Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key regulator of cell fate decision between pro-survival signaling and programmed cell death. The activation of RIPK1 is extensively modulated by posttranslational modification, such as ubiquitination. RIPK1 overactivation mediates autoinflammatory diseases in humans. However, the role of RIPK1 ubiquitination in human autoinflammatory diseases has not been reported, and the mechanism mediating the interaction of cell death and autoinflammation is largely unknown. Here, we report two patients carrying compound heterozygous RIPK1 variants K377E/R390G with recurrent fevers, lymphadenopathy and skin rashes. Mechanistically, K377E and R390G mutations impaired ubiquitination of RIPK1, which suppresses the formation of TNFR1 signaling complex (TNF-RSC) and NF-κB activation, resulting in the loss of CD8+ T cells mediated by RIPK1 activation-induced cell death in the patients. We reveal that the death of CD8+ T cells promotes the secretion of TNF and IFNγ to activate monocytes and macrophages, which triggers further production of proinflammatory cytokines to amplify autoinflammation. Disruption of the communication between T cells and monocytes/macrophages through pharmacologic blockade of TNF and IFNγ attenuated proinflammatory cytokine production in macrophages. Collectively, our results demonstrate a crucial role of RIPK1 ubiquitination in regulating CD8+ T cell death and restraining autoinflammation. Our study demonstrates the mechanism for a group of autoinflammatory diseases mediated by RIPK1 activation-induced cell death, and highlights an important role of CD8+ T cells in driving autoinflammation.### Competing Interest StatementJ.Y. is a consultant of Denali Therapeutics. The rest of authors declare no competing financial interests.### Funding StatementThe works of Q.Z. were supported by grants 82225022, 32141004 and 32321002 from the National Natural Science Foundation of China. The works of X.Y. were supported by the Hundred-Talent Program of Zhejiang University. J.D. received grant 32300618 from the National Natural Science Foundation of China. J.W. received the grant 2023M733104 from China Postdoctoral Science Foundation. L.G. received the grant LHDMY23H100005 from Zhejiang Provincial Natural Science Foundation of China.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Patients were evaluated under protocols approved by Institutional Review Board and Ethical Committee at the Children's Hospital of Zhejiang University School of Medicine (protocol 2021-IRB-172).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

This study aimed to investigate the effect of Pikang oral liquid (PK) on psoriasis and analyze its possible mechanism from the perspective of metabolism. A psoriasis-form mouse model established using imiquimod (IMQ) was used to evaluate the anti-psoriatic effects of PK. The serum samples were analyzed by high-resolution nuclear magnetic resonance (1 H NMR)-based metabonomics. Nine amino acids were further quantitatively analyzed by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS). This study suggested that PK treatment markedly attenuated IMQ-induced psoriasis in a dose-dependent manner. 1 H NMR-based multivariate trajectory analysis revealed that PK had a certain regression effect on eight differential metabolites. The quantitative results showed that PK could significantly regulate the serum levels of alanine, histidine and arginine to healthy control levels. The anti-psoriasis mechanism of PK may be associated with the restoration of the disturbance in the amino acid metabolism, energy metabolism and lipid metabolism and so on. Quantitative results further confirmed that amino acid metabolism play an key role in the pathogenesis of psoriasis. Our investigation provided a holistic view of PK for intervention psoriasis and provided the scientific information in vivo about a clinical value of PK for psoriasis.

We presented a novel radiomics approach using multimodality MRI to predict the expression of an oncogene (O6-Methylguanine-DNA methyltransferase, MGMT) and overall survival (OS) of glioblastoma (GBM) patients. Specifically, we employed an EffNetV2-T, which was down scaled and modified from EfficientNetV2, as the feature extractor. Besides, we used evidential layers based to control the distribution of prediction outputs. The evidential layers help to classify the high-dimensional radiomics features to predict the methylation status of MGMT and OS. Tests showed that our model achieved an accuracy of 0.844, making it possible to use as a clinic-enabling technique in the diagnosing and management of GBM. Comparison results indicated that our method performed better than existing work.

