this study, independent risk factors for MCI in elderly patients with T2DM were investigated, and an individualized nomogram model was developed.MethodsIn this study, clinical data of elderly patients with T2DM admitted to the endocrine ward of the hospital from November 2021 to March 2023 were collected to evaluate cognitive function using the Montreal Cognitive Assessment scale. To screen the independent risk factors for MCI in elderly patients with T2DM, a logistic multifactorial regression model was employed. In addition, a nomogram to detect MCI was developed based on the findings of logistic multifactorial regression analysis. Furthermore, the accuracy of the prediction model was evaluated using calibration and receiver operating characteristic curves. Finally, decision curve analysis was used to evaluate the clinical utility of the nomogram.ResultsIn this study, 306 patients were included. Among them, 186 patients were identified as having MCI. The results of multivariate logistic regression analysis demonstrated that educational level, duration of diabetes, depression, glycated hemoglobin, walking speed, and sedentary duration were independently correlated with MCI, and correlation analyses showed which influencing factors were significantly correlated with cognitive function (p

ObjectiveThe purpose of this study was to investigate the current research status, focus areas, and developmental trends in the field of Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) through an analysis of scientific literature.MethodsThe relevant research articles on MOGAD published from 1947 to 2022 were retrieved from the Web of Science database. The quantitative output of MOGAD related research articles, their distribution by country/region, data on collaborative publishing, influential authors, high-yield institutions, keywords, hotspots, and development trends were analyzed. Additionally, visual knowledge maps were generated using VOSviewer and Citespace.ResultsThere has been a steady increase in the number of MOGAD related publications indicating that the subject has garnered increasing interest among researchers globally. The United States has been the leading contributor with 496 papers (19.25%), followed by China (244, 9.63%), Japan (183, 7.10%), the United Kingdom (154, 5.98%), and Germany (149, 5.78%). Among these countries, the United Kingdom boasts the highest citation frequency at the rate of 46.49 times per paper. Furthermore, active collaboration in MOGAD related research is observed primarily between the United States and countries such as Canada, Germany, Australia, Italy, the United Kingdom and Japan. Mayo Clinic ranks first in total articles published (109) and frequency of citations per article (77.79). Takahashi Toshiyuki from Tohoku University is the most prolific author, while Multiple Sclerosis and Related Disorders is the most widely read journal in this field. “Disease Phenotype”, “Treatment”, “Novel Coronavirus Infection and Vaccination”, “Immunopathological Mechanisms”, “Clinical characteristics of children” and “Prognosis” are the primary keywords clusters in this field. “Novel Coronavirus Infection and Vaccination” and “Immunopathological Mechanisms” are research hotspots and have great development potential.ConclusionThe past three decades have witnessed a significant expansion of research on MOGAD. The pathogenetic mechanism of MOGAD is poised to be the prominent research focus in this field in the foreseeable future.

BackgroundFor patients with extensive-stage small cell lung cancer (ES-SCLC), serplulimab plus chemotherapy is beneficial as the first-line treatment. It is uncertain whether serplulimab plus chemotherapy will be more cost-effective. The aim of this study was to evaluate from the perspective of the Chinese healthcare system to assess the cost-effectiveness of serplulimab plus chemotherapy for patients with ES-SCLC.Materials and methodsThis study employed a partitioned survival model. Patients in the model were selected from ASTRUM-005 for their clinical characteristics and outcomes. In order to assess the robustness of the model, we conducted deterministic one-way sensitivity analyzes as well as probabilistic sensitivity analyzes. Subgroup analyzes were also conducted. Costs, quality-adjusted life-years (QALYs), life-years, incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were analyzed.ResultsBased on the base-case analysis, serplulimab plus chemotherapy contributed to an increase in 0.826 life-years and 0.436 QALYs; an incremental cost of $52,331, yielded ICER of $120,149/QALY. Based on the willingness to pay (WTP) threshold of $37,669/QALY and $86,569/QALY, the INHB was −0.954 QALYs and − 0.169 QALYs and the INMB was -$35,924 and -$14,626, respectively. Based on the probabilistic sensitivity analysis results, serplulimab plus chemotherapy was unlikely to be cost-effective at a WTP threshold of $37,669/QALY and $86,569/QALY. One-way sensitivity analysis indicated that cost of serplulimab and body weight had the greatest impact on the model. Serplulimab plus chemotherapy could be cost-effective at a WTP threshold of $86,569/QALY when the cost of serplulimab was less than $5.24/mg or when the weight of the patient was less than 40.96 kg. Regardless of the WTP threshold at $37,669/QALY or $86,569. Serplulimab plus chemotherapy was not cost-effective in all subgroups.ConclusionSerplulimab plus chemotherapy was not cost-effective, despite having a prior clinical benefical and a relative safety profile compared with chemotherapy. With the reduction in the price of serplulimab, ES-SCLC patients treated with serplulimab plus chemotherapy may be able to achieve a favorable cost-effectiveness rate.

