Background/Objectives: Autophagy plays a role in systemic lupus erythematosus (SLE) pathogenesis. Nevertheless, the specific genetic determinants underpinning this process remain poorly characterized. Summary data-based Mendelian randomization (SMR) analysis was therefore utilized to pinpoint autophagy-related genes associated with SLE risk. Methods: We analyzed 700 autophagy-related genes, integrating methylation quantitative trait loci (mQTL), expression QTL (eQTL) from blood and relevant tissue, and protein QTL (pQTL) data with genome-wide association studies (GWAS) data on SLE from the IEU dataset (discovery). GWAS data from FinnGen and the GWAS Catalog were used as replication datasets. Colocalization analysis identified shared genetic variants. Blood samples from 10 healthy control and 20 SLE patients were collected and analyzed for the expression of candidate genes. Results: Our SMR analysis identified suggestive associations between NLRP6 expression (OR = 0.528, 95%CI = 0.291-0.96) and p27Kip1 protein abundance (OR = 0.269, 95%CI = 0.08-0.904) with SLE susceptibility in the discovery cohort, supported by colocalization evidence. Additionally, we found that the methylation of the NLRP6 promoter (cg06432119) was significantly increased, while NLRP6 expression and p27Kip1 level were significantly decreased in SLE patients compared to controls. Furthermore, NLRP6 mRNA expression was significantly negatively correlated with the SLE severity (SLEDAI-2000). Conclusions: These findings not only prioritized candidate genes via SMR analysis but also provided evidence of epigenetic dysregulation of NLRP6 and its correlation with disease activity in SLE, thereby offering novel insights into the underlying mechanisms.

T-cell lymphoma (TCL) is a prevalent malignancy characterized by the aberrant proliferation of T cells. The molecular mechanism underlying TCL remains poorly understood, and effective therapeutic strategies are still limited. Maprotiline, a highly selective norepinephrine reuptake blocker, is primarily used in the treatment of various types of depression. Intriguingly, its potential therapeutic utility and underlying mechanisms in TCL have not been previously explored. In this study, we demonstrated for the first time that maprotiline significantly inhibits proliferation and migration while promoting apoptosis in TCL cells. Furthermore, in vivo experiments using TCL xenograft mouse models revealed that maprotiline treatment effectively suppresses tumor progression while maintaining a favorable safety profile with minimal toxicity. Mechanistically, our findings reveal that maprotiline exerts its anti-tumor effect by regulating the AKT/mTOR signaling pathway in TCL. Notably, we discovered that maprotiline substantially enhances the sensitivity of TCL cells to histone deacetylase inhibitor, thereby unveiling a promising combination therapeutic strategy for TCL treatment. These findings not only expand our understanding of maprotiline's pharmacological potential beyond its conventional antidepressant use, but also provide a novel therapeutic avenue for addressing the clinical challenges in TCL management.

Frost stress poses a serious threat to the potato industry. C-repeat binding factors (CBFs) are key transcription factors involved in plant cold responses and the adaptive evolution of land plants. However, their function and underlying mechanisms in potato remain poorly understood. This study analyzed homologous CBF2 genes from 46 potato genotypes and revealed significant structural variations, including a critical site (site A) that is closely associated with cold tolerance. There are at least 2 site A types, including the cold-tolerant Solanum commersonii type and the cold-sensitive Solanum tuberosum type. Overexpression of ScCBF2 significantly enhanced potato cold tolerance, whereas StCBF2 overexpression had a limited effect. We demonstrated that both ScCBF2 and StCBF2 improve cold resistance by regulating glutathione S-transferase tau (GSTU)- and ZAT10-mediated reactive oxygen species scavenging systems. Notably, ScCBF2 uniquely upregulated Galactinol synthase 3 (GolS3), promoting raffinose biosynthesis. Compared with StCBF2, ScCBF2 exhibited a stronger binding affinity to the GolS3 promoter, resulting in higher transcriptional activation. Overexpression of ScGolS3 increased leaf raffinose content and cold tolerance. Furthermore, we confirmed the critical role of site A in the ScCBF2-GolS3 regulatory pathway. In summary, this study highlights the functional divergence caused by structural variations in CBF2, with differential regulation of GolS3 contributing to cold tolerance. Our work provides insights into the molecular mechanisms underlying cold tolerance in potato and offers potential targets for improving frost resistance in this vital crop.

