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Fungal laccases play important roles in the degradation of lignocellulose. In this study, the laccase producing cotton straw medium for Pleurotus ostreatus was optimized by single-factor and orthogonal experiments, and to investigate the role of Lacc1 gene, one of the laccase-encoding genes, in the degradation of cotton straw lignin, an overexpression strain of Lacc1 gene was constructed, which was analyzed for the characteristics of lignin degradation. The results demonstrated that the culture conditions with the highest lignin degradation efficiency of the P. ostreatus were the cotton straw particle size of 0.75 mm, a solid–liquid ratio of 1:3 and containing 0.25 g/L of Tween in the medium, as well as an incubation temperature of 26 °C. Two overexpression strains (OE L1-1 and OE L1-4) of Lacc1 gene were obtained, and the gene expression increased 12.08- and 33.04-fold, respectively. The results of 1H-NMR and FTIR analyses of significant changes in lignin structure revealed that Lacc1 gene accelerated the degradation of lignin G-units and involved in the cleavage of β-O-4 linkages and the demethylation of lignin units. These findings will help to improve the efficiency of biodelignification and expand our understanding of its mechanism.

Background Juvenile Idiopathic Arthritis (JIA) represents the most prevalent chronic rheumatic disease in childhood. Its etiology is multifactorial, with growing evidence pointing to a significant genetic contribution to disease susceptibility. Recent genomic studies have identified a range of inherited variants associated with distinct arthritis phenotypes, among which LACC1 -related arthritis has emerged as a notable contributor, particularly in familial cases with variable clinical presentations. In this study, we report the clinical and genetic characterization of a novel LACC1 c.658G>A (p. Asp220Asn) variant identified in multiple affected individuals within a large consanguineous extended family, providing further insights into the genetic underpinnings of familial juvenile arthritis. Methods whole exome sequencing (WES) was performed on affected patients and findings were confirmed using sanger sequencing in family members. In-silico protein modeling was performed for model evaluation and visualization. LACC1 protein expression was measured in isolated and differentiated macrophages from selected patients and their carrier relatives. Allele frequency of LACC1 variants were analyzed in available in-house datasets. Results Four affected patients with non-systemic seronegative juvenile arthritis of different severities were found to have a novel homozygous mutation in LACC1 c.658G>A (p. Asp220Asn). Parents of affected patients were all heterozygous carriers. LACC1 protein expression showed variability, but it was markedly reduced in the index patient with the most severe phenotype. Analysis of allele frequency of other LACC1 variants showed equivalent distribution in both JIA and non-JIA genetic datasets. Conclusion Characterizing the molecular mechanisms of LACC1 -related arthritis may refine the biological taxonomy of JIA. This work contributes to the understanding of monogenic juvenile arthritis forms and supports the integration of LACC1 testing into the diagnostic approach for familial or atypical cases.

Objective This study investigates the predictive capacity of LACC1 regarding the response to upadacitinib (UPA) in individuals with rheumatoid arthritis (RA). Methods The study involved sixty adult patients with active RA who either did not respond well to or could not tolerate methotrexate. The regimen involved UPA monotherapy at 15 mg/day, while maintaining a fixed dose of glucocorticoids was acceptable. Follow-up was planned for 24 weeks. Treatment response was assessed using Clinical Disease Activity Index, Simplified Disease Activity Index, tender joint count (TJC), swollen joint count, and Health Assessment Questionnaire. Moreover, parameters associated with treatment response to UPA were measured. Results Serum LACC1 levels may be protective in predicting response to UPA therapy. Age, prolonged disease duration, increased use of csDMARDs, low neutrophil counts, and higher inflammatory markers were strongly associated with non-good response. Prolonged disease duration, increased TJC/68, low neutrophil count, and high GM-CSF levels were all independent unfavorable predictors of good response to UPA treatment, while higher serum LACC1 levels were more helpful in predicting good response. Patients with an extended disease course, high TJC/68, and significantly increased inflammatory cytokines should be advised of the potential for poor early outcomes. Conclusion Higher serum LACC1 levels are associated with better efficacy of UPA, with implications for optimizing clinical individualized dosing strategies.

Temporomandibular joint osteoarthritis (TMJOA) is a multifaceted degenerative disease characterized by progressive cartilage degradation, chronic pain, and functional limitations of the TMJ, significantly affecting patients’ quality of life. Although metabolic homeostasis in chondrocytes is crucial for cartilage health, the mechanisms underlying metabolic dysregulation in TMJOA remain poorly characterized. This study aimed to investigate the metabolic imbalance in TMJOA cartilage and explore novel therapeutic strategies targeting metabolic reprogramming. RNA sequencing revealed a significant imbalance between glycolysis and oxidative phosphorylation (OXPHOS) in TMJOA cartilage, with a marked shift toward glycolysis, which is associated with inflammation and cartilage degradation. To counteract this imbalance, Laccase domain-containing 1 (Lacc1), a metabolic regulator involved in both inflammation and metabolic homeostasis, was selected for investigation, as its role in chondrocytes had not been explored. We engineered macrophage-derived extracellular vesicles (EVs) to overexpress Lacc1 (OE-EVs), aiming to restore metabolic balance and modulate inflammation in chondrocytes. In vitro, OE-EVs significantly reduced IL-1β-induced inflammation, inhibited glycolysis by decreasing key glycolytic enzymes, improved mitochondrial function by decreasing mitochondrial superoxide levels, and the restoration of normal mitochondrial structure. In vivo, micro-computed tomography (Micro-CT) and histological analyses demonstrated that OE-EVs effectively alleviated inflammation and promoted cartilage repair, as indicated by a 1.55-fold increase in toluidine blue-stained cartilage area compared to the TMJOA group, reflecting improved cartilage matrix integrity and proteoglycan retention. These findings highlight the therapeutic potential of Lacc1-engineered EVs to target mitochondrial metabolism, reestablish metabolic homeostasis, and reduce inflammation in TMJOA, offering a novel and promising strategy for improving clinical outcomes in TMJOA patients. Graphical abstract

