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Aberrant hypoxic stress will initiate a cascade of pathological consequence observed prominently in tumorigenesis. Understanding of hypoxia's role in tumorigenesis is highly essential for developing effective therapeutics, which necessitates reliable tools to specifically distinguish hypoxic tumor cells (or tissues) and correlate their dynamics with the status of disease in complex living settings for precise theranostics. So far, disparate hypoxia‐responsive probe molecules and prodrugs were designed via chemical or enzymatic reactions, yet their capability in real‐time reporting pathogenesis development is often compromised due to unrestricted diffusion and less selectivity towards the environmental responsiveness. Herein we present an oxygen‐insensitive nitroreductase (NTR)‐activatable glycan metabolic reporter (pNB‐ManNAz) capable of covalently labeling hypoxic tumor cells and tissues. Under pathophysiological hypoxic environments, the caged non‐metabolizable precursor pNB‐ManNAz exhibited unique responsiveness to cellular NTR, culminating in structural self‐immolation and the resultant ManNAz could incorporate onto cell surface glycoproteins, thereby facilitating fluorescence labeling via bioorthogonal chemistry. This NTR‐responsive metabolic reporter demonstrated broad applicability for multicellular hypoxia labeling, particularly in the dynamic monitoring of orthotopic tumorigenesis and targeted tumor phototherapy in vivo. We anticipate that this approach holds promise for investigating hypoxia‐related pathological progression, offering valuable insights for accurate diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Objective: One of the leading causes of morbidity and mortality among patients with systemic lupus erythematosus (SLE) is infections. The expression of the ectonucleotidase CD38 on the surface of CD8+ T cells has been linked to compromised cytotoxic function. The aim of this prospective study was to assess whether the presence of CD8+CD38+ in the peripheral blood of patients with SLE can serve as a biomarker for infectious complications. Methods: A cohort of 80 patients with SLE were recruited over 18 months. The rate of clinically significant infections and presence of CD8+CD38+ T cells in the peripheral blood were monitored at each clinic visit. The patients were classified into high CD38+ and low CD38+ CD8+ T cells using flow cytometry and a previously established cutoff rate of 28.4%. Results: A total of 20 infections were registered over the study period. We observed that the patients with an expanded CD8+CD38+ T cell population in the peripheral blood had a higher rate of recurrent infections and a higher likelihood of infection compared with patients with a low CD8+CD38+ T cell population. The levels of CD38 in CD8+ T cells remained stable over time in the studied subjects. Conclusion: High levels of CD8+CD38+ T cells in the peripheral blood of patients with SLE identify a subgroup prone to infections for whom proper clinical measures should be applied. [ABSTRACT FROM AUTHOR]

Objective: There is a notable absence of extensive Chinese studies involving monogenic congenital hyperinsulinism (CHI). The purpose of this large retrospective Chinese cohort with monogenic CHI from a national children's medical center was to analyze the genetic and clinical characteristics. Methods: We compared clinical characteristics grouped by genotypes based on CHI‐targeted next‐generation sequencing (tNGS) and performed subgroup analyses by onset time. Results: Totally, 121 non‐consanguineous patients were enrolled. Among them, 79 patients (65.3%) had variants in ATP‐sensitive potassium channel (KATP) genes (62 heterozygotes and 17 compound heterozygotes), 35 (28.9%) in glutamate dehydrogenase 1 (GLUD1), and 7 (5.8%) in rare genes (hydroxyacyl‐CoA dehydrogenase [HADH], glucokinase [GCK], and hepatocyte nuclear factor 4 alpha [HNF4A]). Ten patients had ATP binding cassette subfamily C member 8 (ABCC8) variants (p.G111R), and 12 had GLUD1 variants (p.S498L), suggesting two potential founder variants. Three ABCC8 variants (p.G1478R, p.L580_S581insFASL, and p.S986 ∗) and two HNF4A variants (p.R63W and p.V382I) were previously reported to be associated with diabetes. Non‐surgical treatment was effective in 65.9% of patients with KATP variants, while in 100% of those with non‐KATP variants. For the subgroup of KATP variants, neonatal‐onset patients tended to present with mild symptoms (67.9% versus 19.3%), had a higher proportion of surgical intervention (24.5% versus 3.8%), and displayed higher levels of serum insulin and C‐peptide than non‐neonatal onset ones (p < 0.001). Conclusion: The absence of homozygous variants in KATP genes and a quite higher proportion of GLUD1 variants than previous cohorts, may explain a high response rate of non‐surgical treatment in this study. Surgery might be considered for neonatal‐onset children, especially when KATP variants were discovered but not for those carried variants reported to cause diabetes in later life. While expanding the genotypic spectrum, we also highlight the clinical significance of genetic screening. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid‐binding Ig‐like lectin 10 (Siglec‐10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec‐10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec‐10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec‐10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec‐10 modulates immune responses and facilitates immune escape in cancer. Siglec‐10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec‐10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec‐10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics. [ABSTRACT FROM AUTHOR]

The Chemistry & Industry article "Highlights" covers various topics in organic chemistry, including the synthesis of an E-selectin antagonist and decarboxylative cyclisation of 3-alkynyl-2-pyrones. It also discusses the development of a molecular scale vehicle on a copper road and the efficient conversion of CO2 to multicarbon products. Additionally, the article highlights advancements in PFAS removal, oil spill remediation, and atmospheric water harvesting technologies. The research presented in the article showcases innovative approaches to address environmental and chemical challenges. [Extracted from the article]

Objective: Our objective was to evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH)‐associated genes among patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in patients with sJIA from an established cohort. Sequence data from control participants were obtained in silico (database of Genotypes and Phenotypes: phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test package. Significance was defined as P < 0.05 after 100,000 permutations. Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome‐derived target data from 3,000 controls. Quality control operations produced a set of 480 cases and 2,924 ancestrally matched control participants. RVT of cases and controls revealed a significant association with rare protein‐altering variants (minor allele frequency [MAF] < 0.01) of STXBP2 (P = 0.020) and ultrarare variants (MAF < 0.001) of STXBP2 (P = 0.006) and UNC13D (P = 0.046). A subanalysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare UNC13D variants (P = 0.0047) between the groups. Additionally, patients with sJIA more often carried two or more HLH variants than did controls (P = 0.007), driven largely by digenic combinations involving LYST. Conclusion: We identified an enrichment of rare HLH variants in patients with sJIA compared with controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to elucidate the alterations in Follistatin‐like protein 1 (FSTL1) and its association with the pathological process of periodontitis. Methods: This study included 48 patients with periodontitis and 42 healthy controls. The expression level of FSTL1 in the gingiva was determined by RT‐qPCR, validated using the dataset GSE16134, and subsequently examined by western blotting. Bioinformatics analysis revealed a single‐cell distribution of FSTL1, characteristic of angiogenesis and immune cell infiltration. The expression and distribution of FSTL1, vascular endothelial marker protein CD31 and myeloperoxidase (MPO), the indicator of neutrophil activity, were determined by immunohistochemistry (IHC). A series of correlation analyses was performed to determine the associations between FSTL1 and clinical parameters, including probing depth (PD) and clinical attachment loss (CAL), and their potential role in angiogenesis (CD31) and neutrophil infiltration (MPO). Results: FSTL1 was significantly upregulated in the gingiva of patients with periodontitis compared to their healthy counterparts. In addition, FSTL1 was positively correlated with the clinical parameters PD (r =.5971, p =.0005) and CAL (r =.6078, p =.0004). Bioinformatic analysis and IHC indicated that high FSTL1 expression was significantly correlated with angiogenesis and neutrophil infiltration in periodontitis. Moreover, receiver operating characteristic (ROC) analysis demonstrated that FSTL1 could serve as an independent indicator for evaluating the severity of periodontitis (area under the curve [AUC] = 0.9011, p <.0001). Conclusion: This study demonstrated FSTL1 upregulation in periodontitis and its potential contribution to the disease via angiogenesis and neutrophil infiltration. [ABSTRACT FROM AUTHOR]

Sialic acid is a unique sugar moiety that resides in the distal and most accessible position of the glycans on mammalian cell surface and extracellular glycoproteins and glycolipids. The potential for sialic acid to obscure underlying structures has long been postulated, but the means by which such structural changes directly affect biological processes continues to be elucidated. Here, we appraise the growing body of literature detailing the importance of sialic acid for the generation, differentiation, function and death of haematopoietic cells. We conclude that sialylation is a critical post‐translational modification utilized in haematopoiesis to meet the dynamic needs of the organism by enforcing rapid changes in availability of lineage‐specific cell types. Though long thought to be generated only cell‐autonomously within the intracellular ER‐Golgi secretory apparatus, emerging data also demonstrate previously unexpected diversity in the mechanisms of sialylation. Emphasis is afforded to the mechanism of extrinsic sialylation, whereby extracellular enzymes remodel cell surface and extracellular glycans, supported by charged sugar donor molecules from activated platelets. [ABSTRACT FROM AUTHOR]

The biggest obstacles in treating cancer with traditional chemotherapy are unpleasant side effects and drug resistance. A growing amount of interest has been exhibited in using aptamers as target ligands for targeted cancer therapy and specific cancer cell identification due to their distinct benefits. Aptamer‐conjugated nano‐materials have recently provided new prospects in cancer treatment with their improved therapeutic efficacy and capability of reducing toxicity. Consequently, they are not perceived as alien substances our body, which allows their comfortable acceptance. Several tumor markers such as nucleolin, mucin, and the epidermal growth factor receptor can be effectively recognized by aptamers. In addition, glycoproteins on the surface of tumor cells can be recognized using aptamers. So surface modification of drug by aptamer are accomplished for enhanced tumor‐specific recognition by which drug‐specific accretion, internalization, and drug retention in tumors increased through specific ligand‐mediated interactions and thus therapeutic index is increased. Here, we highlight some promising classes of aptamer‐conjugated nanoparticles for the specific recognition of cancer cells and targeted drug delivery and the molecular mechanism and immunomodulatory regulation of these aptamer have been focused. [ABSTRACT FROM AUTHOR]

Background. ATP binding cassette transporter A1 (ABCA1) is a candidate gene within a POAG susceptibility locus by GWAS analysis, and it is involved in IOP modulation via the Cav1/eNOS/NO signaling pathway. We aim to examine the phenotype of ABCA1 deletion in the ABCA1 gene knockout (Abca1−/−) mice. Methods. The anterior segments of Abca1−/− eyes were imaged by slit‐lamp microscopy and anterior segment OCT. IOPs were measured by rebound tonometry. By perfusing enucleated eyes at various pressures, the aqueous humor outflow facility was determined. The mRNA expressions of ABCA1, Cav1, and eNOS were measured by RT‐qPCR. The protein expressions were analyzed by western blot and immunofluorescence staining. Results. There was no significant difference in the anterior segment morphology of Abca1−/− mice. IOP and aqueous humor outflow facility did not change in Abca1−/− mice compared with wild‐type mice. mRNA and protein expressions of ABCA1 were significantly lower in the outflow tissue of Abca1−/− eyes. The expressions of Cav1 and eNOS were both significantly upregulated in the outflow tissue of Abca1−/− eyes. Conclusion. ABCA1 deletion does not affect IOP and aqueous humor outflow function but the Cav1/eNOS/NO pathway is changed in Abca1−/− mice. The function of ABCA1 in aqueous humor outflow still requires further research. [ABSTRACT FROM AUTHOR]

The glycosylphosphatidylinositol (GPI)‐anchored protein cluster of differentiation 109 (CD109) is expressed on many human cell types and modulates the transforming growth factor β (TGF‐β) signaling network. CD109 belongs to the alpha‐macroglobulin family of proteins, known for their protease‐triggered conformational changes. However, the effect of proteolysis on CD109 and its conformation are unknown. Here, we investigated the interactions of CD109 with proteases. We found that a diverse selection of proteases cleaved peptide bonds within the predicted bait region of CD109, inducing a conformational change that activated the thiol ester of CD109. We show CD109 was able to conjugate proteases with this thiol ester and decrease their activity toward protein substrates, demonstrating that CD109 is a protease inhibitor. We additionally found that CD109 has a unique mechanism whereby its GPI‐anchored macroglobulin 8 (MG8) domain dissociates during its conformational change, allowing proteases to release CD109 from the cell surface by a precise mechanism and not unspecific shedding. We conclude that proteolysis of the CD109 bait region affects both its structure and location, and that interactions between CD109 and proteases may be important to understanding its functions, for example, as a TGF‐β co‐receptor. [ABSTRACT FROM AUTHOR]

Background and Aims: To further substantiate the role of antibody‐mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane‐bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course. Methods: We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters. Results: The genotype frequencies of rs28371582, a 21‐bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p.009; Del/Del genotype 16.8% vs. 7.7%, p.005, odds ratio: 2.43 [1.27–4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040–0.490, p.019). The presence of CD59 rs141385724 was associated with less severe pre‐diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083–1.80, p.032). Interpretation: MMN susceptibility is associated with a 21‐bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long‐term disease outcome. Taken together, these results point out the relevance of the pre‐C5 level of the complement cascade in the inflammatory processes underlying MMN. [ABSTRACT FROM AUTHOR]

Objective: Investigating T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3), Galectin 9 (Gal‐9), CD160 expression and tumor‐infiltrating lymphocytes (TILs) and correlation with clinicopathological characteristics of salivary adenoid cystic carcinoma (SACC). Methods: Sixty cases of SACC were detected by immunohistochemical staining to evaluate TIM‐3, Gal‐9, and CD160 expression and analyze the correlation between TIM‐3, Gal‐9, CD160 expression and clinicopathologic features by rank‐sum test. The association of TILs with TIM‐3, Gal‐9, and CD160 expression in SACC stromal was done by Chi‐square test. Results: TIM‐3 and CD160 overexpression were correlated with recurrence of SACC (p = 0.029, p = 0.007, respectively). High Gal‐9 expression was correlated with pathological classification (p = 0.018). The average percentage of TILs was 18.2% in SACC and most of TILs were more likely to occur in minor salivary glands (p = 0.038). Pairwise positive correlations were observed between the expression of TIM‐3, Gal‐9, and CD160 in tumor cells as well as in TILs, respectively. Conclusion: Low density of TILs was characteristic of the SACC microenvironment, with upregulation of TIM‐3, Gal‐9, and CD160 all occurring. However, TIM‐3, Gal‐9, and CD160 expression in the stromal dependent on the number of TILs represent potential therapeutic targets in SACC. [ABSTRACT FROM AUTHOR]

Objectives: Radiation injury is common after radiotherapy for head and neck cancer. Radiotherapy can reshape the immune microenvironment and cause immunosuppression, including dysregulation of immune checkpoints (ICs). However, the relationship between oral ICs expression after radiation and the development of second primary tumors is unclear. Methods: Clinical specimens of second primary oral squamous cell carcinoma after radiotherapy (s‐OSCC) and primary OSCC (p‐OSCC) were collected. The expression and prognostic value of PD‐1, VISTA, and TIM‐3 were analyzed using immunohistochemistry. To further clarify the relationship between radiation and ICs alteration, a rat model was constructed to explore the spatiotemporal changes of ICs in the oral mucosa after radiation. Results: In carcinoma tissue, the expression of TIM‐3 was higher in s‐OSCC than in p‐OSCC, while the expression of PD‐1 and VISTA was similar between the groups. In para‐carcinoma tissue, the expression of PD‐1, VISTA, and TIM‐3 was higher in s‐OSCC. High ICs expression was associated with poor survival. In the rat model, ICs were locally upregulated in the irradiated tongue. Moreover, there was a bystander effect, in which the ICs were also upregulated in the unirradiated site. Conclusion: Radiation may upregulate ICs expression in oral mucosa and contribute to the development of s‐OSCC. [ABSTRACT FROM AUTHOR]

