Objective:This study aimed to evaluate the feasibility and safety of surgical intervention for patients with stage Ⅳ esophageal cancer who demonstrated tumor regression following first-line treatment.Methods:This was a descriptive case series. The inclusion criteria for surgery were as follows: (1) an initial diagnosis of stage Ⅳ esophageal cancer, i.e. cT4b or cM1; (2) the presence of residual tumor following first-line therapy deemed potentially resectable upon reassessment; and (3) sufficient organ function to tolerate surgical procedures. Clinical data were retrospectively collected for 63 patients with stage Ⅳ esophageal cancer who underwent surgery following first-line therapy at Sun Yat-sen University Cancer Center between January 2014 and December 2023. Of these patients, 12 were initially staged as IVA, and 51 as IVB. Post-treatment restaging revealed that 9 patients achieved a clinical complete response, while 3 were downstaged to stage Ⅰ, 14 to stage Ⅱ, 24 to stage Ⅲ, and 13 to stage ⅣB (with regression of distant metastatic lesions enabling curative resection). Surgical approaches included right thoracic esophagectomy ( n=55), left thoracic esophagectomy ( n=4), and transmediastinal esophagectomy ( n=4). Additionally, 7 patients required extended organ resection. Two-field lymph node dissection was performed in 49 patients, while 14 underwent three-field lymph node dissection. Postoperative management varied: 31 patients received no adjuvant therapy, 11 underwent immunochemotherapy, 8 received immunotherapy alone, 8 underwent chemotherapy, 4 received chemoradiotherapy, and 1 received combined radiotherapy and immunotherapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS), with secondary endpoints including surgical outcomes and postoperative complications. Results:All 63 patients successfully underwent surgery without intraoperative mortality. R0 resection was achieved in 58 cases (92.1%), while R1 and R2 resections were performed in 1 case (1.6%) and 4 cases (6.3%), respectively. The mean operative time was 357±135 minutes. Postoperative complications were observed in 27 cases (42.9%), with 9 cases (14.3%) classified as Clavien-Dindo grade Ⅲ or Ⅴ. One patient (1.6%) died perioperatively. The median follow-up duration was 21 months (range: 4–107 months). The median OS was 64.8 months (95% CI: 50.9–78.6 months), and the median PFS was 68.0 months (95% CI: 53.9–82.3 months). Among 24 patients with supraclavicular lymph node metastases, 6 experienced recurrence and 8 died. Of 25 patients with abdominal metastases, 3 had recurrence and subsequently died. All 4 patients with lung metastases and both patients with bone metastases experienced recurrence and death.Conclusions:Surgical intervention is a feasible and safe treatment option for selected patients with stage Ⅳ esophageal cancer who demonstrate the potential for curative resection following first-line therapy.

Objective To develop and evaluate a diagnostic model for autoimmune liver disease(AILD)using clinical indicators.Methods A total of 181 AILD patients(AILD group)diagnosed in the Department of Gastroenterology or Rheumatology and Immunology,the First Medical Center of Chinese PLA General Hospital,from June 2019 to February 2024,133 patients with hepatitis B virus cirrhosis(HBVC)(HBVC group),and 100 healthy individuals(HC group)were included in the study cohort for retrospective analysis.Clinical data,blood routine tests,and biochemical indicators were compared among the groups.Propensity score matching was used to balance the effects of factors such as gender and age.Multivariate logistic regression analysis was applied to identify characteristic indicators for AILD.Receiver operating characteristic(ROC)curves were used to evaluate the diagnostic efficacy of single and combined indicators,and the optimal diagnostic model for AILD was constructed.The Hosmer-Lemeshow test was performed to assess the model's goodness-of-fit,while ROC analysis was employed to evaluate the predictive validity.Additionally,an independent validation cohort,including 91 AILD patients(AILD validation group),82 HBVC patients(HBVC validation group),and 40 healthy individuals(HC validation group)who visited during the same period,was used to validate the diagnostic model.False-positive and false-negative rates were calculated to assess the diagnostic efficacy and clinical utility of the model.Results The age and the proportion of male patients in AILD and HBVC groups were higher than those in HC group,and the proportion of male patients in AILD group was higher than in HBVC group,the differences were statistically significant(P＜0.05).Prior to matching,compared with HC group,HBVC group and AILD group had significantly lower levels of