Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that severely affects the health of the elderly, marked by its incurability, high prevalence, and extended latency period. The current approach to AD prevention and treatment emphasizes early detection and intervention, particularly during the pre-AD stage of mild cognitive impairment (MCI), which provides an optimal “window of opportunity” for intervention. Clinical detection methods for MCI, such as cerebrospinal fluid monitoring, genetic testing, and imaging diagnostics, are invasive and costly, limiting their broad clinical application. Speech, as a vital cognitive output, offers a new perspective and tool for computer-assisted analysis and screening of cognitive decline. This is because elderly individuals with cognitive decline exhibit distinct characteristics in semantic and audio information, such as reduced lexical richness, decreased speech coherence and conciseness, and declines in speech rate, voice rhythm, and hesitation rates. The objective presence of these semantic and audio characteristics lays the groundwork for computer-based screening of cognitive decline. Speech information is primarily sourced from databases or collected through tasks involving spontaneous speech, semantic fluency, and reading, followed by analysis using computer models. Spontaneous language tasks include dialogues/interviews, event descriptions, narrative recall, and picture descriptions. Semantic fluency tasks assess controlled retrieval of vocabulary items, requiring participants to extract information at the word level during lexical search. Reading tasks involve participants reading a passage aloud. Summarizing past research, the speech characteristics of the elderly can be divided into two major categories: semantic information and audio information. Semantic information focuses on the meaning of speech across different tasks, highlighting differences in vocabulary and text content in cognitive impairment. Overall, discourse pragmatic disorders in AD can be studied along three dimensions: cohesion, coherence, and conciseness. Cohesion mainly examines the use of vocabulary by participants, with a reduction in the use of nouns, pronouns, verbs, and adjectives in AD patients. Coherence assesses the ability of participants to maintain topics, with a decrease in the number of subordinate clauses in AD patients. Conciseness evaluates the information density of participants, with AD patients producing shorter texts with less information compared to normal elderly individuals. Audio information focuses on acoustic features that are difficult for the human ear to detect. There is a significant degradation in temporal parameters in the later stages of cognitive impairment; AD patients require more time to read the same paragraph, have longer vocalization times, and produce more pauses or silent parts in their spontaneous speech signals compared to normal individuals. Researchers have extracted audio and speech features, developing independent systems for each set of features, achieving an accuracy rate of 82% for both, which increases to 86% when both types of features are combined, demonstrating the advantage of integrating audio and speech information. Currently, deep learning and machine learning are the main methods used for information analysis. The overall diagnostic accuracy rate for AD exceeds 80%, and the diagnostic accuracy rate for MCI also exceeds 80%, indicating significant potential. Deep learning techniques require substantial data support, necessitating future expansion of database scale and continuous algorithm upgrades to transition from laboratory research to practical product implementation.

ObjectivePhotoacoustic pump-probe imaging can effectively eliminate the interference of blood background signal in traditional photoacoustic imaging, and realize the imaging of weak phosphorescence molecules and their triplet lifetimes in deep tissues. However, background differential noise in photoacoustic pump-probe imaging often leads to large fitting results of phosphorescent molecule concentration and triplet lifetime. Therefore, this paper proposes a novel triplet lifetime fitting method for photoacoustic pump-probe imaging. By extracting the phase of the triplet differential signal and the background noise, the fitting bias caused by the background noise can be effectively corrected. MethodsThe advantages and feasibility of the proposed algorithm are verified by numerical simulation, phantom and in vivo experiments, respectively. ResultsIn the numerical simulation, under the condition of noise intensity being 10% of the signal amplitude, the new method can optimize the fitting deviation from 48.5% to about 5%, and has a higher exclusion coefficient (0.88>0.79), which greatly improves the fitting accuracy. The high specificity imaging ability of photoacoustic pump imaging for phosphorescent molecules has been demonstrated by phantom experiments. In vivo experiments have verified the feasibility of the new fitting method proposed in this paper for fitting phosphoometric lifetime to monitor oxygen partial pressure content during photodynamic therapy of tumors in nude mice. ConclusionThis work will play an important role in promoting the application of photoacoustic pump-probe imaging in biomedicine.

