Transcranial direct stimulation over left inferior frontal gyrus improves language production and comprehension in post-stroke aphasia: A double-blind randomized controlled study.

Transcranial direct current stimulation (tDCS) targeting Broca's area has shown promise for augmenting language production in post-stroke aphasia (PSA). However, previous research has been limited by small sample sizes and inconsistent outcomes. This study employed a double-blind, parallel, randomized, controlled design to evaluate the efficacy of anodal Broca's tDCS, paired with 20-minute speech and language therapy (SLT) focused primarily on expressive language, across 5 daily sessions in 45 chronic PSA patients. Utilizing the Western Aphasia Battery-Revised, which assesses a spectrum of linguistic abilities, we measured changes in both expressive and receptive language skills before and after intervention. The tDCS group demonstrated significant improvements over sham in aphasia quotient, auditory verbal comprehension, and spontaneous speech. Notably, tDCS improved both expressive and receptive domains, whereas sham only benefited expression. These results underscore the broader linguistic benefits of Broca's area stimulation and support the integration of tDCS with SLT to advance aphasia rehabilitation.

Neu5Gc-mediated high-affinity interaction is dispensable for CD22 cis-ligands to regulate B cell signaling.

CD22 (also known as Siglec-2) is an inhibitory receptor expressed in B cells. CD22 specifically recognizes α2,6 sialic acid and interacts with α2,6 sialylated membrane proteins expressed on the same cell (cis-ligands) and those derived from outside of the cell (trans-ligands). Previously, CD22 cis-ligands were shown to regulate the activity of CD22, thereby regulating both BCR ligation-induced signaling and low-level "tonic" signaling in the absence of BCR ligation that regulates the survival and differentiation of B cells. Mouse CD22 prefers Neu5Gc to Neu5Ac thereby binding to α2,6-linked Neu5Gc with high affinity. Although human CD22 binds to a distinct α2,6 sialylated glycan with high affinity, expression of high-affinity ligands is regulated in a conserved and stringent manner. However, how high- versus low-affinity CD22 ligands regulate B cells is poorly understood. Here we demonstrate that the interaction of CD22 with the endogenous ligands enhances BCR ligation-induced signaling but reduces tonic signaling in Cmah-/- mouse B cells deficient in Neu5Gc as well as wild-type B cells. Moreover, Cmah-/- B cells do not show alterations in the phenotypes correlated to tonic signaling. These results indicate that low-affinity interaction of the CD22 cis-ligands with CD22 is sufficient for the regulation of B cell signaling, and suggest that expression of high-affinity CD22 ligands might be involved in the regulation of B cells by competing for the binding of CD22 with exogenous trans-ligands of CD22.

Effect of abamectin on osmoregulation in red swamp crayfish (Procambarus clarkii).

As a widely used pesticide, abamectin could be a threat to nontarget organisms. In this study, the toxic mechanism of abamectin on osmoregulation in Procambarus clarkii was explored for the first time. The results of this study showed that with increasing abamectin concentration, the membrane structures of gill filaments were damaged, with changes in ATPase activities, transporter contents, biogenic amine contents, and gene expression levels. The results of this study indicated that at 0.2 mg/L abamectin, ion diffusion could maintain osmoregulation. At 0.4 mg/L abamectin, passive transport was inhibited due to damage to the membrane structures of gill filaments, and active transport needed to be enhanced for osmoregulation. At 0.6 mg/L abamectin, the membrane structures of gill filaments were seriously damaged, and the expression level of osmoregulation-related genes decreased, but the organisms were still mobilizing various transporters, ATPases, and biogenic amines to address abamectin stress. This study provided a theoretical basis for further study of the effects of contaminations in aquatic environment on the health of crustaceans.

Ultra-broadband multi-tone frequency measurement based on the recirculating frequency shift of a frequency modulated continuous wave.