BackgroundThe optimal first-line immune checkpoint inhibitor (ICI) treatment strategy for metastatic or early triple-negative breast cancer (TNBC) has not yet been determined as a result of various randomized controlled trials (RCTs). The purpose of this study was to compare the efficacy and safety of ICIs in patients with metastatic or early TNBC.MethodsRCTs comparing the efficacy and safety of ICIs in patients with TNBC were included in the studies. Based on PRISMA guidelines, we estimated pooled hazard ratios (HRs) and odds ratios (ORs) using random-effects models of Bayesian network meta-analysis. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included pathologic complete response rate (pCR), grade ≥ 3 treatment-related adverse events (trAEs), immune-related adverse events (irAEs), and grade ≥ 3 irAEs.ResultsThe criteria for eligibility were met by a total of eight RCTs involving 4,589 patients with TNBC. When ICIs were used in patients without programmed death-ligand 1 (PD-L1) selection, there was a trend toward improved PFS, OS, and pCR, without significant differences. Pembrolizumab plus chemotherapy is superior to other treatment regimens in terms of survival for TNBC patients based on Bayesian ranking profiles. Subgroup analysis by PD-L1 positive population indicated similar results, and atezolizumab plus chemotherapy provided better survival outcomes. Among grade ≥ 3 trAEs and any grade irAEs, there was no statistically significant difference among different ICI agents. The combination of ICIs with chemotherapy was associated with a higher incidence of grade ≥ 3 irAEs. Based on rank probability, the ICI plus chemotherapy group was more likely to be associated with grade ≥ 3 trAEs, any grade irAEs, and grade ≥ 3 irAEs. Hypothyroidism and hyperthyroidism were the most frequent irAEs in patients receiving ICI.ConclusionsICI regimens had relatively greater efficacy and safety profile. Pembrolizumab plus chemotherapy and atezolizumab plus chemotherapy seem to be superior first-line treatments for intention-to-treat and PD-L1-positive TNBC patients, respectively. It may be useful for making clinical decisions to evaluate the efficacy and safety of different ICIs based on our study.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022354643.

BackgroundThe efficiency and safety of sacituzumab govitecan (SG) for the therapy of hormone receptor-positive (HR+)/human epidermal receptor 2-negative (HER2-) metastatic breast cancer (BC) has been demonstrated. The aim of this study is to evaluate its cost-effectiveness on HR+/HER2- metastatic BC from the third-party payer perspective in the United States.MethodsWe performed the cost-effectiveness of SG and chemotherapy using a partitioned survival model. TROPiCS-02 provided clinical patients for this study. We evaluated the robustness of this study by one-way and probabilistic sensitivity analyses. Subgroup analyses were also conducted. The outcomes were costs, life-years, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefit (INHB), and incremental net monetary benefit (INMB).ResultsSG treatment was related to an increase of 0.284 life years and 0.217 QALYs over chemotherapy, as well as a cost increase of $132,689, reaching an ICER of $612,772/QALY. The INHB was -0.668 QALYs, and the INMB was -$100,208. SG was not cost-effective at the willingness to pay (WTP) threshold of $150,000/QALY. The outcomes were sensitive to patient body weight and cost of SG. SG may be cost-effective at the WTP threshold of $150,000/QALY if the price is less than $3.997/mg or the weight of patients is under 19.88 kg. Based on the subgroup analysis, SG did not prove cost-effective in all subgroups at the WTP threshold of $150,000/QALY.ConclusionFrom a third-party payer standpoint in the United States, SG was not cost-effective, even though it had a clinically significant advantage over chemotherapy for the treatment of HR+/HER2- metastatic BC. The cost-effectiveness of SG can be improved if the price is substantially reduced.