The innate immune system can be boosted in response to subsequent triggers by pre-exposure to microbes or microbial products, known as “trained immunity”. Compared to classical immune memory, innate trained immunity has several different features. Firstly, the molecules involved in trained immunity differ from those involved in classical immune memory. Innate trained immunity mainly involves innate immune cells (e.g., myeloid immune cells, natural killer cells, innate lymphoid cells) and their effector molecules (e.g., pattern recognition receptor (PRR), various cytokines), as well as some kinds of non-immune cells (e.g., microglial cells). Secondly, the increased responsiveness to secondary stimuli during innate trained immunity is not specific to a particular pathogen, but influences epigenetic reprogramming in the cell through signaling pathways, leading to the sustained changes in genes transcriptional process, which ultimately affects cellular physiology without permanent genetic changes (e.g., mutations or recombination). Finally, innate trained immunity relies on an altered functional state of innate immune cells that could persist for weeks to months after initial stimulus removal. An appropriate inducer could induce trained immunity in innate lymphocytes, such as exogenous stimulants (including vaccines) and endogenous stimulants, which was firstly discovered in bone marrow derived immune cells. However, mature bone marrow derived immune cells are short-lived cells, that may not be able to transmit memory phenotypes to their offspring and provide long-term protection. Therefore, trained immunity is more likely to be relied on long-lived cells, such as epithelial stem cells, mesenchymal stromal cells and non-immune cells such as fibroblasts. Epigenetic reprogramming is one of the key molecular mechanisms that induces trained immunity, including DNA modifications, non-coding RNAs, histone modifications and chromatin remodeling. In addition to epigenetic reprogramming, different cellular metabolic pathways are involved in the regulation of innate trained immunity, including aerobic glycolysis, glutamine catabolism, cholesterol metabolism and fatty acid synthesis, through a series of intracellular cascade responses triggered by the recognition of PRR specific ligands. In the view of evolutionary, trained immunity is beneficial in enhancing protection against secondary infections with an induction in the evolutionary protective process against infections. Therefore, innate trained immunity plays an important role in therapy against diseases such as tumors and infections, which has signature therapeutic effects in these diseases. In organ transplantation, trained immunity has been associated with acute rejection, which prolongs the survival of allografts. However, trained immunity is not always protective but pathological in some cases, and dysregulated trained immunity contributes to the development of inflammatory and autoimmune diseases. Trained immunity provides a novel form of immune memory, but when inappropriately activated, may lead to an attack on tissues, causing autoinflammation. In autoimmune diseases such as rheumatoid arthritis and atherosclerosis, trained immunity may lead to enhance inflammation and tissue lesion in diseased regions. In Alzheimer’s disease and Parkinson’s disease, trained immunity may lead to over-activation of microglial cells, triggering neuroinflammation even nerve injury. This paper summarizes the basis and mechanisms of innate trained immunity, including the different cell types involved, the impacts on diseases and the effects as a therapeutic strategy to provide novel ideas for different diseases.