Background The aim of this study was to explore the mechanism whereby LACC1 regulates the intestinal flora in a mouse model of inflammatory bowel disease (IBD). Methods C57BL/6 and Lacc1 −/− mice were used to establish a mouse model of IBD induced by dextran sodium sulfate (DSS). The effects of Lacc1 deletion in mice were evaluated. Changes in the body weight and stool blood were recorded daily. After 7 days of successful modeling, the mice were sacrificed, blood was collected from the eyeballs, the entire colon was dissected and separated, and the length of the colon was measured. Results Compared with the wild-type (WT) DSS model group, the Lacc1 −/− DSS model group showed a significantly higher disease activity index score ( P  < 0.05), significantly faster weight loss ( P  < 0.05), and a significantly shorter colon ( P  < 0.05), indicating that the colonic mucosal tissue was seriously damaged in the Lacc1 −/− DSS model group ( P  < 0.05). Serum IL-1β, IL-6, TNF-α, and IFN-γ levels were significantly higher in the Lacc1 −/− DSS model group than the WT DSS model group. Principal coordinate analysis showed that there were significant microbiome differences between the WT, Lacc1 −/− , WT DSS model, and Lacc1 −/− DSS model groups ( P  < 0.05). Linear discriminant analysis effect size analysis showed that under natural conditions, Lacc1 −/− mice had significant changes in their intestinal flora compared with control mice (LDA value > 3 or < 3, P  < 0.05). Conclusions Lacc1 deletion aggravates DSS-induced IBD in mice.

Abstract Background Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential. Methods Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn's disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping. Results By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity. Conclusions Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD.

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases with probably differential underlying physiopathology. Despite the revolutionary era of biologics, some patients remain difficult to treat because of disease severity, drug adverse events, drug allergy or association with severe comorbidities, i.e., uveitis, interstitial lung disease and macrophagic activation syndrome. Janus Kinase (JAK) inhibitors are small molecules that target JAK/Signal Transducers and Activators of Transcription (STAT) pathways, which could then prevent the activity of several proinflammatory cytokines. They may provide a useful alternative in these cases of JIA or in patients actually affected by Mendelian disorders mimicking JIA, such as type I interferonopathies with joint involvement, and might be the bridge for haematopoietic stem cell transplantation in these disabling conditions. As these treatments may have side effects that should not be ignored, ongoing and further controlled studies are still needed to provide data underlying long-term safety considerations in children and delineate subsets of JIA patients that will benefit from these promising treatments.

Background Some juvenile idiopathic arthritis (JIA) patients have a familial aggregation of the disease, and a few have been found to have a juvenile arthritis (JA) phenotype caused by a genetic mutation. JA due to LACC1 defects is a rare condition and it was never reported in China. Methods The clinical and molecular characteristics of a child with LACC1 gene mutation‐related juvenile arthritis, diagnosed by high‐throughput sequencing in Wuhan children's Hospital in 2021 were analyzed retrospectively; The literature and database were reviewed to summarize the clinical data and genotype characteristics of patients with JA caused by LACC1 gene mutation. Results Here, we report a 19‐month‐old Chinese male patient who presented with bilateral limb edema without a history of fever. Laboratory tests showed had moderate anemia and signs of inflammation: hemoglobin of 76 g/L, white blood cell count of 20.53 × 109, and platelet count of 1194 × 109; MRI showed the patient had synovitis and tenosynovitis in bilateral hands and wrists. Whole‐exome sequencing (WES) detected compound heterozygous variants, novel c.446_449dupTAAA and c.889T>C, in the LACC1 gene. Of the 52 patients reported in the literature (including this case), 38.9% had clinical symptoms of systemic juvenile idiopathic arthritis (sJIA), which tended to be caused by loss‐of‐function (LOF) mutation. Findings in this study expanded the spectrum of pathogenic variants and reveal the phenotypic heterogeneity of LACC1‐JA. Conclusions Our study reported a rare case of juvenile arthritis, which is due to the compound heterozygous mutation of LACC1, including a new novel frameshift mutation c.446_449dupTAAA, and LACC1 C297R variant causes disease by potentially modifying the local conformation of proteins. The clinical and genetic findings in our study show that LACC1‐JA is highly heterogeneous, and gene testing is required for juvenile arthritis patients with a high inflammatory response at a young onset age. Our study reported a rare case of juvenile arthritis, which is due to the compound heterozygous mutation of LACC1, including a new novel frameshift mutation c.446_449dupTAAA, and LACC1 C297R variant causes disease by potentially modifying the local conformation of proteins.

To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1–12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1–10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed’s syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries.