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.

Modified electro-convulsive therapy (MECT) is one of the most potent treatments for major depressive disorder (MDD). However, it remains a second-line option due to significant side effects, such as transient memory loss. The relationship between therapeutic efficacy and cognitive impairment warrants further investigation to develop improved treatment regimens. In this review, we examine recent evidence from magnetic resonance imaging (MRI) studies aiming to identify structural and functional brain changes specifically associated with both the antidepressant effects and the amnesic outcomes of MECT. MECT induces widespread alterations across multiple brain systems. Increases in gray matter volume (GMV) have been observed in the prefrontal, temporal, and parietal cortices, as well as in subcortical regions such as the hippocampus (HP), amygdala, and striatum. Strengthening of myelination has also been reported along the dorsolateral prefrontal-limbic pathways. Functional changes include increased spontaneous neural activity in prefrontal areas, reorganization of intrinsic connectivity within the default mode network (DMN), and altered functional connectivity (FC) among the DMN, salience network (SN), and central executive network (CEN). Correlational studies have identified structural and functional alterations linked to antidepressant efficacy, including right hippocampal volume enlargement, prefrontal cortical thickening, reduced iron deposition in the striatum, decreased FC within certain DMN nodes, and enhanced effective connectivity from the dorsolateral prefrontal cortex (DLPFC) to the right angular gyrus. In contrast, the amnesic effects have been associated with increased volumes in the left hippocampus and bilateral dentate gyrus; enhanced FC in the left angular gyrus and left posterior cingulate cortex (PCC); increased FC between the right ventral anterior insula and DLPFC; and reduced FC in the left thalamus and bilateral precuneus. Changes in the hippocampus appear to correlate with both antidepressant efficacy and memory impairment. Clinical studies have found no significant correlation between the severity of memory impairment and the reduction in depressive symptoms, suggesting that the therapeutic and adverse effects may arise from distinct regional or subregional mechanisms. Supporting this hypothesis, recent findings show that increased right hippocampal volume is significantly associated with reduced depression scores, whereas increased volume in the left dentate gyrus correlates with declines in delayed recall performance. Additionally, enhanced connectivity between the anterior hippocampus and middle occipital gyrus (MOG) has been linked to mood improvement, while decreased FC between the mid-hippocampus and angular gyrus has been associated with impairments in memory integration. In conclusion, current evidence suggests that the antidepressant and memory-impairing effects of MECT may localize to distinct hippocampal subregions. These effects likely result from differential modulation of local neural activity and functional connectivity, leading to divergent behavioral outcomes. Given that both effects may originate in deep and spatially constrained structures such as the hippocampus, small-sample studies and conventional methodologies may fail to differentiate them effectively. Future research should employ large-scale, longitudinal designs utilizing high-field MRI and multimodal neuroimaging to characterize MECT-induced structure-function coupling in the hippocampus and its integration at the network level. Additionally, multiscale analyses spanning molecular, circuit, and network dimensions would be beneficial.

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.
Nipah Virus/chemistry* ; Cryoelectron Microscopy ; Viral Proteins/genetics* ; RNA-Dependent RNA Polymerase/genetics* ; Phosphoproteins/genetics* ; Humans ; Models, Molecular ; Protein Binding

Intracellular overexpression of cytoglobin (Cygb) has been shown to reduce extracellular matrix deposition and promote liver fibrosis recovery, but its mechanism is not yet clear. This study constructed and expressed a fusion protein (TAT-Cygb) of cell penetrating peptide TAT and Cygb, to investigate the effect of fusion protein TAT-Cygb on regulating hepatic stellate cells (HSCs) ferroptosis. Cultured human hepatic stellate cells line (LX2) were treated with TAT-Cygb and erastin in vitro, respectively. The effects of ferroptosis phenotype in LX2 cells induced by TAT-Cygb, including cell viability, cell morphology, iron ion (Fe²⁺) content, lipid peroxidation product levels, and antioxidant system indicators, were investigated using trypan blue staining, transmission electron microscopy, Prussian blue staining, and reagent kits detection. After co-treatment with TAT-Cygb and ferrostain-1, the levels of Fe²⁺, reactive oxygen species (ROS), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) were measured by reagent kits. The protein expression levels of alpha smooth actin (α-SMA), collagen I and fibronectin were detected by Western blot, and the protein expression level of epidermal growth factor receptor (EGFR) and desmin relevant to fibrosis were observed by immunofluorescence. The results showed that TAT-Cygb could significantly reduce the viability of LX2 cells and trigger events relevant to ferroptosis, including promoting intracellular Fe²⁺ accumulation, and inducing mitochondrial morphological changes, and intensifying lipid peroxidation products accumulation, and decreasing the level of antioxidant indexes, which played a similar role as erastin; Fer-1 significantly weakened the increase in Fe²⁺, ROS, MDA, 4-HNE levels induced by TAT-Cygb, as well as the decrease in NADPH and GSH levels, while also weakening the TAT-Cygb-induced over-expression levels of α-SMA, collagen I and fibronectin, and TAT-Cygb-induced under-expression levels of EGFR and desmin. This cellular level study indicated that TAT-Cygb can induce ferroptosis of activated HSCs. This study revealed the potential mechanism of TAT-Cygb anti-liver fibrosis, and provided the experimental basis for further research on the molecular mechanism of TAT-Cygb realizing biological function by regulating the ferroptosis pathway.

