To analyze and explore the key targets and molecular mechanisms of action of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity and the relationship between corresponding compounds based on network pharmacology.

Using network pharmacology, a "traditional Chinese medicine–chemical composition–key target–pathway" analysis was conducted on Radix Paeoniae Alba for the treatment of Toosendan Fructus-induced hepatotoxicity. The possible mechanism of action was analyzed in terms of function.

The core targets, such as interleukin (IL)-6, tumor necrosis factor (TNF), heat shock protein 90 alpha family class A member 1 (HSP90AA1), peroxisome proliferator-activated receptor gamma (PPARG), prostaglandin-endoperoxide synthase 2 (PTGS2), heme oxygenase 1 (HMOX1), Jun proto-oncogene (JUN), caspase-3, estrogen receptor 1 (ESR1), and aryl hydrocarbon receptor (AHR) were screened from the targets of Radix Paeoniae Alba against Toosendan Fructus-induced hepatotoxicity. Biological process (BP) of toxic targets (BP terms) involved "response to drug; activation of cysteine-type endopeptidase activity involved in apoptotic process," positive regulation of transcription. Cellular components (CC terms) mainly involved cytosol and membrane rafts. Molecular function (MF) terms included "protein homodimerization activity," RNA polymerase II transcription factor activity and enzyme binding, etc." The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway included the TNF signaling pathway, cancer pathways, and apoptosis.

Radix Paeoniae Alba might alleviate Toosendan Fructus-induced hepatotoxicity through IL6, TNF, HSP90AA1, PPARG, PTGS2, HMOX1, and other targets, possibly via the activation of cysteine-type endopeptidase activity involved in these pathways.

To use network pharmacology and molecular docking technology to explore material basis and molecular mechanism of Coix lacryma-jobi, Hedyotis diffusa, Curcuma zedoaria, and Salvia chinensis on the treatment of pre-cancerous stomach diseases. Our findings provide a theoretical foundation for further clinical research.

We searched and screened the targets of four pharmaceutical components for activity against precancerous lesions of gastric cancer (PLGC) using the GeneCards and OMIM network databases. The Chinese medicine composition-target network was constructed using Cytoscape3.7.2 software, and the protein interoperability network of the four drugs for PLGC treatment was constructed using the string data platform. The core target was found by topological analysis. Finally, biopathic and enrichment analyses were carried out on the drug-disease intersection target.

A total of 19 active ingredients and 123 component targets were collected for four enterolytic drugs. For PLGC, 1487 targets were identified, and 64 targets were collected for pharmaceutical components and diseases. A topological analysis was performed with a value greater than the mean degree (29.0), and 64 key core targets were obtained (including TP53, EGFR, TNF, and VEGFA), and the key targets were screened for TP53, EGFR, TNF, and VEGFA, among others, through network topology and protein interoperability network analyses. GO functional enrichment analysis resulted in 1337 bio-process entries, 46 cell composition entries, and 74 molecular function entries. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis and screening resulted in 254 signaling pathways, including stomach cancer, breast cancer, prostate cancer, non-small cell lung cancer, and colon cancer.

The four enterolysis drugs may be used to prevent and control PLGC by acting on TP53, EGFR, TNF, and VEGFA targets and relevant gastric cancer, inflammatory, and immune pathways.

To evaluate the benefits of traditional Chinese herbal medicine (TCHM) plus triple therapy (TT) in the management of Helicobacter pylori (H. pylori)-induced chronic atrophic gastritis (CAG).

A comprehensive access and electronic database search were carried out from inception to June 2020. Prospective randomized trials (TCHM plus TT vs. TT) were selected to assess the eradication rate of H. pylori (ER of H. pylori), clinical symptom relief rate (SRR), treatment-related adverse reactions (TRAR) and 95% confidence intervals (CI) in the meta-analysis and cumulative meta-analysis (CMA). Meta-regression analysis was used to analyze heterogeneity between studies and publication bias.

