Structural basis for FGF hormone signalling.

α/ßKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23)1,2 and their cognate cell-surface FGF receptors (FGFR1-4) thereby stabilizing the endocrine FGF-FGFR complex3-6. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities6. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23-FGFR-αKlotho-HS quaternary complexes featuring the 'c' splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component. These structures, supported by cell-based receptor complementation and heterodimerization experiments, reveal that a single HS chain enables FGF23 and its primary FGFR within a 1:1:1 FGF23-FGFR-αKlotho ternary complex to jointly recruit a lone secondary FGFR molecule leading to asymmetric receptor dimerization and activation. However, αKlotho does not directly participate in recruiting the secondary receptor/dimerization. We also show that the asymmetric mode of receptor dimerization is applicable to paracrine FGFs that signal solely in an HS-dependent fashion. Our structural and biochemical data overturn the current symmetric FGFR dimerization paradigm and provide blueprints for rational discovery of modulators of FGF signalling2 as therapeutics for human metabolic diseases and cancer.

Deep learning guided optimization of human antibody against SARS-CoV-2 variants with broad neutralization.

SignificanceSARS-CoV-2 continues to evolve through emerging variants, more frequently observed with higher transmissibility. Despite the wide application of vaccines and antibodies, the selection pressure on the Spike protein may lead to further evolution of variants that include mutations that can evade immune response. To catch up with the virus's evolution, we introduced a deep learning approach to redesign the complementarity-determining regions (CDRs) to target multiple virus variants and obtained an antibody that broadly neutralizes SARS-CoV-2 variants.

Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

A Nanofluorescent Probe for Evaluating the Fluctuation of Aminopeptidase N in Nonalcoholic Fatty Liver Disease and Hepatic Fibrosis.

Aminopeptidase N (APN/CD13) is a widely expressed transmembrane ectoenzyme that is crucial for maintaining normal physiological activities. It exhibits abnormal activity closely associated with hepatic fibrosis and nonalcoholic fatty liver disease (NAFLD). Therefore, there is a high demand for noninvasive detection of aminopeptidase N (APN) in the diagnosis and research of related diseases. Here, we developed a small molecule fluorescent probe, Hcy-APN, which is a fluorescent probe with high sensitivity and selectivity for the detection of APN. Furthermore, we synthesized the fluorescent nanoprobe Hcy-APN@MSN by self-assembling Hcy-APN and mesoporous silica nanoparticles in solution using a combination of molecular probe design and nanofunctionalization strategies. The detection limit of this probe was 1.5 ng/mL. Hcy-APN@MSN exhibits more stable spectral characteristics compared to Hcy-APN and is suitable for detecting APN activity in live cells and mice. Hcy-APN@MSN was utilized for in vivo and intracellular imaging of NAFLD and hepatic fibrosis at different stages, as well as for a systematic assessment of APN levels in the liver. The results confirm an elevation in the expression levels of APN in NAFLD and hepatic fibrosis models. Furthermore, we investigated the inhibitory effect of the APN inhibitor bestatin in nonalcoholic fatty liver and hepatic fibrosis disease models, confirming its regulatory effect on APN levels in cells and in vivo in both disease models. Therefore, this study may offer diagnostic possibilities for detecting NAFLD and hepatic fibrosis.

Integrated mRNA-seq and miRNA-seq analysis reveals key transcription factors of HNF4α and KLF4 in ADPKD.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disorder affecting the kidneys. Understanding epigenetic regulatory mechanisms and the role of microRNAs (miRNAs) is crucial for developing therapeutic interventions. Two mRNA datasets (GSE7869 and GSE35831) and miRNA expression data (GSE133530) from ADPKD patients were used to find differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs), with a focus on genes regulated by hub transcription factors (TFs) and their target genes. The expression of hub TFs was validated in human kidneys and animal models through Western Blot (WB) and RT-PCR analysis. The location of the hub TF proteins in kidney cells was observed by a laser confocal microscope. A total of 2037 DEGs were identified. DEM analysis resulted in 59 up-regulated and 107 down-regulated miRNAs. Predicted target DEGs of DEMs indicated two top dysregulated TFs: hepatocyte nuclear factor 4 alpha (HNF4α) and Kruppel-like factor 4 (KLF4). RT-PCR, WB, and immunochemistry results showed that mRNA and protein levels of HNF4α were significantly decreased while KLF4 levels were significantly up-regulated in human ADPKD kidneys and Pkd1 conditional knockout mice compared with normal controls. Laser confocal microscopy revealed that KLF4 was mainly located in the cytoplasm while HNF4α was in the nucleus. Functional enrichment analysis indicated that genes regulated by HNF4α were mainly associated with metabolic pathways, while KLF4-regulated genes were linked to kidney development. Drug response prediction analysis revealed potential drug candidates for ADPKD treatment, including BI-2536, Sepantronium, and AZD5582. This integrated analysis provides new epigenetic insights into the complex miRNA-TF-mRNA network in ADPKD and identifies HNF4α and KLF4 as key TFs. These findings offer valuable resources for further research and potential drug development for ADPKD.

