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Objective To study the demographic and clinical characteristics, correlation of genotype and phenotype and treatment of Blau syndrome to facilitate early diagnosis and timely treatment of Blau syndrome. Methods Seventy-two patients with Blau syndrome from 11 centers from May 2006 to April 2022 were retrospectively analyzed, and their general information, clinical data, laboratory examination and treatment medication were collected. Results The distribution of patients with Blau syndrome was uniform in geographical north and south of China, and there was no obvious gender bias. The mean age of onset was (14.30±12.81) months, and the age of diagnosis was (55.18±36.22) months. 35% of patients with Blau syndrome happened before 1 year old, and all patients developed before 5 years old. 87.50% (63/72) had granulomatous arthritis, 65.28% (47/72) had rash, 36.11% (26/72) had ocular involvement, 27.78% (20/72) had fever, and 15.28% (11/72) had pulmonary involvement. Arthritic manifestations of Blau syndrome were most at risk, followed by rash, ocular involvement, and fever.The first 25 months of the disease, the risk of developing a rash was the greatest. The risk of developing arthritis was the greatest between 25 months and 84 months. The main mutations were p.R334Q and p.R334W, and patients with p.R334Q mutation had relatively high incidence of fever (35.71%[5/14] vs. 14.29%[1/7], P=0.43) and ocular involvement (42.86%[6/14]vs. 28.57%[2/7], P=0.51). There was a relatively high incidence of rash (85.71%[6/7] vs. 64.29%[9/14], P=0.59) in patients with the p.R334W mutation. Forty-five patients(62.50%)were treated with a combina-tion of glucocorticoid and methotrexate. Twenty-two patients were treated with tumor necrosis factor antagonist in addition to glucocorticoid and methotrexate. Conclusions The risk of different clinical manifestations of Blau syndrome from high to low was arthritis, followed by rash, ocular involvement and fever. The main treatment was glucocorticoid combined with methotrexate, to which biological agents could be added.

Objective: Glucocorticoid‐induced tumor necrosis factor receptor superfamily–related protein (GITR), with its ligand (GITRL), plays an important role in CD4+ T cell–mediated autoimmunity. This study aimed to investigate the underlying mechanisms of GITRL in primary Sjögren syndrome (pSS). Methods: Patients with pSS and healthy controls were recruited. Serum GITRL and Th17‐related cytokines were determined. RNA sequencing was performed to decipher key signal pathways. Nonobese diabetes (NOD) mice were adopted as experimental Sjögren models and recombinant adeno‐associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo. Results: Serum GITRL was significantly higher in patients with pSS and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement, and disease activity. Serum GITRL was correlated with Th17‐related cytokines. GITRL promoted the expansion of Th17 and Th17.1 cells. Expansion of granulocyte‐macrophage colony‐stimulating factor positive (GM‐CSF+) CD4+ T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM‐CSF could stimulate GITRL expression on monocytes. RNA sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and the expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL–mTORC1–GM‐CSF positive loop in pathogenic Th17 response in pSS. Administration of an rAAV vector expressing short hairpin RNA targeting GITRL alleviated disease progression in NOD mice. Conclusion: Our results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL–mTORC1–GM‐CSF loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS. [ABSTRACT FROM AUTHOR]

Globally, natural habitats have suffered tremendous damage from human activities, a phenomenon that is increasingly evident in basin regions. The management of natural habitats in basin regions is dependent on understanding of the various impacts of human activities on these ecosystems. Despite the various studies that have been conducted on the effects of human activities on habitats in basin regions, there is still a lot of doubt regarding the impact of these activities on the quality of basin ecosystems. To fill this gap, this study employs a series of spatial analysis methods and logistic regression modeling to delve into the spatial and temporal patterns of human activities and habitat quality in the Yangtze River Basin (YRB) as well as the differences in the impacts of human activities on habitat quality in the sub-basins of the YRB. The findings indicate a 0.408% decline in the overall environmental quality of the YRB area from 2000 to 2020, accompanied by a 15.396% surge in human activities. Notably, the southeastern Qilian Mountains and the mountainous regions in the northwestern sector of the Sichuan Basin emerge as pivotal areas for habitat quality restoration. Conversely, the southwestern Qilian Mountains and the urban clusters in the Yangtze River Delta (YRD) face significant habitat quality deterioration. Spatial regression analyses reveal a noteworthy trend: the burgeoning human activities in the Yangtze River region pose a substantial threat to habitat recovery efforts. Further differential analyses focusing on the upper, middle, and lower basin segments underscore that human activities exert the most pronounced impact on habitat quality within the lower basin region, while the upper basin experiences the least influence. The implications of this study are manifold. It furnishes valuable policy insights for the comprehensive management and targeted preservation of habitats across the YRB. By delineating areas of habitat restoration and degradation and highlighting the differential impacts of human activities across basin segments, this research lays a solid foundation for informed decision making in habitat conservation and ecosystem management within the YRB. [ABSTRACT FROM AUTHOR]