BACKGROUND Macrophage activation syndrome (MAS), a sub-type of hemophagocytic lymphohistiocytosis (HLH) secondary to autoimmune rheumatic diseases, is a critical and potentially fatal condition characterized by an excessive inflammatory response. Despite the established efficacy of the HLH-2004 guideline in diagnosing and treating HLH over the years, ongoing discussion persists regarding its application, especially for HLH secondary to complicated conditions, such as autoimmune rheumatic diseases combined with severe infection. Etoposide (VP-16), a topoisomerase II inhibitor that effectively induces DNA damage and subsequent apoptosis in hyperactivated immune cells, has been widely used for the treatment of HLH. However, its suppressive effect on immune system may also cause potential exacerbation of infection in autoimmune rheumatic disease-induced HLH patients complicated with severe infection. Therefore, the use of VP-16 in such cases was inconclusive. CASE SUMMARY In this case study, we propose a potentially effective strategy for managing a patient diagnosed with secondary HLH complicated with systemic lupus erythematosus (SLE) and chronic coronavirus disease 2019 infection. Our approach involves early administration of low-dose VP-16 (100 mg twice a week, 300 mg in total), combined with methylprednisolone, cyclophosphamide, and cyclosporine A. The administration of etoposide effectively led to improvements in various indices of HLH. CONCLUSION Low dose etoposide proves to be an effective approach in alleviating HLH while mitigating the risk of infection.

Solanum commersonii(2n=2x=24,1EBN,Endosperm Balance Number),native to the southern regions of Brazil,Uruguay,and north-eastern Argentina,is the first wild potato germplasm collected by botanists and exhibits a remarkable array of traits related to disease resistance and stress tolerance.In this study,we present a high-quality haplotype-resolved genome of S.commersonii.The two identified haplotypes demonstrate chromosome sizes of 706.48 and 711.55 Mb,respectively,with corresponding chromosome anchoring rates of 94.2 and 96.9％.Additionally,the contig N50 lengths are documented at 50.87 and 45.16 Mb.The gene annotation outcomes indicate that the haplotypes encompasses a gene count of 39 799 and 40078,respectively.The genome contiguity,completeness,and accuracy assessments collectively indicate that the current assembly has produced a high-quality genome of S.commersonii.Evolutionary analysis revealed significant positive selection acting on certain disease resistance genes,stress response genes,and environmentally adaptive genes during the evolutionary process of S.commersonii.These genes may be related to the formation of diverse and superior germplasm resources in the wild potato species S.commersonii.Furthermore,we utilized a hybrid population of S.commersonii and S.verrucosum to conduct the mapping of potato freezing tolerance genes.By combining BSA-seq analysis with traditional QTL mapping,we successfully mapped the potato freezing tolerance genes to a specific region on Chr07,spanning 1.25 Mb,with a phenotypic contribution rate of 18.81％.In short,current research provides a haplotype-resolved reference genome of the diploid wild potato species S.commersonii and establishes a foundation for further cloning and unraveling the mechanisms underlying cold tolerance in potatoes.

Background: Investigating the function of SATB1 in hepatocytes is essential for developing therapeutic strategies for autoimmune hepatitis (AIH). Although SATB1 has been extensively studied in immune cells, its specific activity in hepatocytes within the context of AIH remains unclear. Methods: SATB1 expression in AIH hepatocytes was assessed by qRT-PCR, Western blotting, flow cytometry, and immunohistochemistry. In vivo modulation used RNA interference viruses and overexpression plasmids. SATB1 ' s proinflammatory effects were analyzed with protein microarray, immunohistochemistry, and flow cytometry. Chemotactic effects on RAW264.7 macrophages were tested in vitro, with mechanisms explored by dualluciferase assays and CUT&RUN qPCR. Liver injury was evaluated by histopathology and serum biochemistry. Results: SATB1 was significantly upregulated in hepatocytes of AIH patients and models, showing a stronger increase in hepatocytes than in CD45+ cells, and positively correlated with liver injury severity. In vivo RNAimediated SATB1 inhibition reduced liver inflammation, while SATB1 overexpression aggravated AIH progression. Both interference and overexpression experiments confirmed that SATB1 promotes liver injury by facilitating the infiltration of proinflammatory (Ly6Chigh) macrophage. In vitro, supernatant from SATB1overexpressing hepatocytes enriched chemokine signaling pathways, leading to increased CCL2 expression and release, which attracted macrophages and drove their proinflammatory polarization. Mechanistically, SATB1 promoted CCL2 transcription by binding to its DNA and recruiting p300/CBP. Conclusions: This study reveals that SATB1 is upregulated in hepatocytes in AIH. Elevated SATB1 levels in liver cells contribute to autoimmune hepatitis by increasing CCL2 expression, promoting the recruitment of inflammatory monocyte-derived macrophage, and reshaping the composition of the liver immune microenvironment.

