OBJECTIVE To explore the ameliorative effect and potential mechanism of vitexin on inflammation in ulcerative colitis （UC） mice. METHODS The UC mice model was established by continuous administration of 3% dextran sulfate sodium solution for 5 days. Mice with successful modeling were randomly divided into UC group， vitexin low- and high-dose groups （vitexin-L and vitexin-H groups， 40， 80 mg/kg）， mesalazine group （400 mg/kg）， and vitexin-H+recombinant Jagged canonical Notch ligand 1 （rJagged-1） group （vitexin-H+rJagged-1 group， 80 mg/kg vitexin+1 mg/kg rJagged-1）， with 12 mice in each group. Another 12 normal mice were used as the control （CK） group. Mice in each group were administered the corresponding drugs or the corresponding drugs and normal saline by gavage and intraperitoneal injection once daily for 7 consecutive days. General conditions were observed during the experiment. At 24 h after the last administration， the disease activity index （DAI） score was evaluated. Colonic histopathological morphology was observed and scored. Macrophage polarization levels in the spleen and colon tissues were measured. The protein expressions of interleukin-6 （IL-6）， IL-10， tumor necrosis factor-α （TNF-α）， transforming growth factor-β 1 （TGF-β 1 ）， Jagged-1， Notch1 and Notch intracellular domain （NICD） in colonic tissues were determined. RESULTS Compared with the UC group， the symptoms （reduced food and water intake， dull fur， etc.） and pathological changes （epithelial cell shedding， inflammatory cell infiltration， etc.） were significantly improved in the vitexin-L， vitexin-H and mesalazine groups. DAI scores， colonic histopathological scores， M1 macrophage contents in spleen tissue， M1/M2 macrophage ratios， M1 macrophage proportions in colon tissue， and protein expressions of IL-6， TNF-α， Jagged-1， Notch1 and NICD in colon tissue were significantly decreased （ P ＜0.05）. Meanwhile， the M2 macrophage contents in spleen tissue， M2 macrophage proportions in colon tissue， and protein expressions of IL-10 and TGF-β 1 in colon tissue were significantly increased （ P ＜0.05）. Moreover， the improvement effects in the vitexin-H and mesalazine groups were significantly superior to those in the vitexin-L group （ P ＜0.05）. Compared with the vitexin-H group， the above symptoms and pathological changes were aggravated， and all quantitative indicators were significantly reversed in the vitexin-H+rJagged-1 group （ P ＜0.05）. CONCLUSIONS Vitexin can ameliorate the inflammation of UC mice， which is associated with its inhibition of the Jagged-1/Notch1 pathway and regulation of macrophage polarization （inhibition of M1-type polarization and promotion of M2-type polarization）.

ObjectiveThe widespread adoption of portable fundus cameras for primary care and community screening is hindered by limitations in current autofocus(AF) technologies. Image-based methods relying on sharpness evaluation require iterative searches, resulting in slow convergence, while projection-based techniques are susceptible to optical artifacts and calibration errors. To address these challenges, this study introduces a novel AF system based on direct wavefront sensing, designed to deliver simultaneous high speed, high precision, and operational robustness within the compact form factor essential for portable ophthalmic devices. MethodsOur approach fundamentally reimagines the AF process by directly measuring the ocular wavefront aberration. We developed a custom portable fundus camera integrating a miniaturized Shack-Hartmann wavefront sensor (SHWS) into the optical path. An 850 nm laser diode projects a point source onto the retina via oblique illumination to minimize corneal reflections. Light scattered from this spot carries the eye’s refractive error through the imaging optics and is directed to the SHWS, positioned at a plane optically conjugate to the primary color CMOS imaging sensor. A microlens array within the SHWS samples the incident wavefront, generating a pattern of focal spots on a CCD. Real-time centroid analysis of these spots provides a map of local wavefront slopes. These measurements are processed through a singular value decomposition (SVD) algorithm to fit a Zernike polynomial basis set, enabling real-time reconstruction of the wavefront phase. The defocus component (S) is extracted from the second-order Zernike coefficients, providing a direct, quantitative measure of the refractive error in diopters. This value serves as a precise error signal in a closed-loop control system, which commands a voice-coil actuated focusing lens to its null position in a single, deterministic step, eliminating the need for iterative search algorithms. ResultsComprehensive evaluation demonstrated the system’s high performance. Testing on a calibrated model eye (OEMI-7) established a highly linear relationship between the computed defocus S and the focusing lens position across a ±20 Diopter (D) compensation range, achievable within a 5 mm mechanical travel. The system achieved a focusing precision of 0.08 D, corresponding to an 18-fold improvement over a conventional projection spot-size method tested under identical conditions. The total focus acquisition time, encompassing wavefront measurement, computation, and lens actuation, averaged under 0.5 s. Clinical validation with 25 human