ObjectiveIn the realm of forensic science, dust is a valuable type of trace evidence with immense potential for intricate investigations. With the development of DNA sequencing technologies, there is a heightened interest among researchers in unraveling the complex tapestry of microbial communities found within dust samples. Furthermore, striking disparities in the microbial community composition have been noted among dust samples from diverse geographical regions, heralding new possibilities for geographical inference based on microbial DNA analysis. The pivotal role of microbial community data from dust in geographical inference is significant, underscoring its critical importance within the field of forensic science. This study aims to delve deeply into the nuances of fungal community composition across the urban landscapes of Beijing, Fuzhou, Kunming, and Urumqi in China. It evaluates the accuracy of biogeographic inference facilitated by the internal transcribed spacer 2 (ITS2) fungal sequencing while concurrently laying a robust foundation for the operational integration of environmental DNA into geographical inference mechanisms. MethodsITS2 region of the fungal genomes was amplified using universal primers known as 5.8S-Fun/ITS4-Fun, and the resulting DNA fragments were sequenced on the Illumina MiSeq FGx platform. Non-metric multidimensional scaling analysis (NMDS) was employed to visually represent the differences between samples, while analysis of similarities (ANOSIM) and permutational multivariate analysis of variance (PERMANOVA) were utilized to statistically evaluate the dissimilarities in community composition across samples. Furthermore, using Linear Discriminant Analysis Effect Size (LEfSe) analysis to identify and filter out species that exhibit significant differences between various cities. In addition, we leveraged SourceTracker to predict the geographic origins of the dust samples. ResultsAmong the four cities of Beijing, Fuzhou, Kunming and Urumqi, Beijing has the highest species richness. The results of species annotation showed that there were significant differences in the species composition and relative abundance of fungal communities in the four cities. NMDS analysis revealed distinct clustering patterns of samples based on their biogeographic origins in multidimensional space. Samples from the same city exhibited clear clustering, while samples from different cities showed separation along the first axis. The results from ANOSIM and PERMANOVA confirmed the significant differences in fungal community composition between the four cities, with the most pronounced distinctions observed between Fuzhou and Urumqi. Notably, the biogeographic origins of all known dust samples were successfully predicted. ConclusionSignificant differences are observed in the fungal species composition and relative abundance among the cities of Beijing, Fuzhou, Kunming, and Urumqi. Employing fungal ITS2 sequencing on dust samples from these urban areas enables accurate inference of biogeographical locations. The high feasibility of utilizing fungal community data in dust for biogeographical inferences holds particular promise in the field of forensic science.

Objective To understand the current situation of healthcare-associated infection(HAI)in China,pro-vide data support and decision-making basis for formulating scientific and effective strategies for HAI prevention and control.Methods A nationwide cross-sectional survey on HAI was conducted among various types and levels of medical institutions in China according to a unified protocol of bedside surveys and case investigations.Results In 2024,a total of 5 736 medical institutions and 2 751 765 patients were surveyed.Among them,34 889 HAI cases were identified,with a prevalence rate of 1.27％.The number of HAI episodes was 38 032,and case prevalence rate was 1.38％.The prevalence rate of HAI in medical institutions in different regions of China ranged from 0.66％to 2.35％.Among medical institutions of different scales,those with a bed capacity of ≥900 had the high-est incidence of HAI,reaching 1.65％.The most common infection site was the lower respiratory tract(44.66％),followed by the urinary tract(12.94％),surgical site(9.32％),upper respiratory tract(7.02％),and bloodstream infection(5.78％).The top 3 departments with the highest HAI rates were the general intensive care unit(10.02％),department of neurosurgery(5.51％),and department(group)of hematology(5.34％).A total of 23 238 strains of HAI pathogens were detected,with 10 714 strains(46.10％)from lower respiratory tract speci-mens.The top 5 detected strains were Klebsiella pneumoniae(14.76％),Pseudomonas aeruginosa(13.33％),Escherichia coli(12.79％),Acinetobacter baumannii(9.23％),and Staphylococcus aureus(7.88％).231 944 pa-tients underwent class Ⅰ incision surgery were monitored,with 1 647 cases experienced surgical site infection,and the prevalence rate of surgical site infection was 0.71％.The number of patients who should undergo pathogen de-tection(patients receiving therapeutic and therapeutic combined prophylactic antimicrobial agents)was 715 179,while the actual number was 480 492,with a pathogen detection rate of 67.18％.425 225 patients received patho-genic detection before treatment,with a detection rate of 59.46％.Conclusion The overall HAI prevalence in Chi-na is lower,showing disparities among medical institutions of different regions and scales.Therefore,precise imple-mentation of measures is necessary for HAI prevention and control,with a focus on high-risk institutions and high-risk departments,key areas,and critical procedures.All levels of medical institutions should continuously reduce the incidence of HAI by strengthening monitoring,standardizing the use of antimicrobial agents,and reinforcing basic HAI prevention and control measures.