Introduction: Flow cytometry‐based paroxysmal nocturnal hemoglobinuria (PNH) testing involves utilization of monoclonal antibodies against GPI‐linked proteins and FLAER. The ability of FLAER to bind to a wide variety of GPI‐linked structures and to be utilized across different leukocyte subsets is remarkable. We hypothesize that FLAER as a standalone reagent may be equally effective for detecting PNH clones. The present study intends to compare the results of a FLAER alone‐based strategy to the recommended FLAER+GPI‐linked protein‐based approach for applicability in clinical settings. Methods: EDTA‐anticoagulated blood samples from patients for PNH workup were tested for PNH by multiparametric flow cytometry. A conventional panel comprising gating markers (CD45 for WBC, CD15 for granulocytes, and CD64 for monocytes) and a combination of FLAER and GPI‐linked markers, such as CD24 and CD14, henceforth referred to as the "routine panel," was employed. Second, a "FLAER‐only panel" comprising the gating markers and FLAER alone (excluding the GPI‐linked markers CD24 and CD14) was set up. The samples were processed using the lyse‐wash‐stain‐wash technique, and events were acquired on BC Navios Ex flow cytometer (Beckman Coulter, Inc., USA) and analyzed on Kaluza Software 2.1. The presence of a PNH clone was reported at a value of ≥0.01%. Results: A total of 209 patients were tested. Both panels found a PNH clone in 20.1% of patients (n = 42/209) with a 100% concordance rate. The PNH clone range for granulocytes was 0.01%–89.68%, and for monocyte was 0.04%–96.09% in the routine panel. The range in the FLAER‐only panel for granulocytes was 0.01%–89.61%, and for monocytes, it was 0.01%–96.05%. Pearson correlation statistics revealed a significant correlation between the size of the PNH clone of granulocytes and monocytes among the two panels tested (granulocytes r = 0.9999, p < 0.0001, 95% CI = 0.9999 to 1.000; monocytes r = 0.9974, p < 0.0001, 95% CI = 0.9966–0.9980). Conclusion: Based on our results, FLAER as a standalone marker is specific and sensitive for identifying PNH clones in granulocytes and monocytes, even for high‐sensitivity PNH assay. The proposed "FLAER‐only panel" panel is efficient and cost‐effective for highly sensitive PNH testing in two different cell lineages, especially in resource‐limited clinical settings. [ABSTRACT FROM AUTHOR]

Microbial cells must continually adapt their physiology in the face of changing environmental conditions. Archaea living in extreme conditions, such as saturated salinity, represent important examples of such resilience. The model salt‐loving organism Haloferax volcanii exhibits remarkable plasticity in its morphology, biofilm formation, and motility in response to variations in nutrients and cell density. However, the mechanisms regulating these lifestyle transitions remain unclear. In prior research, we showed that the transcriptional regulator, TrmB, maintains the rod shape in the related species Halobacterium salinarum by activating the expression of enzyme‐coding genes in the gluconeogenesis metabolic pathway. In Hbt. salinarum, TrmB‐dependent production of glucose moieties is required for cell surface glycoprotein biogenesis. Here, we use a combination of genetics and quantitative phenotyping assays to demonstrate that TrmB is essential for growth under gluconeogenic conditions in Hfx. volcanii. The ∆trmB strain rapidly accumulated suppressor mutations in a gene encoding a novel transcriptional regulator, which we name trmB suppressor, or TbsP (a.k.a. "tablespoon"). TbsP is required for adhesion to abiotic surfaces (i.e., biofilm formation) and maintains wild‐type cell morphology and motility. We use functional genomics and promoter fusion assays to characterize the regulons controlled by each of TrmB and TbsP, including joint regulation of the glucose‐dependent transcription of gapII, which encodes an important gluconeogenic enzyme. We conclude that TrmB and TbsP coregulate gluconeogenesis, with downstream impacts on lifestyle transitions in response to nutrients in Hfx. volcanii. [ABSTRACT FROM AUTHOR]

This article discusses a rare case of mucinous cystadenoma of the renal pelvis, a benign tumor of the kidney. The patient, a 71-year-old Chinese female, presented with swelling and pain in the right lumbar region. After various examinations and procedures, including CT scans and laparoscopic nephrectomy, the tumor was successfully removed. The patient had a good recovery and showed no signs of recurrence or metastasis during the 1-month follow-up. This case provides valuable insights into the diagnosis and treatment of mucinous cystadenoma of the renal pelvis, which is a rare and challenging condition. [Extracted from the article]

Aim: Autoimmune nodopathies have specific clinicopathologic features, antibodies directed against nodal proteins (neurofascin 186) or paranodal proteins (neurofascin 155, contactin 1, contactin‐associated protein 1 (Caspr1)), and usually have a poor response to first‐line therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Anti‐Caspr1 nodopathy treated with autologous hematopoietic stem cell transplantation (AHSCT) has not been previously reported. Methods: We report the first case of an anti‐Caspr1 antibody‐positive nodopathy refractory to high‐intensity immunosuppressive treatment, including rituximab, that responded dramatically to AHSCT. Results: A 53‐year‐old woman presented with a rapidly progressive generalized ataxic, painful motor, and inflammatory neuropathy supported by neurophysiologic and MRI studies. Initial tests for antibodies to nodal/paranodal proteins were negative. She was treated with multiple courses of intravenous immunoglobulin and methylprednisolone, plasma exchange, rituximab, and cyclophosphamide without significant clinical benefit. Repeated testing for antibodies to nodal/paranodal proteins yielded a positive result for anti‐Caspr1/IgG4 isotype antibodies. Given the poor response to multiple high intensity treatments and the relatively young age of the patient, we decided to perform AHSCT at 30 months post‐onset. Immediately after AHSCT, she stopped all immunomodulatory or immunosuppressive therapy. The Overall Neuropathy Limitation Score improved from 8/12 to 4/12 at 6 months post‐AHSCT. At 3 months post‐AHSCT, IgG4 against Caspr1 was negative and no reactivity against paranodes could be detected. Conclusion: We report a particularly severe anti‐Caspr1 antibody autoimmune nodopathy that responded dramatically to AHSCT. Although the rarity of the disease limits the possibility of larger studies, AHSCT may be a valuable therapy in treatment‐refractory cases. [ABSTRACT FROM AUTHOR]

Hydrocephalus is a disorder caused by excess fluid accumulation in the brain and results in brain damage with consequent cognitive and physical problems. This condition has no cure; the only treatment is brain surgery. Experimental data indicate that P‐glycoprotein (P‐gp) plays a crucial role in the pathogenesis of hydrocephalus due to its function in clearing macromolecules from the brain. Numerous medications frequently used are classified as P‐gp inducers or inhibitors, and comprehending their effects may aid in attaining improved patient outcomes. Therefore, in this single‐center retrospective study, we examined the risk of the need for ventriculoperitoneal shunt placement over 10 years among 4588 adult patients with hydrocephalus not exposed to any P‐gp inhibitors/inducers or exclusively exposed to either P‐gp inhibitors or inducers. Our analysis shows that patients exposed to P‐gp inhibitors had a 3.2 times higher risk of requiring ventriculoperitoneal shunt surgery (P <.0001). In contrast, the relative risk was not significantly affected (P =.07) among those exposed to P‐gp inducers. Our findings indicate the need for caution when prescribing P‐gp inhibitors to patients with hydrocephalus. Additional studies using larger cohorts are required to confirm whether P‐gp inducers in patients with hydrocephalus can mitigate the risk of ventriculoperitoneal shunt. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC) subsets play a crucial role in shaping anti‐tumour immunity. Cancer escapes from the control immune system by hijacking DC functions. Yet, bases for such subversion are only partially understood. Tumour cells display aberrant glycan motifs on surface glycoproteins and glycolipids. Such carbohydrate patterns can be sensed by DCs through C‐type lectin receptors (CLRs) that are critical to shape and orientate immune responses. We recently demonstrated that melanoma tumour cells harboured an aberrant 'glyco‐code,' and that circulating and tumour‐infiltrating DCs from melanoma patients displayed major perturbations in their CLR profiles. To decipher whether melanoma, through aberrant glycan patterns, may exploit CLR pathways to mislead DCs and evade immune control, we explored the impact of glycan motifs aberrantly found in melanoma (neoglycoproteins [NeoGP] functionalised with Gal, Man, GalNAc, s‐Tn, fucose [Fuc] and GlcNAc residues) on features of human DC subsets (cDC2s, cDC1s and pDCs). We examined the ability of glycans to bind to purified DCs, and assessed their impact on DC basal properties and functional features using flow cytometry, confocal microscopy and multiplex secreted protein analysis. DC subsets differentially bound and internalised NeoGP depending on the nature of the glycan. Strikingly, Fuc directly remodelled the expression of activation markers and immune checkpoints, as well as the cytokine/chemokine secretion profile of DC subsets. NeoGP interfered with Toll like receptor (TLR)‐signalling and pre‐conditioned DCs to exhibit an altered response to subsequent TLR stimulation, dampening antitumor mediators while triggering pro‐tumoral factors. We further demonstrated that DC subsets can bind NeoGP through CLRs, and identified GalNAc/MGL and s‐Tn/ C‐type lectin‐like receptor 2 (CLEC2) as potential candidates. Moreover, DC dysfunction induced by tumour‐associated carbohydrate molecules may be reversed by interfering with the glycan/CLR axis. These findings revealed the glycan/CLR axis as a promising checkpoint to exploit in order to reshape potent antitumor immunity while impeding immunosuppressive pathways triggered by aberrant tumour glycosylation patterns. This may rescue DCs from tumour hijacking and improve clinical success in cancer patients. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER‐localized eukaryotic glycoprotein secretion checkpoint, UDP‐glucose glycoprotein glucosyl‐transferase (UGGT). The enzyme recognizes a misfolded glycoprotein and flags it for ER retention by re‐glucosylating one of its N‐linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT‐mediated ER retention can cause rare disease, even if the mutant glycoprotein retains activity ("responsive mutant"). Using confocal laser scanning microscopy, we investigated here the subcellular localization of the human Trop‐2‐Q118E, E227K and L186P mutants, which cause gelatinous drop‐like corneal dystrophy (GDLD). Compared with the wild‐type Trop‐2, which is correctly localized at the plasma membrane, these Trop‐2 mutants are retained in the ER. We studied fluorescent chimeras of the Trop‐2 Q118E, E227K and L186P mutants in mammalian cells harboring CRISPR/Cas9‐mediated inhibition of the UGGT1 and/or UGGT2 genes. The membrane localization of the Trop‐2 Q118E, E227K and L186P mutants was successfully rescued in UGGT1−/−cells. UGGT1 also efficiently reglucosylated Trop‐2‐Q118E‐EYFP in cellula. The study supports the hypothesis that UGGT1 modulation would constitute a novel therapeutic strategy for the treatment of pathological conditions associated to misfolded membrane glycoproteins (whenever the mutation impairs but does not abrogate function), and it encourages the testing of modulators of ER glycoprotein folding quality control as broad‐spectrum rescue‐of‐secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants. [ABSTRACT FROM AUTHOR]