Extremely limited drug retention and depigmentation represent the greatest barriers against vitiligo treatment advancement. Here, inspired by biological melanosomes, the primary melanin transporter, we developed biomimetic melanosomes to combat reactive oxygen species (ROS)-mediated melanocyte damage and depigmentation. Briefly, methylprednisolone (MPS) and melanin-mimicking polydopamine (PDA) were encapsulated inside lysine-proline-valine (KPV)-modified deformable liposomes (KPV-Lipos). Owing to their phospholipid bilayer flexibility and the specific affinity for melanocortin 1 receptor (MC1R), KPV-Lipos exhibited 1.43-fold greater skin deposition than traditional liposomes. The binding of KPV and its receptor also contributed to activating the cAMP-tyrosinase (TYR) signaling pathway, improving the endogenous melanin content. In addition, PDA mimicked melanosomes as it effectively increased the exogenous melanin content and scavenged ROS. Meanwhile, MPS inhibited inflammatory cytokine secretion, limiting the depigmented area. Ultimately, the biomimetic melanosomes affected the skin color of mice with H2O2-induced vitiligo. These melanosomes show potential as a universal platform for the self-supply of melanin by self-driven melanin synthesis with exogenous supplementation. Furthermore, this study offers ideas for the production of artificial packed melanosome substitutes for melanocyte-related diseases.

An important reason of cancer proliferation is the change in DNA methylation patterns, characterized by the localized hypermethylation of the promoters of tumor-suppressor genes together with an overall decrease in the level of 5-methylcytosine (5mC). Therefore, identifying the 5mC sites in the promoters is a critical step towards further understanding the diverse functions of DNA methylation in genetic diseases such as cancers and aging. However, most wet-lab experimental techniques are often time consuming and laborious for detecting 5mC sites. In this study, we proposed a deep learning-based approach, called BiLSTM-5mC, for accurately identifying 5mC sites in genome-wide DNA promoters. First, we randomly divided the negative samples into 11 subsets of equal size, one of which can form the balance subset by combining with the positive samples in the same amount. Then, two types of feature vectors encoded by the one-hot method, and the nucleotide property and frequency (NPF) methods were fed into a bidirectional long short-term memory (BiLSTM) network and a full connection layer to train the 22 submodels. Finally, the outputs of these models were integrated to predict 5mC sites by using the majority vote strategy. Our experimental results demonstrated that BiLSTM-5mC outperformed existing methods based on the same independent dataset.

Hypertonic dextrose prolotherapy (HDP) is an injection of a concentrated dextrose solution for the purpose of local treatment of musculoskeletal pain and possible enhancement of repair mechanisms. This systematic review and meta-analysis examines the clinical utility of HDP injection for treatment of knee osteoarthritis (OA). Randomized controlled trials (RCTs) utilizing HDP to treat knee OA were retrieved from MEDLINE, EMBASE, and Cochrane Library (CENTRAL). Identification and inclusion of RCTs utilizing intra-articular and extra-articular administration of HDP vs administration of other injectate or physical therapy as control for knee OA were included. Primary clinical outcomes were changes in knee WOMAC, pain and function score. Secondary outcomes were adverse events related to HDP. For continuous outcomes with same or different measurements, we calculated, respectively the weighted mean difference (WMD) or the standardized mean difference (SMD), respectively. Results were pooled using DerSimonian and Laird random effect models across the included studies and heterogeneity between studies was estimated using the I 2 index. Five studies comprising a total of 319 treated patients met inclusion criteria and were included in the final analysis. At a mean of 22.8 weeks follow-up, HDP treatment significantly improved total WOMAC score (WMD = 13.77, 95% CI: 6.75–20.78; p < 0.001; I 2 = 90%), pain (SMD = 1.33, 95% CI: 0.49–2.17; p < 0.001; I 2 = 91%) and knee function (SMD = 1.30, 95% CI: 0.45–2.14; p < 0.001; I 2 = 91%) compared with control group. There were no severe adverse events related to dextrose injection reported in all the included studies. HDP is a promising treatment for knee OA with a reasonable safety profile. Further research in mechanism of HDP activity and long-term follow-up study will be needed for exploring this novel therapy modality.

