Identification of genetic features that are associated with amplitude of low-frequency fluctuation changes in schizophrenia using omics analysis.

Genetic risk for schizophrenia is thought to trigger variation in clinical features of schizophrenia, but biological processes associated with neuronal activity in brain regions remain elusive. In this study, gene expression features were mapped to various sub-regions of the brain by integrating low-frequency amplitude features and gene expression data from the schizophrenia brain and using gene co-expression network analysis of the Allen Transcriptome Atlas of the human brain from six donors to identify genetic features of brain regions and important associations with neuronal features. The results indicate that changes in the dynamic amplitude of low-frequency fluctuation (dALFF) are mainly associated with transcriptome signature factors such as cortical layer synthesis, immune response, and expanded membrane transport. Further modular disease enrichment analysis revealed that the same set of signature genes associated with dALFF levels was enriched for multiple neurological biological processes. Finally, genetic profiling of individual modules identified multiple core genes closely related to schizophrenia, also potentially associated with neuronal activity. Thus, this paper explores genetic features of brain regions in the schizophrenia closely related to low-frequency amplitude ratio levels based on imaging genetics, which suggests structural endophenotypes associated with schizophrenia.

Epidemiology and viral loads of respiratory syncytial virus in hospitalized children prior to and during COVID-19 pandemic in Hangzhou, China.

Non-pharmaceutical interventions (NPIs) implemented to control SARS-CoV-2 have significantly influenced the activity of respiratory pathogens. This study investigated epidemiological changes among hospitalized patients with respiratory syncytial virus (RSV) before (2017-2019) and during (2020-2022) the COVID-19 pandemic in Hangzhou, China. We also examined viral load distribution across demographic and temporal variables. Nasopharyngeal swabs were collected and RSV loads were quantified using reverse transcriptase polymerase chain reaction (RT-qPCR). RSV epidemic characteristics, seasonal dynamics, and viral load distributions were compared between pre- and pandemic years. General linear models were employed to assess associations between viral loads and age. Among 19 742 cases, 1576 and 2092 tested positive during the pre- and pandemic years, respectively. From February to July 2020, the implementation of NPIs led to the cessation of RSV circulation. However, after these measures were relaxed, RSV cases resurged over two consecutive seasons during the pandemic, notably affecting older children compared to those in the pre-pandemic years (1.00 years, IQR: 0.50-2.00 vs. 0.58 years, IQR: 0.27-1.00, p < 0.001). Specifically, in 2021-2022, an off-season resurgence of RSV began earlier (mid-June), lasted longer (40 weeks), and involved more positive cases (1238 cases) than both 2020-2021 and pre-pandemic years. Viral load distribution demonstrated a clear age-related relationship in both pre- and pandemic years, with younger children consistently showing higher viral loads, independently of gender and season (all p-values for trends <0.001). These findings highlight the impact of NPIs on RSV epidemiology and underscore the need to prioritize RSV infection prevention in younger children from the perspective of viral load.

Solasonine induces apoptosis of the SGC-7901 human gastric cancer cell line in vitro via the mitochondria-mediated pathway.

Solasonine, a steroidal glycoalkaloid isolated from the herbal plant Solanum nigrum Linn., has shown active against multiple human cancers; however, there is little knowledge on the activity of solasonine against gastric cancer until now. This study aimed to examine the effect of solasonine on the biological behaviours of human gastric cancer SGC-7901 cells. The results showed that solasonine suppressed SGC-7901 cell proliferation in a dose-dependent manner. Solasonine treatment mainly induced the cell cycle arrest at G2 phase in SGC-7901 cells. Treatment with solasonine resulted in significant down-regulation of Bcl-2 and Caspase-3 protein expression and reduced Bax and Bcl-xL protein expression in SGC-7901 cells. Solasonine shows a comparable inhibitory effect on the proliferation of human gastric cancer SGC-7901 cells with cisplatin, and solasonine induces of SGC-7901 cell apoptosis through triggering the endoplasmic reticulum stress pathway and the mitochondrial pathway. Our data indicate that solasonine may be a promising agent for the treatment of gastric cancer.