Drug resistance is a considerable obstacle to gastric cancer (GC) treatment. The current work aimed to elucidate the functional mechanism of CD109 in 5‐fluorouracil (5‐FU) resistance in GC. In this study, we demonstrated that CD109 was extremely heightened in 5‐FU‐resistant GC cells. CD109 deficiency lessened the IC50 value, impaired cell viability and metastatic capability, and induced cell apoptosis after 5‐FU treatment in cells. In addition, we found that PAX5 bound p300 increased the enrichment of H3K27ac at the promoter region of the CD109 gene, which resulted in the upregulation of CD109 in GC. Moreover, we also revealed that CD109 triggered 5‐FU resistance via activating the JNK/MAPK signaling. Blockage of JNK/MAPK signaling using JNK inhibitor, SP600125, abolished CD109 upregulation‐induced changes of IC50 values, cell viability, metastasis and apoptosis in NCI‐N87/5‐FU and SNU‐1/5‐FU cells. Importantly, CD109 silencing enhanced the therapeutic efficacy of 5‐FU, leading to reduced tumor growth in vivo. In conclusion, our results unveiled that H3K27 acetylation activated‐CD109 enhanced 5‐FU resistance of GC cells via modulating the JNK/MAPK signaling pathway, which might provide an attractive therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase‐4 (DPP‐4), also known as CD26, is a 110‐kDa cell surface glycoprotein with enzymatic and signal transducing activity. DPP‐4/CD26 is expressed by various cells, including CD4+ and CD8+ T cells, B cells, dendritic cells, macrophages, and NK cells. DPP‐4 inhibitors (DPP‐4i) were introduced to clinics in 2006 as new oral antihyperglycemic drugs approved for type 2 diabetes mellitus treatment. In addition to glucose‐lowering effects, emerging data, from clinical studies and their animal models, suggest that DPP‐4i could display anti‐inflammatory and immunomodulatory effects as well, but the molecular and immunological mechanisms of these actions are insufficiently investigated. This review focuses on the modulatory activity of DPP‐4i in the immune system and the possible application of DPP‐4i in other immune‐related diseases in patients with or without diabetes. [ABSTRACT FROM AUTHOR]

The emerging viruses SARS‐CoV‐2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS‐CoV‐2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme‐1/site‐1 protease (SKI‐1/S1P), respectively. We report improved luciferase‐based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high‐throughput manner. We identified 23 FDA‐approved small molecules, among them monensin which displayed broad activity against furin and SKI‐1/S1P. Monensin inhibited arenaviruses and SARS‐CoV‐2 in a dose‐dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS‐CoV‐2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS‐CoV‐2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad‐spectrum antivirals with therapeutic potential to combat current and future emerging viruses. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the association of GCF TREM‐1, PGLYRP1, and IL‐1β levels with periodontal health in pre‐ and postmenopausal women. Background: Triggering receptor expressed on myeloid cells 1 (TREM‐1), activated through its ligand peptidoglycan recognition protein 1 (PGLYRP1), stimulates proinflammatory cytokine production, such as interleukin (IL)‐1β, during periodontal inflammation. Postmenopausal changes may modulate these immune‐inflammatory functions. No clinical study has yet investigated the effect of menopause on TREM‐1, PGLYRP1, and IL‐1β levels in gingival crevicular fluid (GCF). Methods: This cross‐sectional study included 148 women (age range = 35–65 years), divided into postmenopausal women (PMW) (n = 76, mean age = 54 ± 5 years) and regularly menstruating premenopausal women (RMPW) (n = 72, mean age = 40 ± 4 years). Clinical periodontal parameters were recorded. TREM‐1, PGLYRP1, and IL‐1β levels were quantified with enzyme‐linked immunosorbent assays. Pearson's Chi‐squared test and Mann–Whitney‐U test were used to compare categorical and numerical variables, respectively. Spearman's Rho correlation analysis was used to test the linear relationship between variables. Analyte level data were categorized based on the periodontal diagnosis and menopause status (2 × 2 nonparametric factorial ANOVA). Results: No significant differences in TREM‐1, PGLYRP1, and IL‐1β levels between PMW and RMPW were observed (p >.05). Mean values of periodontal indexes including probing depth did not differ significantly between PMW and RMPW groups (p =.474). TREM‐1 levels were significantly higher in both PMW and RMPW with periodontitis, compared to gingivitis or health (p =.0021). Conclusion: Menopause‐related changes have no observable effect on GCF levels of TREM‐1, PGLYRP1, and IL‐1β. Higher GCF TREM‐1 levels in women with periodontitis regardless of their menopausal status indicate that TREM‐1 may be an indicator for periodontitis both in premenopausal and postmenopausal women. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cells targeting the CD19 (cluster of differentiation 19) cell surface glycoprotein have emerged as a highly effective immunologic therapy in patients with relapsed or refractory B‐cell malignancies. The engagement of CAR T cells with CD19 on the surface of neoplastic B cells causes a systemic cytokine release, which can compromise the blood‐brain barrier and cause an immune effector cell‐associated neurotoxicity syndrome (ICANS). In a small proportion of ICANS patients who demonstrate neuroimaging abnormalities, certain distinct patterns have been recognized, including signal changes in the thalami, external capsule, and brainstem, the subcortical and/or periventricular white matter, the splenium of the corpus callosum, and the cerebellum. On careful review of the underlying pathophysiology of ICANS, we noticed that these changes closely mirror the underlying blood‐brain barrier disruption and neuroinflammatory and excitotoxic effects of the offending cytokines released during ICANS. Furthermore, other uncommon complications of CD19 CAR T‐cell therapy such as posterior reversible encephalopathy syndrome, ocular complications, and opportunistic fungal infections can be catastrophic if not diagnosed in a timely manner, with neuroimaging playing a significant role in management. In this narrative review, we will summarize the current literature on the spectrum of neuroimaging findings in ICANS, list appropriate differential diagnoses, and explore the imaging features of other uncommon central nervous system complications of CD19 CAR T‐cell therapy using illustrative cases from two tertiary care institutions. [ABSTRACT FROM AUTHOR]