Impact of heavy metals exposure on herpes simplex virus type I infection: A population-based cross-sectional study.

This study aims to investigate the significant relationship between serum heavy metals (lead [Pb], cadmium [Cd], mercury [Hg]) and the risk of herpes simplex virus type 1 (HSV-1) infection. Data were derived from the National Health and Nutrition Examination Survey (NHANES) conducted in the United States from 2007 to 2016. This nationally representative survey, conducted by the National Center for Health Statistics, assessed the health status of participants through interviews, physical examinations, and laboratory tests. After excluding participants lacking serum Pb, Cd, and Hg data, as well as those missing HSV-1 testing data and pregnant women, the analysis included 13 772 participants, among whom 3363 were adolescents. A survey-weighted multivariate logistic regression model was used to evaluate the association between heavy metal exposure and the risk of HSV-1 infection, and to explore the dose-response relationship between them. In adults and adolescents, serum concentrations of Pb and Cd were higher in those infected with HSV-1 than in those not infected. However, an increase in serum Hg concentration was observed only in infected adolescents. After adjusting for potential confounders, elevated serum Pb and Cd concentrations in adults were associated with an increased risk of HSV-1 infection. Higher serum Pb and Cd concentrations were associated with an increased risk of HSV-2 infection, irrespective of HSV-1 infection status. In adults, serum concentrations of Pb and Hg showed an approximately linear relationship with HSV-1 infection risk (p for nonlinearity > 0.05), whereas the dose-response relationship between serum Cd concentration and HSV-1 infection was nonlinear (p for nonlinearity = 0.004). In adolescents, serum concentrations of heavy metals (Pb, Cd, Hg) showed an approximately linear relationship with HSV-1 infection (p for nonlinearity > 0.05). Furthermore, the study examined the relationship between serum heavy metal levels and the risk of HSV-1 infection across different genders, races, income levels, weight statuses, and immune statuses. In conclusion, there is a significant association between serum heavy metal concentrations and HSV-1 infection, which warrants further investigation into the causal relationship between them.

Bicyclol mitigates lipopolysaccharide-induced acute lung injury through myeloid differentiation factor 88 inhibition.

Acute lung injury (ALI) remains a significant clinical challenge due to the absence of effective treatment alternatives. This study presents a new method that employs a screening platform focusing on MyD88 affinity, anti-inflammatory properties, and toxicity. This platform was used to evaluate a 300-compound library known for its anti-inflammatory potential. Among the screened compounds, Bicyclol emerged as a standout, exhibiting MyD88 binding and a significant reduction in LPS-stimulated pro-inflammatory factors production in mouse primary peritoneal macrophages. By targeting MyD88, Bicyclol disrupts the MyD88/TLR4 complex and MyD88 polymer formation, thereby mitigating the MAPKs and NF-κB signaling pathways. In vivo experiments further confirmed Bicyclol's efficacy, demonstrating alleviated ALI symptoms, decreased inflammatory cytokines level, and reduced inflammatory cells presence in lung tissues. These findings were associated with a decrease in mortality in LPS-challenged mice. Overall, Bicyclol represents a promising treatment option for ALI by specifically targeting MyD88 and limiting inflammatory responses.

Detection of uridine diphosphate glucuronosyltransferase 1A1 for pancreatic cancer imaging and treatment via a "turn-on" fluorescent probe.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is expressed ubiquitously in cancer cells and can metabolize exogenous substances. Studies show higher UGT1A1 levels in pancreatic cancer cells than normal cells. Therefore, we need a method to monitor the activity level of UGT1A1 in pancreatic cancer cells and in vivo. Here, we report a fluorescent probe, BCy-panc, for UGT1A1 imaging in cells and in vivo. Compared with other molecular probes, this probe is readily prepared, with high selectivity and sensitivity for the detection of UGT1A1. Our results show that BCy-panc rapidly detects UGT1A1 in pancreatic cancer. In addition, there is an urgent need for evidence to clarify the relationship between UGT1A1 and pancreatic cancer development. The present investigation found that the increase of UGT1A1 by chrysin was effective in inducing apoptosis in pancreatic cancer cells. These results indicate that the synergistic effect of chrysin and cisplatin at the cellular level is superior to that of cisplatin alone. The UGT1A1 level may be a biomarker for early diagnosis of cancer. Meanwhile, UGT1A1 plays a crucial role in pancreatic cancer, and the combination of chrysin and cisplatin may provide effective ideas for pancreatic cancer treatment.