volunteers (50 eyes, refractive range -15 D to +10 D) confirmed practical efficacy. The wavefront-sensing AF succeeded in 92% of attempts with a mean time of 0.5 s, substantially outperforming a projection-based benchmark which achieved only a 32% success rate with an average time of 4.25 s. The system provided instantaneous directional guidance and maintained stability during minor ocular movements. Objective assessment of image quality, via amplitude contrast of retinal vasculature, showed consistent and significant enhancement following AF correction across the entire tested diopter range. ConclusionThis work successfully implements and validates a direct wavefront-sensing autofocus paradigm for portable fundus cameras. By directly quantifying and compensating for the optical defocus aberration, this method bypasses the fundamental limitations of image-processing and projection-based techniques, enabling rapid, precise, and deterministic diopter compensation. The developed system delivers an exceptional combination of a wide operational range (±20 D), high accuracy (0.08 D), fast convergence (0.5 s), and a compact physical footprint. This technology provides a practical and high-performance focusing solution capable of enhancing the reliability, throughput, and diagnostic utility of portable retinal imaging in large-scale screening applications. Future efforts will be directed towards system cost optimization and performance adaptation for diverse ocular conditions.

Background/Aims: Regorafenib is recommended by guidelines and trials as a sequential second-line therapy following progression on first-line sorafenib or lenvatinib in hepatocellular carcinoma (HCC). However, efficacy is limited, highlighting the urgent need to screen suitable patients and develop sensitization strategies. Methods: Acquired sorafenib- or lenvatinib-resistant (SR or LR) HCC cell lines and organoids were established. Genome-wide CRISPR library screen was performed in SR or LR cell strains to identify synthetic lethal targets of regorafenib. RNA-seq and FITC-regorafenib efflux assay were used to elucidate ERBB3-driven downstream signaling. Preclinical mouse models of cell line- and patient-derived xenografts and clinical cohorts of HCC patients were employed to validate the efficacy of ERBB3-guided patient stratification. Results: Screening with CRISPR library, we showed that inhibition of ERBB3 was synthetic lethal with regorafenib in SR or LR cell strains and organoids. Mechanistically, SR or LR triggered feedback activation of ERBB3 signaling and mediated regorafenib efflux via ERBB3-HIF1A-ABCB1 cascade pathway, limiting sensitivity to regorafenib. Moreover, ERBB3-low tumors following SR or LR exhibited significant sensitivity to regorafenib, suggesting its potential as a predictive biomarker to screen optimal candidates for sequential therapy. Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo. Conclusions This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after SR or LR.

OBJECTIVE To improve the research capacity and research enthusiasm of dispensing pharmacists in pharmacy intravenous admixture services （PIVAS）， facilitate their career development， and further promote the sustainable development of hospital pharmacy disciplines. METHODS A full-chain pharmacy practice research path covering topic orientation， topic evaluation， and implementation was explored and constructed for PIVAS. Multiple approaches including framework condensation for topic selection， department empowerment and improved incentive mechanisms were adopted to systematically boost the research competence and enthusiasm of PIVAS dispensing pharmacists. Four dimensions of indicators， including PIVAS research output， operational level， career development of staff and external influence， were compared between the pre-implementation period （2020- 2022） and post-implementation period （2023-2025） to evaluate the implementation effect of the path. RESULTS After the application of the PIVAS pharmacy practice research path， the number of published papers and comprehensive quality score of papers increased by 150.00% and 161.90% respectively compared with those before implementation. The number of approved research projects and comprehensive quality score of projects rose by 166.67% and 225.00%， and the number of authorized patents increased by 100.00%. The monthly number of external errors decreased from （0.42±0.18） pieces/month pre-implementation to （0.28±0.23） pieces/month post-implementation （P＞0.05）. Dispensing efficiency was elevated from （121.83±2.48） bags/（hour· person） to （139.00±3.46） bags/（hour·person） （P＜0.05）. The research participation rate of PIVAS dispensing pharmacists grew from 15.00% to 50.00%， and the overall satisfaction rate of staff increased from 55.00% to 85.00% （P＜0.05）. Within the 3 years after path implementation， our hospital PIVAS received a total of 22 trainees from external medical institutions， and the number of external institutional visits increased by 374.07% versus the pre-implementation stage. CONCLUSIONS The constructed pharmacy practice research path for PIVAS can significantly improve PIVAS research output， operational efficiency and external influence， and effectively promote the career growth of dispensing pharmacists working in PIVAS.

