BACKGROUND & AIMS:Large-scale cohort studies on interventional radiological treatments for Budd-Chiari syndrome (BCS), including percutaneous angioplasty (PTA) with or without routine stenting and transjugular intrahepatic portosystemic shunt (TIPS), are lacking. We aimed to evaluate the long-term outcomes of these treatments in Chinese BCS patients. METHODS:Consecutive patients diagnosed with BCS in 6 Chinese tertiary centers were retrospectively screened for eligibility between January 2010 and May 2019. The roles of the treatment modalities, as well as their associated clinical outcomes, were assessed. RESULTS:Overall, 997 patients were enrolled, with obstruction types classified as inferior vena cava (15.7%), hepatic vein (16.2%), and combined (68.1%). The majority (93.5%) presented with moderate-to-severe symptoms, with 60.7% (n = 607) showing a disease course exceeding 6 months. All patients received anticoagulation, among them, 117 (11.7%) patients underwent medical therapy alone, including 65 asymptomatic or mildly symptomatic patients, and 52 with failed, unfeasible, or declined recanalization; 834 (83.7%) patients successfully recanalized through PTA alone (n = 566) or PTA with routine stenting (n = 268); 90 (9.0%) patients received TIPS placement (comprising 46 initial and 44 converted procedures); and no patients underwent liver transplantation. With a median follow-up of 57.3 months, 103 (10.5%) deaths occurred, primarily from liver failure. The 5-year rates for overall, TIPS-free, stenting-TIPS-free, and intervention-free survival were 90.2% (95% confidence interval [CI]: 88.2%-92.3%), 83.0% (95% CI: 80.5%-85.6%), 59.3% (95% CI: 56.2%-62.6%), and 10.6% (95% CI: 8.8%-12.7%), respectively (P < .001), with consistent outcomes across BCS subtypes. CONCLUSIONS:With predominantly inferior vena cava obstruction presented and recanalization used, interventional radiological treatment could achieve a good long-term outcome in Chinese patients with BCS.

Background: Acne vulgaris is a common inflammatory disease associated with various sequelae after skin lesion remission. Acne erythema has been considered simple erythema or a vascular lesion; however, because the understanding of this disease has improved, acne erythema is currently considered an early scar with erythematous components. Aims: This study evaluated the efficacy of using both a 595-nm pulsed dye laser (PDL) and 1565-nm nonablative fractional laser (NAFL) for the treatment of erythematous scars caused by acne. Methods: Ninety patients with acne scars were equally randomized to two groups. Group A (n = 45) received treatment with the NAFL. Group B (n = 45) received treatment with the PDL and NAFL. Each patient underwent one treatment session and 4 weeks of follow-up. Results: Qualitative (chi(2) = 12.415; p < 0.05) and quantitative (t = 2.675; p < 0.05) scores of Groups A and B were determined using a global scarring grading system and exhibited statistically significant differences. The quantitative score of Group A was higher than that of Group B (6.67 +/- 3.46 vs. 4.98 +/- 2.44). The erythema areas of the groups differed significantly after treatment, with Group B exhibiting more notable score improvements (5.00 [3.10, 7.10] vs. 2.80 [1.65, 4.60]; Z = 3.072; p < 0.05). The erythema regression rate of Group B (88.9%) was significantly higher than that of Group A (66.7%) (chi(2) = 20.295; p < 0.001). Adverse events, including redness and swelling (86.6%), scabbing (78.8%), and purpura (36.6%), occurred within 7 days for 86.6% of patients. Conclusions: The combined use of the PDL and NAFL is safe and effective for erythematous acne scars.