We proposed an ultra-broadband multi-tone frequency measurement (FM) approach based on frequency modulated continuous wave (FMCW). This work aims to achieve wide-range multi-tone FM without image interference, using electrical components with narrow bandwidth and low sampling rate, while maintaining high FM accuracy. The FM range is largely increased by extending the bandwidth of the optical FMCW through a recirculating frequency shift (RFS) loop, from 0.001 GHz-16 GHz to 0.001 GHz-437.5 GHz. The bandwidth-extended optical FMCW coherently beats with a continuous wave (CW) light modulated by the signal under test (SUT) at the balanced photodetector (BPD). The following low-pass filter (LPF) outputs pulses at the time when the frequencies of FMCW and SUT are equal, constructing frequency-to-time mapping (FTTM). Owing to the zero-intermediate-frequency (zero-IF) architecture, image interference is avoided. In addition, the up- and down-chirps of FMCW are used to achieve self-reference, avoiding the utilizing of reference signals, which realizes high FM accuracy. In the experiment, a FM within 0.1 GHz-43.5 GHz is demonstrated using an available microwave generator (MG) with a maximum output frequency of 43.5 GHz. The FM errors are kept within ±10 MHz for all frequencies with a mean and standard deviation of -0.3 MHz and 3.17 MHz, respectively. The multi-tone resolution is about 60 MHz at the FMCW chirp rate of 3.1998 G H z/µ s, which is consistent with the theoretical result. According to the theoretical derivation, the multi-tone resolution can be improved to 1 MHz by lowering the FMCW chirp rate.

CD72 is an inhibitory pattern recognition receptor that recognizes ribosomes and suppresses production of anti-ribosome autoantibody.

B cell responses to nucleic acid-containing self-antigens that involve intracellular nucleic acid sensors play a crucial role in autoantibody production in SLE. CD72 is an inhibitory B cell co-receptor that down-regulates BCR signaling, and prevents the development of SLE. We previously showed that CD72 recognizes the RNA-containing self-antigen Sm/RNP, a target of SLE-specific autoantibodies, and induces B cell tolerance to Sm/RNP by specifically inhibiting B cell response to this self-antigen. Here, we address whether CD72 inhibits B cell response to ribosomes because the ribosome is an RNA-containing self-antigen and is a target of SLE-specific autoantibodies as well as Sm/RNP. We demonstrate that CD72 recognizes ribosomes as a ligand, and specifically inhibits BCR signaling induced by ribosomes. Although conventional protein antigens by themselves do not induce proliferation of specific B cells, ribosomes induce proliferation of B cells reactive to ribosomes in a manner dependent on RNA. This proliferative response is down-regulated by CD72. These results suggest that ribosomes activate B cells by inducing dual signaling through BCR and intracellular RNA sensors and that CD72 inhibits B cell response to ribosomes. Moreover, CD72-/- but not CD72+/+ mice spontaneously produce anti-ribosome autoantibodies. Taken together, CD72 induces B cell self-tolerance to ribosomes by recognizing ribosomes and inhibiting RNA-dependent B cell response to this self-antigen. CD72 appears to prevent development of SLE by inhibiting autoimmune B cell responses to multiple RNA-containing self-antigens. Because these self-antigens but not protein self-antigens induce RNA-dependent B cell activation, self-tolerance to RNA-containing self-antigens may require a distinct tolerance mechanism mediated by CD72.

Matrix metalloproteinase-8 regulates dendritic cell tolerance in late polymicrobial sepsis via the nuclear factor kappa-B p65/ß-catenin pathway.

Background: Tolerogenic dendritic cells (DCs) are associated with poor prognosis of sepsis. Matrix metalloproteinases (MMPs) have been shown to have immunomodulatory effects. However, whether MMPs are involved in the functional reprogramming of DCs is unknown. The study aims to investigate the role of MMPs in sepsis-induced DCs tolerance and the potential mechanisms. Methods: A murine model of late sepsis was induced by cecal ligation and puncture (CLP). The expression levels of members of the MMP family were detected in sepsis-induced tolerogenic DCs by using microarray assessment. The potential roles and mechanisms underlying MMP8 in the differentiation, maturation and functional reprogramming of DCs during late sepsis were assessed both in vitro and in vivo. Results: DCs from late septic mice expressed higher levels of MMP8, MMP9, MMP14, MMP19, MMP25 and MMP27, and MMP8 levels were the highest. MMP8 deficiency significantly alleviated sepsis-induced immune tolerance of DCs both in vivo and in vitro. Adoptive transfer of MMP8 knockdown post-septic bone marrow-derived DCs protected mice against sepsis-associated lethality and organ dysfunction, inhibited regulatory T-cell expansion and enhanced Th1 response. Furthermore, the effect of MMP8 on DC tolerance was found to be associated with the nuclear factor kappa-B p65/ß-catenin pathway. Conclusions: Increased MMP8 levels in septic DCs might serve as a negative feedback loop, thereby suppressing the proinflammatory response and inducing DC tolerance.