33 studies contained 3,226 participants were included. Compared with the TT group, TCHM plus TT group showed a significantly higher ER of H. pylori (OR=4.14, 95% CI: 3.21-5.35; P=0.000) and SRR (OR=4.50, 95% CI: 3.59-5.64). Meanwhile, the TRAR of TCHM plus TT remedy was significantly lower than TT monopoly (RR=0.43, 95% CI: 0.29-0.64; P=0.000). The results of the CMA, sorted by publication year, duration of treatment, and sample size, confirmed that combined treatment remedy was superior to TT monopoly in respect of ER of H. pylori and SRR.

The present study obtained reliable and convincing evidence suggesting that TCHM plus TT remedy was efficacious and safe in treating H. pylori-induced CAG.

From ancient times to the present, the plague has had a huge impact on human life. Traditional Chinese medicine has also accumulated valuable epidemic prevention theories and methods from the practice of anti-epidemic, and formed a unique epidemic prevention thinking. Chinese medicine is good at using the thinking of the three talents of heaven, earth and human beings to adjust the epidemic situation according to the time and place, and uses the thinking of five transports and six qi to predict the development trend of the epidemic and guide the clinical treatment rules. Physicians of later generations summed up the characteristics of epidemics and put forward many theories and ideas of traditional Chinese medicine for epidemic prevention, including Wu Youxing's theory of suffocating qi and the thinking of dialectical treatment of Jiu Chuan, the differentiation and treatment method of Wei qi and nourishing blood of rotten throat Dansha, and the essence of grasping the essence of Lingnan famous Chinese medicine. Deng Tietao's thoughts on the diagnosis and treatment of SARS in the fight against SARS, etc. This article will summarize the thinking theories of traditional Chinese medicine for epidemic prevention and control and China's traditional epidemic prevention measures, and give an overview and explanation in combination with the current domestic new coronavirus prevention and control work.

We analysed four gene microarray datasets by GEO2R and obtained differential genes expressed in oesophageal cancer. To further elaborate the functions of DGEs, this study performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs. We constructed protein interaction networks of DGEs through the String database and screened core genes. We used the GEPIA online database with the Kaplan-Meier plotter database to verify the expression of Hub genes in expressed normal versus tumour tissues and the effect of Hub genes on overall and disease-free survival in oesophageal cancer. To further understand the relationship between Hub gene and tumour metastasis, we analysed the difference in Hub gene expression in patients without metastatic oesophageal cancer versus those with metastatic oesophageal cancer with the help of the HCMDB database. The relationship between Hub genes and tumour immune infiltration was analysed by the TIMER database. We obtained a total of 149 DEGs, of which 49 were up-regulated genes and 100 were down-regulated genes. These DGEs were importantly enriched in IL-17 signalling pathway, ECM-receptor interactions, p53 signalling pathway, estrogen signalling pathway, complement and coagulation cascade response. We screened 10 Hub genes, MMP9, CXCL8, COL1A1, TIMP1, POSTN, MMP3, MMP1, COL3A1, SERPINE1, LUM, among 149 DGEs. hub genes were all up-regulated in expression in esophageal cancer tissues, in addition, MMP9, T1MP1, CXCL8, POSTN and The expression of COL3A1, LUM, MMP1, MMP3, MMP9, POSTN, SERPINE1 and TIMP1 was positively correlated with the infiltration of immune cells in the tumor microenvironment. In conclusion, our study identified 10 signature genes for oesophageal cancer. These genes are associated with the development, metastasis, prognosis and immune infiltration of oesophageal cancer and may be markers of development, metastasis and prognosis as well as targets for immunotherapy.

Liver stiffness (LS) measured by shear wave elastography (SWE) is often influenced by hepatic inflammation. The aim was to develop a dual-task convolutional neural network (DtCNN) model for the simultaneous staging of liver fibrosis and inflammation activity using 2D-SWE.

A total of 532 patients with chronic hepatitis B (CHB) were included to develop and validate the DtCNN model. An additional 180 consecutive patients between December 2019 and April 2021 were prospectively included for further validation. All patients underwent 2D-SWE examination and serum biomarker assessment. A DtCNN model containing two pathways for the staging of fibrosis and inflammation was used to improve the classification of significant fibrosis (≥F2), advanced fibrosis (≥F3) as well as cirrhosis (F4).