N6-methyladenosine (m6A) stands as the most prevalent modified form of RNA in eukaryotes, pivotal in various biological processes such as regulating RNA stability, translation, and transcription. All members within the YT521-B homology (YTH) gene family are categorized as m6A reading proteins, capable of identifying and binding m6A modifications on RNA, thereby regulating RNA metabolism and functioning across diverse physiological processes. YTH domain-containing 2 (YTHDC2), identified as the latest member of the YTH family, has only recently started to emerge for its biological function. Numerous studies have underscored the significance of YTHDC2 in human physiology, highlighting its involvement in both tumor progression and non-tumor diseases. Consequently, this review aims to further elucidate the pathological mechanisms of YTHDC2 by summarizing its functions and roles in tumors and other diseases, with a particular focus on its downstream molecular targets and signaling pathways.

Background and Aim: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining “high-risk” have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. Approach and Results: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). Conclusions: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.

Baveno VII workshop recommends management of acute variceal bleeding (AVB) in cirrhotic patients with nonmalignant portal vein thrombosis (PVT) should be performed according to the guidelines for patients without PVT. Nevertheless, whether PVT affects the outcome of patients with cirrhosis and AVB remains unclear. The aim of this study was to assess the clinical impact of PVT on the outcomes in the pre-emptive TIPSS eligible patients with cirrhosis and AVB. From December 2010 to June 2016, 1219 consecutive cirrhotic patients admitted due to AVB with (n = 151; 12.4

Background & AimsAmong individuals with Child-Pugh B cirrhosis and acute variceal bleeding (AVB), the Baveno VII workshop recommended pre-emptive TIPS in those with a Child-Pugh score of 8-9 and active bleeding at initial endoscopy (Child B8-9 + AB criteria). Nevertheless, whether this criterion is superior to the CLIF-Consortium acute decompensation score (CLIF-C ADs) remains unclear.MethodsData on 1,021 consecutive individuals with Child-Pugh B cirrhosis and AVB from 13 university hospitals in China who were treated with pre-emptive TIPS (n = 297) or drug plus endoscopic treatment (n = 724) between 2010 to 2019 were retrospectively analysed. A competing risk regression model was used to compare the outcomes between the two groups after adjusting for confounders. The concordance-statistic for benefit (c-for-benefit) was used to evaluate a models’ ability to predict treatment benefit (risk difference between treatment groups).ResultsPre-emptive TIPS was associated with reduced mortality compared to drug plus endoscopic treatment (adjusted hazard ratio 0.62, 95% CI 0.44 to 0.88). A higher baseline CLIF-C AD score was associated with greater survival benefit (i.e., larger absolute mortality risk reduction). After adjusting for confounders, a survival benefit was observed in individuals with CLIF-C ADs ≥48 or Child-Pugh B8-9 with active bleeding, but not in those with CILF-C ADs <48, no active bleeding or Child-Pugh B7 with active bleeding. The c-for-benefit of CILF-C ADs for predicting survival benefit was higher than that of Child B8-9+AB criteria.ConclusionsIn individuals with Child-Pugh B cirrhosis and AVB, CLIF-C ADs predicts survival benefit from pre-emptive TIPS and outperforms the Child B8-9+AB criteria. Prospective validation should be performed to confirm this result, especially for other aetiologies of cirrhosis.Impact and implicationsIn this study, among individuals with Child-Pugh B cirrhosis and acute variceal bleeding, the CLIF-Consortium acute decompensation (CLIF-C AD) score could predict the survival benefit from pre-emptive TIPS, with patients with higher CLIF-C AD scores benefiting more from pre-emptive TIPS. Furthermore, the CLIF-C AD score outperformed the Child B8-9 plus active bleeding criteria in terms of discriminating between those who obtained more benefit vs. less benefit from pre-emptive TIPS. Depending on prospective validation, the CLIF-C AD score could be used as the model of choice to determine who should undergo pre-emptive TIPS.

results to 16-23%, maintaining adequate NPV and PPV (above 90%) (Figure 1A).The combined algorithms were validated in an independent (Verona) cohort of eighty-one patients.A nomogram based on LSM, SSM and PLT was developed to predict the individual probability of CSPH presence (AUROC = 0.966) (Figure 1B); the model performed significantly better than the Anticipate model ( p < 0.05).During follow-up, 21-63% of first decompensation events occurred in the patients within the "grey zone" according to the models based only on LSM and PLT, whereas almost all decompensation events occurred in the "rule-in" zone defined by the models including SSM.