BackgroundIn patients with advanced non-small cell lung cancer (aNSCLC), cemiplimab plus chemotherapy prolonged overall survival (OS) and progression-free survival (PFS) significantly compared to chemotherapy alone. The cost-effectiveness of these drugs is still uncertain. The aim of this study is to assess the cost-effectiveness of cemiplimab plus chemotherapy compared with chemotherapy for the treatment of aNSCLC from the third-party payer perspective in the United States.Materials and methodsThe cost-effectiveness of cemiplimab with chemotherapy versus chemotherapy for the treatment of aNSCLC was evaluated using a partitioned survival model containing three mutually incompatible health states. The clinical characteristics and outcomes used in the model were gathered from EMPOWER-Lung 3 trial. We have conducted deterministic one-way sensitivity analysis and probabilistic sensitivity analysis in order to evaluate the robustness of the model. The primary outcomes considered were the costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB).ResultsTreatment of aNSCLC with cemiplimab plus chemotherapy increased efficacy by 0.237 QALYs and was associated with an increased total cost of $50,796 compared to chemotherapy alone, resulting in an ICER of $214,256/QALY gained. At a WTP threshold of $150,000/QALY, the INHB of cemiplimab plus chemotherapy was 0.203 QALYs and the INMB was $304,704 compared to chemotherapy alone. The probabilistic sensitivity analysis revealed that there was only a 0.04% chance that cemiplimab with chemotherapy would be cost-effective at a WTP threshold of $150,000/QALY. The performance of model was mainly determined by the price of cemiplimab, according to a one-way sensitivity analysis.ConclusionsFrom the third-party payer perspective, cemiplimab combined chemotherapy is unlikely to be a cost-effective option for the treatment of aNSCLC at the WTP threshold of $150,000/QALY in the United States.

BackgroundSugemalimab is a newly developed inhibitor of programmed death ligand 1 (PD-L1). As a first-line treatment for metastatic non-small-cell lung cancer (NSCLC), sugemalimab plus chemotherapy (Sugema-Chemo) has been proven effective. Still, its cost-effectiveness has not yet been determined. The objective of this study was to assess the cost-effectiveness of Sugema-Chemo from a health care perspective in China.MethodsA partitioned survival model was used. According to the GEMSTONE-302 trial, the clinical characteristics and outcomes of the patients were obtained. The outcomes were costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB) and incremental net monetary benefits (INMB). The robustness of the model was further evaluated, as well as subgroup analyses. When the ICER was lower than the willingness to pay (WTP) threshold ($38,017/QALY or $86,376/QALY, defined as three times the per capita gross domestic product value of the general region and Beijing), the cost-effectiveness of Sugema-Chemo was assumed for general regions or Beijing.ResultsCompared with chemotherapy alone, Sugema-Chemo resulted in an incremental gain of 0.82 QALYs, an incremental gain of 1.26 life-years, as well as an average increase cost of $72,472. The ICER was $88,744/QALY. Model outcomes were susceptible to average body weight and cost of sugemalimab. Sugema-Chemo was cost-effective at a WTP threshold of 86,376/QALY if the average body weight was 50% being considered cost-effective in most subgroups at the $86,376/QALY threshold. However, Sugema-Chemo did not achieve cost-effectiveness (0%) in any of the subgroups when WTP was set at $38,017/QALY.ConclusionSugema-Chemo might not be cost-effective in patients with metastatic NSCLC in China. In deciding between Sugema-Chemo and chemotherapy alone, it is essential to consider both the body weight of patients and the price of sugemalimab. A price reduction of sugemalimab under the National Healthcare Security Administration may be an effective measure to improve the cost-effectiveness of the drug.

ObjectiveWe aimed at summarizing the perceptions and responses to cognitive decline, assessing the disease management, identifying deficiencies and proposing new strategies for improvement in people with diabetes (PWDs).MethodsA comprehensive search was performed in the following nine databases: PubMed, EMBASE, Web of Science, The Cochrane Library, PsycINFO, CINAHL, WanFang, CNKI, and VIP. The Joanna Briggs Institute (JBI) Critical Appraisal Tool for qualitative research was utilized to evaluate the quality of included studies. Descriptive texts and quotations relating to patient experience were extracted from the included studies and thematically analyzed.ResultsEight qualitative studies met the inclusion criteria and 2 overarching themes were identified: (1) self-perception of cognitive decline referred to perceived cognitive symptoms, lack of knowledge and, impaired self-management and coping in multiple methods; (2) reported benefits of cognitive interventions referred to how cognitive interventions improved disease management, attitudes and needs of PWDs.ConclusionPWDs described misconceptions about their cognitive decline and suffered from them during disease management. This study provides a patient-specific reference for cognitive screening and intervention in PWDs, supporting disease management with cognitive decline in clinical practice.