hemoglobin(HB),red blood cell count(RBC),white blood cell count(WBC),platelet count(PLT),and albumin(ALB)(P＜0.05),but significantly higher levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),gamma-glutamyl transferase(GGT),total bilirubin(TBIL),and direct bilirubin(DBIL)(P＜0.05).Compared with HBVC group,AILD group had significantly higher levels of WBC,PLT,ALB,ALP,and GGT(P＜0.05 or P＜0.001)but significantly lower levels of TBIL and DBIL(P＜0.001).After maching,compared with HC group,AILD group still had significantly lower levels of HB,RBC,WBC,PLT,and ALB,but significantly higher levels of ALT,AST,ALP,GGT,TBIL,and DBIL(P＜0.05).Compared with HBVC group,AILD group had significantly higher levels of HB,RBC,WBC,PLT,ALB,ALT,ALP,and GGT,but significantly lower levels of DBIL(P＜0.05).ROC analysis results showed that AST,GGT,ALP,and DBIL had high predictive values for differentiating AILD from HC(AUC=0.843,0.804,0.802,0.773),while PLT,WBC,GGT,and ALP had high predictive values for differentiating AILD from HBVC(AUC=0.780,0.739,0.729,0.702).For distinguishing AILD from HC,the combined model of AST,ALP,and DBIL(Model e)had an AUC of 0.887,with a sensitivity of 82.2％,and a specificity of 94.7％.For distinguishing AILD from HBVC,the combined model of ALP,GGT,and PLT(Model D)had an AUC of 0.829,with a sensitivity of 78.5％and a specificity of 80.6％.Conclusions The combined diagnostic model based on AST,ALP,and DBIL can effectively differentiate healthy individuals without liver diseases from AILD patients,while the combined diagnostic model based on PLT,ALP,and GGT can effectively distinguish HBVC from AILD patients.

Objective To investigate the mechanisms by which paeoniflorin improves tissue and cell damage caused by diabetic retinopathy(DR)through the hypoxia-induced factor-1α(HIF-1α)pathway.Methods Thirty rats were ran-domly divided into a control group(10 normal rats),a DR group(10 diabetic model rats)and a paeoniflorin group(10 dia-betic model rats given 80 mg·kg-1 paeoniflorin by gavage).Rat retinal microvascular endothelial cells(rRMECs)were di-vided into a control group(cultured with 5 mmol·L-1 glucose),a high glucose group(cultured with 30 mmol·L-1 glu-cose)and a paeoniflorin group(cultured with 30 mmol·L-1 glucose and 20 mol·L-1 paeoniflorin).The three groups of cells were all cultured for 24 h.Fasting blood glucose was measured by a glucose meter.Hematoxylin and eosin(HE)stai-ning was used to detect the retinal histopathological structure.The levels of HIF-1α and vascular endothelial growth factor(VEGF)proteins and mRNAs in retinal tissues and rRMECs were detected by Western blotting and real time quantitative polymerase chain reaction(RT-qPCR).The proliferative ability of rRMECs was detected by the EdU kit.The serum levels of total cholesterol(TC),triglyceride(TG),low density cholesterol(LDL-C),interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)in retinal tissues and rRMECs were detected by kits.The activity and invasive ability of rRMECs were measured by CCK-8 and Transwell assay,respectively.The levels of HIF-1α and VEGF proteins in rRMECs were detected by immunofluorescence staining.Results Compared with those in the DR group,the fasting blood glucose,TC,TG and LDL-C levels in the paeoniflorin group were significantly decreased(all P＜0.05).The retinal tissue was loose with an un-clear boundary in the DR group,compared with that in the control group.The retinal tissue in the paeoniflorin group was less loose with a clearer boundary than that in the DR group.The levels of HIF-1α and VEGF proteins and mRNAs,TNF-αand IL-6 in retinal tissues of the DR group were significantly higher than those of the control group(all P＜0.05).The lev-els of HIF-1α and VEGF proteins and mRNAs,TNF-α and IL-6 in retinal tissues of the paeoniflorin group were significantly lower than those in the DR group(all P＜0.05).The activity,proliferation and invasive abilities of rRMECs in the high glu-cose group were higher than those in the control group(all P＜0.05).Compared with those in the high glucose group,rRMECs in the paeoniflorin group showed decreased cell activity,proliferation and invasive abilities(all P＜0.05).The lev-els of HIF-1α and VEGF proteins and mRNAs,TNF-α and IL-6 in the rRMECs of the high glucose group were higher than those of the control group(all P＜0.05).The levels of HIF-1α and VEGF proteins and mRNAs,TNF-α and IL-6 in the rRMECs of the paeoniflorin group were lower than those of the high glucose group(all P＜0.05).Conclusion Paeoni-florin can down-regulate the HIF-1α/VEGF pathway to improve the inflammatory injury of the retinal tissue and inhibit rRMEC activity,proliferation and invasive abilities in DR rats,thereby preventing angiogenesis and reducing the incidence of DR.