Objectives Objective response rate (ORR) under mRECIST criteria after transarterial chemoembolization (TACE) is a well-perceived surrogate endpoint of overall survival (OS). However, its optimal time point remains controversial and may be influenced by tumor burden. We aim to investigate the surrogacy of initial/best ORR in relation to tumor burden. Methods A total of 1549 eligible treatment-naive patients with unresectable hepatocellular carcinoma (HCC), Child-Pugh score <= 7, and performance status score <= 1 undergoing TACE between January 2010 and May 2016 from 17 academic hospitals were retrospectively analyzed. Based on "six-and-twelve" criteria, tumor burden was graded as low, intermediate, and high if the sum of the maximum tumor diameter and tumor number was <= 6, > 6 but <= 12, and > 12, respectively. Results Both initial and best ORRs interacted with tumor burden. Initial and best ORRs could equivalently predict and correlate with OS in low (adjusted HR, 2.55 and 2.95, respectively, both p < 0.001; R = 0.84, p = 0.035, and R = 0.97, p = 0.002, respectively) and intermediate strata (adjusted HR, 1.81 and 2.22, respectively, both p < 0.001; R = 0.74, p = 0.023, and R = 0.9, p = 0.002, respectively). For high strata, only best ORR exhibited qualified surrogacy (adjusted HR, 2.61, p < 0.001; R = 0.70, p = 0.035), whereas initial ORR was not significant (adjusted HR, 1.08, p = 0.357; R = 0.22, p = 0.54). Conclusions ORR as surrogacy of OS is associated with tumor burden. For patients with low/intermediate tumor burden, initial ORR should be preferred in its early availability upon similar sensitivity, whereas for patients with high tumor burden, best ORR has optimal sensitivity. Timing of OR assessment should be tailored according to tumor burden.

Autophagy plays a protective role in oxidative stress‒induced melanocyte death. Dysregulated autophagy increases the sensitivity of melanocytes in response to oxidative damage and promotes melanocyte degeneration in vitiligo. However, the molecular mechanism underlying this process is not fully understood. In this study, using RNA-sequencing technology, we compared the transcriptome change between normal and vitiligo melanocytes with or without treatment of oxidative stress. We found that ATG5 and ATG12, the critical components for autophagosome formation, were significantly reduced in vitiligo melanocytes under oxidative stress. Mechanistically, HSF1 is the prime transcription factor for both ATG5 and ATG12, accounting for the reduced level of ATG5 and ATG12 in vitiligo melanocytes. Deficiency of HSF1 led to accumulation of intracellular ROS, imbalance of mitochondrion membrane potential, and apoptosis in melanocytes exposure to oxidative stress. Furthermore, overexpression of HSF1 could ameliorate oxidative stress‒induced melanocytes death through the activation of autophagy by upregulating ATG5 and ATG12. These findings suggested that targeting HSF1-ATG5/12 axis could prevent oxidative stress‒induced melanocyte death and may be used as a therapeutic strategy for vitiligo treatment.