Objective To observe the effects of pegylated losenatide injection combined with metformin tablets on serum metabolism,lipid levels and intestinal flora in obese type 2 diabetes mellitus(T2DM)patients after axial gastrectomy.Methods Obese T2DM patients who underwent axial gastrectomy were divided into treatment group and control group by cohort methods.The control group was treated with metformin hydrochloride tablet 0.5 g orally,tid.The treatment group was treated by subcutaneous injection of pegylated losenatide injection 0.2 mg once a week on the basis of control group.Both groups were treated continuously for 3 months.Body mass index(BMI),serum metabolic indexes,blood lipid levels,blood glucose levels,intestinal flora and adverse drug reactions were compared between the two groups.Results In this study,a total of 70 subjects were included in the treatment group,and 50 subjects were included in the control group.After three months of treatment,the BMI indices of the treatment and control groups were(26.35±2.36)and(29.34±3.59)kg·m-2,respectively;the glutathione peroxidase levels were(192.42±13.18)and(134.27±12.86)U;interleukin-6 levels were(6.14±1.78)and(7.65±2.09)μg·L-1;fasting blood glucose levels were(5.36±0.41)and(7.43±0.78)mmol·L-1;total cholesterol levels were(2.55±0.67)and(3.47±0.79)mmol·L-1 for the treatment and control groups,respectively.The levels of Bifidobacteria,Bacteroides,Lactobacilli,Enterobacteria,and Enterococci in the treatment group were(8.79±1.36),(9.62±1.37),(6.74±2.15),(7.98±0.61),and(7.23±1.29)logN·g-1,respectively;in the control group,these levels were(7.98±1.79),(8.13±1.45),(5.71±2.41),(9.21±0.88),and(8.15±1.54)logN·g-1.The differences in the above indicators between the treatment and control groups were statistically significant(all P＜0.05).The main adverse drug reactions in the treatment group included nausea,headache,dizziness,elevated blood pressure,and indigestion.In the control group,the main adverse drug reactions were nausea,headache,and indigestion.The total incidence of adverse drug reactions in the treatment and control groups was 8.57％and 6.00％,respectively,with no statistically significant difference(P＞0.05).Conclusion Pegylated losenatide injection combined with metformin tablets has a significant effect on axial gastrectomy in obese type 2 diabetes patients.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Shiwei-Ruxiang-capsule (SWRXC) is a classic formulation widely used in the treatment of rheumatoid arthritis (RA). The study used liquid chromatography-tandem mass spectrometry (LC-MS/MS) serum untargeted metabolomics and high-throughput 16S rRNA gene sequencing association analysis to elucidate the mechanism of action of SWRXC for the treatment of Freund's complete adjuvant-induced RA. The results showed that SWRXC significantly improved symptoms and reduced serum cytokine levels in RA rats. Based on LC-MS/MS technology, metabolomics identified tryptophan metabolism, nucleotide metabolism and purine metabolism as the most relevant pathways for treatment. In addition, 16S rRNA sequencing results showed that SWRXC could ameliorate RA-induced intestinal microbial oncogenesis in rats. In conclusion, SWRXC can improve the morphology and structure of RA joint tissues, reduce serum factor levels, and may play a role in improving RA by modulating related metabolic pathways such as tryptophan metabolism, nucleotide metabolism and purine metabolism, and altering the composition of intestinal flora. Animal protocols were approved by the Animal Ethics Committee of Qinghai Normal University (No. 2021041203).

Objective: This study systematically explore the efficacy and safety of fourth-generation chimeric antigen receptor T-cells (CAR-T), which express interleukin 7 (IL7) and chemokine C-C motif ligand 19 (CCL19) and target CD19, in relapsed or refractory large B-cell lymphoma. Methods: Our center applied autologous 7×19 CAR-T combined with tirelizumab to treat 11 patients with relapsed or refractory large B-cell lymphoma. The efficacy and adverse effects were explored. Results: All 11 enrolled patients completed autologous 7×19 CAR-T preparation and infusion. Nine patients completed the scheduled six sessions of tirolizumab treatment, one completed four sessions, and one completed one session. Furthermore, five cases (45.5%) achieved complete remission, and three cases (27.3%) achieved partial remission with an objective remission rate of 72.7%. Two cases were evaluated for disease progression, and one died two months after reinfusion because of uncontrollable disease. The median follow-up time was 31 (2-34) months, with a median overall survival not achieved and a median progression-free survival of 28 (1-34) months. Two patients with partial remission achieved complete remission at the 9th and 12th months of follow-up. Therefore, the best complete remission rate was 63.6%. Cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome were controllable, and no immune-related adverse reactions occurred. Conclusion: Autologous 7×19 CAR-T combined with tirelizumab for treating relapsed or refractory large B-cell lymphoma achieved good efficacy with controllable adverse reactions.
Humans ; Antibodies, Monoclonal/therapeutic use* ; Antigens, CD19 ; Chemokine CCL19 ; Immunotherapy, Adoptive ; Interleukin-7 ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Programmed Cell Death 1 Receptor ; Receptors, Chimeric Antigen