Objective Jejunal interposition is an important option for restoring gastrointestinal continuity in patients with complex esophageal cancer in whom the stomach is unavailable for reconstruction due to previous gastrectomy, tumor involvement, failed gastric conduit, or other constraints. Although the jejunum offers a caliber similar to the esophagus, a rich blood supply, and preserved peristaltic function, anatomical variations in mesenteric length and vascular arcades render long-segment and high-level reconstruction susceptible to excessive tension, mesenteric torsion, venous congestion, and inadequate distal perfusion. This consensus aims to provide standardized recommendations for the application of jejunal interposition in this specific patient population. Methods This consensus was developed in accordance with the WHO Handbook for Guideline Development and Chinese national guideline development standards, with reference to the Appraisal of Guidelines for Research & Evaluation Ⅱ(AGREE Ⅱ), Reporting Items for Practice Guidelines in Healthcare (RIGHT), and Scientific, Transparent and Applicable Rankings (STAR) checklists. The project was registered on the international practice guidelines registry platform (PREPARE-2026CN1384). The working group systematically searched Chinese and English evidence addressing 12 clinical questions. Evidence was graded using the Oxford Centre for Evidence-Based Medicine (OCEBM) 2009 system, with structured appraisal of risk of bias, inconsistency, indirectness, and imprecision. Recommendations were formulated through two rounds of Delphi surveys and a face-to-face consensus meeting, with an agreement threshold of ≥75%. Results The consensus generated 12 recommendations covering indications, selection between jejunum and colon, preoperative assessment, surgical approach and reconstruction route, pedicled jejunal interposition (PJI), supercharged pedicled jejunal interposition (SPJ), indocyanine green (ICG) perfusion assessment, perioperative nutrition, management of anastomotic leakage, long-term follow-up, and special treatment scenarios. Given that the available direct evidence is predominantly derived from single-center retrospective cohorts and case series, recommendations extrapolated from general esophagectomy or other gastrointestinal surgical evidence are deliberately phrased with caution. Conclusion Jejunal interposition is a safe and effective approach for digestive tract reconstruction in patients with complex esophageal cancer in whom the stomach is unavailable. This consensus emphasizes that clinical decision-making should be individualized based on the patient's prior treatment history, reconstruction height, vascular anatomy, technical availability, and institutional experience in the Chinese context.