Both fibrosis and inflammation affected LS measurements by 2D-SWE. The proposed DtCNN performed the best among all the classification models for fibrosis stage [significant fibrosis AUC=0.89 (95% CI: 0.87–0.92), advanced fibrosis AUC=0.87 (95% CI: 0.84–0.90), liver cirrhosis AUC=0.85 (95% CI: 0.81–0.89)]. The DtCNN-based prediction of inflammation activity achieved AUCs of 0.82 (95% CI: 0.78–0.86) for grade ≥A1, 0.88 (95% CI: 0.85–0.90) grade ≥A2 and 0.78 (95% CI: 0.75–0.81) for grade ≥A3, which were significantly higher than the AUCs of the single-task groups. Similar findings were observed in the prospective study.

The proposed DtCNN improved diagnostic performance compared with existing fibrosis staging models by including inflammation in the model, which supports its potential clinical application.

Cardiac troponin T (cTnT) is independently associated with cardiovascular complications in patients with chronic kidney disease (CKD). The present study aimed to determine the factors related to cTnT levels in pre-dialysis CKD patients, which result in increased cardiovascular risk.

A total of 147 patients, with a mean age of 69.1 ± 14.7 years old, were enrolled. These participants were classified to estimated glomerular filtration rate (eGFR) and albuminuria categories, according to the Kidney Disease Improving Global Outcomes 2012 criteria. The estimated pulse wave velocity (ePWV), as an index of arterial stiffness, was calculated using an equation, which included age and mean blood pressure. Coronary arterial disease (CAD) and left ventricular hypertrophy (LVH) were also recorded. The cTnT concentrations were measured by high-sensitivity immunoassay. The significant correlation between cTnT and different variables was determined, and the significant risk factors for high cTnT levels were defined.

A significant correlation was observed between cTnT serum concentrations and age, triglycerides/HDL-C, ePWV, glucose, phosphate (P), intact-parathyroid hormone (i-PTH), serum uric acid and albuminuria, although the association with eGFR was shown to be significantly inverse. The multifactorial model revealed that current smoking (p = 0.03, OR = 8.3, 1.15–60.3), CAD (p = 0.001, OR = 25.2, 5.6–113.6), low eGFR (p = 0.001, OR = 0.9, 0.8–0.9), high ePWV (p = 0.04, OR = 2.6, 1.0–6.8), and primary renal disease (p = 0.001, OR = 3.8, 1.7–8.5) are independent risk factors for elevated cTnT levels, after adjusting for age, gender, obesity and albuminuria.

Arterial stiffness, smoking, primary renal disease and unregulated metabolic abnormalities may have an independent association between high cTnT levels and low eGFR in pre-dialysis CKD patients, with or without overt cardiovascular disease.

Natural killer (NK) cells are a gatekeeper of the body’s innate defense system against cancers and infections. A growing body of literature from us and others finds that NK cells promote anti-cancer immune surveillance, and that defects in NK cell development are associated with poor clinical prognosis of cancers. In preclinical studies, NK cells were found to drive tumor regression and delay tumor relapse. Because NK cells are potentially less damaging to the body and are easier to develop than T cell-based therapies, efforts are being made to improve NK cell cytotoxicity and in vivo persistence for use as an adoptive, off-the-shelf immunotherapy. In this review, we discuss how tumor-intrinsic and -extrinsic factors suppress NK cells in the cancer microenvironment. We also outline current strategies that restore NK surveillance in cancer and challenges facing the clinical use of NK cell-based therapies.

A considerable number of autoimmune hepatitis (AIH) patients completely or partially fail on first-line treatment. Several studies on the use of calcineurin inhibitors (CNIs) in the treatment of AIH have been published without focusing on indication. The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients, specifically focusing on indication: first-line intolerant and with first-line insufficient response (failure to achieve or maintain remission), and with second versus third-line treatment.

A literature search included studies on the use of CNIs in adult AIH. Patients with past or present use of CNIs from the Dutch AIH group cohort were added. The primary endpoint was biochemical remission while using CNIs. Secondary endpoints were biochemical response, treatment failure, and adverse effects.

Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients. The CNI remission rate was 53% in patients with insufficient response to first-line treatment and 67% in patients intolerant to first-line treatment. CNIs were used as second-line treatment in 73% with a remission rate of 52% and as third-line treatment in 22% with a remission rate of 26%. Cyclosporine was discontinued in 13% and tacrolimus in 11% of patients because of adverse events.

CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treatment. Prospective studies are needed.

Coagulation testing is essential for the diagnosis and management of a variety of hemophilia, thrombophilia, and complicated coagulopathies. This is often used prior to surgery, or as a follow-up investigation for patients being scrutinized for bleeding diathesis, or to monitor the anticoagulant therapy. When the results are abnormal, a mixing study is often the initial reflexive test that can provide valuable information to conclude the assessment, or help guide further investigations. If the mixing “corrects” the test results, a factor deficiency would be suspected. Otherwise, the presence of an inhibitor would be more likely. However, defining “correction” remains difficult and controversial. There are several available methods to determine whether a result is corrected. Each method has its own advantages and limitations. It is noteworthy that although a complete correction can be interpreted as factor deficiency, a partial or incomplete correction does not rule out the coexistence of factor deficiency and the presence of a coagulation inhibitor. Hence, caution should be taken in interpreting mixing study results for patients who are taking direct-acting oral anticoagulants. Ideally, mixing study results are interpreted in correlation with the patient’s clinical history, including bleeding or thrombosis history, and the use of anticoagulants. This review aimed to evaluate the methods used in interpreting coagulation mixing studies and to discuss their respective advantages and limitations

Polymerase chain reaction (PCR) techniques provide rapid detection of pathogens. This pilot study evaluated the diagnostic utility and clinical impact of multiplex real-time PCR (mRT-PCR, SeptiFast) vs. conventional microbial culture (CMC) in bile samples of patients with chronic cholestatic liver diseases (cCLDs), endoscopic retrograde cholangio-pancreatography (ERCP), and peri-interventional-antimicrobial-prophylaxis (pAP).

We prospectively collected bile samples from 26 patients for microbiological analysis by CMC and mRT-PCR. Concordance of the results of both methods was determined by Krippendorff's alpha (α) for inter-rater reliability and the Jaccard index of similarity.

mRT-PCRbile and CMCbile results were concordant for only Candida albicans (α=0.8406; Jaccard index=0.8181). mRT-PCRbile detected pathogens in 8/8 cases (100%), CMCbile in 7/8 (87.5%), and CMCblood in 5/8 (62.5%) with clinical signs of infection. mRT-PCRbile, CMCbile, and CMCblood had identical detection results in 3/8 (37.5%) with clinical signs of infection (two Klebsiella spp. and one Enterococcus faecium). The total pathogen count was significantly higher with mRT-PCRbile than with CMCbile (62 vs. 31; χ2=30.031, p<0.001). However, pathogens detected by mRT-PCRbile were more often susceptible to pAP according to the patient infection/colonization history (PI/CH) and surveillance data for antibiotic resistance in our clinic (DARC). Pathogens identified by mRT-PCRbile and resistant to pAP by PI/CH and DARC were likely to be clinically relevant.

mRT-PCR in conjunction with CMCs for bile analysis increased diagnostic sensitivity and may benefit infection management in patients with cholestatic diseases. Implementation of mRT-PCR in a bile sample-based diagnostic routine can support more rapid and targeted use of antimicrobial agents in cCLD-patients undergoing ERCP and reduce the rate/length of unnecessary administration of broad-spectrum antibiotics.

To date, the omentum-derived determinants of ovarian cancer (OC) metastasis to the omentum have not been well elucidated. We aimed to identify the pathogenesis, potential biomarkers, and prognostic indicators underlying the omental metastasis of OC.

The expression profile GSE120196 included datasets of omental tissues from four patients with benign gynecologic diseases and cancer-infiltrated omental tissues from ten patients with high-grade serous OC. Using this dataset, we performed an analysis of differentially expressed genes (DEGs), gene ontology, Kyoto Encyclopedia of Genes and Genome, and pathway networks. The most significant module based on protein-protein interaction (PPI) network was selected, and the genes in the module were identified as hub genes. Furthermore, survival analysis and translational level of hub genes were performed to verify the results.