Proteomic profiling of kidney samples in patients with pure membranous and proliferative lupus nephritis.

Renal injury in lupus nephritis (LN) does not manifest as one uniform entity. The clinical presentation, management, and prognosis of membranous LN (MLN) differ from that of the proliferative LN (PLN). Differentiating the molecular mechanisms involved in MLN and PLN and discovering the reliable biomarkers for early diagnosis and target therapy are important. We compared the kidney protein expression patterns of 11 pure MLN and 12 pure PLN patients on formalin-fixed paraffin-embedded (FFPE) kidney tissues using label-free liquid chromatography-mass spectrometry (LC-MS) for quantitative proteomics analysis. FunRich software was used to identify proteins in differentially expressed pathways. Quantitative comparisons of differentially expressed proteins in each patient were further analyzed based on protein intensity levels determined by LC-MS. The protein-protein interaction (PPI) network of the differentially expressed genes (DEGs) was established through Search Tool for the Retrieval of Interacting Genes database (STRING) website, visualized by Cytoscape. A total of 5112 proteins were identified. In total, 12 significantly upregulated (fold change ≥2, p < 0.05) proteins were identified in the MLN group and 220 proteins (fold change ≥2, p < 0.05) were upregulated in the PLN group. Further analysis showed that the most significant upregulated pathway involved in MLN was histone deacetylase (HDAC) class I pathway, and the three most significant upregulated pathways in PLN were interferon signaling, interferon gamma signaling, and the immune system. Next, we selected sirtuin-2 (SIRT2) in MLN, and vascular cell adhesion protein 1 (VCAM1) and Bcl-xl in PLN for further mass spectrometry (MS) intensity and PPI analysis. SIRT2 expression was significantly increased in the MLN group compared with the PLN group, and VCAM1, Bcl-xl expression was significantly increased in the PLN group compared with the MLN group, based on MS intensity. These results may help to improve our understanding of the underlying molecular mechanisms of MLN and PLN and provide potential targets for the diagnosis and treatment of different subclasses of LN.

Significance of Mannan Binding Lectin-Associated Serine Protease 2 in Urinary Extracellular Vesicles in IgA Nephropathy.

PURPOSE: Immunoglobulin A (IgA) nephropathy (IgAN) is a common chronic glomerulonephritis and the main cause of end-stage renal diseases. Recent evidence suggests that mannan binding lectin associated serine proteases 2 (MASP2) is related to IgAN; therefore, we investigated the expression and significance of MASP2 in serum and urinary extracellular vesicles (UEVs) in patients with IgAN. METHODS: Thirty-eight patients with IgAN and 17 healthy controls were enrolled in this study. UEVs were extracted by ultracentrifugation. The separation by ultra-high-speed centrifuge was verified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Candidate internal references (TSG101, CD9, flotillin, ß-actin and GAPDH) were identified by western blotting in the control group, and the expression of MASP2 in the UEVs was compared. The levels of MASP2 in the serum and UEVs in the IgAN and control groups were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: TEM and NTA results demonstrated that UEVs were successfully extracted. Western blotting results confirmed that TSG101 was suitable as an internal reference for this study. Compared with the control group, the IgAN group showed positive expression of MASP2. MASP2 levels in the UEVs, determined by ELISA, showed significant differences between IgAN and control groups, which were significantly positively correlated with the level of urinary microalbumin. CONCLUSIONS: The level of MASP2 in UEVs was related to IgAN and shows promise as a biomarker for evaluating the severity of renal injury and prognosis of IgAN, thereby helping to elucidate the role of MASP2 in the mannan-binding lectin pathway.

von Willebrand factor variants in C3 glomerulopathy: A Chinese cohort study.