Objective To compare the efficacy and safety of bridging therapy and direct thrombectomy in patients with acute ischemic stroke caused by basilar artery occlusion within 4.5 h.Methods Retrospective consecutive patients with acute basilar artery occlusion stroke within 4.5 h of onset admitted to five centers from January 2018 to August 2024 were included and divided into a bridging therapy(intravenous thrombolysis with alteplase given prior to emergency endovascular treatment)group and a direct thrombectomy group according to the treatment modality.Baseline and clinical data were collected from patients,including age,sex,systolic and diastolic blood pressure on admission,past history(including history of hypertension,diabetes mellitus,coronary artery disease,atrial fibrillation,hyperlipidemia,and history of stroke),history of smoking,pre-morbid modified Rankin scale(mRS)scores,National Institutes of Health stroke scale(NIHSS)score on admission,posterior circulation Alberta stroke program early CT score on admission,basilar artery CT angiography score,history of pre-procedural antiplatelet aggregation medications,history of pre-procedural anticoagulant medications,choice of arterial puncture access(via femoral or radial artery),site of vascular occlusion(proximal basilar artery,mid-basilar artery,distal basilar artery),trial of Org 10172 in acute stroke treatment(TOAST)classification,American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral circulation classification,time from onset to admission,time from admission to puncture,time from puncture to revascularization,time from onset to revascularisation,type of embolisation procedure(stenting,aspiration,and combined),immediate post-procedure extended thrombolysis in cerebral infarction(eTICI)classification,and intra-procedural related complications(arterial entrapment,distal occlusion and arterial perforation).The main efficacy indicators(good prognosis[mRS score 0-3 90 d postoperatively],death[mRS score 6 90 d postoperatively],and good recanalisation[eTICI grade ≥2b50]within the immediate postoperative period)and safety indicators(incidence of symptomatic intracranial haemorrhage[sICH]within 7 days post-procedure)were compared between the two groups.The two groups were matched 1∶1 using propensity score matching(PSM)to compare differences in effectiveness and safety indices before and after PSM.Variables with P＜0.05 in the baseline and clinical data comparison between the two groups were included in multifactorial Logistic regression analysis for correction,the differences in safety and efficacy between the two groups were compared before and after correction.Results A total of 206 patients with acute ischemic stroke caused by basilar artery occlusion within 4.5 h of onset were included,comprising 151 males and 55 females.The age ranged from 26 to 93 years old,with an average of(65±13)years old.Among them,101 patients(49.0％)were in the bridging therapy group and 105(51.0％)in the direct thrombectomy group.After 1∶1 PSM,each group consisted of 69 patients.(1)The differences in the proportion of patients with atrial fibrillation between the bridging therapy group and the direct thrombectomy group(16.8％[17/101]vs.28.6％[30/105]),the distribution of pre-morbid mRS scores,and the distribution of TOAST subtypes were statistically significant(all P＜0.05);the differences in the residual baseline and clinical data of the two groups were not statistically significant(all P＞0.05).After 1∶1 PSM,the differences in all baseline and clinical data between the two groups were not statistically significant(all P＞0.05).(2)No statistically significant differences were observed between the bridging therapy group and direct thrombectomy group in the good prognosis rate at 90 d postoperatively,morbidity and mortality rates at 90 d postoperatively,or good revascularization rate in the immediate postoperative period(all P＞0.05).However,the risk of sICH at 7 d postoperatively was higher in the bridging therapy group(9.5％[10/105]vs.19.8％[20/101];OR,2.346,95％CI 1.038-5.299,P=0.037).After correcting for variables with statistically significant differences in baseline and clinical data between the direct thrombectomy group and bridging therapy groups(atrial fibrillation,pre-onset mRS score,and TOAST classification)using a multifactorial Logistic regression model,the results showed no statistically significant differences in the effectiveness and safety metrics between the two groups(all P＞0.05).(3)The results after 1∶1 PSM showed that the bridging therapy group had a higher risk of sICH(11.6％[8/69]vs.26.1％[18/69];OR,2.691,95％CI 1.081-6.700,P=0.033).No statistically significant differences were observed between the two groups in terms of good prognosis rate at 90 d postoperatively,disease-related mortality rate at 90 d postoperatively,or rate of good revascularization in the immediate postoperative period(all P＞0.05).Conclusions In patients with acute basilar artery occlusion stroke within 4.5 h of onset,the effectiveness of bridging therapy and direct thrombectomy was similar,but the incidence of sICH was higher with bridging therapy.The results of this study still need further validation through prospective studies with larger sample sizes.