Background: Diabetic metabolism causes changes of the chemical milieu including accumulation of reactive carbonyl species, for example, methylglyoxal (MGO). MGO activates chemosensitive TRPA1 on nociceptors, but the contribution to neuronal pathophysiology causing pain and hyperalgesia in diabetic neuropathy is not fully understood. Methods: We employed single‐nerve‐fiber recordings in type 2 diabetes patients with (spDN) and without cutaneous pain (DN) and in streptozotocin‐diabetic and healthy mice. In mice, we measured Ca++ transients in cultured DRG neurons and stimulated CGRP release from hairy skin. Results: In diabetic patients, we recorded a large proportion of pathologically altered nerve C‐fibers (79%). In spDN patients we found a higher percentage (72%) of spontaneously active C‐nociceptors than in DN patients (15%). The proportion of spontaneous activity was highest among pathological fibers with mechanoinsensitive fiber properties which are particularly sensitive to MGO in contrast to mechanosensitive fibers. Mouse polymodal nociceptors, in contrast to purely mechanosensitive C‐fibers, showed highest prevalence of TRPA1‐related chemosensitivity. In diabetic mice about 37% of polymodal nociceptors developed spontaneous activity and exhibited significantly greater MGO responses, indicating sensitized TRPA1 receptors. Low‐threshold mechanosensitive Aδ‐fibers were vigorously activated by MGO but independently of TRPA1 activation. Interpretation: Our translational findings suggest that TRPA1‐expressing C‐nociceptors, which in human correspond to mechanoinsensitive and in mice to polymodal nociceptors, are especially vulnerable to develop spontaneous activity. Those two different nociceptor classes might share the functional role as dicarbonyl‐sensitive chemosensors and represent the critical nociceptor population that support the development of pain and hyperalgesia in diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia as the primary clinical symptom. The production and accumulation of aggregated β-amyloid (Aβ) in patient brain tissues is one of the hallmarks of AD pathogenesis. Microglia, brain-resident macrophages, produce inflammatory cytokines in response to Aβ oligomers or fibrils exacerbating Aβ pathology in AD. HMO6 cells were treated with Aβ42 in the presence or absence of 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) to determine its potential immunomodulatory effects, and the expression of pro-/anti-inflammatory cytokines, M1/M2-associated markers, Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 2 (TREM2) was examined. 1,25(OH)2D3 was found to suppress Aβ-induced expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), M1 markers (CD86 and iNOS), and TLR2/4, whilst increasing the expression of anti-inflammatory cytokines (IL-4, IL-10, and CCL17) and M2 markers (CD206 and Arg-1). Furthermore, 1,25(OH)2D3 promoted TREM2 expression and Aβ uptake by HMO6 cells, and the enhancement of Aβ uptake and M2 polarization was revealed to be TREM2-dependent. The findings of this study suggest that 1,25(OH)2D3 facilitates M2 polarization and Aβ uptake in a TREM2-dependent manner. [ABSTRACT FROM AUTHOR]

Surface and secreted glycoproteins are essential to cells and regulate many extracellular events. Because of the diversity of glycans, the low abundance of many glycoproteins, and the complexity of biological samples, a system‐wide investigation of extracellular glycoproteins is a daunting task. With the development of modern mass spectrometry (MS)‐based proteomics, comprehensive analysis of different protein modifications including glycosylation has advanced dramatically. This review focuses on the investigation of extracellular glycoproteins using MS‐based proteomics. We first discuss the methods for selectively enriching surface glycoproteins and investigating protein interactions on the cell surface, followed by the application of MS‐based proteomics for surface glycoprotein dynamics analysis and biomarker discovery. We then summarize the methods to comprehensively study secreted glycoproteins by integrating various enrichment approaches with MS‐based proteomics and their applications for global analysis of secreted glycoproteins in different biological samples. Collectively, MS significantly expands our knowledge of extracellular glycoproteins and enables us to identify extracellular glycoproteins as potential biomarkers for disease detection and drug targets for disease treatment. [ABSTRACT FROM AUTHOR]

Aim: Fas ligand (FasL) belongs to the tumour necrosis factor superfamily regulating bone turnover, inflammation, and apoptosis. The appendicular and axial skeleton phenotype of mature Faslgld mice has been reported. The impact of FasL on the alveolar bone providing support for the teeth at mature stages under healthy and induced inflammatory conditions remains unknown. Materials and Methods: We performed a phenotypical analysis of mice carrying the homozygous Faslgld mutation and wild‐type (WT) mice (C57BL/6) under healthy conditions and upon ligature‐induced periodontitis. After 12 days, micro‐computed tomography analysis revealed the distance between the cement enamel junction and the alveolar bone crest. Additional structural parameters, such as the bone volume fraction (BV/TV) and the periodontal ligament space volume, were measured. Histological analyses were performed to visualize the catabolic changes at the defect site. Results: Healthy Faslgld mice were found to have more periodontal bone than their WT littermates. Faslgld had no significant effect on inflammatory osteolysis compared to WT controls with ligatures. Histology revealed eroded surfaces at the root and in the inter‐proximal bone in both strains. Conclusions: Our findings suggest that FasL is a catabolic factor in alveolar bone homeostasis but it does not affect the inflammatory osteolysis. [ABSTRACT FROM AUTHOR]

MOG antibody disorder presenting as a combined central and peripheral demyelination (CCPD) is uncommon. CCPD has been associated with other primary demyelination syndromes such as multiple sclerosis, neuromyelitis optica or chronic inflammatory demyelinating polyneuropathy. Here, the authors describe the diagnosis and management of a 21‐year‐old female with historically sequential demyelinating plaques in her right thalamus, cervical cord, left optic nerve and electrophysiology suggestive of bilateral ulnar nerve demyelination. [ABSTRACT FROM AUTHOR]

Background: Anti‐PD‐1/PD‐L1 therapeutics have been widely used in the clinic in various tumors, including advanced esophageal cancer, showing remarkable treatment efficacy. Factors determining the response to anti‐PD‐1/PD‐L1 therapeutics are numerous, including the tumor microenvironment, such as CD8+ T cells and expression of PD‐1/PD‐L1. Our study aimed to explore the effect of chemoimmunotherapy on the expression of CD8+ T cells, TIM‐3, and FOXP3+ in tumor, paratumor tissues, and the expression of PD‐L1, IDO, in tumor, paratumor tissues, and lymph nodes, and analyze the correlation among these markers. Methods: A total of 18 patients were allocated into two treatment groups: a treatment group and a concurrent control group. A total of 38 tissue samples, 114 slides (tumor, paratumor, and lymph node) were collected in the treatment group, and 37 tissue samples, 111 slides (tumor, paratumor, and lymph node) were collected in the concurrent control group. Results: The expression of PD‐L1, CD8+, FOXP3+, TIM‐3, and IDO in tumors, paratumor tissues, but not lymph nodes, was significantly affected by chemoimmunotherapy. Compared with patients without chemoimmunotherapy, the expression of CD8+ T cells, IDO, and PD‐L1 was significantly decreased in tumor and paratumor tissues after chemoimmunotherapy, while FOXP3+ expression was significantly decreased only in tumor tissues, and TIM‐3 expression was significantly decreased only in paratumor tissues. Moreover, the correlation between these markers was also completely altered after chemoimmunotherapy. In addition, N staging was associated with high expression of CD8 in advanced esophageal squamous cell carcinoma in the concurrent control group. Conclusion: This study provides new insight into the effects of CI treatment on isolated CD8+ T cell infiltration, PD‐L1, IDO, FOXP3+ and TIM‐3 expression as well as their cross‐talk in different tissues enabling a better understanding of the impact of CI treatment on the immune microenvironment. [ABSTRACT FROM AUTHOR]

There is accumulating evidence of BCMA and GPRC5D loss after treatment with T-cell redirecting therapies in patients with relapsed/refractory multiple myeloma (RRMM). While complete CD38 loss is not observed upon relapses after treatment with anti-CD38 monoclonal antibodies (mAb), there is downregulation of surface CD38 expression and decreased number and function of NK cells, which renders these patients resistant to retreatment with anti-CD38 mAb. Here, we provide preclinical evidence that RRMM patients previously exposed to anti-CD38 mAb could benefit from T-cell-based immunotherapy that depend less on CD38 antigen density and NK-cell activity, such as the novel CD38/CD3xCD28 trispecific T-cell engager, SAR442257., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