C3 glomerulopathy (C3G) is a rare renal disease characterized by predominant glomerular C3 staining. Complement alternative pathway dysregulation due to inherited complement defects is associated with C3G. To identify novel C3G-related genes, we screened 86 genes in the complement, coagulation and endothelial systems in 35 C3G patients by targeted genomic enrichment and massively parallel sequencing. Surprisingly, the most frequently mutated gene was VWF. Patients with VWF variants had significantly higher proteinuria levels, higher crescent formation and lower factor H (FH) levels. We further selected two VWF variants to transiently express the von Willebrand factor (vWF) protein, we found that vWF expression from the c.1519A > G variant was significantly reduced. In vitro results further indicated that vWF could regulate complement activation, as it could bind to FH and C3b, act as a cofactor for factor I-mediated cleavage of C3b. Thus, we speculated that vWF might be involved in the pathogenesis of C3G.

Potential urine biomarkers for the diagnosis of prediabetes and early diabetic nephropathy based on ISN CKHDP program.

BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM), and the most frequent cause of end-stage renal disease (ESRD) in many countries. Urinary extracellular vesicles (UEVs) are considered a rich non-invasive source of markers for renal diseases. In this study, UEV enrichment and analysis in diabetic nephropathy (DN) was performed in a community epidemiological survey supported through the ISN CKHDP program. MATERIALS AND METHODS: Patients were divided into five groups according to severity of kidney damage. A hydrostatic dialysis method was used for UEV enrichment followed by quantitation using Coomassie protein assays and subsequent adjustment using urinary creatinine levels. UEVs were then characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting of tumor susceptibility gene product TSG101. Two-dimensional DIGE (2D-DIGE) was used to analyze differential protein expression in the UEVs. Mass spectrometry (MS) was conducted and MASCOT search engine was used to identify potential biomarkers. RESULTS: Bradford protein assay showed that protein concentration of UEVs in diabetics with kidney injury increased significantly as compared to normal controls. UEVs present a round, cup-shaped, membrane-encapsulated structure under TEM, and the main peak of UEVs show 55 - 110 nm nanoparticles with NTA. MS and MASCOT identified 22 differential proteins, and MASP2, CALB1, S100A8, and S100A9 were selected as potential biomarkers of early DN based on bioinformatic analysis. DISCUSSION: Our results show UEV proteome changes in different stages of DN. The results of this study show four unique proteins that undergo changes in early DN. These promising discoveries may prompt a new field of research focused on improving the diagnosis of DN.

Comparison of Hydrostatic Filtration Dialysis with Ultracentrifugation Methods for the Identification and Proteomic Profiling of Urinary Extracellular Vesicles.

BACKGROUND: Urinary extracellular vesicles (UEVs) carry rich markers of their parent cells, so they can serve as possible biomarkers of kidney diseases. METHODS: In this study, we isolated urinary extracellular vesicles from five individuals using a simple, clinically applicable method called hydrostatic filtration dialysis (HFD) and compared it to the gold-standard ultracentrifuga-tion (UC) with transmission electron microscopy (TEM). We also employed a proteomic approach using pooled human urine samples from the same five individuals to profile the protein composition of UEVs to evaluate the effectiveness of these two methods. RESULTS: Notably, using TEM, we found that all isolations contained 0 - 400 nm vesicles with the traditionally reported morphology, although the TEM results showed that the UEVs isolated from HFD compared to those from UC are larger and more extensive. We obtained a total of 2,564 UEV proteins in the two methods. We showed a large overlap (2,185 > 85%) between the proteins identified by both isolation methods. The result also showed that the obtained proteins in extracellular vesicles, which are isolated with these methods, are consistent with the results in currently available databases. However, in the associated gene ontologies, the enriched proteins found by the two methods showed some differences. CONCLUSIONS: The HFD method is clinically feasible and allows large-scale protein profiling of UEV biomarkers. The results of this study also provide valuable UEV protein data from the methodological comparison, which might be valuable to other researchers.