Objective Sleep is an important physiological process for maintaining normal cognitive functions,but with the accelerated pace and increased work pressure in modern society,sleep deprivation has become a common phenomenon.It has been shown that sleep deprivation interferes with higher cognitive functions such as working memory,but the specific mechanism of its effect is still not completely clear.The present study aimed to systematically investigate the effects of 36 hours of sleep deprivation on the stages of the working memory processing chain and its neural mechanisms through behavioral and event-related potential(ERP)techniques.Methods Using a randomized controlled experimental design,48 healthy adult subjects were recruited and randomly assigned to sleep deprivation and control groups.All subjects completed a 2-back phonological working memory task,and behavioral data(response time and correctness)and ERP data(P2,N2,and P3 component wave amplitudes)were collected at 0 and 36 hours,respectively.The effects of sleep deprivation on working memory behavioral performance and neurophysiological indices were assessed by ANOVA.Results Behavioral results showed that the sleep deprivation group had a significantly longer response time after 36 hours,but no significant decrease in correctness,indicating a decrease in response efficiency but stable accuracy.ERP results showed that P2 amplitude did not change significantly before and after sleep deprivation,indicating that the early perception and categorization stages were limitedly affected by sleep deprivation;whereas,N2 and P3 amplitudes decreased significantly after sleep deprivation,reflecting that later cognitive processing such as conflict monitoring and resource allocation and other late cognitive processing were significantly disturbed.Conclusion Through ERP technology,this study uncovers the phased impact of 36-hour sleep deprivation on the working memory processing chain.The study found that early perceptual and categorization stages may be less susceptible to the effects of sleep deprivation,likely due to their relatively automatic processing and lower demand for cognitive resources.In contrast,during later stages of cognitive processing,particularly in higher-order functions such as conflict monitoring and resource allocation,sleep deprivation significantly impaired task performance efficiency by disrupting prefrontal cortex function.This finding deepens the understanding of the mechanisms underlying the effects of sleep deprivation and provides a scientific basis for cognitive intervention and management strategies in high-stress occupational groups.Future studies can further explore the long-term effects of sleep deprivation and its neural mechanisms by combining multimodal techniques.

Objective To analyze the gene expression characteristics of chronic rhinosinusitis with nasal polyps(CRSwNP)using bioinformatics methods,aim to investigate the potential biomarkers and their diagnostic value of CRSwNP.Methods(1)The CRSwNP Gene expression data set was downloaded from the American Gene Expression Omnibus(GEO)database.The differentially expressed genes(DEGs)between CRSwNP patients and healthy controls were screened through data analysis.Gene Ontology(GO)functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were performed on the identified DEGs.Protein-protein interaction(PPI)networks were constructed utilizing the STRING database,and the key genes were identified by using the cytoHubba plugin.The"Cibersort"package was used to analyze the influence of key genes on common immune cells.(2)Thirty-two patients diagnosed with CRSwNP in the First Affiliated Hospital of Hebei North University from June 2022 to June 2023 were selected as the CRSwNP group,and 21 patients with simple deviation of nasal septum without a history of sinusitis during the same period were selected as control group.The pathological characteristics of specimens in the two groups were examined using hematoxylin-eosin(HE)staining.Immunohistochemistry and Western blotting were used to detect the expression levels of key genes in CRSwNP.The levels of key proteins in plasma were detected using ELISA,and ROC curve was used to analyze its efficacy in diagnosing CRSwNP.Results(1)Analysis of three gene expression database sets(GSE36830,GSE23552,and GSE194282)showed that there were 156 DEGs in CRSwNP.GO functional enrichment and KEGG pathway analysis indicated that the functions of the above DEGs were mostly related to immune functions.Key genes such as cytochrome b-245 β chain(CYBB)and colony-stimulating factor 1 receptor(CSF1R)were identified.(2)The results of HE staining revealed that the epithelial of CRSwNP tissue was metaplastic into stratified squamous epithelium with interstitial edema.Both immunohistochemistry and Western blotting analyses indicated that the expression levels of CYBB and CSF1R in the CRSwNP group were significantly increased compared to control group(P＜0.05).ELISA results demonstrated that CYBB[(21.20±3.00)μg/ml vs.(17.66±1.66)μg/ml,P＜0.05]and CSF1[(477.37±86.63)pg/ml vs.(370.71±66.24)pg/ml,P＜0.05]in CRSwNP group were significantly increased compare to control group.ROC curve analysis showed that plasma concentrations of CYBB and CSF1 had AUCs of 0.888(95%CI 0.802-0.974)and 0.821(95%CI 0.711-0.931)for diagnosing of CRSwNP,respectively;their combined AUC was 0.927(95%CI 0.851-1.000).Conclusions CYBB and CSF1R may be involved in the occurrence and development of CRSwNP.Plasma CYBB and CSF1 have high diagnostic value for CRSwNP.