A major reason for colorectal cancer (CRC) chemoresistance is the enhanced migration and invasion of cancer cells, such as the cell acquisition of epithelial-mesenchymal transition (EMT). Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been considered as a pro-oncogene in multiple cancers. However, the precise functional mechanism of lncRNA MALAT1 in chemoresistance and EMT is not well known. In the present study, we focused on the effect of oxymatrine on CRC cells and further investigated the role of MALAT1 in oxymatrine-induced resistance and EMT process. The human CRC cell line HT29 was exposed to increasing doses of oxymatrine to establish stable cell lines resistant to oxymatrine. The established HT29 oxymatrine resistant cells showed an EMT phenotype including specific morphologic changes, enhanced migratory and invasive capacity, and downregulation of E-cadherin protein expression. Subsequently, high-throughput HiSeq sequencing and RT-qPCR showed that lncRNA MALAT1 was significantly upregulated in the oxymatrine resistant cells (P<0.01), while knockdown of MALAT1 partially reversed the EMT phenotype in HT29 resistant cells. Furthermore, oxymatrine treatment suppressed the migration and invasion ability of CRC cells, however, this effect was significantly reversed by overexpression of MALAT1. Finally, we investigated the clinical role of MALAT1 and found that high lncRNA MALAT1 expression level is associated with poor prognosis in CRC patients receiving oxymatrine treatment (P<0.01). In conclusion, we demonstrate that lncRNA MALAT1 is a stimulator for oxymatrine resistance in CRC and it may provide therapeutic and prognostic information for CRC patients.

What is known and objectiveCalcineurin inhibitor (CNI)-based immunosuppressive regimen is widely used for preventing rejection in solid organ transplantation. Hyperkalemic renal tubular acidosis (RTA) caused by CNI is uncommon and potentially underappreciated. We reported four such cases to increase awareness of this risk and to provide recommendations for its management based on our experience.Case summaryFour middle-aged males underwent solid organ transplant (two kidneys, one liver, one heart) and were treated with CNI-based immunosuppressive regimen (one cyclosporine A, three tacrolimus). On post-operative day 13-35, hyperkalemic hyperchloremic non-gap metabolic acidosis developed. All patients had relatively preserved renal function, normal urine output and plasma aldosterone level. Reduction in CNI dosage was partly effective; the patient on cyclosporine A was treated with fludrocortisone, and two others temporarily switched to sirolimus (SRL).What is new and conclusionWe should alert for CNI-induced hyperkalemic RTA in transplant recipients. By CNI dosage reduction or adding low dose fludrocortisone, or temporarily switching to SRL, the prognosis of CNI-induced hyperkalemic RTA is favourable.

Background: Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, is a vital element in the glucose transport of malignant cells, and abnormally expressed in a great number of human solid cancers. But the association between GLUT1 overexpression and clinical outcome in gastric cancer setting remains to be clarified. Therefore, we carried out this study to evaluate the correlation between GLUT1 expression and clinicopathological and prognostic characteristics in gastric cancer. Methods: The mRNA level of GLUT1 expression in different subtypes of gastric cancer was assessed by using Oncomine database. The correlation between GLUT1 expression levels and clinical survival in gastric cancer patients with diverse clinicopathologic parameters was analyzed by using Kaplan-Meier plotter database. The COSMIC and cBioPortal databases were used for analysis of GLUT1 mutation characteristics and alteration frequency. Results: Oncomine database showed elevated expression of GLUT1 in different subtypes of gastric cancer. Prognostic analysis revealed that elevated expression status of GLUT1 mRNA was associated with poor overall survival and first progression survival of gastric cancer patients. Low alteration frequency was observed in gastric cancer. Conclusions: GLUT1 is upregulated in gastric cancer, and its overexpression is related with unfavorable clinical survival, indicating that GLUT1 expression is a significant prognostic biomarker of gastric cancer. Legal entity responsible for the study: Dr. Ji Wang Funding: National Natural Science Foundation of China (No. 81602471 and No. 81672729) and by grant from Sub project of China National Program on Key Basic Research Project (973 Program) (No. 2014CB744505). Disclosure: All authors have declared no conflicts of interest.