Selective Memory to Apoptotic Cell-Derived Self-Antigens with Implications for Systemic Lupus Erythematosus Development.

Autoimmune diseases are characterized by pathogenic immune responses to self-antigens. In systemic lupus erythematosus (SLE), many self-antigens are found in apoptotic cells (ACs), and defects in removal of ACs from the body are linked to a risk for developing SLE. This includes pathological memory that gives rise to disease flares. In this study, we investigated how memory to AC-derived self-antigens develops and the contribution of self-memory to the development of lupus-related pathology. Multiple injections of ACs without adjuvant into wild-type mice induce a transient primary autoimmune response without apparent anti-nuclear Ab reactivity or kidney pathology. Interestingly, as the transient Ab response reached baseline, a single boost injection fully recalled the immune response to ACs, and this memory response was furthermore transferable into naive mice. Additionally, the memory response contains elements of pathogenicity, accompanied by selective memory to selective Ags. Thus, we provide evidence for a selective self-memory that underlies progression of the response to self-antigens with implications for SLE development therapy.

[Analysis and prenatal diagnosis of deafness-related gene mutations in patients with nonsyndromic hearing loss].

OBJECTIVE: To analyze deaf-related genes in patients with nonsyndromic hearing loss (NSHL) and set up a prenatal diagnosis system for such patients. METHODS: Nine NSHL families were collected. Potential mutations of GJB2 (35delG, 176del16, 235delC, 299delAT), SLC26A4 (2168A> G, IVS7-2A> G), GJB3 (538C> T) and mtDNA (1494C> T, 12S rRNA 1555A> G) were detected by direct sequencing. Maternal blood contamination was excluded prior to the testing. RESULTS: Sixteen patients from 4 families were detected with GJB2 mutations, 8 patients from 2 families were found with SLC26A4 mutations, and 4 patients from 2 families were found with mutations in mtDNA. For 2 patients from one remaining family, no mutations were found with above genes. CONCLUSION: A diagnostic system for NSHL has been established, which may provide a basis for prenatal diagnosis and genetic counseling to NSHL families.

[Analysis of genomic copy number variation for a Chinese patient with split hand/split foot malformation].

OBJECTIVE: To employ single nucleotide polymorphisms (SNP) microarray to detect copy number variations (CNVs) for the diagnosis of disease and molecular classification. METHODS: For a patient with split-hand/split-foot malformation, genome-wide copy number variants SNP microarray was applied. Tiny copy number variations were verified by real-time fluorescent quantitative PCR. RESULTS: The results of SNP microarray has revealed that the patient has carried a 0.39 Mb duplication in 10q24.31-24.32 (102 955 122-103 348 688), which has encompassed genes including LBX1, BTRC and POLL. By real-time fluorescent quantitative PCR, duplicate area encompassing the pathogenic genes have been verified. The results for LBX1, BTRC, POLL genes were all consistent with the SNP microarray test. Moreover, a duplication was detected in exon 9 of FBXW4 gene which is in nearby. CONCLUSION: SNP chips can efficiently identify tiny CNVs (< 1.0 Mb). In combination with real-time fluorescence quantitative PCR, this may provide valuable information for prenatal diagnosis.

Performance comparison of two automated digital morphology analyzers for leukocyte differential in patients with malignant hematological diseases: Mindray MC-80 and Sysmex DI-60.