Cognitive behavioral therapy(CBT)has consistently received much attention in the intervention approach of adolescent depression,with its application potential expanding alongside technological advancements.CBT primarily alleviates depressive symptoms by identifying and restructuring negative automatic thoughts,and incorporating behavioral activation strategies to improve emotional regulation and coping skills.Traditional face-to-face CBT(FtF-CBT)demonstrates significant advantages in establishing therapeutic alliances and addressing severe depressive symptoms in adolescents.In contrast,internet-based CBT(i-CBT)demonstrates comparable efficacy in adolescents with mild to moderate depression,while offering additional benefits such as lower cost and increased flexibility.Blended CBT(b-CBT),which integrates both online and offline modalities,enhances accessibility while retaining the personalized guidance and real-time feedback characteristic of in-person interventions,potentially improving overall treatment effectiveness.With the rapid development of digital health technologies,artificial intelligence,and virtual reality,future research is expected to further enhance the precision and efficiency of CBT in treating adolescent depression,providing a solid foundation for clinical application and theoretical advancement.

Objective:This study aims to establish an animal model that accurately replicates the clinical symptoms and pathologi-cal changes of late-stage human TMJOA,with the goal of providing a standardized and reliable animal experimental method for sub-sequent research on the disease.Methods:Forty-eight male New Zealand rabbits aged 4 to 6 months were randomly divided into a model group and a sham group.The animals in the model group underwent bilateral temporomandibular joint disc perforation surgery,while the animals in the sham group underwent a sham surgery.The modeling effects were assessed at 4,8,and 12 weeks post-surgery using nociceptive behavior assessments,passive mouth opening measurements,histological analysis(HE,Safranin O-fast green staining),immunohistochemistry,immunofluorescence staining,and magnetic resonance imaging(MRI).Results:Animals in the model group exhibited distinct TMJOA symptoms,including joint pain and restricted mouth opening.Histologically,typical osteo-arthritis changes were evident.The Mankin osteoarthritis score was significantly higher(P＜O.05).Conclusion:The TMJ disc perfo-ration model resmbled the same clinical manifestations and pathological changes seen in human TMJOA.