Objective To investigate the regulatory effect of circular RNA ASAP1(circASAP1)targeting microRNA-4500(miR-4500)on the proliferation and apoptosis of osteosarcoma cells.Methods Human osteosarcoma cells(Saos-2)were selected as the experimental subjects and cul-tured in DMEM medium containing 10％fetal bovine serum while maintaining 5％CO2.The expres-sions of circASAP1 and miR-4500 in osteosarcoma tissues were detected using RT-qPCR.Saos-2 cells were transfected with si-NC(40 nmol/L),si-circASAP1(40 nmol/L),pcDNA(0.4 μg),pcDNA-circASAP1(0.4 μg),miR-NC(40 nmol/L),miR-4500 mimics(40 nmol/L),si-circASAP1+anti-miR-NC(40 nmol/L),and si-circASAP1+anti-miR-4500(40 nmol/L),respectively.Cell proliferation and apoptosis were assessed using CCK-8,colony formation assays,and flow cytometry.The interaction between circASAP1 and miR-4500 was analyzed using a dual-luciferase reporter assay.Results Compared with adjacent non-tumor tissues,the expression of circASAP1 was significantly upregulated,while that of miR-4500 was significantly downregulated in osteosarcoma tissues(P＜0.001).Compared with the si-NC group,the si-circASAP1 group exhibited significantly decreased circASAP1 expression,optical density(OD)values,and the number of cell colonies(P＜0.001).Compared with the si-NC group,the si-circASAP1 group showed significantly upregulated levels of cleaved-caspase3 protein,cleaved-caspase9 protein,and the apoptosis rate(P＜0.001).StarBase search revealed specific binding sequences between miR-4500 and circASAP1.Co-transfection of miR-4500 mimics and WT-circASAP1 significantly reduced the relative luciferase activity of the cells[(0.34±0.03)versus(0.95±0.06),t=27.280,P＜0.001].The expression of miR-4500 in the pcDNA-circASAP1 group was significantly lower than that in the pcDNA group,whereas the ex-pression of miR-4500 in the si-circASAP1 group was significantly higher than that in the si-NC group(P＜0.001).Compared with the miR-NC group,the miR-4500 group exhibited significantly in-creased miR-4500 expression,cleaved-caspase3 protein levels,cleaved-caspase9 protein levels,and the apoptosis rate,while the OD values and the number of colonies significantly decreased(P＜0.001).Compared with the si-circASAP1+anti-miR-NC group,the si-circASAP1+anti-miR-4500 group showed significantly decreased miR-4500 expression,cleaved-caspase3 protein levels,cleaved-caspase9 protein levels,and the apoptosis rate,while the OD values and the number of col-onies significantly increased(P＜0.001).Conclusion The expression of circASAP1 is increased,while that of miR-4500 is decreased in osteosarcoma tissues.Moreover,circASAP1 promotes the proliferation and inhibits the apoptosis of osteosarcoma cells by targeting miR-4500.

Objective:To investigate the effects and mechanisms of angiotensin-converting enzyme 2 (ACE2) and Captopril (CAP) on mechanical ventilation-induced lung injury (VILI) in mice.Methods:Seventy-two healthy male BALB/c mice were randomly assigned (using a random number table) into six groups ( n=12 per group): normal control (NC) group, VILI group, ACE2 group, VILI+ACE2 group, CAP group, and VILI+CAP group. One hour prior to mechanical ventilation, the ACE2 and VILI+ACE2 groups were intraperitoneally injected with ACE2 at a dose of 0.1 mg/kg, while the CAP and VILI+CAP groups were intraperitoneally injected with CAP at a dose of 2.5 mg/kg. Following mechanical ventilation, serum samples were collected and enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory factors [platelet activating factor (PAF), endothelin-1 (ET-1), soluble intercellular adhesion molecule-1 (sICAM-1), prostaglandin E2 (PGE2)] and cardiovascular system related indicators [von Willebrand factor (vWF), thrombomodulin (TM), angiotensin (Ang) (1-9), Ang (1-7), prostacyclin I 2 (PGI2)]. Bronchoalveolar lavage fluid (BALF) was gathered, and total protein concentration was determined using BCA method, and sICAM-1 levels were measured by ELISA. Lung tissues were collected and subjected to hematoxylin and eosin staining (HE staining) for the assessment of pathological lung injury and lung injury scoring. Western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were utilized to detect the relative expression levels of ACE2 protein and mRNA, respectively. Statistical analysis was performed using IBM SPSS 20.0 software. Intergroup comparisons were conducted using one-way analysis of variance followed by the least significant difference (LSD) test. Results:No statistically significant differences were observed in the levels of PAF, ET-1, sICAM-1, vWF, TM, Ang(1-9), Ang(1-7), and PGI2 in serum and lung tissues between the ACE2/CAP groups and the NC group (all P>0.05). Compared with the VILI group, the VILI+ACE2 and VILI+CAP groups exhibited significantly decreased serum and lung tissue levels of PAF, ET-1, sICAM-1, and vWF (all P<0.05), while the levels of TM, Ang(1-9), Ang(1-7), and PGI2 were significantly increased (all P<0.05). Pathological lung injury was alleviated, and the lung wet/dry weight ratio was significantly reduced (all P<0.05) in the VILI+ACE2 and VILI+CAP groups. Furthermore, both ACE2 protein and mRNA expression levels were significantly increased in these groups (all P<0.05). Conclusion:Both ACE2 and CAP can inhibit inflammation and protect the cardiovascular system, possibly by promoting the ACE2/Ang(1-9)/Ang(1-7) axis, thereby exerting a protective effect against VILI.