A total of 301 upregulated DEGs and 128 downregulated DEGs were identified. Pathways in cancer, focal adhesion and Wnt signaling were found to play critical roles. Ten hub genes were identified from PPI network analysis. Expression levels of two key genes, COL1A1 and VCAN, were significantly associated with worse prognosis of patients with advanced ovarian cancer.

Our findings suggest that pathways in cancer, focal adhesion, Wnt signaling, and expression levels of two key genes, COL1A1 and VCAN, may become novel targets for the diagnosis and therapy of ovarian cancer with omental metastasis.

Uptake of breast cancer screening has been decreasing in England since 2007. However, the associated factors are unclear. On the other hand, survival among breast cancer patients have recently increased. We conducted a quasi-experimental analysis to test whether the trend-change in proportional incidence of non-screened cancers coincided with that in five-year net-survival.

We extracted population-based proportional incidence and age-standardized five-year net-survival data from Public Health England that included English women with invasive breast cancer diagnosed during 1995–2011 (linked to death certificates, followed through 2016). Piece-wise log-linear models with change-point/joinpoint were used to estimate temporal trends.

Among 254,063 women in England with invasive breast cancer diagnosed during 1995–2011, there was downward-to-upward trend-change in proportional incidence of non-screened breast cancers (annual percent change [APC]=5.6 after 2007 versus APC=−3.5 before 2007, p<0.001) in diagnosis-year 2007, when a steeper upward-trend in age-standardized five-year net survival started (APC=5.7 after 2007/2008 versus APC=0.3 before 2007/2008, p<0.001). Net-survival difference of screened versus non-screened cancers also significantly narrowed (18% in 2007/2008 versus 5% in 2011). Similar associations were found in all strata of race, cancer stage, grade, and histology, except in Black patients or patients with stage I, stage III, or grade I cancer.

There was a downward-to-upward trend-change in proportional incidence of non-screened breast cancers in 2007 that coincided with a steeper upward-trend in age-standardized five-year net survival among English women in 2007. Survival benefits of breast cancer screening decreased during 2007–2011. The data support reduction of breast cancer screening in some patients, but future validation studies are warranted.

The current World Health Organization classification of neuroendocrine neoplasms of the digestive system separates these tumors into two major categories: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. These two groups are considered fundamentally different tumors, with different molecular abnormalities, prognoses, and treatment strategies. The cornerstone of the classification is proliferative rate of the tumor cells, as assessed by mitotic rate and Ki-67 labeling index. However, the range of mitotic rate and Ki-67 labeling index overlaps between high-grade, well-differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. In order to accurately separate these two entities, a systematic approach is necessary, which includes attention to the morphology, accurate assessment of the proliferative rate, review of any additional pathology materials, judicial use of immunohistochemistry, and correlation with clinical features. With this approach, the majority of tumors can be correctly classified as either high-grade, well-differentiated neuroendocrine tumor or poorly differentiated neuroendocrine carcinoma. This review aimed to evaluate the current World Health Organization classification system for neuroendocrine neoplasms of the digestive system, focusing on the differentiation between well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas.

Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused by mutations in the JAG1 and NOTCH2 genes. AGS has been rarely reported in adult patients, mainly because its characteristics in adults are subtle. The study aimed to improve the understanding of adult AGS by a descriptive case series.

Eight adults diagnosed with AGS at our hospital between June 2016 and June 2019 were included in the study. Clinical data, biochemical results, imaging results, liver histopathology, and genetic testing were analyzed.

Three female and five male patients with a median age of 24.5 years at the time of diagnosis were included in the analysis. The clinical manifestations were adult-onset (62.5%, 5/8), cholestasis (50%, 4/8), butterfly vertebrae (62.5%, 5/8), systolic murmurs (12.5%, 1/8), typical facies (12.5%, 1/8), posterior embryotoxon, and renal abnormalities (0/8). Genetic sequencing showed that all patients had mutations, with four occurring in the JAG1 gene and four in the NOTCH2 gene. Six were substitution mutations, one was a deletion mutation, and one was a splicing mutation. Five had been previously reported; but the others, one JAG1 mutation and two NOTCH2 mutations were unique and are reported here for the first time.