BACKGROUND:Previous studies have demonstrated that acupuncture at the governor meridian has precise efficacy in the treatment of ischemic stroke and can improve cerebral ischemia-reperfusion injury by attenuating pyroptosis,but the upstream regulatory mechanisms are not yet fully clarified.OBJECTIVE:To observe the neuroprotective effect of electroacupuncture in model rats of cerebral ischemia-reperfusion injury.METHODS:Twenty-seven Sprague-Dawley rats were randomly divided into sham surgery,model,and electroacupuncture groups,with nine rats in each group.Modified suture method was used to establish cerebral ischemia-reperfusion model rats in the model and electroacupuncture groups.The electroacupuncture group was subjected to electroacupuncture at"Baihui,""Fengfu,"and"Dazhui"acupoints,20 minutes each,once a day,for 7 consecutive days.After treatment,neurological deficit scoring and pole test were performed to assess behavioral changes.Tri-phenyl tetrazolium chloride staining was used to assess cerebral infarction size in rats.Hematoxylin-eosin staining was performed to observe morphological changes in cerebral cortex tissue on the infarcted side of rats.Immunofluorescence analysis was used to determine Iba-1 and reactive oxygen species levels in cerebral cortex tissue on the infarcted side of rats,ELISA method was used for measuring interleukin-1β,interleukin-6 and tumor necrosis factor α levels in cerebral cortex tissue on the infarcted side of rats.Real-time fluorescence quantitative PCR and western blot were used to detect mRNA and protein expression levels of thioredoxin interaction protein,nod-like receptor associated protein 3(NLRP3),Caspase-1 and interleukin-1β in cerebral cortex tissue on the infarcted side of rats respectively,and the interaction between thioredoxin interaction protein and NLRP3 was analyzed by immunoprecipitation.RESULTS AND CONCLUSION:(1)Compared with the sham surgery group,rats in the model group showed an increase in neurological deficit score,pole test score,cerebral infarction volume(P<0.05),the immunofluorescence expression of Iba-1 and reactive oxygen species(P<0.05),the levels of interleukin-1β,interleukin-6 and tumor necrosis factor α(P<0.05),and the mRNA and protein expression of thioredoxin interaction protein,NLRP3,Caspase-1 and interleukin-1β in cerebral cortex tissue(P<0.05).Hematoxylin-eosin staining in the model group showed neuronal degeneration and necrosis,with fragmented and dissolved nuclei and cellular vacuoles.(2)Compared with the model group,rats in the electroacupuncture group showed a reduction in neurological deficit score,pole climbing test score,cerebral infarction volume(P<0.05),the immunofluorescence expression of Iba-1 and reactive oxygen species(P<0.05),the levels of interleukin-1β,interleukin-6 and tumor necrosis factor α(P<0.05),and the mRNA and protein expression of thioredoxin interaction protein,NLRP3,Caspase-1 and interleukin-1β in cerebral cortex tissue(P<0.05).Hematoxylin-eosin staining showed that the pathological damage of neurons in cerebral cortex tissue on the infarcted side of rats in the electroacupuncture group was significantly attenuated,with significantly reduced cell necrosis and vacuolation.(3)Immunoprecipitation assay showed an interaction between thioredoxin interaction proteins and NLRP3 in the cerebral cortical tissues on the infarcted side of rats in the model group.To conclude,electroacupuncture has a significant therapeutic effect against cerebral ischemia-reperfusion injury,possibly by inhibiting the reactive oxygen species/thioredoxin interaction protein/NLRP3 cell pyroptosis signaling pathway and activation of microglia to reduce the release of inflammatory factors.

Aim To investigate the anti-acute lung injury(ALI)effect of Sterculiae Lychnophorae Semen(SLS)and its mechanism.Methods The main ac-tive components of SLS and their core targets and path-ways of action against ALI were obtained by network pharmacology methods.Subsequently,molecular doc-king technology and in vitro cellular experiments were applied for validation.Results A total of 19 core tar-gets were obtained,including HSP90AA1,CASP3,TNF,MAPK8 and MAPK14.The mechanisms may in-volve signaling pathways such as cancer,PI3K/Akt and MAPK.Molecular docking confirmed that the key targets of SLS formed a better binding activity with the relevant active ingredients.The in vitro results showed that SLS was able to protect the PM2.5-contaminated BEAS-2B cells,inhibit their NO,IL-1β and TNF-αlevels,and reduce the expression of p-p38 MAPK and p-JNK proteins.Conclusions The study successfully predicts the active ingredients,targets and signaling pathways of SLS against ALI,and in vitro experiments demonstrate that SLS might protect BEAS-2B cells from PM2.5 stimulus-induced inflammation and apoptosis by inhibiting the over-activation of p38 MAPK and JNK signaling pathways.