Diet and species are important factors affecting the rumen microbiota, with roughage stimulating rumen development and concentrate feeds being broken down by the decomposition of Ruminal flora to provide the organism with a large amount of energy. This study aimed to explore the effects of host and dietary factors on rumen flora composition and diversity, as well as on host metabolism. The study reports the research conducted on 5-month-old male Small-tail Han sheep and 5-month-old male Boer goat, each with an average weight of 33.87 ± 1.70 kg. Five animals of each species were divided into two groups, namely, the S group (Small-tail Han sheep) and the B group (Boer goat). The experiment was carried out in two various periods, namely, X and Y for groups S and B, respectively. The rations were fed with concentrate-to-roughage ratios of 3:7 and 5:5, respectively. Growth performance was measured by the weight increase index. The results showed that, under the same raising conditions, the ratio between body weight increases and the amount of feed was lower in the S group than in the B group, but the differences were not significant. According to the analysis of the apparent digestibility ratio of nutrition ingredients, the XS group had a significantly higher apparent digestibility ratio for acid detergent fiber than the XB group (p < 0.05). Even though the analysis of rumen fermentation parameters showed that the rumen pH has no significant differences between the XS and XB groups, it was significantly lower in the YS group than in the YB group. The XS group contained a significantly lower content of total volatile fatty acids than the XB group (p < 0.05). Analysis of the 16S rDNA sequencing results revealed that, compared to the B group, the S group was highly enriched with the following bacteria: Proteobacteria, γ-proteobacteria, Aeromonadales, and Succinivibrionaceae. Thus, the host species affected the abundance and diversity of rumen bacteria. Feed utilization efficiency of Small-tail Han sheep was higher than Boer goats, which might be specifically associated with Succinivibrionaceae. The results from this study show that animals belonging to the same family but different genera and species can differ in metabolic pathways even when they are provided with the same animal feed.

Background and objectiveTislelizumab is a programmed cell death protein-1 (PD-1) inhibitor. Tislelizumab plus chemotherapy as first-line option for advanced non-squamous non-small cell lung cancer (NSCLC), compared with chemotherapy alone, resulted in significantly prolonged survival outcomes; however, evidence regarding its relative efficacy and cost is lacking. We aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy compared with that of chemotherapy alone, from the health care perspective in China.MethodsA partitioned survival model (PSM) was used for this study. The survival data were obtained from the RATIONALE 304 trial. Cost-effectiveness was defined as incremental cost-effectiveness ratio (ICER) less than the willingness to pay (WTP) threshold. Incremental net health benefits (INHB), incremental net monetary benefits (INMB), and subgroup analyses were also assessed. Sensitivity analyses were further established to assess the model stability.ResultsCompared with chemotherapy alone, tislelizumab plus chemotherapy increased by 0.64 quality-adjusted life-years (QALYs) and 1.48 life-years, and yielded an increase of $16,631 in cost per patient. The INMB and INHB were $7,510 and 0.20 QALYs at a WTP threshold of $38,017/QALY, respectively. The ICER was $26,162/QALY. The outcomes were most sensitive to the HR of OS for tislelizumab plus chemotherapy arm. The probability of tislelizumab plus chemotherapy being considered cost-effective was 87.66% and >50% in most of the subgroups at the WTP threshold of $38,017/QALY. At the WTP threshold of $86,376/QALY, the probability achieved 99.81%. Furthermore, the probability of tislelizumab plus chemotherapy being considered cost-effective in subgroups of patients with liver metastases and PD–L1 expression ≥50% were 90.61 and 94.35%, respectively.ConclusionTislelizumab plus chemotherapy is likely to be cost-effective as a first-line treatment for advanced non-squamous NSCLC in China.

Alexander's disease (AxD) is a rare autosomal dominant hereditary disorder that is caused by the mutations in the GFAP gene, which encodes the glial fibrillary acidic protein (GFAP). This neurogenerative disease has many clinical manifestations, and the onset of disease spans a wide range of ages, from newborns to children, adults, and even the elderly. An overaccumulation of the expression of GFAP has a close causal relationship with the pathogenesis of Alexander's disease. Usually, the disease has severe morbidity and high mortality, and can be divided into three distinct subgroups that are based on the age of clinical presentation: infantile (0–2 years), juvenile (2–13 years), and adult (>13 years). Children often present with epilepsy, macrocephaly, and psychomotor retardation, while adolescents and adults mainly present with muscle weakness, spasticity, and bulbar symptoms. Atonic seizures are a type of epilepsy that often appears in the Lennox–Gastaut syndrome and myoclonic–astatic epilepsy in early childhood; however, the prognosis is often poor. Atonic episodes are characterized by a sudden or frequent reduction in muscle tone that can be local (such as head, neck, or limb) or generalized. Here, we report a 4-year-old girl whose main symptoms were intermittent head drop movements, which could break the frontal frame and even bleed in severe conditions. A video-encephalography (VEEG) showed that the nodding movements were atonic seizures. A head magnetic resonance imaging (MRI) revealed abnormal signals in the bilateral paraventricular and bilateral subfrontal cortex. The gene detection analyses indicated that the GFAP gene exon 1 c.262 C>T was caused by a heterozygous mutation, as both her parents were of the wild-type. The girl had no other abnormal manifestations except atonic seizures. She could communicate normally and go to kindergarten. After an oral administration of sodium valproate, there were no atonic attacks. Although epilepsy is a common symptom of Alexander's disease, atonic seizures have not been reported to date. Therefore, we report a case of Alexander's disease with atonic seizures as the main symptom and provide a review of the literature.