BACKGROUND: The MC-80 (Mindray, Shenzhen, China), a newly available artificial intelligence (AI)-based digital morphology analyzer, is the focus of this study. We aim to compare the leukocyte differential performance of the Mindray MC-80 with that of the Sysmex DI-60 and the gold standard, manual microscopy. METHODS: A total of 100 abnormal peripheral blood (PB) smears were compared across the MC-80, DI-60, and manual microscopy. Sensitivity, specificity, predictive value, and efficiency were calculated according to the Clinical and Laboratory Standards Institute (CLSI) EP12-A2 guidelines. Comparisons were made using Bland-Altman analysis and Passing-Bablok regression analysis. Additionally, within-run imprecision was evaluated using five samples, each with varying percentages of mature leukocytes and blasts, in accordance with CLSI EP05-A3 guidelines. RESULTS: The within-run coefficient of variation (%CV) of the MC-80 for most cell classes in the five samples was lower than that of the DI-60. Sensitivities for the MC-80 ranged from 98.2% for nucleated red blood cells (NRBC) to 28.6% for reactive lymphocytes. The DI-60's sensitivities varied between 100% for basophils and reactive lymphocytes, and 11.1% for metamyelocytes. Both analyzers demonstrated high specificity, negative predictive value, and efficiency, with over 90% for most cell classes. However, the DI-60 showed relatively lower specificity for lymphocytes (73.2%) and lower efficiency for blasts and lymphocytes (80.1% and 78.6%, respectively) compared with the MC-80. Bland-Altman analysis indicated that the absolute mean differences (%) ranged from 0.01 to 4.57 in MC-80 versus manual differential and 0.01 to 3.39 in DI-60 versus manual differential. After verification by technicians, both analyzers exhibited a very high correlation (r = 0.90-1.00) with the manual differential results in neutrophils, lymphocytes, and blasts. CONCLUSIONS: The Mindray MC-80 demonstrated good performance for leukocyte differential in PB smears, notably exhibiting higher sensitivity for blasts identification than the DI-60.

Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus.

Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell-derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.

AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment.

Autoimmune polyendocrine syndrome Type I (APS I) results in multiple endocrine organ destruction and is caused by mutations in the Autoimmune regulator gene (AIRE). In the thymic stroma, cells expressing the AIRE gene dictate T cell education and central tolerance. Although this function is the most studied, AIRE is also expressed in the periphery in DCs and stromal cells. Still, how AIRE regulated transcription modifies cell behaviour in the periphery is largely unknown. Here we show that AIRE is specifically expressed by 33D1(+) DCs and dictates the fate of antibody secreting cell movement within the spleen. We also found that AIRE expressing 33D1(+) DCs expresses self-antigens as exemplified by the hallmark gene insulin. Also, as evidence for a regulatory function, absence of Aire in 33D1(+) DCs led to reduced levels of the chemokine CXCL12 and increased co-stimulatory properties. This resulted in altered activation and recruitment of T-follicular helper cells and germinal centre B cells. The altered balance leads to a change of the early response to a T cell-dependent antigen in Aire(-/-) mice. These findings add to the understanding of how specific DC subtypes regulate the early responses during T cell-dependent antibody responses within the spleen and further define the role of AIRE in the periphery as regulator of self-antigen expression and lymphocyte migration.

SR-A/MARCO-mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens.

Phagocytic and pathogen sensing receptors are responsible for particle uptake and inflammation. It is unclear how these receptors' systems influence each other's function to shape an innate response. The class-A scavenger receptors SR-A (scavenger receptor A) and MARCO (macrophage receptor with collagenous structure) are 2 well-characterized phagocytic receptors that are unable to initiate inflammatory responses by themselves, yet are implicated in the pathogenesis of various inflammatory disorders. However, the mechanism for such an apparent discrepancy is still unclear. We utilized SR-A(-/-), MARCO(-/-), and SR-A(-/-)-MARCO(-/-) mice, along with microbe-derived, environmental, and synthetic polyanions to assess the inflammatory responses following combinatorial ligation of SR-A/MARCO and selected Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) by their shared ligands. In addition to ligating SR-A and MARCO, these agonists also selectively activated the cell-surface sensor TLR4, endosomal TLR3, and the cytosolic NOD2 and NALP3 (NACHT domain-, leucine-rich repeat-, and pyrin domain-containing protein 3). We show that, following recognition of common ligands, SR-A and MARCO attenuate TLR4-mediated responses while enhancing responses by the intracellular TLR3, NOD2, and NALP3. We conclude that SR-A/MARCO-mediated rapid ligand internalization prevented sensing by surface TLRs while increasing ligand availability in intracellular compartments, thus allowing sensing and robust responses by intracellular sensors.

Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen.

Marginal zone macrophages (MZMs) are a small subset of specialized splenic macrophages known to interact with apoptotic material entering the spleen from circulation. To evaluate whether MZMs regulate immunity to apoptotic material we depleted MZMs and assessed innate and adaptive immune responses to apoptotic cells administered systemically. MZM depletion altered the spatial localization of apoptotic cells, which accumulated in T-cell areas of the lymphoid follicles. MZM depletion also enhanced phagocytosis of apoptotic cells by red pulp (CD68(+)F4/80(+)) macrophages, which expressed increased CD86, MHCII, and CCR7. MZM depletion led to increased production of proinflammatory cytokines and enhanced lymphocyte responsiveness to apoptotic cell antigens. Furthermore, we found that MZM depletion accelerated autoimmune disease progression in mice genetically prone to systemic lupus erythematosus and caused significant mortality in wild-type mice repeatedly exposed to exogenous apoptotic thymocytes. These findings support the hypothesis that MZMs are central in the clearance of apoptotic cells to minimize the immunogenicity of autoantigens.

Pulmonary exposure to single-walled carbon nanotubes does not affect the early immune response against Toxoplasma gondii.

BACKGROUND: Single-walled carbon nanotubes (SWCNT) trigger pronounced inflammation and fibrosis in the lungs of mice following administration via pharyngeal aspiration or inhalation. Human exposure to SWCNT in an occupational setting may occur in conjunction with infections and this could yield enhanced or suppressed responses to the offending agent. Here, we studied whether the sequential exposure to SWCNT via pharyngeal aspiration and infection of mice with the ubiquitous intracellular parasite Toxoplasma gondii would impact on the immune response of the host against the parasite. METHODS: C57BL/6 mice were pre-exposed by pharyngeal administration of SWCNT (80 + 80 µg/mouse) for two consecutive days followed by intravenous injection with either 1x103 or 1x104 green fluorescence protein and luciferase-expressing T. gondii tachyzoites. The dissemination of T. gondii was monitored by in vivo bioluminescence imaging in real time for 7 days and by plaque formation. The inflammatory response was analysed in bronchoalveolar lavage (BAL) fluid, and by assessment of morphological changes and immune responses in lung and spleen. RESULTS: There were no differences in parasite distribution between mice only inoculated with T. gondii or those mice pre-exposed for 2 days to SWCNT before parasite inoculum. Lung and spleen histology and inflammation markers in BAL fluid reflected the effects of SWCNT exposure and T. gondii injection, respectively. We also noted that CD11c positive dendritic cells but not F4/80 positive macrophages retained SWCNT in the lungs 9 days after pharyngeal aspiration. However, co-localization of T. gondii with CD11c or F4/80 positive cells could not be observed in lungs or spleen. Pre-exposure to SWCNT did not affect the splenocyte response to T. gondii. CONCLUSIONS: Taken together, our data indicate that pre-exposure to SWCNT does not enhance or suppress the early immune response to T. gondii in mice.

Structural insights into the catalytic and inhibitory mechanisms of the flavin transferase FmnB in Listeria monocytogenes.