Objective To investigate the relationship between preoperative serum high mobility group protein 1(HMGB1),macrophage inflammatory protein-1α(MIP-1α),osteopontin(OPN)and the prognosis of patients with basal ganglia intracerebral hemorrhage after neuroendoscopic surgery.Methods From March 2022 to March 2024,98 patients with cerebral hemorrhage in basal ganglia treated by neuroendoscopic removal were selected.Serum HMGB1,MIP-1 a and OPN were detected before operation,and they were followed up for 1 month after operation.Cox regression analysis was used to analyze the risk factors affecting the prognosis of patients with cerebral hemorrhage in basal ganglia.Kaplan-Meier survival curve and Log-rank test were used to analyze the survival rate of patients with cerebral hemorrhage in basal ganglia.Results Among the 98 patients with cerebral hemorrhage in basal ganglia,21 patients died within 1 month after neuroendoscopic removal,and the mortality rate was 21.43％.The proportion of patients with midline shift ≥ 10 mm(76.19％)and hematoma volume[(51.18±7.62)ml]in the death group were higher than those in the survival group[14.29％and(31.93±5.66)ml],and the hematoma clearance rate[(78.13±5.86)％]was lower than that in the survival group[(90.58±6.29)％](P＜0.05).The preoperative levels of HMGB1,MIP-1 α and OPN in the death group were(12.44±2.26)ng/ml,(417.25±134.12)pg/ml and(12.32±3.19)ng/ml,respectively.The survival groups were(7.52±2.37)ng/ml,(200.35±31.36)pg/ml and(6.29±2.37)ng/ml,respectively.There was a statistically significant difference between the two groups(P＜0.05).Cox regression analysis showed that preoperative high HMGB1(HR=1.629,95％CI:1.274-2.083),high MIP-1α(HR=2.875,95％CI:1.384-5.972),high OPN(HR=1.429,95％CI:1.073-1.093)were risk factors for death within 1 month after neuroendoscopic removal of basal ganglia intracerebral hemorrhage(P＜0.05).Survival curve analysis showed that the survival rate of high HMGB1,high MIP-1α and high OPN at 1 month after operation was significantly lower than that of low HMGB1,low MIP-1α and low OPN(Long-rank x2=7.539,6.028,8.220,P＜0.05).Conclusion The prognosis of patients with basal ganglia intracerebral hemorrhage with high HMGB1,high MIP-1α and high OPN before neuroendoscopic surgery was poor.Preoperative HMGB1,MIP-1α and OPN may be used as indicators for postoperative evaluation of neuroendoscopic removal in patients with basal ganglia intracerebral hemorrhage.

Background and Aims:Primary hepatic diffuse large B-cell lymphoma(DLBCL)is rare and carries a poor prognosis,with no large-scale evidence supporting the value of chemotherapy.This study used real-world,large-sample data from the SEER database to evaluate the prognostic impact of chemotherapy in patients with primary hepatic DLBCL.Methods:Clinical data of patients pathologically diagnosed with primary hepatic DLBCL between 2000 and 2019 were extracted from the SEER database and grouped according to whether they received chemotherapy.Kaplan-Meier survival analysis,Cox proportional hazards models,and random survival forest models were employed to identify factors influencing overall survival(OS)and cancer-specific survival(CSS),and subgroup analyses were performed.Results:A total of 594 patients were included,with a median age of 66 years;435(73.2%)received chemotherapy.After a median follow-up of 17.5 months,the median OS was 81(7-173)months in the chemotherapy group versus 11(2-171)months in the non-chemotherapy group.The OS and CSS rates in the chemotherapy group were significantly higher than those in the non-chemotherapy group(67.99%vs.47.77%;71.03%vs.52.87%,both P<0.05).Multivariate analysis showed that chemotherapy was an independent protective factor for OS(HR=0.39,95%CI=0.31-0.48)and CSS(HR=0.37,95%CI=0.29-0.48).In the random survival forest model,chemotherapy ranked highest in variable importance.Subgroup analyses produced consistent results.Conclusion:Chemotherapy is an independent prognostic factor for patients with primary hepatic DLBCL and can significantly improve survival.The R-CHOP regimen may be the preferred therapeutic option.