Background Periocular fine lines and wrinkles usually appear as a first visible sign of facial aging. Fractional ablative laser has been used to treat periorbital wrinkles. Objective To compare the efficacy on treatment of static periorbital wrinkles using different emission modes of CO2 fractional laser. Methods A total of 30 patients with static periorbital wrinkles were enrolled. The subjects were randomly assigned into two split-face groups: One side was treated with a deep (n = 15) or mid-mode of CO2 superficial laser (n = 15), and the other side of periocular region was treated by a fusion mode in combination of both modes (n = 30). Results The patients in three groups showed significant improvements on indexes of periocular wrinkles, skin textures, and elasticity at three-month follow-up as compared with baseline (p < 0.05). Fusion mode resulted in a significantly progressive improvement on periocular wrinkles at three-month follow-up as compared with one-month follow-up (p < 0.05), which were not observed in other modes. Fusion mode delivered better improvements of periocular wrinkles and skin textures as compared to deep and mid-modes at three-month follow-up (p < 0.05). Fusion mode also resulted in better scores of global esthetic improvement scale and patient satisfaction as compared to other modes at both follow-ups. Conclusion The fusion mode has a synergistic effect in periorbital static wrinkle treatment, which is worthy of further evaluation and investigation.

The development of invariant natural killer T (iNKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that miR-155 was highly expressed in early iNKT cells upon thymic selection, and then its expression is gradually downregulated during iNKT cell development. However, the mice with miR-155 germline deletion had normal iNKT cell development. To address if downregulated miR-155 is required for iNKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of iNKT cell development, diminished iNKT17 and iNKT1 cells, augmented iNKT2 cells, and these defects were cell intrinsic. Furthermore, defective iNKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune iNKT cell development. MiR-155 modulated Jarid2, a critical component of a histone modification complex, and Tab2, the upstream activation kinase complex component of NF-κB, which function additively in iNKT development and in promoting balanced iNKT1/iNKT2 differentiation. In addition, miR-155 also targeted Rictor, a signature component of mTORC2 that controls iNKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate iNKT cell development and functional lineage, as well as secondary innate CD8 T cell development.

目的 评估多源相控点阵射频改善眶周中重度静态性皱纹的临床疗效和安全性观察.方法 选取第四军医大学西京皮肤医院激光美容中心2019年4月—9月收治的15例眶周中重度静态性皱纹患者作为研究对象,采用多源相控点阵射频进行治疗,共3次,每次间隔时间1个月.使用CK多功能皮肤测试仪以及Antera3D?皮肤成像分析系统检测对比治疗前后眶周上下眼睑的皱纹及黑色素的变化.结果 3次治疗后15例患者眶周皱纹较治疗前有明显改善,差异有统计学意义(P＜0.01);黑色素较治疗前无明显变化,患者满意率达80％.治疗中所有患者均能耐受,术后有不同程度的肿胀、红斑及结痂,未见瘢痕、水疱.结论 多源相控点阵射频对于改善患者眶周静态皱纹效果显著.

Background Polydioxanone (PDO) thread insertion and monopolar radio frequency (RF) treatment are two common antiaging modalities. The efficacy and safety profile of PDO in combination with RF treatment is unknown. Aims To investigate pathological changes in skin in response to PDO + RF treatment in an animal model. Methods PDO threads were implanted into the skin of young white domestic pigs. RF treatment was performed on the PDO insertion sites 2 weeks after the PDO procedure. Skin biopsies were taken at 6 and 12 weeks after PDO for histological examination. Results Both PDO and PDO + RF treatments induced the fibrous granular formation surrounding the PDO threads. There were more exaggerated inflammatory responses such as development of nodular panniculitis and adipocyte necrosis in the skin at 6 weeks after PDO + RF as compared with PDO alone, which was largely resolved at 12 weeks. All treatments led to thickened and replicated interlobular septa, many of which were connected to the collagenous network in dermis. In all treatment groups, the cross-sectional areas of the dermal collagenous bundles were significantly increased at both endpoint times as compared with the baseline level. PDO + RF treatment did not lead to increases in neocollagenesis as compared with PDO or RF treatment alone. Conclusions Our data showed that RF and PDO induced comparable levels of collagen remodeling in the skin. PDO + RF treatment did not exhibit evident synergistic effects of derma collagen remodeling but rather amplified the inflammatory responses in the skin. Therefore, combined treatment is not recommended.