BackgroundThe previous meta-analysis indicated that physical exercise could play a crucially therapeutic role in reducing perinatal depression symptoms in women. However, the efficacy varies across different exercise types, forms, intensities, and duration.AimThe purpose of this study was to review and evaluate the effects of different types, forms, intensities, and duration of exercise for improving perinatal depressive symptoms.DesignA systematic review and meta-analysis.MethodsRandomized controlled trials until December 2021 were searched from seven databases, including PubMed, EMBASE, Medline, CINAHL, Web of Science, Cochrane Library, and PsycINFO. The risk of bias in eligible trials was evaluated using the Cochrane Risk of Bias tool. When high heterogeneity was tested, we used random-effects models. A funnel plot was used to assess the publication bias. This review was performed under the PRISMA guidelines, Consensus on Exercise Reporting (CERT) checklist and Cochrane Handbook. The certainty of the body of evidence was assessed using the GRADE method.ResultsOf 1,573 records, 20 trials were identified in this study. The results of this review revealed that women with perinatal depression symptoms gained benefits from physical exercise [OR = 0.62, 95% CI (0.45, 0.86), P = 0.004; MD = −0.57, 95% CI (−0.83, −0.30), P < 0.0001]. Type of walking [SMD = −1.06, 95% CI (−1.92, −0.19), P < 0.00001], form of “Individual + group-based”exercise [SMD = −0.91, 95% CI (−0.80, −0.03), P = 0.04], intensity of ≥150 min per week [SMD = −0.84, 95% CI (−1.53, −0.15), P = 0.02], and ≥12 weeks duration [SMD = −0.53, 95% CI (−0.75, −0.31), P < 0.00001] seemed to generate more prominent improvement on perinatal depression symptoms.ConclusionPhysical exercise showed a significant effect on reducing perinatal depressive symptoms. This meta-analysis provides an important update on exercise’s efficacy in treating perinatal depression. Further higher quality and large-scale trials are needed to substantiate our findings.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022296230].

BackgroundRecently, an increasing number of studies have uncovered the aberrant expression of methyltransferase-like family (METTL) plays an important role in tumorigenesis, such as METTL3 (an m6A writer). In our recent work, we discovered METTL24 expression was highly associated with the hazard ratio (HR) of kidney renal clear cell carcinoma (KIRC) compared to other tumors, implying a special function of METTL24 in KIRC carcinogenesis. Until now, the functions and mechanisms of METTL24 in KIRC have remained mostly unknown.MethodsThe mRNA expression of METTL24 in KIRC was analyzed using the TIMER 2.0, GEPIA, and UALCAN databases. The immunohistochemical assay was performed to validate METTL24 expression in our self-built Chinese cohort (n tumor = 88, n normal = 85). The gene set enrichment analysis (GSEA) was used to investigate the biological processes in which METTL24 might be engaged. The Spearman analysis was used to evaluate the expression correlations between METTL24 and a range of immunological variables, and the effects of METTL24 on the infiltration levels of multiple immune cells were explored using TCGA data. The upstream transcription factors of METTL24 were screened through a multi-omics analysis.ResultsMETTL24 expression in KIRC tissues was significantly decreased compared to normal adjacent kidney tissues, which was associated with the lower survival rate of KIRC patients. METTL24 potentially participated in the immune-relevant biological processes such as cytokine binding, NF-kappa B binding, MHC protein complex, and interleukin-12 action. Besides, METTL24 expression was linked to a number of immune checkpoints, cytokines, chemokines, and chemokine receptors, and also correlated with the infiltration levels of 10 types of immune cells in KIRC. Meanwhile, METTL24 expression differently affected the overall survival rates (OS) of KIRC patients with high or low levels of immune infiltration. Finally, CTCF and EP300 were discovered to be the probable transcription factors of METTL24 in KIRC.ConclusionThis study revealed that METTL24 might serve as a prognostic marker in KIRC and as one immune-relevant target for clinical treatment.