Kv1.3,a voltage-gated potassium channel,is highly expressed in T lymphocytes,the nervous system,and vascular smooth muscle cells.It plays a critical role in membrane excitability and electrical signal transduction,serving as an important target for studying T-cell function and providing a promising direction for developing therapeutics against autoimmune and inflammatory diseases.Therefore,the de-velopment of specific inhibitors of Kv1.3 channel has emerged as a novel therapeutic strategy for these disorders.In this study,we isolated and purified a novel Kv1.3-inhibitory peptide toxin,LmKTx13,from the venom of the scorpion Lychas mucronatus using reversed-phase high-performance liquid chroma-tography(RP-HPLC).LmKTx13 consists of 38 amino acid residues,including six cysteines that form three disulfide bonds.Whole-cell patch-clamp recordings revealed that LmKTx13 potently inhibited Kv1.3 with an IC50 of 7.92±3.0 nmol/L.Selectivity analysis showed that 2 μmol/L LmKTx13 also in-hibited Kv1.2 and Kv1.7,but exhibited no significant effects on other potassium channel subtypes or voltage-gated sodium channels.Further investigation into the mechanism demonstrated that LmKTx13 acts as a pore-blocking inhibitor of Kv1.3.By analyzing the effects of LmKTx13 on Kv1.3 channel gating ki-netics and performing sequence alignment of the pore regions of Kv1.3 and Kv1.5,we constructed site-directed mutants and identified the pore region of Kv1.3 as the critical binding site for LmKTx13.Key residues involved in the interaction included T425,G427,and H451.In summary,we discovered a no-vel pore-blocking Kv1.3 inhibitor,LmKTx13,from L.mucronatus venom,which exhibits high affinity and selectivity for Kv1.3.These findings highlight its potential as a potential lead molecule for developing Kv1.3-targeted therapeutics.

Aim To investigate the effects of Agrimonia pilosa(AP)on the proliferation and apoptosis of non-small cell lung cancer(NSCLC)H1299 cells using non-targeted metabolomics and other methods,and to explore the underlying molecular mechanisms.Meth-ods Taking H1299 cells as the research object,the effect of AP on cell proliferation and apoptosis was de-tected through CCK-8 method,colony formation,LDH,Hoechst 33258 staining,AO/EB staining,flow cytometry detection,RT qPCR and other experiments.The main differential metabolites were detected by the metabolomics method of ultra-high phase liquid chro-matography and mass spectrometry(UHPLC-Q-Orbi-trap MS),and related metabolic pathways were ana-lyzed.Results Compared with the control group,AP treatment was able to significantly inhibit the prolifera-tion and colony formation of H1299 cells,while the re-lease of LDH increased in a dose-dependent manner.Fluorescence microscopy and flow cytometry and RT-qPCR analysis revealed that H1299 cells underwent crumpling and increased nuclear fragmentation after AP administration,blocked in G0/G1 phase,up-regulated apoptotic genes caspase-3 and Bax,and down-regulated apoptosis-inducing effects of Bcl-2.Metabolomics anal-ysis screened 35 differential metabolites,which were PC(O-30∶1),D-Glutamic acid,PE(18∶0/15∶0),etc.The main metabolic pathways involved includ-ed amino acid metabolism,glycerophospholipid metabo-lism and purine metabolism so on.Conclusions AP may exert its pharmacological effects by interfering with multiple metabolic pathways in H1299 cells,inhibiting cell proliferation and promoting apoptosis.