Objective:To analyze the distribution of allergen components of dust mite in children with airway allergic diseases.Methods:This was a cross-sectional study. The clinical data of children with dust mite-induced allergic asthma (AA) complicated with allergic rhinitis (AR) or allergic rhinitis who were treated in Department of Allergy,Beijing Children′s Hospital from January 2019 to October 2022 were retrospectively analyzed. The spedific IgE (sIgE) levels to Der p1,Der p2,Der p5,Der p7,Der p10,Der p21,Der p23 and Der f1,Der f2 were detected by protein chip method. The distribution of dust mite sensitized components and the sIgE levels in children with different airway allergic diseases and different ages were compared.Results:Among 138 children with airway allergic diseases,there were 97 boys and 41 girls,age (6.86±2.61) years old,and there were 106 cases of AA combined AR (AAAR group) and 32 cases of AR alone (AR group). The sensitization rates of Der p2 was the highest (75.4%,104/138),followed by Der f2 (74.6%,103/138),Der f1 (73.9%,102/138),Der p1 (71.7%,99/138),Der p21 (19.6%,27/138),Der p5 (16.7%,23/138),Der p23 (14.5%,20/138),Der p7 (11.6%,16/138) and Der p10 (2.9%,4/138). The co-sensitization rate of Der p1,Der p2,Der f1 and Der f2 was the highest (31.2%,43/138). There was no significant difference in sensitization rate of dust mites components between AAAR group and AR group(all P>0.05). AAAR group had higher levels of sIgE to Der p23 than AR group [0.1 (0,0.1) IU/ml vs. 0 (0,0.1) IU/ml,Z=-2.819, P=0.005]. There were no significant differences in the positive rate of dust mite components and sIgE levels between children aged≤6 and>6 years old with airway allergic diseases(all P>0.05). Conclusions:Der p1,Der p2,Der f1 and Der f2 are the major components of dust mites sensitizing airway allergic diseases in children. Der p1,Der p2,Der f1 and Der f2 are the main co-sensitizing components in children with dust mite-induced airway allergic diseases. Compared with AR,the sIgE level to Der p23 in children with AAAR is higher.

This study investigated the effects and underlying mechanisms of vanillic acid(VA) against cardiac fibrosis(CF) induced by isoproterenol(ISO) in mice. Male C57BL/6J mice were randomly divided into control group, VA group(100 mg·kg~(-1), ig), ISO group(10 mg·kg~(-1), sc), ISO + VA group(10 mg·kg~(-1), sc + 100 mg·kg~(-1), ig), ISO + dynamin-related protein 1(Drp1) inhibitor(Mdivi-1) group(10 mg·kg~(-1), sc + 50 mg·kg~(-1), ip), and ISO + VA + Mdivi-1 group(10 mg·kg~(-1), sc + 100 mg·kg~(-1), ig + 50 mg·kg~(-1), ip). The treatment groups received the corresponding medications once daily for 14 consecutive days. On the day after the last administration, cardiac functions were evaluated, and serum and cardiac tissue samples were collected. These samples were analyzed for serum aspartate aminotransferase(AST), lactate dehydrogenase(LDH), creatine kinase-MB(CK-MB), cardiac troponin I(cTnI), reactive oxygen species(ROS), interleukin(IL)-1β, IL-4, IL-6, IL-10, IL-18, and tumor necrosis factor-α(TNF-α) levels, as well as cardiac tissue catalase(CAT), glutathione(GSH), malondialdehyde(MDA), myeloperoxidase(MPO), superoxide dismutase(SOD), total antioxidant capacity(T-AOC) activities, and cytochrome C levels in mitochondria and cytoplasm. Hematoxylin-eosin, Masson, uranium acetate and lead citrate staining were used to observe morphological and mitochondrial ultrastructural changes in the cardiac tissues, and myocardial injury area and collagen volume fraction were calculated. Flow cytometry was applied to detect the relative content and M1/M2 polarization of cardiac macrophages. The mRNA expression levels of macrophage polarization markers [CD86, CD206, arginase 1(Arg-1), inducible nitric oxide synthase(iNOS)], CF markers [type Ⅰ collagen(Coll Ⅰ), Coll Ⅲ, α-smooth muscle actin(α-SMA)], and cytokines(IL-1β, IL-4, IL-6, IL-10, IL-18, TNF-α) in cardiac tissues were determined by quantitative real-time PCR. Western blot was used to detect the protein expression levels of Coll Ⅰ, Coll Ⅲ, α-SMA, Drp1, p-Drp1, voltage-dependent anion channel(VDAC), hexokinase 1(HK1), NOD-like receptor protein 3(NLRP3), apoptosis-associated speck-like protein(ASC), caspase-1, cleaved-caspase-1, gasdermin D(GSDMD), cleaved