ObjectiveTo explore the pharmacodynamic ingredients of Zhenqi Fuzheng granules （ZFG） for immunomodulatory through spectrum-effect relationship analysis， which provides experimental basis for improving the quality standard of ZFG. MethodEighteen batches of ZFG from six manufacturers were collected for analysis. The fingerprints were established by high performance liquid chromatography （HPLC）. Acetonitrile （A）-0.1% formic acid aqueous solution （B） were adopted as the mobile phase with gradient elution （0-15 min， 5%A； 15-23 min， 5%-8%A； 23-30 min， 8%-11%A； 30-45 min， 11%-18%A； 45-60 min， 18%-21%A； 60-67 min， 21%-23%A； 67-90 min， 23%-37%A）， the detection wavelength was 220 nm. Chemometric analysis such as similarity analysis and hierarchical cluster analysis （HCA） were subsequently used to analyze the similarities and chemical differences among these samples. A cyclophosphamide-induced immunodeficiency mouse model was used to evaluate the immune-enhancing effects of the products from different manufacturers. The spectrum-effect relationship between HPLC fingerprints and the immunomodulatory effects was examined using Spearman bivariate correlation analysis. HPLC coupled with mass spectrometry （HPLC-MSⁿ） was used to identify the spectrum-effect related peaks with electrospray ionization， positive and negative ion modes， and scanning range of m/z 100-1 500. ResultThe HPLC fingerprint of ZFG was established， and twenty peaks with good resolution were selected as common peaks. The results of quality analysis and pharmacodynamic test showed there were significant differences in both ingredients content and immune-enhancing effects of ZFG from different manufacturers. Through spectrum-effect relationship study， twelve peaks were screened as bioactive ingredients peaks. Thereafter， eight peaks among them were subsequently identified by HPLC-MSⁿ. They were salidroside （peak 2）， echinacoside （peak 5）， calycosin-7-glucoside （peak 6）， isomer of specnuezhenide （peak 7）， isonuezhenide （peak 9）， calycosin （peak 11）， nuezhenide G₁₃ or oleonuezhenide （peak 14）， and formononetin （peak 18）， respectively. ConclusionThere are differences in quality and efficacy of ZFG produced by different manufacturers. Through spectrum-effect relationship analysis， the medicinal ingredients of ZFG for immune-enhancing effects are screened， which can provide reference for the improvement of its quality standard.

ObjectiveTo investigate the therapeutic effect of Xuebijing injection （XBJ） on sodium taurocholate （Na-Tc）-induced severe acute pancreatitis （SAP） in rats. MethodForty rats were randomly assigned into 5 groups： sham operation group， SAP model group， and low-， medium-， and high-dose （4， 8， 12 mL·kg·d^-1， respectively） XBJ groups. SAP model was established by retrograde injection of Na-Tc （1 mL·kg^-1） into the biliary and pancreatic ducts. XBJ was injected intraperitoneally 3 days before and 0.5 h after modeling. The ascitic fluid volume and the pancreas weight-to-body weight ratio were measured. The pathological changes of pancreatic tissue were observed via hematoxylin-eosin （HE） staining. The protein levels of formyl peptide receptor 1 （FPR1） and nucleotide-binding oligomerization domain-like receptor 3 （NLRP3） in pancreatic tissue were detected by immunohistochemistry. Western blot was employed to determine the expression levels of NADH-ubiquinone oxidoreductase chains 1-6 （MT-ND1， MT-ND2， MT-ND3， MT-ND4， MT-ND5， and MT-ND6） in rat plasma. ResultCompared with sham operation group， the SAP model group showcased increased ascitic fluid volume and pancreas weight-to-body weight ratio （P<0.05）， serious lesions in pancreatic tissue， increased total pathological score （P<0.05）， and up-regulated protein levels of FPR1 and NLRP3 in pancreatic tissue （P<0.05）. The model group had lower MT-ND2 level （P<0.05） and higher MT-ND1， MT-ND3， and MT-ND6 levels in plasma （P<0.05） than the sham operation group， while MT-ND4 and MT-ND5 had no significant differences between the two groups. Compared with SAP model group， the XBJ treatment decreased ascitic fluid volume and pancreas weight-to-body weight ratio （P<0.01）， ameliorated pancreatic lesions， and down-regulated the protein levels of FPR1 and NLRP3 in pancreatic tissue （P<0.01）. The treatments， especially high-dose XBJ （P<0.01）， down-regulated the expression of MT-ND1 （P<0.01）， MT-ND3 （P<0.01）， MT-ND6 （P<0.01）， and MT-ND4 and did not change that of MT-ND5. ConclusionXBJ may antagonize partial mitochondrial N-formyl peptides and excessive inflammatory response mediated by FPR1/NLRP3 to treat SAP in rats.