Risk model for predicting mortality in patients with necrotizing soft tissue infections in the intensive care unit.

BACKGROUND: The goal of this study is to look into the factors that lead to death in patients with necrotizing soft tissue infections（NSTIs） in the intensive care unit and create a mortality risk model. METHODS: The clinical data of 106 patients with necrotizing soft tissue infections admitted to intensive care unit(ICU) of the First Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2021 were retrospectively analyzed. Univariate analysis and multivariate analysis were performed to evaluate the risk factors impacting patient mortality. The regression coefficient in binary logistic regression analysis was converted into the item score in the model, and then the model score of each patient was calculated. Finally, an ROC curve was constructed to evaluate the efficiency of the model for predicting mortality. Thirteen patients with NSTIs admitted to ICU between January 2022 and November 2022 were used to validate the model. RESULTS: The death group had 44 patients, while the survival group had 62 patients. The overall mortality was 41.5%. Binary logistic regression analysis showed that risk factors for mortality were age≥ 60 years(OR:4.419; 95%CI:1.093-17.862; P = 0.037), creatinine ≥ 132µmol/L(OR:11.166; 95%CI:2.234-55.816; P = 0.003), creatine kinase ≥ 1104 U/L(OR:4.019; 95%CI:1.134-14.250; P = 0.031), prothrombin time ≥ 24.4 s(OR:11.589; 95%CI:2.510-53.506; P = 0.002), and invasive mechanical ventilation (OR:17.404; 95%CI:4.586-66.052; P＜0.000). The AUC of the model for predicting mortality was 0.940 (95% CI:0.894-0.986). When the cut-off value for the model was 4 points, the sensitivity was 95.5% and the specificity was 83.9%. CONCLUSION: The death risk model in this study for NSTIs patients in the intensive care unit shows high sensitivity and specificity. Patients with a score of ≥ 4 points have a higher risk of mortality.

Extended endoscopic endonasal approach to the chiasmatic cistern: An anatomical study of the arachnoid.

This paper studied the arachnoid of the chiasmatic cistern (CC) and the methods for increasing the exposure of the CC from an endoscopic perspective. Eight anatomical specimens with vascular injection were used for endoscopic endonasal dissection. The anatomical characteristics of the CC were studied and documented, and anatomical measurements were collected. The CC is an unpaired five-walled arachnoid cistern located between the optic nerve, optic chiasm, and the diaphragma sellae. The average exposed area of the CC before the anterior intercavernous sinus (AICS) was transected was 66.67 ± 33.76 mm2 . After the AICS was transected and the pituitary gland (PG) was mobilized, the average exposed area of the CC was 95.90 ± 45.48 mm2 . The CC has five walls and a complex neurovascular structure. It is located in a critical anatomical position. The transection of the AICS and mobilization of the PG or the selective sacrifice of the descending branch of the superior hypophyseal artery can improve the operative field.

Correlation between the Expression of Serum Elabela,LRG1 Levels and Disease Activity Index in Patients with Ulcerative Colitis / 现代检验医学杂志