N-terminal gasdermin D(GSDMD-N), IL-1β, IL-18, B-cell lymphoma-2(Bcl-2), B-cell lymphoma-xl(Bcl-xl), Bcl-2-associated death promoter(Bad), Bcl-2-associated X protein(Bax), apoptotic protease activating factor-1(Apaf-1), pro-caspase-3, cleaved-caspase-3, pro-caspase-9, cleaved-caspase-9, poly(ADP-ribose) polymerase-1(PARP-1), and cleaved-PARP-1 in cardiac tissues. The results showed that VA significantly improved cardiac function in mice with CF, reduced myocardial injury area and cardiac index, and decreased serum levels of AST, CK-MB, cTnI, LDH, ROS, IL-1β, IL-6, IL-18, and TNF-α. VA also lowered MDA and MPO levels, mRNA expressions of IL-1β, IL-6, IL-18, and TNF-α, and mRNA and protein expressions of Coll Ⅰ, Coll Ⅲ, and α-SMA in cardiac tissues, and increased serum levels of IL-4 and IL-10, cardiac tissue levels of CAT, GSH, SOD, and T-AOC, and mRNA expressions of IL-4 and IL-10. Additionally, VA ameliorated cardiac pathological damage, inhibited myocardial cell apoptosis, inflammatory infiltration, and collagen fiber deposition, reduced collagen volume fraction, and alleviated mitochondrial damage. VA decreased the ratio of F4/80~+CD86~+ M1 cells and the mRNA expressions of CD86 and iNOS in cardiac tissue, and increased the ratio of F4/80~+CD206~+ M2 cells and the mRNA expressions of CD206 and Arg-1. VA also reduced protein expressions of p-Drp1, VDAC, NLRP3, ASC, caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-1β, IL-18, Bad, Bax, Apaf-1, cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP-1, and cytoplasmic cytochrome C, and increased the expressions of HK1, Bcl-2, Bcl-xl, pro-caspase-3, pro-caspase-9 proteins, as well as the Bcl-2/Bax and Bcl-xl/Bad ratios and mitochondrial cytochrome C content. These results indicate that VA has a significant ameliorative effect on ISO-induced CF in mice, alleviates ISO-induced oxidative damage and inflammatory response, and its mechanism may be closely related to the inhibition of Drp1/HK1/NLRP3 and mitochondrial apoptosis signaling pathways, suppression of myocardial cell inflammatory infiltration and collagen fiber deposition, reduction of collagen volume fraction and CollⅠ, Coll Ⅲ, and α-SMA expressions, thus mitigating CF.
Animals ; Isoproterenol/adverse effects* ; Male ; Mice ; Signal Transduction/drug effects* ; Vanillic Acid/administration & dosage* ; Dynamins/genetics* ; Mice, Inbred C57BL ; Fibrosis/genetics* ; Apoptosis/drug effects* ; Mitochondria/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Myocardium/metabolism* ; Humans

By employing the analytic hierarchy process(AHP), the CRITIC method(a weight determination method based on indicator correlations), and the AHP-CRITIC hybrid weighting method, the weight coefficients of evaluation indicators were determined, followed by a comprehensive score comparison. The grey correlation analysis was then performed to analyze the results calculated using the hybrid weighting method. Subsequently, a backpropagation-artificial neural network(BP-ANN) model was constructed to predict the extraction process parameters and optimize the extraction process for Shenxiong Huanglian Jiedu Granules(SHJG). In the extraction process, an L_9(3~4) orthogonal experiment was designed to optimize three factors at three levels, including extraction frequency, water addition amount, and extraction time. The evaluation indicators included geniposide, berberine, ginsenoside Rg_1 + Re, ginsenoside Rb_1, ferulic acid, and extract yield. Finally, the optimal extraction results obtained by the orthogonal experiment, grey correlation analysis, and BP-ANN method were compared, and validation experiments were conducted. The results showed that the optimal extraction process involved two rounds of aqueous extraction, each lasting one hour; the first extraction used ten times the amount of added water, while the second extraction used eight times the amount. In the validation experiments, the average content of each indicator component was higher than the average content obtained in the orthogonal experiment, with a higher comprehensive score. The optimized extraction process parameters were reliable and stable, making them suitable for subsequent preparation process research.
Drugs, Chinese Herbal/analysis* ; Neural Networks, Computer