BACKGROUND:Oxidative stress has a vital role in the early stages of vitiligo. Autoantigens released from apoptotic melanocytes (MC) under oxidative stress are involved in the presentation and recognition of antigens. However, the transport of autoantigens to the cell surface and their release to the extracellular environment are still unclear. Apoptotic bodies (ABs) have always been considered as a key source of immunomodulators and autoantigens. Yet, the role of ABs in the immune mechanism of vitiligo is still unknown.PURPOSE:To explore whether MC's autoantigens translocate into ABs during oxidative stress-induced apoptosis and study the molecular mechanisms underlying autoantigen migration and AB formation.METHODS:PIG3V (an immortalized human vitiligo melanocyte cell line) were treated with H2O2, and ABs were separated. Transmission electron microscopy, flow cytometry, Western blot, mass spectrometry, and other methods were used to determine the relocation of specific antigens in PIG3V cells to ABs. After pretreatment with specific inhibitors (Rho kinase (Y-27632), myosin light chain kinase (MLCK, ML-9), pan-caspase (zVAD-FMK), and JNK (SP600125)), the pathway of autoantigen translocation into ABs and the formation of apoptotic bodies were determined.RESULTS:When treated with 0.8 mM H2O2, ABs were released from these cells. Autoantigens such as tyrosinase-related protein 1 (TYRP-1) and cleavage nuclear membrane antigen Lamin A/C (Asp230) were concentrated in ABs. The expression of autoantigens and the formation of ABs increased in a time- and dose-dependent manner after treatment with H2O2, while the application of specific inhibitors inhibited the formation of apoptotic bodies, i.e., the expression of antigens.CONCLUSION:Vitiligo autoantigens translocate into ABs in the process of apoptosis induced by oxidative stress. The cytoskeletal protein activation pathway and the JNK-related apoptosis pathway are involved in the transport of autoantigens and the formation of ABs. ABs may be the key bridge between MC cell apoptosis and cellular immunity.

Background and Aims Optimal candidates for early transjugular intrahepatic portosystemic shunt (TIPS) in patients with Child‐Pugh B cirrhosis and acute variceal bleeding (AVB) remain unclear. This study aimed to test the hypothesis that risk stratification using the Chronic Liver Failure Consortium Acute Decompensation score (CLIF‐C ADs) may be useful to identify a subgroup at high risk of mortality or further bleeding that may benefit from early TIPS in patients with Child‐Pugh B cirrhosis and AVB. Approach and Results We analyzed the pooled individual data from two previous studies of 608 patients with Child‐Pugh B cirrhosis and AVB who received standard treatment between 2010 and 2017 in China. The concordance index values of CLIF‐C ADs for 6‐week and 1‐year mortality (0.715 and 0.708) were significantly better than those of active bleeding at endoscopy (0.633 [P < 0.001] and 0.556 [P < 0.001]) and other prognostic models. With X‐tile software identifying an optimal cutoff value, patients were categorized as low risk (CLIF‐C ADs <48), intermediate risk (CLIF‐C ADs 48‐56), and high risk (CLIF‐C ADs >56), with a 5.6%, 16.8%, and 25.4% risk of 6‐week death, respectively. Nevertheless, the performance of CLIF‐C ADs for predicting a composite endpoint of 6‐week death or further bleeding was not satisfactory (area under the receiver operating characteristics curve [AUC], 0.588). A nomogram incorporating components of CLIF‐C ADs and albumin, platelet, active bleeding, and ascites significantly improved the prediction accuracy (AUC, 0.725). Conclusions In patients with Child‐Pugh B cirrhosis and AVB, risk stratification using CLIF‐C ADs identifies a subgroup with high risk of death that may derive survival benefit from early TIPS. With improved prediction accuracy for 6‐week death or further bleeding, the data‐driven nomogram may help to stratify patients in randomized trials. Future external validation of these findings in patients with different etiologies is required.