The clinical manifestations highlighted by the current diagnostic criteria for most adults with AGS are atypical. Those who do not meet the criteria but are highly suspicious of having AGS need further evaluation, especially genetic testing.

Alanine aminotransferase (ALT) is a common clinical indicator of liver inflammation. The current Chinese guidelines for the management of chronic hepatitis B (CHB) recommend antiviral treatment for patients with detectable hepatitis B virus (HBV) DNA and persistent ALT levels (ALTs) exceeding the upper limit of normal. However, it has been recently reported that patients with chronic HBV infection, especially HBeAg-negative patients with persistently normal ALTs, may have liver biopsy findings of significant inflammation and fibrosis. For HBeAg-negative patients with chronic HBV infection and normal ALTs, many controversial questions have been asked. To treat or not? When to initiate the treatment? Which drug is appropriate? In this review, we summarize the available data on the management of HBeAg-negative patients with chronic HBV infection and normal ALTs with the aim of improving the current clinical management.

The recent histologic subtyping of lung adenocarcinoma has demonstrated the prognostic values of histologic patterns in this malignancy. However, the histological features of lung squamous cell carcinoma (SCC) are much less established. This short review discusses several promising histological prognostic markers for SCC, including tumor budding, tumor cell nesting, and the spreading of tumors through air spaces. Wherever appropriate, the biological significance of these morphological features was also discussed. The investigators consider that histological prognostic markers are highly valuable in understanding the cancer biology of SCC, and in guiding clinical treatment. However, larger clinical cohorts are needed to better establish the prognostic values of the aforementioned histological markers. The application of modern technologies, including machine-learning, would make the histological analysis accurate and reproducible.

Morphologic variants of well-differentiated pancreatic neuroendocrine tumors (PanNETs) are uncommon. These variants may mimic non-PanNETs, and when under recognized, it would lead to misdiagnosis by fine-needle aspiration (FNA) biopsy. The present report describes the unique cytomorphologic features and diagnostic clues of pigmented, pleomorphic, clear cell/lipid-rich and oncocytic variants of well-differentiated PanNETs. The differential diagnoses of each morphologic variant are also discussed. Ancillary immunohistochemical studies with appropriate markers are crucial in the diagnostic work-up. Raising the awareness of PanNET morphologic variants is essential for preventing diagnostic pitfalls, and rendering an accurate diagnosis during the FNA diagnostic work-up of pancreatic lesions.

Hridayarnava Rasa is traditionally used cardio tonic in Ayurveda. This drug was selected for the evaluation of stabilization of erythrocyte membrane (EM) in high-fat diet induced atherosclerosis via rabbit model.

A total of 24 male white New Zealand rabbits were randomly divided into 6 groups (n = 4 each). Rabbits in group 1 were fed a standard pellet diet, those in group II rabbits a high-fat diet (HFD), those in groups III, IV and V increasing doses of H. Rasa and an HFD, and those in group VI an HFD diet plus Atorvastatin.

There was a significant reduction in rabbit sodium/potassium adenosine triphosphatase (Na+/K+ ATPase) at 30 (58.51%), 60 (61.40%), and 90 (64.92%) days of an HFD diet compared to the control group. Upon treatment with H. Rasa, the activity of Na+/K+ ATPase in groups III, IV, and V increased at 30, 60 and 90 days, respectively, compared to HFD induced rabbits. The Na+ concentration also increased significantly in HFD-administered rabbits at 30, 60 and 90 days as compared to controls. Serum K+ concentration was reduced at days 30, 60 and 90 in the HFD group and was increased in group V as compared to the control group. These levels improved with H. Rasa treatment whereas the atorvastatin-treated group exhibited an improvement only between dose levels 2 and 3.

These results suggest that HFD diminishes EM stabilization in atherosclerosis whereas H. Rasa protects EM by maintaining the Na+/K+ ATPase activity through a Na+/K+ pump. In atherosclerosis, an HFD reduces EM stabilization after administration of H. Rasa, which maintains Na+/K+ ATPase activity through a Na+/K+ pump.