Lipoproteins and apolipoproteins are crucial in lipid metabolism, functioning as essential mediators in the transport of cholesterol and triglycerides and being closely related to the pathogenesis of multiple systems, including cardiovascular. Lipoproteins a (Lp(a)), as a unique subclass of lipoproteins, is a low-density lipoprotein(LDL)-like particle with pro-atherosclerotic and pro-inflammatory properties, displaying high heritability. More and more strong evidence points to a possible link between high amounts of Lp(a) and cardiac conditions like atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis (AS), making it a risk factor for heart diseases. In recent years, Lp(a)'s role in other diseases, including neurological disorders and cancer, has been increasingly recognized. Although therapies aimed at low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) have achieved significant success, elevated Lp(a) levels remain a significant clinical management problem. Despite the limited efficacy of current lipid-lowering therapies, major clinical advances in new Lp(a)-lowering therapies have significantly advanced the field. This review, grounded in the pathophysiology of lipoproteins, seeks to summarize the wide-ranging connections between lipoproteins (such as LDL-C and HDL-C) and various diseases, alongside the latest clinical developments, special emphasis is placed on the pivotal role of Lp(a) in cardiovascular disease, while also examining its future potential and mechanisms in other conditions. Furthermore, this review discusses Lp(a)-lowering therapies and highlights significant recent advances in emerging treatments, advocates for further exploration into Lp(a)'s pathogenic mechanisms and its potential as a therapeutic target, proposing new secondary prevention strategies for high-risk individuals.

BACKGROUND:Pulmonary embolism (PE) is a severe and acute cardiovascular syndrome with high mortality among patients with autoimmune inflammatory rheumatic diseases (AIIRDs). Accurate prediction and timely intervention play a pivotal role in enhancing survival rates. However, there is a notable scarcity of practical early prediction and risk assessment systems of PE in patients with AIIRD. METHODS:In the training cohort, 60 AIIRD with PE cases and 180 age-, gender-, and disease-matched AIIRD non-PE cases were identified from 7254 AIIRD cases in Tongji Hospital from 2014 to 2022. Univariable logistic regression (LR) and least absolute shrinkage and selection operator (LASSO) were used to select the clinical features for further training with machine learning (ML) methods, including random forest (RF), support vector machines (SVM), neural network (NN), logistic regression (LR), gradient boosted decision tree (GBDT), classification and regression trees (CART), and C5.0 models. The performances of these models were subsequently validated using a multicenter validation cohort. RESULTS:In the training cohort, 24 and 13 clinical features were selected by univariable LR and LASSO strategies, respectively. The five ML models (RF, SVM, NN, LR, and GBDT) showed promising performances, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.962-1.000 in the training cohort and 0.969-0.999 in the validation cohort. CART and C5.0 models achieved AUCs of 0.850 and 0.932, respectively, in the training cohort. Using D-dimer as a pre-screening index, the refined C5.0 model achieved an AUC exceeding 0.948 in the training cohort and an AUC above 0.925 in the validation cohort. These results markedly outperformed the use of D-dimer levels alone. CONCLUSION:ML-based models are proven to be precise for predicting the onset of PE in patients with AIIRD exhibiting clinical suspicion of PE. TRIAL REGISTRATION:Chictr.org.cn : ChiCTR2200059599.