Objective:To explore the efficacy of intensive repetitive transcranial magnetic stimulation (irTMS) in treatment-resistant depression (TRD) and its impact on cognitive function and systemic immune-inflammation index (SII).Methods:Forty-eight TRD patients were divided into observation group and control group using random number table method, with 24 patients in each group. The observation group was treated with irTMS, and the stimulation site was the left dorsolateral prefrontal lobe. The stimulation intensity was 110% of the motor threshold, and the stimulation frequency was 15 Hz. The stimulation interval was 26 s, and 3 000 pulses were stimulated each time. Stimulating 5 times per day, with an interval of 50 min, and continuous treatment for 5 days. The total stimulation amount for 5 days was 75 000 pulses. The control group was treated with pseudo stimulation. Before treatment (T0), 5 days after treatment (T1), and 1 month after treatment (T2), 17-item Hamilton depression scale (HAMD-17) was used to assess depressive mood. Evaluating cognitive function using the Wisconsin card sorting test.A fully automated blood cell analyzer was used to detect platelet count (PLT), neutrophil count (NC), and lymphocyte count (LC), calculate the systemic immune inflammation index (SII), SII=PLT × NC/LC. Statistical analysis was conducted using SPSS 20.0 software. The comparison between two sets of repeated measurement data was performed using repeated measurement analysis of variance.Simple effect analysis was performed if the interaction effect was significant.Pearson analysis was used for correlation testing.Results:The interaction effect between the time and group of HAMD-17 scores was significant ( F=121.784, P<0.05). The results of simple effects analysis showed that the HAMD-17 scores of the observation group at T1 and T2 ((12.07±4.08) and (14.78±4.99), respectively) were lower than those of the control group ((23.78±5.87) and (24.67±7.00), P<0.05). The treatment response rate and remission rate of the observation group at T1 were higher than those of the control group ( χ2=4.090, 7.378, both P<0.05).The treatment response rate and remission rate of the observation group at T2 were higher than those of the control group ( χ2=4.463, 4.547, both P<0.05). The time and group interaction effects of the percentage of correct response and conceptualization level in the Wisconsin card sorting test were significant ( F=30.087, 20.004, P<0.05). The results of simple effects analysis showed that the percentage of correct response and conceptualization level in the observation group at T1 and T2 were higher than those in the control group (all P<0.05). The time and group interaction effect of SII was significant ( F=8.173, P<0.05). The results of simple effects analysis showed that there was no statistically significant difference in SII between the two groups at T0 ( P>0.05). The SII at T1 and T2 in the observation group was lower than that in the control group ( P<0.05). In the observation group, the changes in SII from T2 to T0 was positively correlated with the change in HAMD-17 scores ( r=0.527, P<0.05), and negatively correlated with the percentage of correct responses to the Wisconsin card sorting test ( r=-0.412, P<0.05) and the percentage of conceptualization level ( r=-0.411, P<0.05). Conclusion:irTMS is effective in treating TRD and can improve patients' cognitive function and immune inflammation damage.