Vitiligo is a depigmentation disorder that develops as a result of the progressive disappearance of epidermal melanocytes. The elevated level of amino acid metabolite homocysteine (Hcy) has been identified as circulating marker of oxidative stress and known as a risk factor for vitiligo. However, the mechanism underlying Hcy-regulated melanocytic destruction is currently unknown. The present study aims to elucidate the effect of Hcy on melanocytic destruction and its involvement in the pathogenesis of vitiligo. Our results showed that Hcy level was significantly elevated in the serum of progressive vitiligo patients. Notably, Hcy induced cell apoptosis in melanocytes via activating reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. More importantly, folic acid, functioning in the transformation of Hcy, could lower the intracellular Hcy level and further reverse the apoptotic effect of Hcy on melanocytes. Additionally, Hcy disrupted melanogenesis whereas folic acid supplementation could reverse the melanogenesis defect induced by Hcy in melanocytes. Taken together, Hcy is highly increased in vitiligo patients at progressive stage, and our in vitro studies revealed that folic acid could protect melanocytes from Hcy-induced apoptosis and melanin synthesis inhibition, indicating folic acid as a potential benefit agent for patients with progressive vitiligo.

Autoimmune diseases are increasingly linked to aberrant gut microbiome and relevant metabolites. However, the association between vitiligo and the gut microbiome remains to be elucidated. Thus, we conducted a case-control study through 16S rRNA sequencing and serum untargeted-metabolomic profiling based on 30 vitiligo patients and 30 matched healthy controls. In vitiligo patients, the microbial composition was distinct from that of healthy controls according to the analysis on α- and β-diversity (P < 0.05), with a characteristic decreased Bacteroidetes: Firmicutes ratio. Meanwhile, the levels of 23 serum metabolites (including taurochenodeoxycholate and L-NG-monomethyl-arginine) in the vitiligo patients were different from those in the healthy individuals and showed significant correlations with some microbial markers. We found that Corynebacterium 1, Ruminococcus 2, Jeotgalibaca and Psychrobacter were correlated significantly with disease duration and serum IL-1β level in vitiligo patients. And Psychrobacter was identified as the most predictive features for vitiligo by machine learning analysis (“importance” = 0.0236). Finally, combining multi-omics data and joint prediction models with accuracies up to 0.929 were established with dominant contribution of Corynebacterium 1 and Psychrobacter. Our findings replenished the previously unknown relationship between gut dysbiosis and vitiligo circulating metabolome and enrolled the gut-skin axis into the understanding of vitiligo pathogenesis.

Adipose tissue is an important metabolic organ, and transplantation of white adipose tissue plays crucial roles in glucose homoeostasis and energy metabolism. However, how adipose tissue affects glucose utilization is poorly understood. PAI-1-knockout (PAI-1KO) mice were previously shown to be resistant to a high-fat diet and obesity. We used microPET/CT (positron emission tomography/computed tomography), gene microarray, and biochemical assays to measure changes in systemic and myocardial glucose metabolism in mice subjected to transplantation of adipose tissue from PAI-1KO and wild-type mice. Here, we show that transplanting subcutaneous white adipose tissue (scWAT) from PAI-1KO mice into high-fat diet (HFD)-fed mice reduced levels of serum total cholesterol and triglycerides, and improved glucose tolerance in the HFD-fed mice. microPET/CT imaging revealed that cardiac glucose uptake was increased in the heart but not in the liver, hindlimb muscles, or abdominal subcutaneous white adipose tissue in HFD-fed mice transplanted with PAI-1KO scWAT, suggesting that the transplanted PAI-1KO scWAT exerted endocrine effects in the heart. In addition, transplantation of scWAT from PAI-1KO mice upregulated mitochondrial gene expression in cardiac muscle, increased the expression of glucose transporters 1 and 4 in cardiac tissues and was associated with an increased NAD+/NADH ratio. Together, these findings suggest that modulating PAI-1 in scWAT may provide a promising approach for intervening in glucose metabolism.