Hemophagocytic lymphohistiocytosis (HLH) is a severe and life-threatening hyperinflammatory condition characterized by excessive activation of macrophages and T cells and resulted in multi-organ dysfunction. HLH can be a primary disease or secondary to infections, malignancy, and some autoimmune diseases, including adult-onset Still’s disease (AOSD) and systemic lupus erythematosus (SLE). However, it is rare for HLH to occur as a secondary condition to drug-induced lupus erythematosus (DILE). In this report, we present a case of HLH as an unusual complication during SLE treatment in a 31-year-old male patient. The patient initially suffered from active chronic hepatitis B (CHB) and was treated with pegylated INFα-2b (Peg-INFα-2b), tenofovir disoproxil and lamivudine. After 19 months, CHB obtained biochemical and virological response with HBsAg positive to HBsAb. The patient developed fever, headache, and cytopenia after Peg-INFα-2b treatment for 33 months, and laboratory studies revealed that ANA and anti dsDNA were positive. He displayed 5 features meeting the HLH-2004 criteria for diagnosis including fever, pancytopenia, hyperferritinemia, high levels of soluble CD25, and hemophagocytosis on bone marrow biopsy. The patient was initiated with a combination treatment of intravenous methylprednisolone pulse therapy, oral cyclosporine, and etoposide (VP-16), which was followed by a course of oral prednisolone, intravenous cyclophosphamide pulse therapy, and entecavir with complete response. To our knowledge, this is the first report of IFN-α induced SLE complicating with HLH. Physicians should consider the potential autoimmune side effects of IFN-α therapy and be alert to insidious HLH in patients diagnosed with SLE.

A multi-parental population is an innovative tool for mapping large numbers of loci and genetic modifications, particularly where they have been used for breeding and pre-breeding in crops. Frost injury is an environmental stress factor that greatly affects the growth, development, production efficiency, and geographical distribution of crops. No reported study has focused on genetic mapping and molecular marker development using diallel populations of potatoes. In this study, 23 successful cross combinations, obtained by a half diallel cross among 16 parents, including eight frost-tolerant advanced breeding lines and eight cultivars, were used to map the genetic loci for frost tolerance and to create a molecular marker-assisted selection (MAS) system. Three candidate regions related to frost tolerance on chromosomes II, V, and IX were mapped by bulked segregant analysis (BSA). Furthermore, six SNP markers associated with frost tolerance from candidate regions were developed and validated. Above all, a MAS system for the frost tolerance screening of early breeding offspring was established. This study highlights the practical advantages of applying diallel populations to broaden and improve frost-tolerant germplasm resources.

Our genomic investigation confirms the mechanism of 2n eggs formation in S. malmeanum and aid in optimizing the use of wild germplasm. Wild potatoes are a valuable source of agronomic traits. However, substantial reproductive barriers limit gene flow into cultivated species. 2n gametes are instrumental in preventing endosperm abortion caused by genetic imbalances in the endosperm. However, little is known about the molecular mechanisms underlying the formation of 2n gametes. Here, the wild species Solanum malmeanum Bitter (2x, 1EBN, endosperm balance number) was used in inter- and intrapoloid crosses with other Solanum species, with viable seeds being produced only when S. malmeanum was used as the female parent to cross the 2EBN Solanum genus and with the likely involvement of 2n gametes. Subsequently, we substantiated the formation of 2n eggs in S. malmeanum using fluorescence in situ hybridization (FISH) and genomic sequencing technology. Additionally, the transmission rate of maternal heterozygous polymorphism sites was assessed from a genomic perspective to analyze the mode of 2n egg formation in S. malmeanum × S. tuberosum and S. malmeanum × S. chacoense crosses; each cross acquired an average of 31.12