BackgroundPembrolizumab and cemiplimab have been approved as treatment for advanced non-small-cell lung cancer (NSCLC) with high programmed death ligand-1 (PD-L1) expression. This study aimed to evaluate the cost-effectiveness of pembrolizumab compared with that of cemiplimab in the treatment of advanced NSCLC with high PD-L1 expression from a societal perspective in the United States.Materials and methodsCost-effectiveness analysis integration of the network meta-analysis framework was performed using data from the EMPOWER-Lung 1, KEYNOTE 024, and KEYNOTE 042 phase 3 randomized clinical trials. A network meta-analysis including 2289 patients was constructed, and the Markov and partitioned survival (PS) models were used to assess the cost-effectiveness of pembrolizumab compared with that of cemiplimab for the treatment of high PD-L1 expression (≥50% of tumor cells). The time horizon was 10 years. The main outcomes were overall costs, incremental cost-effectiveness ratios (ICERs), quality-adjusted life-years (QALYs), life-years, incremental net health benefits (INHB), and incremental net monetary benefits (INMB). The robustness of the model was verified using one-way and probabilistic sensitivity analyses, and subgroup analyses were conducted.ResultsTreatment of advanced NSCLC with high PD-L1 expression with pembrolizumab achieved 0.093 QALYs and was associated with an incremental cost of $10,657 compared with cemiplimab, yielding an ICER of $114,246/QALY. The ICER in the PS model was similar to that in the Markov model, with a difference of $3,093/QALY. At a willingness-to-pay (WTP) threshold of $100,000/QALY, INHB, and INMB of pembrolizumab were -0.013 QALYs and -$1,329, respectively, and the probability of cemiplimab was 51% when compared with pembrolizumab. When the WTP threshold increased to $150,000/QALY, the INHB and INMB of pembrolizumab were 0.022 QALYs and $3,335, respectively, and the probability of pembrolizumab was 51.85%. One-way sensitivity analysis indicated that the models were sensitive to pembrolizumab and cemiplimab costs. Subgroup analysis revealed that treatment with pembrolizumab was related to a higher INHB in several subgroups, including patients with brain metastases at baseline.ConclusionOur findings suggest that the WTP threshold should be considered when choosing between cemiplimab and pembrolizumab to treat advanced NSCLC with high PD-L1 expression. Reducing the cost of pembrolizumab may lead to valuable outcomes.

Introduction: Alzheimer’s disease (AD) is a severe dementia with clinical and pathological heterogeneity. Our study was aim to explore the roles of endoplasmic reticulum (ER) stress-related genes in AD patients based on interpretable machine learning.Methods: Microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. We performed nine machine learning algorithms including AdaBoost, Logistic Regression, Light Gradient Boosting (LightGBM), Decision Tree (DT), eXtreme Gradient Boosting (XGBoost), Random Forest, K-nearest neighbors (KNN), Naïve Bayes, and support vector machines (SVM) to screen ER stress-related feature genes and estimate their efficiency of these genes for early diagnosis of AD. ROC curves were performed to evaluate model performance. Shapley additive explanation (SHAP) was applied for interpreting the results of these models. AD patients were classified using a consensus clustering algorithm. Immune infiltration and functional enrichment analysis were performed via CIBERSORT and GSVA, respectively. CMap analysis was utilized to identify subtype-specific small-molecule compounds.Results: Higher levels of immune infiltration were found in AD individuals and were markedly linked to deregulated ER stress-related genes. The SVM model exhibited the highest AUC (0.879), accuracy (0.808), recall (0.773), and precision (0.809). Six characteristic genes (RNF5, UBAC2, DNAJC10, RNF103, DDX3X, and NGLY1) were determined, which enable to precisely predict AD progression. The SHAP plots illustrated how a feature gene influence the output of the SVM prediction model. Patients with AD could obtain clinical benefits from the feature gene-based nomogram. Two ER stress-related subtypes were defined in AD, subtype2 exhibited elevated immune infiltration levels and immune score, as well as higher expression of immune checkpoint. We finally identified several subtype-specific small-molecule compounds.Conclusion: Our study provides new insights into the role of ER stress in AD heterogeneity and the development of novel targets for individualized treatment in patients with AD.

In recent years, the Burden of Amplitudes and Epileptiform Discharges (BASED) score has been used as a reliable, accurate, and feasible electroencephalogram (EEG) grading scale for infantile spasms. However, manual EEG annotation is, in general, very time-consuming, and BASED scoring is no exception. Convolutional neural networks (CNNs) have proven their great potential in many EEG classification problems. However, very few research studies have focused on the use of CNNs for BASED scoring, a challenging but vital task in the diagnosis and treatment of infantile spasms. This study proposes an automatic BASED scoring framework using EEG and a deep CNN. The feasibility of using CNN for automatic BASED scoring was investigated in 36 patients with infantile spasms by annotating their long-term EEG data with four levels of the BASED score (scores 5, 4, 3, and ≤2). In the validation set, the accuracy was 96.9% by applying a multi-layer CNN to classify the EEG data as a 4-label problem. The extensive experiments have demonstrated that our proposed approach offers high accuracy and, hence, is an important step toward an automatic BASED scoring algorithm. To the best of our knowledge, this is the first attempt to use a CNN to construct a BASED-based scoring model.

Objective: Nivolumab improves overall survival (OS) and is associated with fewer adverse events than sorafenib for the treatment of advanced hepatocellular carcinoma (aHCC). However, the cost-effectiveness of nivolumab compared with sorafenib treatment for aHCC remains unclear. This study evaluated the cost-effectiveness of nivolumab and sorafenib in the treatment of aHCC.Materials and methods: A partitioned survival model that included three mutually exclusive health states was used to evaluate the cost-effectiveness of nivolumab and sorafenib for treating aHCC. The clinical characteristics and outcomes of the patients in the model were obtained from the CheckMate 459. We performed deterministic one-way sensitivity and probabilistic sensitivity analyses to evaluate the robustness of the model. Subgroup analyses were also performed. Costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were measured.Results: The base case analysis showed that compared with sorafenib, treatment with nivolumab was associated with an increment of 0.50 (2.45 vs. 1.95) life-years and an increment of 0.32 (1.59 vs. 1.27) QALYs, as well as a $69,762 increase in cost per patient. The ICER was $220,864/QALY. The INHB and INMB were −0.15 QALYs and −$22,362 at a willingness-to-pay (WTP) threshold of $150,000/QALY, respectively. The probabilistic sensitivity analysis demonstrated that the probability of nivolumab being cost-effective was only 10.38% at a WTP threshold of $150,000/QALY. The model was most sensitive to the costs of sorafenib and nivolumab according to the one-way sensitivity analysis. When the price of sorafenib exceeded $0.93/mg or nivolumab was less than $24.23/mg, nivolumab was more cost-effective. The subgroup analysis illustrated that the probability of cost-effectiveness was >50% in the Barcelona Clinic Liver Cancer Stage B subgroups for nivolumab at a WTP threshold of $150,000/QALY. This study also showed that the probability of cost-effectiveness was

To investigate the responses of amino acid metabolism in portal-drained viscera (PDV), liver, and mammary glands (MGs) to a graded gradual decrease of post-ruminal Lys supply, four multi-catheterized lactating goats were used in a 4 × 4 Latin square experiment. Goats were fasted for 12 h and then received a 33-h abomasal infusion of an amino acid mixture and glucose. Treatments consisted of a graded decrease of Lys content in the infusate to 100 (complete), 60, 30, or 0% as in casein. Lys-removed infusions decreased the production of milk, milk protein, fat, and lactose linearly and also decreased arterial Lys concentrations linearly (p < 0.05). Net PDV uptake decreased linearly (p < 0.05) with decreasing PDV loss ratio (p < 0.05). Although liver removal of Lys decreased linearly (p < 0.05), the removal ratio relative to portal absorption changed small, which was about 10% in all four treatments. Reduced Lys supply resulted in a linear decrease in the utilization of Lys in the peripheral tissues (except mammary, p < 0.05) and the release of more Lys in MGs. Although net mammary uptake of Lys declined linearly (p < 0.05), lactating goats can partially offset the negative effect of decreased circulating Lys concentrations by increasing mammary affinity (p < 0.05) and increasing mammary blood flow (p < 0.05). Graded removal of Lys from the infusate linearly decreased mammary uptake-to-output ratios of Lys (p < 0.05) suggesting that mammary catabolism of Lys decreased. Meanwhile, the treatments linearly increased circulating concentrations of glucagon and linearly decreased prolactin (p < 0.05). In conclusion, the results of the present study indicated that there were several mechanisms used to mitigate a Lys deficiency, including reduced catabolism of Lys in PDV and peripheral tissues (including MGs) and linearly increased mammary blood flow and mammary affinity together with increased mammary uptake and U:O of branched-chain amino acids (BCAA). Given these changes, the decline in milk protein production could be attributed to the combined effect of mass action with Lys and hormonal status.

ObjectiveStudies have long shown that uncontrolled inflammatory responses in the brain play a key role in epilepsy pathogenesis. Microglias play an important role in epileptic-induced neuroinflammation, but their role after epileptic seizures is still poorly understood. Alleviating epilepsy and its comorbidities has become a key area of interest for pediatricians.MethodsA pilocarpine-induced rat model of epilepsy was established. The rats were randomly divided into four groups: a control group, epilepsy group, TLR4 inhibitor group (epilepsy+TAK-242), and NF-κB antagonist group (epilepsy+BAY11–7082).Results1. The results of TUNEL staining showed that the expression in rats in the epilepsy group was the most obvious and was significantly different from that in rats in the control, EP+BAY and EP+TAK groups. 2. The expression of TLR4 and NF-κB was highest in rats in the epilepsy group and was significantly different from that in rats in the control, EP+BAY and EP+TAK groups. 3. The fluorescence intensity and number of IBA-1-positive cells in rats in the epilepsy group were highest and significantly different from those in rats in the control, EP+BAY and EP+TAK groups. Western blot analysis of IBA-1 showed that the expression in rats in the epilepsy group was the highest and was statistically significant. 4. CD68 was the highest in rats in the epilepsy group and was statistically significant. 5. In the open-field experiment, the central region residence time of rats in the EP group was delayed, the central region movement distance traveled was prolonged, the total distance traveled was prolonged, and the average speed was increased. Compared with rats in the EP group, rats in the EP+BAY and EP+ TAK groups exhibited improvements to different degrees.ConclusionAt the tissue level, downregulation of the TLR4/NF-κB inflammatory pathway in epilepsy could inhibit microglial activation and the expression of the inflammatory factor CD68, could inhibit hyperphagocytosis, and inhibit the occurrence and exacerbation of epilepsy, thus improving cognitive and emotional disorders after epileptic seizures.

Background: Pancreatic adenocarcinoma (PDAC) is the most aggressive among all solid malignancies with delayed disease detection and limited effective treatment. However, due to the intricate heterogeneity and exclusive tumor microenvironment (TME), the development of effective therapy has been facing enormous challenges. The lysyl oxidases (LOXs) underpin the shaping of the TME to promote cancer growth, metastasis and modulate response to treatment.Materials and Methods: The mRNA expression, prognostic, and clinicopathological data for LOXs in PDAC from multiple open-access databases were summarized and analyzed. The protein expression was verified by immunohistochemistry (IHC). Co-expressed genes of LOXs were predicted and elaborated by LinkedOmics. Functional enrichment analysis of LOXs co-expressed genes was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). TIMER and TISIDB were applied to analyze the relationship between LOXs expression and immune infiltration.Results: The mRNA expression levels of LOX, LOXL1 and LOXL2 were significantly higher in PDAC, the expression levels of LOXL3 and LOXL4 were contrary in different databases. High mRNA levels of LOX and LOXL2 were associated with advanced PDAC stage, while elevated LOX and LOXL3 expression correlated with high tumor grade. The IHC staining showed higher expression levels of LOX, LOXL1 and LOXL2, lower expression level of LOXL3 in PDAC tissues, while the protein expression of LOXL4 made no difference. Functional enrichment analysis showed a close relationship with extracellular matrix (ECM) regulation, except that LOXL3 and its ligands were highly associated with immune-related functions. Further analysis suggested that LOX and LOXL3 strongly correlated with tumor-infiltrating lymphocytes (TILs), various immune signatures, and immune checkpoints. Finally, survival analysis revealed high LOX and LOXL2 expression predicted worse overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS).Conclusion: These findings indicated that the LOX family, especially LOX and LOXL2, might have a prospective value in PDAC oncogenesis, and they may become prognostic biomarkers, revealing a promising field in targeted therapy.

The transcription factor NF-κB plays an important role in modulation of inflammatory pathways, which are associated with inflammatory diseases, neurodegeneration, apoptosis, immune responses, and cancer. Increasing evidence indicates that TRIM proteins are crucial role in the regulation of NF-κB signaling pathways. In this study, we identified TRIM67 as a negative regulator of TNFα-triggered NF-κB activation. Ectopic expression of TRIM67 significantly represses TNFα-induced NF-κB activation and the expression of pro-inflammatory cytokines TNFα and IL-6. In contrast, Trim67 depletion promotes TNFα-induced expression of TNFα, IL-6, and Mcp-1 in primary mouse embryonic fibroblasts. Mechanistically, we found that TRIM67 competitively binding β-transducin repeat-containing protein (β-TrCP) to IκBα results inhibition of β-TrCP-mediated degradation of IκBα, which finally caused inhibition of TNFα-triggered NF-κB activation. In summary, our findings revealed that TRIM67 function as a novel negative regulator of NF-κB signaling pathway, implying TRIM67 might exert an important role in regulation of inflammation disease and pathogen infection caused inflammation.

Autoimmune encephalitis (AE) is an immune-mediated disease involving the central nervous system, usually caused by antigen-antibody reactions. With the advent of autoantibody-associated diseases, AE has become a hot research frontier in neuroimmunology. The first-line conventional treatments of autoimmune encephalitis consist of steroids, intravenous immunoglobulin (IVIG), plasma exchange (PLEX), and second-line therapy includes rituximab. Despite considerable research and expanding clinical experience, current treatments are still ineffective for a significant number of patients. Although there is no clear consensus, clinical trial evidence limited, and the level of evidence for some of the drugs based on single reports, third-line therapy is a viable alternative for refractory encephalitis patients. With the current rapid research progress, a breakthrough in the treatment of AE is critical. This article aims to review the third-line therapy for refractory AE