Importance: Systemic lupus erythematosus (SLE) is a diffuse connective tissue disease with complex clinical manifestations and prolonged course. The early diagnosis and condition monitoring of SLE are crucial to disease prognosis. Objective: To assess the diagnostic value of long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) in childhood‐onset SLE (cSLE). Methods: Fifty‐seven children diagnosed with SLE, 40 children diagnosed with juvenile idiopathic arthritis (JIA), and 40 healthy children were included. Peripheral blood samples from each patient were collected. A quantitative polymerase chain reaction was used to confirm the expression of lncNEAT1_1 and lncNEAT1_2 in peripheral blood. Associations among parameters were analyzed using the Mann‐Whitney U test or independent sample t‐test. Results: The expression of both lncNEAT1_1 and lncNEAT1_2 in patients with cSLE were significantly higher than that of healthy control and patients with JIA. Receiver operating characteristic curves revealed an area under the curve (AUC) of 0.633 (95% confidence interval [CI], 0.524–0.742; P = 0.024) for lncNEAT1_1. The AUC of lncNEAT1_2 was 0.812 (95% CI, 0.727–0.897; P < 0.0001) to discriminate individuals with cSLE from health control and children with JIA with a sensitivity of 0.622 and a specificity of 0.925. Moreover, lncNEAT1_2 expression was higher in patients with cSLE presenting with fever, lupus nephritis, elevated erythrocyte sedimentation rate, active disease activity, and decreased C3 level, compared with those without these conditions. However, no similar correlation was observed for lncNEAT1_1. Interpretation: The expression of lncNEAT1_2 was significantly elevated in children with SLE, especially those with fever, renal involvement, and low C3 levels. These findings suggest that lncNEAT1_2 may represent a potential biomarker for cSLE. [ABSTRACT FROM AUTHOR]

Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumorigenesis and progression in murine colon carcinoma models. Immune profiling of the TME revealed broad mobilizations of [IgG1.sup.+] plasma cells, [CD8.sup.+] T cells, [CD103.sup.+] DCs, and active tertiary lymphoid structure formation, suggesting an effective antitumor microenvironment in hIgG1-G396R CRC patients. Mechanistically, this variant potentiated tumorassociated antigen-specific (TAA-specific) plasma cell differentiation and thus antibody production. These elevated TAA-specific IgG2c antibodies in turn efficiently boosted the antibody-dependent tumor cell phagocytosis and TAA presentation to effector [CD8.sup.+] T cells. Notably, adoptive transfer of TAA-specific class-switched memory B cells harboring this variant exhibited therapeutic efficacy in murine tumor models, indicating their clinical potential. All these results prompted a prospective investigation of hIgG1-G396R in patients with CRC as a biomarker for clinical prognosis and demonstrated that manipulating the functionality of [IgG1.sup.+] memory B cells in tumors could improve immunotherapy outcomes., Introduction Effective immune responses are indispensable for optimal cancer treatment; however, tumor cells often evade immune clearance by inhibiting neoantigen presentation and inducing immune silencing in the tumor microenvironment (TME) [...]

This paper studies a three-dimensional automated storage and retrieval system that uses conveyors for depth transportation and a crane for both horizontal and vertical transportation. While previous studies put input and output points together at the system bottom, we consider separating and elevating them by proposing four I/O point policies: input and output points at two sides, input and output points elevated at one side, input and output points elevated at two sides, input and output points elevated at a midpoint. We build travel time models to analyse these policies and use simulation for validation. We theoretically find the optimal system structure and compare these I/O point policies, in terms of expected S/R machine travel time. The results show that the square-in-time structure is optimal in most cases and the mid-point elevation I/O point policy performs the best in terms of expected travel time. Moreover, we compare our I/O point policies with the lower mid-point policy. The results show that the mid-point elevation I/O point policy outperforms the I/O point at the lower mid-point by about 6.07 % in terms of expected travel time, while other I/O point policies are dominated by the I/O point at the lower mid-point. [ABSTRACT FROM AUTHOR]