In the medical realm, the pivotal role of pathological Whole Slide Images (WSIs) in detecting cancer, tracking disease progression, and evaluating treatment efficacy is indisputable. Nevertheless, the identification and quantification of lesion areas in these gigapixel WSIs present a significant challenge due to their substantial size and the intricate details of lesions. To address these issues, we developed a novel multi-resolution and multi-scale cross fusion network (M 2 CF-Net), adept at managing large-scale pathological WSIs and capturing both fine details and context. Our model particularly focuses on segmenting local lymphocyte infiltration lesions in pathological WSIs of patients diagnosed with primary Sjogren's syndrome. By employing a patch-based training approach and combining interconnected elements via a multi-scale fusion technique, we enhance our model's capacity to detect and analyze structures and features in minor salivary gland section WSIs. Extensive experiments and ablation studies conducted on real-world clinical datasets affirm our model's superior accuracy in identifying lymphocyte-infiltrated regions over state-of-the-art models, with a performance improvement of up to 4.32% in terms of the Dice Similarity Coefficient.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is characterized by a wide range of dermatological and musculoskeletal manifestations, and its outcome has recently been improved greatly by optimizing management. However, the treatment strategies are not standardized and require further refinement. Secukinumab, a fully human monoclonal antibody targeting IL-17A, is approved for the treatment of autoimmune psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Here, a 53-year-old man was diagnosed with AS, and he presented scattered pustulosis in both hands and feet with a 5-year history of recurrent lumbosacral area pain and abnormal pain in the neck and front chest area. Secukinumab improved the patient's cutaneous lesion and prevented musculoskeletal pain by substituting adalimumab. Although only a few cases have been reported that secukinumab can effectively treat SAPHO syndrome complicated with AS, the efficacy remains controversial. Therefore, we hope to provide a novel valuable therapeutic strategy for SAPHO syndrome management, particularly in patients with skin lesions.

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis.

Freezing severely impacts potato production. Deciphering the pathways and metabolites that regulate the freezing tolerance of potato is useful in cultivation and breeding for hardiness. In the present study, Solanum acaule was identified to be more freezing tolerant than S. tuberosum. Furthermore, the two genotypes before/after exposure to 4 °C for 7 d with additional −1 °C for 12 h were analysed by RNA-seq and metabolomics, and the results were compared with the previous −1 °C for 12 h. The results showed that S. acaule activated numerous genes that differed from those of S. tuberosum. Among the genes, five pathways, such as the hormone signalling pathway, which includes salicylic acid, were enriched. Further metabolomics analysis showed that the content of salicylic acid was improved in S. acaule in response to −1 °C for 12 h. Moreover, exogenous application of 0.1 mM salicylic acid to potato was shown to improve constitutive freezing tolerance and increase the expression of HSFC1. Following transcriptome and metabolome analyses, it was documented that the content of SA that increased in freezing-tolerant S. acaule after exposure to cold condition, associated with the SA signalling pathway, enhanced potato freezing tolerance, probably through HSFC1.

Hepatocytes, the major parenchymal cells in the liver, are responsible for a variety of cellular functions including carbohydrate, lipid and protein metabolism, detoxification and immune cell activation to maintain liver homeotasis. Recent studies show hepatocytes play a pivotal role in liver inflammation. After receiving liver insults and inflammatory signals, hepatocytes may undergo organelle damage, and further respond by releasing mediators and expressing molecules that can act in the microenvironment as well as initiate a robust inflammatory response. In this review, we summarize how the hepatic organelle damage link to liver inflammation and introduce numerous hepatocyte-derived pro-inflammatory factors in response to chronic liver injury.

Dormancy and reducing sugar content in tubers are important traits of potato and are typical quantitative traits. Deciphering the genetic basis of potato tuber dormancy and reducing sugar content is a prerequisite for improving the two traits. DorB5.3, a stable major dormancy QTL (quantitative trait locus) previously mapped across seven environments, has been found to co-localize with REC_B_05-1, a QTL controlling reducing sugar content in potato tubers. In order to determine whether DorB5.3 was a pleiotropic QTL or not, a conditional QTL mapping was carried out, and the results suggested that DorB5.3 and REC_B_05-1 were the same QTL, controlling the dormancy and reducing sugar content in potato tubers simultaneously. Conditional QTL mapping also uncovered three pairs of epistatic QTLs which were independent of the reducing sugar content and were significant for deciphering the genetic basis of dormancy. Five genes were picked out as putative causal genes controlling DorB5.3, according to the genome annotation and transcriptomic data. The pleiotropic DorB5.3 along with the negative correlation between the causal and resultant traits provided a possibility that potato breeders could prolong the dormancy period and scale back the reducing sugar content of potato tubers in one breeding program. The results of this study could pave a way for understanding the genetic basis of both dormancy and reducing sugar content in potato breeding programs.