Objective To investigate the expression of serum Elabela and leucine-rich-alpha-2-glycoprotein-1(LRG1)in ulcerative colitis(UC)patients and their correlation with disease activity index(DAI).Methods A total of 98 patients with UC admitted to Yuncheng Central Hospital from January to December 2022 were selected as the UC group,including 62 patients in active stage and 36 patients in remission stage.According to the severity of the disease,these patients were divided into mild group(n=26),moderate group(n=43)and severe group(n=29).In addition,these patients were grouped into gradeⅠ group(n=25),grade Ⅱ group(n=40)and grade Ⅲ group(n=33)based on the endoscopic activity index(EAI).According to the mucosal healing condition under endoscopy,these patients were divided into the healed group(n=65)and the unhealed group(n=33).Another 51 patients with colonic polyps were selected as control group 1,and 50 healthy individuals were selected as control group 2.Serum Elabela and LRG1 levels were detected by enzyme-linked immunosorbent assay(ELISA).Pearson method was used to analyze the correlation between serum Elabela,LRG1 levels and DAI in UC patients.Receiver operating characteristic(ROC)curve was applied to analyze the predictive value of serum Elabela and LRG1 for endoscopic mucosal healing.Results The levels of Elabela(4.77±1.36 ng/ml)and LRG1(352.12±39.45 ng/ml)in UC group were higher than those in control group 1(2.51±0.53 ng/ml,121.02±21.06 ng/ml)and control group 2(2.35±0.42 ng/ml,120.35±23.49 ng/ml),and the differences were statistically significant(t= 11.410～39.000,all P＜0.05).The levels of Elabela(5.26±0.54 ng/ml)and LRG1(370.42±12.49 ng/ml)in the active group were higher than those in the remission group(3.93±0.42 ng/ml,320.60±8.47 ng/ml),and the differences were statistically significant(t=12.705,21.242,all P＜0.05).The levels of Elabela(5.89±0.20 ng/ml)and LRG1(369.92±16.59 ng/ml)in the severe group were higher than those in the moderate groups(4.51±0.67 ng/ml,356.12±18.75 ng/ml)and mild groups(3.95±0.21 ng/ml,325.65±10.14 ng/ml),and the differences were statistically significant(t=3.205～35.077,all P＜0.05).The levels of Elabela(5.80±0.18 ng/ml)and LRG1(369.16±13.47 ng/ml)in grade Ⅲ group were higher than those in grade Ⅱ group(4.49±0.35 ng/ml,355.46±16.34 ng/ml)and grade Ⅰgroup(3.86±0.16 ng/ml,324.15±8.71 ng/ml),and the differences were statistically significant(t= 3.854～48.725,all P＜0.05).The levels of Elabela(5.12±0.42 ng/ml)and LRG1(367.12±14.27 ng/ml)in unhealed group were higher than those in healed group(4.08±0.37 ng/ml,322.57±10.35 ng/ml),and the differences were statistically significant(t=12.043,15.917,all P＜0.05).The serum levels of Elabela and LRG1 in UC patients were positively correlated with EAI and ESR(r=0.602,0.298;0.576,0.302,all P＜0.05),but negatively correlated with hemoglobin level(r=-0.351,-0.334,all P＜0.05).The area under the curve predicted by the combination of serum Elabela and LRG1 for endoscopic mucosal healing was 0.926(95%CI:0.880～0.958),was higher than the 0.803(95%CI:0.741～0.856)and 0.783(95%CI:0.720～0.838)predicted by Elabela and LRG1 alone,and the difference was statistically significant(Z=4.101,4.228,all P＜0.05).Conclusion The serum levels of Elabela and LRG1 in UC patients increased,and they were related to the increase of DAI and worsening of the condition.Testing serum Elabela and LRG1 can provide a reference for evaluating mucosal healing under UC endoscopy.

Effect of Yam gruel on postoperative healing in patients with Type Ⅱ diabetes complicated with colorectal cancer / 现代临床护理

Objective To investigate the effect of Yam gruel on postoperative incision healing in patients with Type Ⅱ diabetes and complicated with colorectal cancer,hence to provide a better diet plan for postoperative incision healing.Methods A convenience sampling method was used to select 92 patients with Type Ⅱ diabetes who were complicated with colorectal cancer and underwent surgery of laparoscopic radical resection for colorectal cancer in a general hospital in Fujian province.IBM SPSS 25.0 software was used to randomly divide the patients into control group and trial group,with 46 patients per group.Conventional postoperative treatment and care was offered to the patients in control group,while patients in the trial group,after anal exhaust,consumed Yam gruel made from Chinese Yam along with the remaining breakfast after deducting an 84 kcal of energy produced by the gruel for 3 weeks.The two groups were compared in terms of the post-intervention healing time,healing grade,incidence of poor incision healing,and changes in blood glucose before intervention,at 1 week and 3 weeks post-intervention.Results Forty-four patients completed the trial in the trial group,with two left at the third week of intervention.A total of 45 patients completed the study in the control group,with one dropped out of the follow-up after 3 weeks of intervention.After intervention,the incision healing time in the trial group was significantly shorter than that of the control group(P<0.05).Additionally,the healing grade was better(P<0.05),and the incidence of incision infections was significantly lower than that of the control group(P<0.05).Repeated measures ANOVA revealed that there were statistically significances in both groups in either main effects on fasting blood glucose and blood glucose at 2 hours after breakfast(all P<0.001).Particularly,at Week 1 and Week 3 post-intervention,the trial group showed both lower fasting blood glucose and blood glucose at 2 hours after breakfast compared with those in the control group(both P<0.01).Conclusion Yam gruel can reduce the time for incision healing,improve the quality of incision healing and regulate blood sugar.

The Association between Educational Attainment and the Risk of Nonalcoholic Fatty Liver Disease among Chinese Adults: Findings from the REACTION Study

Background/Aims@#Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. @*Methods@#A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. @*Results@#Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. @*Conclusions@#In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Effects of MUC13 on the prognosis and biological behavior of gastric cancer / 中国现代普通外科进展

Objective:To explore the prognostic value of MUC13 expression in gastric cancer(GC)patients and its impact on the biological behavior of GC cells.Methods:Comprehensive anal-ysis of the expression pattern of MUC genes in GC tissues based on the TCGA database to screen for differentially expressed genes.Spearman correlation analysis determined the correlation of ex-pression between MUC genes in GC tissues.Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway(KEGG)enrichment analysis were used to explore the potential biological functions of MUC genes.Univariate COX regression analysis was performed to explore the relationship between all differentially expressed MUC genes and the prog-nosis of GC patients to screen out MUC genes that were significantly related to the prognosis of GC.Clinical GC tissue samples were used to further verify the expression of MUC13 through im-munofluorescence,and its relationship with the clinicopathological characteristics and prognosis of GC was analyzed.siRNA was used to silence the expression of MUC13 in GC cells,and the effect of MUC13 on cell proliferation,migration and invasion was analyzed through CCK-8,colony forma-tion and Transwell experiments.Results:Among all MUC members,the expression levels of MUC1,MUC2,MUC3A,MUC4,MCU5B,MUC12,and MUC13 were significantly upregulated in GC tissues(P＜0.05).There are certain interactions between these MUC genes,and they are mainly en-riched in pathways related to digestive system processes,epithelial structure maintenance,apical plasma membrane,saliva secretion,etc.Importantly,upregulation of MUC13 in GC tissues indicates poor patient prognosis(Log-rank P＜0.05).In addition,MUC13 expression was significantly correlat-ed with the age(P＜0.001)of GC patients and tumor size(P=0.035).Further cell function experiments showed that after silencing MUC13,the proliferation ability of GC cells was significantly reduced(P＜0.05),while their migration and invasion abilities were not significantly affected(P＞0.05).Con-clusions:Highly expressed MUC13 is closely related to the poor prognosis of gastric cancer,par-ticipates in the regulation of tumor progression and is a potential therapeutic target and prognostic marker for gastric cancer.

Based on the interaction between supramolecules of traditional Chinese medicine and enterobacteria to explore the material basis of combination of Rhei Radix et Rhizoma - Coptidis Rhizoma / 药学学报

Based on the interaction between supramolecule of traditional Chinese medicine and enterobacteria, the material basis of Rhei Radix et Rhizoma and Coptidis Rhizoma was explored. Scanning electron microscopy (SEM) and dynamic light scattering (DLS) were used to characterize the morphological differences of Rhubarb single decoction, Coptis single decoction and Rhubarb and Coptis co-decoction. An in vitro antibacterial model (E. coli, E. faecium and B. subtilis) was established to evaluate the damage effect of the combination of Rhei Radix et Rhizoma and Coptidis Rhizoma on enterobacteria. Ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the changes of chemical components of single decoctions and co-decoctions. The co-decoction of Rhei Radix et Rhizoma and Coptidis Rhizoma was turbid after decocting. The spherical particles of 300-400 nm were observed under SEM, and the co-decoction was more uniform and stable than that of single decoction. The interaction between supramolecules formed after the combination of Rhei Radix et Rhizoma and Coptidis Rhizoma and enterobacteria was significantly different from that of single decoction. In the process of interaction between supramolecules and enterobacteria, the spherical state was maintained, and the medicinal ingredients in Coptidis Rhizoma or Rhei Radix et Rhizoma were blocked, which could effectively alleviate the damage to enterobacteria. This study provided a reference for subsequent studies on the regulation of intestinal flora homeostasis by the combination of Rhei Radix et Rhizoma and Coptidis Rhizoma.

Photonic-assisted fast broadband microwave vector network analyzer based on FMCW.

In the paper, we propose a photonic-assisted fast broadband microwave vector network analyzer (FB-VNA) based on frequency modulated continuous wave (FMCW). A photonic recirculating frequency shift (RFS) loop is used to extend the bandwidth of optical FMCW. The bandwidth-extended optical FMCW beats with the continuous wave (CW) light to generate the broadband electrical FMCW, which serves as the incident signal of the device under test (DUT). The response signals of the DUT are modulated on the bandwidth-extended optical FMCW to perform de-chirping. After coherently beating the de-chirped light with the CW light, the broadband response signals of DUT are down-converted to a single-tone intermediate frequency (IF) signal carrying the frequency response of DUT, and the scattering parameters of DUT can be obtained. The single-tone IF signal relaxes the demand on the bandwidth and sampling rate of the electrical backend. Thanks to the RFS loop and the short period of FMCW, the measurement frequency range is highly extended and measurement speed is greatly accelerated at the same time, which can be applied in monitoring sudden changes of DUT features. A bandwidth multiplication of the FMCW from 6-18 GHz to 6-498 GHz is experimentally implemented. With available photodetectors (PDs) and Mach-Zehnder modulators (MZMs), a 6-54 GHz FB-VNA is demonstrated, and the S parameters of a 25-GHz low-pass filter (LPF) is measured within 6 µs. The sudden changes of S21 parameter of DUT simulated by fast adjusting the bias voltage of the MZM used for de-chirping are also characterized by the proposed FB-VNA. The sudden changes as short as 0.01 µs can be captured.

Efficacy and safety of transarterial chemoembolization combined with lenvatinib, programmed death-1 inhibitor, and iodine-125 seed brachytherapy for hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND: Therapy for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) is still controversial. This study was performed to evaluate the efficacy and safety of the combination therapy comprising transarterial chemoembolization (TACE), lenvatinib (L), programmed death-1 inhibitor (P), and iodine-125 seed (I125) brachytherapy relative to TACE in combination with lenvatinib plus programmed death-1 inhibitor therapy and TACE plus lenvatinib therapy. METHODS: The data of HCC patients with PVTT from July 2017 to August 2022 were assessed in this single-center retrospective study. Primary study outcomes were progression-free survival (PFS) and overall survival (OS), while the secondary outcomes were disease control rate (DCR), objective response rate (ORR), and treatment-related adverse events. RESULTS: We enrolled 150 patients totally, including 50 patients treated with TACE plus lenvatinib therapy (TACE+L group), 45 patients treated with TACE in combination with lenvatinib plus programmed death-1 inhibitor therapy (TACE+L+P group), and 55 patients treated with the combination therapy of TACE along with I125 brachytherapy, lenvatinib, and programmed death-1 inhibitor therapy (TACE+L+P+I125 group). The median OS in the TACE+L+P+I125 group (21.0; 95% confidence interval [CI]: 18.4∼23.5 months) was significantly longer than that in the TACE+L group (10; 95% CI: 7.8∼12.1months) (p = 0.006), while it was insignificantly longer than that in the TACE+L+P group (14.0; 95% CI: 10.7∼17.2months) (p = 0.058). The median PFS in the TACE+L+P+I125 group (13.0; 95% CI: 10.2∼15.7 months) was significantly longer than that in the TACE+L group (5.0; 95% CI: 4.2∼5.7 months) (p = 0.014) and the TACE+L+P group (9.0; 95% CI: 6.7∼11.2 months) (p = 0.048). Statistically significant differences between groups were found in DCR (p = 0.015). There were no significant between-group differences in treatment-related adverse events (p > 0.05). CONCLUSIONS: A combination therapy of TACE, lenvatinib, programmed death-1 inhibitor, and I125 seed brachytherapy significantly improve OS, PFS, and DCR and show better survival prognosis for HCC patients accompanied by PVTT.

SUPPLEMENTATION WITH NICOTINAMIDE RIBOSIDE ATTENUATES T CELL EXHAUSTION AND IMPROVES SURVIVAL IN SEPSIS.

ABSTRACT: T cell exhaustion is the main cause of sepsis-induced immunosuppression and is associated with the poor prognosis. Nicotinamide adenine dinucleotide (NAD + ) is well known for its anti-aging effect, but its role in sepsis-induced T cell exhaustion remains to be elucidated. In the present study, using a classic septic animal model, we found that the levels of NAD + and its downstream molecule, which is sirtuins 1 (SIRT1), in T cells in sepsis were decreased. Supplementation with nicotinamide ribose (NR), the precursor of NAD + , right after cecal ligation and puncture significantly increased the levels of NAD + and SIRT1. Supplementation with NR alleviated the depletion of mononuclear cells and T lymphocytes in spleen in sepsis and increased the levels of CD3 + CD4 + and CD3 + CD8 + T cells. Interestingly, both Th1 and Th2 cells were expanded after NR treatment, but the balance of Th1/Th2 was partly restored. Nicotinamide ribose also inhibited the regulatory T cells expansion and programmed cell death 1 expression in CD4 + T cells in sepsis. In addition, the bacteria load, organ damage (lung, heart, liver, and kidney), and the mortality of septic mice were reduced after NR supplementation. In summary, these results demonstrate the beneficial effect of NR on sepsis and T cell exhaustion, which is associated with NAD + /SIRT1 pathway.

Mutual promotion of mitochondrial fission and oxidative stress contributes to mitochondrial-DNA-mediated inflammation and epithelial-mesenchymal transition in paraquat-induced pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is one of the main causes of death in patients with paraquat (PQ) poisoning. This study aimed to evaluate the relationship between mitochondrial fission and oxidative stress in PQ-induced epithelial-mesenchymal transition (EMT) and PF. METHODS: C57BL/6 mice and MLE-12 cells were exposed to PQ to construct a PF model in vivo and in vitro. Histological changes in the lungs were examined by hematoxylin and eosin (H&E) staining. Mitochondrial morphology was detected by MitoTracker® Deep Red FM or transmission electron microscopy (TEM). Western blotting and immunofluorescence were used to determine the expression of protein. The migration ability of the cells was detected by the cell scratch test. Mitochondrial DNA (mtDNA) levels were assessed by real-time polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was applied to detect cytokine levels. Superoxide dismutase (SOD) activity and the levels of glutathione (GSH) and malondialdehyde (MDA) were detected by chemichromatometry. RESULTS: PQ exposure caused EMT and PF in vivo and in vitro. PQ destroyed mitochondrial structure and enhanced the expression of dynamin-related protein 1 (Drp1), which were accompanied by oxidative stress. Inhibiting mitochondrial fission using mitochondrial division inhibitor-1 (Mdivi-1), a selective inhibitor of Drp1, attenuated PQ-induced EMT and oxidative damage. Treatment with N-acetyl-L-cysteine (NAC), an antioxidant, reduced Drp1 expression, attenuated mitochondrial structure damage and inhibited PQ-induced EMT and PF. Both Mdivi-1 and NAC treatment markedly suppressed mtDNA release, the expression of Toll-like receptor 9 (TLR9) and phosphorylation (P)-NF-κB p65 as well as cytokines (interleukin 6 [IL-6], interleukin-1ß [IL-1ß], and tumor necrosis factor-α [TNF-α]) production. CONCLUSION: Mutual promotion of mitochondrial fission and oxidative stress contributes to EMT in PQ-induced PF, which is associated with the mtDNA/TLR9/NF-κB pathway.

Efficacy and safety of hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitors plus programmed death-1 inhibitors for hepatocellular carcinoma refractory to transarterial chemoembolization.

Background: The subsequent therapy for hepatocellular carcinoma (HCC) patients with refractory to transarterial chemoembolization (TACE) is still controversial. This study was performed to evaluate the efficacy and safety of combination therapy comprising hepatic artery infusion chemotherapy (HAIC), lenvatinib, and programmed death-1 inhibitors relative to HAIC combined with lenvatinib. Methods: In this single-center retrospective study, we analyzed data from HCC patients with refractory to TACE from June 2017 to July 2022. Primary study outcomes were overall survival (OS) and progression-free survival (PFS), while the secondary outcomes were the objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events. Results: We enrolled 149 patients finally, including 75 patients who received HAIC combined with lenvatinib plus PD-1 inhibitors therapy (HAIC+L+P group) and 74 patients who received HAIC combined with lenvatinib therapy (HAIC+L group). The median OS in the HAIC+L+P group (16.0; 95% CI: 13.6~18.3 months) was significantly higher compared to the HAIC+L group (9.0; 95% CI: 6.5~11.4 months) (p = 0.002), while the median PFS in the HAIC+L+P group (11.0; 95% CI: 8.6~13.3 months) was significantly higher compared to the HAIC+L group (6.0; 95% CI: 5.0~6.9 months) (p < 0.001). Significant between-group differences in DCR (p = 0.027) were found. Additionally, 48 pairs of patients were matched after propensity matching analysis. The survival prognosis between two groups before propensity matching is similar to that after propensity matching. Moreover, the percentage of patients with hypertension in the HAIC+L+P group was significantly higher compared to the HAIC+L group (28.00% vs. 13.51%; p = 0.029). Conclusions: A combination therapy of HAIC, lenvatinib, and programmed death-1 inhibitors significantly improved oncologic response and prolonged survival duration, showing a better survival prognosis for HCC patients with refractory toTACE.