The necessity to accurately predict recurrence and clinical outcome in early stage colorectal cancer (CRC) is critical to identify those patients who may benefit from adjuvant chemotherapy. Here, we developed and validated a gene‐based risk‐score algorithm for patient stratification and personalised treatment in early stage disease based on alterations in the secretion of metastasis‐related proteins. A quantitative label‐free proteomic analysis of the secretome of highly and poorly metastatic CRC cell lines with different genetic backgrounds revealed 153 differentially secreted proteins (fold‐change >5). These changes in the secretome were validated at the transcriptomic level. Starting from 119 up‐regulated proteins, a six‐gene/protein‐based prognostic signature composed of IGFBP3, CD109, LTBP1, PSAP, BMP1, and NPC2 was identified after sequential discovery, training, and validation in four different cohorts. This signature was used to develop a risk‐score algorithm, named SEC6, for patient stratification. SEC6 risk‐score components showed higher expression in the poor prognosis CRC subtypes: consensus molecular subtype 4 (CMS4), CRIS‐B, and stem‐like. High expression of the signature was also associated with patients showing dMMR, CIMP+ status, and BRAF mutations. In addition, the SEC6 signature was associated with lower overall survival, progression‐free interval, and disease‐specific survival in stage II and III patients. SEC6‐based risk stratification indicated that 5‐FU treatment was beneficial for low‐risk patients, whereas only aggressive treatments (FOLFOX and FOLFIRI) provided benefits to high‐risk patients in stages II and III. In summary, this novel risk‐score demonstrates the value of the secretome compartment as a reliable source for the retrieval of biomarkers with high prognostic and chemotherapy‐predictive capacity, providing a potential new tool for tailoring decision‐making in patient care. [ABSTRACT FROM AUTHOR]

Myocarditis is a complex disease characterized by myocardial inflammatory cell infiltration. The purpose of our study was to investigate the gene and single-cell signature to explore the involvement of immune cells in myocarditis. Gene expressions merged from GSE35182 and GSE35182 datasets were subjected to differential expression gene (DEG) analysis and PPI network construction. The correlation analysis of DEGs with immune cell infiltration was performed. Single-cell RNA sequencing (scRNA-seq) was downloaded from GSE174458. A total of 58 DEGs were identified, including 51 DEGs upregulated and 7 DEGs downregulated in the myocarditis group compared with the control group. GO and KEGG enrichment analyses revealed that myocarditis triggered DEGs mainly involved in immune-related processes and pathways. PPI network analysis identified 20 central hub genes. Occurrence of myocarditis induced significant enrichment of conventional dendritic cell 2 (cDC2), plasmacytoid DC, and plasma cell in myocardial tissue. Mmp12, Gpnmb, and Atp6v0d2 expressions were positively correlated with cDC abundance, of which only Mmp1 and Gpnmb were shared with hub gene list. A total of 20972 cells in scRNA-seq yielded 26 cell clusters and annotated 9 cell types, including fibroblasts, neutrophils, stromal cells, monocytes, basophils, B cells, natural killer T cells, innate lymphoid cells, and T cells, and only proportion of natural killer T cells and monocytes were higher in the myocarditis than in control. Monocytes annotated 3 subclusters including DC, macrophage, and monocytes. Hub genes of Ctss, Mpeg1, Cybb, H2-Ab1, Ly86, CD74, and Lgals3 were highly expressed in monocytes cluster. Among DC-correlated DEGs, Mmp12 was mainly expressed in monocyte cluster, and Gpnmb was mainly expressed in fibroblast cluster, whereas Atp6v0d2 expression has a weaker signal and weaker cell preference. In conclusion, DC infiltration and its associated pivotal genes may be responsible for progression of myocarditis. Our study expands and provides novel information on the immune cell engagement of myocarditis. [ABSTRACT FROM AUTHOR]

Background and Objectives: The junctional epithelium (JE) has been recognized as a defensive organ rich in polymorphonuclear leukocytes (PMNs). However, the migration of PMNs through the JE has not been clearly documented. For mucosal defense, PMNs migrate outwards over the epithelium to defend the intestinal or respiratory tract on the epithelial surface. With this background, the present study investigated whether there is any structural evidence showing the transepithelial migration of PMNs through the JE in gingival mucosa. Methods: Three‐dimensional modeling of gingiva surrounding mouse molars at varying ages was performed by array tomography. Images of the serial sections for array tomography at the 800 nm thickness were obtained using back scattered electron (BSE) detector equipped in the field‐emission scanning electron microscopy (FESEM). Expressions of neutrophil marker or CD47 were immunohistochemically examined on the frozen sections. Results: Array tomography using FESEM and 3‐dimensional modeling clearly showed that a system of epithelial channels developed between keratinocytes and generally ran along the long axis of the JE. Most PMNs were found inside the channels, rather than being scattered throughout the JE. The channels could be traced from the base of the JE to the bottom of the gingival sulcus, although some channels were fragmented and interrupted with short intercellular gaps. Conclusions: These findings suggest that the JE may be an organ for transepithelial migration of PMNs to the bottom of the gingival sulcus through epithelial channels, as occurs in the epithelial lining of other organs such as the intestinal or respiratory tract. [ABSTRACT FROM AUTHOR]

Several factors have been reported to affect graft survival following kidney transplantation. CD52 molecules may increase T cell proliferation and activation, which may contribute to acute graft rejection and graft survival. In the current study, we studied the possible value of preoperative CD52 levels in predicting graft survival following renal transplantation. Ninety-six patients with end-stage renal disease who had kidney transplantation were included in the study from our prospective cohort. Blood samples were taken one day before surgery, and plasma CD52 levels were measured using ELISA (Cloud-Clone Corp., Houston, TX, USA). Acute rejection, acute tubular necrosis, delayed graft function, graft loss, BK infection, cytomegalovirus infection, and graft survival were evaluated. The mean age of recipients was 50.08 ± 12.82 years , and 64.6% were male. The incidence of delayed graft function, acute rejection, graft loss (p < 0.01), BK virus infection, and serum creatinine levels were significantly higher in recipients with high preoperative CD52 levels six months after transplantation (p < 0.05). Kaplan–Meier analysis revealed that three-year graft survival was significantly higher in patients with low preoperative CD52 levels (p < 0.0001). Univariate and multivariate Cox regression analyses showed that serum creatinine levels (hazard ratio HR = 1.7 , p < 0.05), acute rejection (HR = 2.919 , p < 0.05), and preoperative CD52 levels (HR = 3.114 , p < 0.05) were independent prognostic factors for graft survival after kidney transplantation. We showed that high preoperative CD52 levels are associated with higher rates of acute rejection, delayed graft function, and BK virus infection and lower rates of graft survival after kidney transplantation. [ABSTRACT FROM AUTHOR]

Objectives: Signals from inflamed tooth pulp activate thalamic neurons to evoke central sensitization. We aimed to gain insights into the mechanisms mediating the early phase of pulpal inflammation‐induced thalamic neural and glial activation. Materials and Methods: Pulpal inflammation was induced via the application of mustard oil (MO) to the upper first molar of Wistar rats with local anesthesia (LA) or saline injection. After 0.5, 1, 2, and 24 hr, contralateral thalami were subjected to microarrays, a real‐time polymerase chain reaction and immunohistochemistry to identify differentially expressed genes and assess potassium voltage‐gated channel subfamily A member 1 (Kv1.1)‐expressing axons and glial fibrillary acidic protein (GFAP)‐expressing astrocytes. Results: The Kv1.1 gene (Kcna1) was down‐regulated and the density of Kv1.1‐expressing axons decreased in non‐anesthetized rats, but not in anesthetized rats 1 hr after the MO treatment. The density of GFAP‐expressing astrocytes increased in both groups until 24 hr after the MO treatment, with a greater increase being observed in the saline‐injection group than in the LA group. Conclusions: MO induced the transient down‐regulation of Kcna1, transiently reduced the density of Kv1.1‐expressing axons, and increased astrocytes in thalami within 1 hr of pulpal application. These results suggest central sensitization represented by neuronal hyperexcitability and astrocyte activation. [ABSTRACT FROM AUTHOR]

Tenosynovial giant cell tumor (TCGT) is a rare neoplasm affecting the synovium of joints, bursae, and tendon sheaths. The overproduction of colony‐stimulating factor‐1 (CSF‐1) by a minority of the tumor population works in a paracrine fashion to drive tumor growth. Pathology of the reactive, monocytic component has been well elucidated, whereas the populations of neoplastic cells and all the sources of CSF‐1 overproduction are incompletely characterized. Podoplanin (PDPN), or gp38, is a cell surface glycoprotein that is expressed on fibroblast‐like synovial cells and upregulated in rheumatoid arthritis and many cancers; it governs cell mobility, epithelial–mesenchymal transition, and other functions and is associated with lymphangiogenesis and poor prognosis in many solid tumors, which underscores its local and possible systemic effects. We found higher PDPN expression in TGCT than in internal controls of patients' healthy synovium. Flow cytometry partitioned PDPNhigh cells into PDPNhighCD90+ and PDPNhighCD14+ populations. Quantitative real‐time polymerase chain reaction analysis of the PDPNhighCD90+ cells revealed that CSF‐1 expression was 10‐fold higher than in PDPNhighCD14+ cells. Therefore, we conclude that the lining fibroblast‐like synovial cells, which express PDPNhighCD90+, are responsible for the overproduction of CSF‐1 and for driving tumor growth. [ABSTRACT FROM AUTHOR]