Listeria monocytogenes, a food-borne Gram-positive pathogen, often causes diseases such as gastroenteritis, bacterial sepsis, and meningitis. Newly discovered extracellular electron transfer (EET) from L. monocytogenes plays critical roles in the generation of redox molecules as electron carriers in bacteria. A Mg2+-dependent protein flavin mononucleotide (FMN) transferase (FmnB; UniProt: LMRG_02181) in EET is responsible for the transfer of electrons from intracellular to extracellular by hydrolyzing cofactor flavin adenine dinucleotide (FAD) and transferring FMN. FmnB homologs have been investigated in Gram-negative bacteria but have been less well studied in Gram-positive bacteria. In particular, the catalytic and inhibitory mechanisms of FmnB homologs remain elusive. Here, we report a series of crystal structures of apo-FmnB and FmnB complexed with substrate FAD, three inhibitors AMP, ADP, and ATP, revealing the unusual catalytic triad center (Asp301-Ser257-His273) of FmnB. The three inhibitors indeed inhibited the activity of FmnB in varying degrees by occupying the binding site of the FAD substrate. The key residue Arg262 of FmnB was profoundly affected by ADP but not AMP or ATP. Overall, our studies not only provide insights into the promiscuous ligand recognition behavior of FmnB but also shed light on its catalytic and inhibitory mechanisms.

A regulatory role for macrophage class A scavenger receptors in TLR4-mediated LPS responses.

Recognition of microbial components by TLR, key sensors of infection, leads to induction of inflammatory responses. We found that, in vivo, TLR4 engagement by LPS induces up-regulation of the class A scavenger receptors (SR) macrophage receptor with a collagenous structure (MARCO) and SR-A, which occurs, at least in the case of MARCO, via both MyD88-dependent and -independent pathways. When challenging mice with a low dose of LPS followed by a high dose, class A SR-deficient mice showed a higher survival rate than WT mice. This was paired with increased production of IL-10 and anti-LPS Ab, as well as increased activation status of marginal zone B cells. However, the receptors were not crucial for survival when challenging mice i.p. with Neisseria meningitidis or Listeria monocytogenes, but they were found to contribute to microbial capture and clearance. This indicates physiological significance for the up-regulation of class A SR during early stages of bacterial infection. Thus, we believe that we have revealed a mechanism where SR regulate the activation status of the immune system and are involved in balancing a proper immune response to infection. This regulation could also be important in maintaining tolerance since these receptors have been shown to be involved in regulation of self-reactivity.

Visceral Adiposity Index and Chronic Kidney Disease in a Non-Diabetic Population: A Cross-Sectional Study.

PURPOSE: To investigate the correlation between visceral obesity and pathogenesis of chronic kidney disease (CKD) among non-diabetic individuals, and to evaluate the potential of visceral adiposity index (VAI) as a predictor of CKD. PATIENTS AND METHODS: From December 2017 to March 2018, 1877 non-diabetic participants (male n=699, female n=1208) in southern China were recruited for a cross-sectional survey. Males and females were divided into four groups according to gender-specific quartiles of VAI scores. A logistic regression model was established to analyze the correlation between visceral adiposity index and CKD. RESULTS: Visceral adiposity index was positively correlated with CKD and was negatively associated with estimated glomerular filtration rate (eGFR). Using group one as the control, odds ratios (ORs) were calculated to determine the risk of developing CKD as VAI increased (male: group four 2.73 [P<0.005]; female: Group three 1.76 [P<0.05], Group four 2.88 [P<0.005]). When related factors such as history of hypertension, smoking, alcohol use, and physical inactivity were normalized in the logistic model before calculation, ORs became 2.73 (male: P<0.05), and 2.18 (female: P<0.05), respectively. The results differed after normalizing further for systolic blood pressure (SBP), diastolic blood pressure (DBP), hypersensitive c-reactive protein (hsCRP), interleukin-6 (IL-6), homocysteine (Hcy), superoxide dismutase (SOD), and retinol-binding protein (RBP). There were no significant differences in ORs among the female groups. CONCLUSION: Visceral adiposity index was significantly associated with CKD in non-diabetic individuals. It may be a good predictor of the pathogenesis of CKD and was dependent on hsCRP, IL-6, Hcy, SOD, RBP, and blood pressure levels in females and males with VAI scores of 1.41 and higher. Visceral adiposity index may be used to predict CKD in males with VAI less than 0.983.