Effects of propofol on glutamatergic neuronal activity in paraventricular thalamus / 药学学报

This study explored the effects of propofol on the activity of glutamatergic neurons in the paraventricular thalamus (PVT) and the underlying mechanisms at the molecular level using whole-cell patch-clamp techniques. Acute brain slices containing the PVT were obtained from 8 weeks old C57BL/6J mice. The electrophysiological characteristics of PVT neurons were recorded in current-clamp mode, then single-cell sequencing was used to identify neuronal types. The firing frequencies before, during, and after propofol or intralipid application were recorded as FB, FD and FW; and the membrane potentials were recorded as MPB and MPD. Picrotoxin (PTX) was used to block inhibitory gamma-aminobutyric acid type A (GABAA) receptors during the application of propofol at 10 μmol·L-1. Then, GABAA receptor-mediated spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) were recorded, and the effects of 10 μmol·L-1 propofol were investigated. The animal experiments were approved by the Medical Animal Administrative Committee of Shanghai Medical College Fudan University. The results showed that there were no significant differences in FB, FD and FW during intralipid and 2 μmol·L-1 propofol application. With propofol at 5, 10 and 20 μmol·L-1, FD decreased significantly when compared with FB, and FW increased significantly as compared with FD (P < 0.01). The inhibition degree of the three concentration groups was significantly different (P < 0.01). In addition, with propofol at 20 μmol·L-1, MPD hyperpolarized significantly (P < 0.01). In the presence of PTX, 10 μmol·L-1 propofol could not suppress the firing frequency of PVT glutamatergic neurons. Propofol at 10 μmol·L-1 prolonged the decay time of sIPSCs (P < 0.01) and mIPSCs (P < 0.05), and increased the amplitude (P < 0.01) of mIPSCs of PVT glutamatergic neurons. Together, these results indicate that propofol can inhibit the activity of PVT glutamatergic neurons in a concentration-dependent and reversible manner, and the effect is likely to be mediated by postsynaptic GABAA receptors.

Genotyping Characteristics of Human Fecal Escherichia coli and Their Association with Multidrug Resistance in Miyun District, Beijing / 生物医学与环境科学（英文）

OBJECTIVE@#To explore the genotyping characteristics of human fecal Escherichia coli( E. coli) and the relationships between antibiotic resistance genes (ARGs) and multidrug resistance (MDR) of E. coli in Miyun District, Beijing, an area with high incidence of infectious diarrheal cases but no related data.@*METHODS@#Over a period of 3 years, 94 E. coli strains were isolated from fecal samples collected from Miyun District Hospital, a surveillance hospital of the National Pathogen Identification Network. The antibiotic susceptibility of the isolates was determined by the broth microdilution method. ARGs, multilocus sequence typing (MLST), and polymorphism trees were analyzed using whole-genome sequencing data (WGS).@*RESULTS@#This study revealed that 68.09% of the isolates had MDR, prevalent and distributed in different clades, with a relatively high rate and low pathogenicity. There was no difference in MDR between the diarrheal (49/70) and healthy groups (15/24).@*CONCLUSION@#We developed a random forest (RF) prediction model of TEM.1 + baeR + mphA + mphB + QnrS1 + AAC.3-IId to identify MDR status, highlighting its potential for early resistance identification. The causes of MDR are likely mobile units transmitting the ARGs. In the future, we will continue to strengthen the monitoring of ARGs and MDR, and increase the number of strains to further verify the accuracy of the MDR markers.