Objectives. To study the resorption of the herniated lumbar disc (RHLD) and its mechanism in the SD rats of lumbar intervertebral disc herniation treated with Hui medicine moxibustion (HMM). Methods. Forty SD rats were randomly divided into four groups, normal group, lumbar disc herniation (LDH) group, HMM group, and antagonist (HMM+Met12) group, with 10 rats in each group. The rat model of LDH was prepared with the method of lumbar epidural emplacement of the caudal intervertebral disc. In the HMM group and HMM+Met12 groups, 4 weeks after modeling, HMM therapy was performed in the lumbar spine for 3 months with 1 time per day and 20 min each time, the samples were collected 8 weeks after the treatment. The histological degeneration was observed through HE staining, and the neovascularization of intervertebral disc tissues was detected by the expression of CD34 and vascular endothelial growth factor (VEGF). The apoptosis of nucleus pulpous cells was detected by TUNEL assay, and the activity of caspase-3, -8, and -9 and extracellular matrix enzymes was detected by western blotting. Results. HMM treatment significantly improved the behavioral ability of rats with LDH surgery. The morphological structure was obviously destroyed in the LDH group, but disc structure was significantly repaired in the HMM group, and mild structure alterations were observed in the HMM+Met12 group. Higher levels of CD34 and VEGF were detected in the HMM group indicating that neovascularization is formed. The expression level of FasL was significantly increased in the HMM group. The protein expression levels of cleaved-caspase-3, cleaved-caspase-8, and cleaved-caspase-9 in nucleus pulposus (NP) tissues were also elevated when treated with HMM, and the TUNEL staining showed the same results. The protein expression levels of matrix metalloproteinases- (MMP-) 1, MMP-2, MMP-3, MMP-13, and ADAMTS-4 were markedly promoted in the HMM group. Met12, a small peptide antagonist of FasL, significantly reduced the effects of HMM. Conclusion. HMM can promote the formation of neovascularization of lumbar intervertebral disc, support the apoptosis of NP cells through Fas/FasL signaling, and regulate the degradation of extracellular matrix enzyme, which then accelerates the absorption of lumbar intervertebral disc herniation and the recovery of motor function in rats. [ABSTRACT FROM AUTHOR]

Glycosylation of proteins is known to be essential for changing biological activity and stability of glycoproteins on the cell surfaces and in body fluids. Delivering of homogeneous glycoproteins into the endoplasmic reticulum (ER) and the Golgi apparatus would enable us to investigate the function of asparagine‐linked (N‐) glycans in the organelles. In this work, we designed and synthesized an intentionally glycosylated cholera toxin B‐subunit (CTB) to be transported to the organelles of mammalian cells. The heptasaccharide, the intermediate structure of various complex‐type N‐glycans, was introduced to the CTB. The synthesized monomeric glycosyl‐CTB successfully entered mammalian cells and was transported to the Golgi and the ER, suggesting the potential use of synthetic CTB to deliver and investigate the functions of homogeneous N‐glycans in specific organelles of living cells. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is an autoimmune bullous skin disease. Aquaporin 3 (AQP3) is a glycerol/water channel involved in several physiological functions. Evaluation of the tissue expression and localization of AQP3 in the skin of PV patients. Twenty‐seven PV patients and 30 controls were included. The patients were subjected to history taking, clinical evaluation, Autoimmune Bullous Skin Disorder Intensity Score and 4‐mm punch biopsy. The biopsies were stained using anti‐human AQP3 antibody and the immunofluorescence pattern and intensity were evaluated using a scoring system and ImageJ software analysis. AQP3 was expressed in the basal epidermis in 27 (100%) and in the suprabasal epidermis in 19 PV patients (70.4%). It was expressed in all controls in basal and suprabasal layers. Intensity of AQP3 immunofluorescence was strong in 2 (7.4%), moderate in 19 (70.4%) and weak in 6 patients (22.2%) while it was strong in 18 (60%) and moderate in 12 controls (40%). AQP3 expression was significantly lower in patients than controls in the suprabasal epidermis (p = 0.001). Patients with extensive disease had significantly weaker AQP3 intensity than those with marked disease (p = 0.005) Downregulation of AQP3 in patients with PV, especially in the suprabasal layers and in extensive clinical disease, suggests a potential role of AQP3 in the pathogenesis of PV. [ABSTRACT FROM AUTHOR]

Membrane‐associated RING‐CH (MARCH) family member proteins are RING‐finger E3 ubiquitin ligases that are known to downregulate cellular transmembrane proteins. MARCH8 is a novel antiviral factor that inhibits HIV‐1 envelope glycoprotein and vesicular stomatitis virus G by downregulating these envelope glycoproteins from the cell surface, resulting in their reduced incorporation into virions. More recently, we have found that MARCH8 reduces viral infectivity via two different mechanisms. Additionally, several groups have reported further antiviral or virus‐supportive functions of the MARCH8 protein and its other cellular mechanisms. In this review, we summarize the current knowledge about the molecular mechanisms by which MARCH8 can regulate cellular homeostasis and inhibit and occasionally support enveloped virus infection. [ABSTRACT FROM AUTHOR]

Objectives: Exposure of podocytes to angiotensin II (Ang II) enhances the abundance of the cell surface glycoprotein, low‐density lipoprotein receptor (LDLR) and promotes significant changes in the cellular cholesterol content. Recent investigation provides evidence that the small GTPase Rab11 is involved in the regulation of LDLR, but the exact mechanisms remain unknown. In this study, the role of Rab11 in post‐transcriptional regulation of LDLR was evaluated to investigate potential mechanisms of podocyte cholesterol dysregulation in chronic kidney disease. Materials and Methods: Cholesterol content, LDLR and Rab11 expression were assessed in podocytes from Ang II‐infused mice. In vitro, the intracellular localization of LDLR was detected under different conditions. Rab11 expression was modulated and we then explored the effect of anti‐lipid cytotoxicity by detecting LDLR expression and trafficking, cholesterol content and apoptosis in podocytes. Results: Cholesterol accumulation, upregulated expression of LDLR and Rab11 were discovered in podocytes from Ang II‐infused mice. Ang II enhanced the co‐precipitation of LDLR with Rab11 and accelerated the endocytic recycling of LDLR to the plasma membrane. Additionally, silencing Rab11 promoted lysosomal degradation of LDLR and alleviated Ang II‐induced cholesterol accumulation and apoptosis in podocytes. Conversely, overexpression of Rab11 or inhibition of lysosomal degradation up‐regulated the abundance of LDLR and aggravated podocyte cholesterol deposition. Conclusions: Rab11 triggers the endocytic trafficking and recycling of LDLR; overactivation of this pathway contributes to Ang II‐induced podocyte cholesterol accumulation and injury. [ABSTRACT FROM AUTHOR]

Objective: Systemic sclerosis (SSc) is an autoimmune disorder characterized by excessive fibrosis, immune dysfunction, and vascular damage, in which the expression of many growth factors is deregulated. CD146 was recently described as a major actor in SSc. Since CD146 also exists as a circulating soluble form (sCD146) that acts as a growth factor in numerous angiogenic‐ and inflammation‐related pathologies, we sought to identify the mechanisms underlying the generation of sCD146 and to characterize the regulation and functions of the different variants identified in SSc. Methods: We performed in vitro experiments, including RNA‐Seq and antibody arrays, and in vivo experiments using animal models of bleomycin‐induced SSc and hind limb ischemia. Results: Multiple forms of sCD146, generated by both shedding and alternative splicing of the primary transcript, were discovered. The shed form of sCD146 was generated from the cleavage of both long and short membrane isoforms of CD146 through ADAM‐10 and TACE metalloproteinases, respectively. In addition, 2 novel sCD146 splice variants, I5‐13‐sCD146 and I10‐sCD146, were identified. Of interest, I5‐13‐sCD146 was significantly increased in the sera of SSc patients (P < 0.001; n = 117), in particular in patients with pulmonary fibrosis (P < 0.01; n = 112), whereas I10‐sCD146 was decreased (P < 0.05; n = 117). Further experiments revealed that shed sCD146 and I10‐sCD146 displayed proangiogenic activity through the focal adhesion kinase and protein kinase Cε signaling pathways, respectively, whereas I5‐13‐sCD146 displayed profibrotic effects through the Wnt‐1/β‐catenin/WISP‐1 pathway. Conclusion: Variants of sCD146, and in particular the novel I5‐13‐sCD146 splice variant, could constitute novel biomarkers and/or molecular targets for the diagnosis and treatment of SSc and other angiogenesis‐ or fibrosis‐related disorders. [ABSTRACT FROM AUTHOR]

Background Information: Like most other cell surface proteins, α5β1 integrin is glycosylated, which is required for its various activities in ways that mostly remain to be determined. Results: Here, we have established the first comprehensive site‐specific glycan map of α5β1 integrin that was purified from a natural source, that is, rat liver. This analysis revealed striking site selective variations in glycan composition. Complex bi, tri, or tetraantennary N‐glycans were predominant at various proportions at most potential N‐glycosylation sites. A few of these sites were nonglycosylated or contained high mannose or hybrid glycans, indicating that early N‐glycan processing was hindered. Almost all complex N‐glycans had fully galactosylated and sialylated antennae. Moderate levels of core fucosylation and high levels of O‐acetylation of NeuAc residues were observed at certain sites. An O‐linked HexNAc was found in an EGF‐like domain of β1 integrin. The extensive glycan information that results from our study was projected onto a map of α5β1 integrin that was obtained by homology modeling. We have used this model for the discussion of how glycosylation might be used in the functional cycle of α5β1 integrin. A striking example concerns the involvement of glycan‐binding galectins in the regulation of the molecular homeostasis of glycoproteins at the cell surface through the formation of lattices or endocytic pits according to the glycolipid‐lectin (GL‐Lect) hypothesis. Conclusion: We expect that the glycoproteomics data of the current study will serve as a resource for the exploration of structural mechanisms by which glycans control α5β1 integrin activity and endocytic trafficking. Significance: Glycosylation of α5β1 integrin has been implicated in multiple aspects of integrin function and structure. Yet, detailed knowledge of its glycosylation, notably the specific sites of glycosylation, is lacking. Furthermore, the α5β1 integrin preparation that was analyzed here is from a natural source, which is of importance as there is not a lot of literature in the field about the glycosylation of "native" glycoproteins. [ABSTRACT FROM AUTHOR]

Maximum survival area after perforator flap elevation is mainly achieved through vasodilation and angiogenesis, and endothelial Ca2+ signals play a pivotal role in both of them. Transient receptor potential (TRP) channels modulate many endothelial cell functions via mediating the extracellular Ca2+ entry. This study aims to investigate the correlation of TRPV4, TRPV1, and TRPA1 with vascular change after the inferior gluteal artery perforator flap elevation. A total of 50 adult male SD rats were used in this study. Ten rats were used in the part one to assess the flap viability on postoperative day 7. Twenty rats were used in the part two to evaluate blood flow change after flap elevation. The correlation of vascular change with TRPV1, TRPV4, and TRPA1 protein changes was investigated in 20 rats in the part three. The mean flap survival area percentage was 55 ± 5.7%. Blood flow in the overall flap and Zone II after the flap elevation markedly increased from the postoperative day 3. The most marked change of the vasodilation occurred on Days 3 and 5 after flap elevation. The angiogenesis occurred on Day 5 after flap elevation and the microvessel density peaked also on Day 5. Moreover, TRPA1 expression showed a trend towards continuous reduction over time. The expression of TRPV1 and TRPV4 reached the peak value on Day 3. The endothelial NO synthase expression showed an increasing trend at first, followed by a reduction over time, while VEGF expression reached the peak value on Day 3. The vascular changes after flap elevation might be associated with the changes in TRPV4, TRPV1, and TRPA1. [ABSTRACT FROM AUTHOR]

In skeletal muscles, niche factors stimulate satellite cells to activate and induce muscle regeneration after injury. In vitro, matrigel is widely used for myoblast differentiation, however, is unsuitable for clinical applications. Therefore, this study aimed to analyze attachment and differentiation of satellite cells into myotubes on fibrin coatings with selected niche components. The attachment of satellite cells to fibrin alone and fibrin with niche components (laminin, collagen‐IV, laminin‐entactin complex [LEC]) were compared to matrigel. Only on matrigel and fibrin with LEC, Pax7‐positive cells attached well. Then, LEC was selected to analyze proliferation, differentiation, and fusion indices. The proliferation index at day 1 on fibrin‐LEC (22.5%, SD 9.1%) was similar to that on matrigel (30.8% [SD 11.1%]). The differentiation index on fibrin‐LEC (28.7% [SD 6.1%] at day 5 and 32.8% [SD 6.7%] at day 7) was similar to that on matrigel (40.1% [5.1%] at day 5 and 27.1% [SD 4.3%] at day 7). On fibrin‐LEC, the fusion index at day 9 (26.9% [SD 11.5%]) was similar to that on matrigel (25.5% [SD 4.7%]). Our results showed that the addition of LEC enhances the formation of myotubes on fibrin. Fibrin with LEC might be suitable to enhance muscle regeneration after surgery such as cleft palate repair and other muscle defects. [ABSTRACT FROM AUTHOR]

The neuronal membrane glycoprotein M6B (Gpm6b) gene encodes a membrane glycoprotein that belongs to the proteolipid protein family, and is enriched in neurons, oligodendrocytes, and subset of astrocytes in the central nervous system. GPM6B is thought to play a role in neuronal differentiation, myelination, and inactivation of the serotonin transporter via internalization. Recent human genome‐wide association studies (GWAS) have implicated membrane glycoproteins (both GPM6B and GPM6A) in the regulation of traits relevant to psychiatric disorders, including neuroticism, depressed affect, and delay discounting. Mouse studies have implicated Gpm6b in sensorimotor gating and regulation of serotonergic signaling. We used CRISPR to create a mutant Glycoprotein M6B (Gpm6b) allele on a C57BL/6J mouse background. Because Gpm6b is located on the X chromosome, we focused on male Gpm6b mutant mice and their wild‐type littermates (WT) in two behavioral tests that measured aspects of impulsive or flexible decision‐making. We found that Gpm6b deletion caused deficits in a delay discounting task. In contrast, reward sensitivity was enhanced thereby facilitating behavioral flexibility and improving performance in the probabilistic reversal learning task. Taken together these data further delineate the role of Gpm6b in decision making behaviors that are relevant to multiple psychiatric disorders. [ABSTRACT FROM AUTHOR]

In this study, the aim is to compare the recovery pattern among patients with acute myelin oligodendrocyte glycoprotein antibody-seropositive optic neuritis (MOG-Ab + ON) attacks and aquaporin-4 antibody-seropositive ON (AQP4-Ab + ON) or -seronegative ON. At the onset of the first-ever ON attack, the thickness of RNFL (RNFLt) in the MOG-Ab + ON group was significantly thicker than others (P < 0.05), while visual function damage was not significantly different to other groups. One month to six months after onset, the MOG-Ab + ON group showed significantly better visual function (P < 0.05) than the other two groups, while the RNFLt showed no significant difference among the three groups (P > 0.05). MOG-Ab + ON and AQP4-Ab + ON groups showed rapid recovery in the first month and then plateaued. The annual relapse rate was significantly higher in MOG-Ab + ON and AQP4-Ab + ON groups than seronegative ON. The relapse interval of the MOG-Ab + ON group (9.00 ± 7.86 months) was significantly shorter than that of the AQP4-Ab + ON group (45.76 ± 37.82 months) (P < 0.05) but showed no significant difference from that of the seronegative ON group (P > 0.05). To sum up, the recovery patterns were different among these three types of ON. RNFLt was not parallel to the recovery of visual function among these types of ON. MOG-Ab + ON had the mildest visual function damage but the most substantial RNFL changes, while AQP4-Ab + ON suffered the worst function damage. MOG-Ab + ON had a similar relapse rate as AQP4-Ab + ON but a shorter interval, indicating that relapse prevention was necessary and should be initiated as early as possible. [ABSTRACT FROM AUTHOR]