SMARCB1 (INI1) Deficient Tumours of the Uterine Cervix: Report of Two Cases, Including One Associated With an NTRK Fusion.

Pathogenic variants (mutations) and other molecular events involving subunits of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex are common in a wide variety of malignancies. Many of these neoplasms are characterized by undifferentiated morphology. They arise at a variety of sites in the female genital tract but have rarely been reported in the uterine cervix. We report 2 primary cervical neoplasms arising in young women (ages 28 and 29 yr) exhibiting loss of nuclear immunoreactivity with SMARCB1 (INI1). In one case, which had a mixture of epithelioid and spindle cells, molecular studies revealed no SMARCB1 pathogenic variant, but showed a SPECCL1::NTRK 3 fusion, in keeping with an NTRK fusion sarcoma. The second case exhibited rhabdoid morphology and molecular testing confirmed a SMARCB1 pathogenic variant (c.425 T>G:p.(Leu142Ter) which, interpreted in conjunction with the morphology and immunohistochemistry, resulted in classification as a proximal-type epithelioid sarcoma. To our knowledge, this is the first reported cervical neoplasm exhibiting a SMARCB1 pathogenic variant and the first NTRK fusion sarcoma showing SMARCB1 protein loss. We discuss the diagnostic challenges and complexities of the molecular findings.

Inflammation Is More Sensitive than Cell Proliferation in Response to Rapamycin Treatment in Polycystic Kidney Disease.

INTRODUCTION: It has been reported that rapamycin inhibited inflammation in renal interstitial diseases. We therefore hypothesized that rapamycin could attenuate inflammation in polycystic kidney disease (PKD). METHODS: Han:SPRD rats were treated with rapamycin by daily gavage from 4 weeks to 12 weeks of age at the dosage of 0.5 mg/kg/day (low dose) or 1 mg/kg/day (high dose). WT9-12 human PKD cells were treated with various concentrations of rapamycin. RESULTS: Two-kidney/total body weight ratio and cystic index in Cy/+ kidneys were significantly reduced with the treatment of low-dose rapamycin and further reduced by the treatment with high-dose rapamycin. However, the renal function of Cy/+ rats was equally improved by the treatment with either low-dose or high-dose rapamycin. The renal cell proliferation was significantly decreased in Cy/+ kidneys with the treatment of low-dose rapamycin and was further decreased with the treatment of high-dose rapamycin as examined by Ki67 staining. The phosphorylation of S6K in cystic kidneys was decreased by low-dose rapamycin and further decreased by high-dose rapamycin. Both low-dose and high-dose rapamycin treatment decreased macrophage infiltration and the expression of complement factor B (CFB), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) to a similar level. The expression of CFB, MCP-1, and TNF-α and phosphorylation of S6K were inhibited in WT9-12 cells treated with 10 nm rapamycin at 24 h and 48 h, respectively. Moreover, the phosphorylation of Akt was not increased by 1 nm and 10 nm of rapamycin and enhanced by 1 µm rapamycin treatment. Interestingly, WT9-12 cell proliferation could be inhibited by 1 µm rapamycin. CONCLUSION: Low dose of rapamycin could inhibit inflammation and protect renal function in PKD. Inflammation is more sensitive than cell proliferation in response to rapamycin treatment in PKD.

α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.

The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of α-klotho is incompatible with its purported glycosidase activity. Thus, shed α-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling.

NIR-activatable nitric oxide generator based on nanoparticles loaded small-molecule photosensitizers for synergetic photodynamic/gas therapy.

BACKGROUND: Therapeutic approaches that combine conventional photodynamic therapy (PDT) with gas therapy (GT) to sensitize PDT are an attractive strategy, but the molecular structure design of the complex lacks effective guiding strategies. RESULTS: Herein, we have developed a nanoplatforms Cy-NMNO@SiO2 based on mesoporous silica materials loaded NIR-activatable small-molecule fluorescent probe Cy-NMNO for the synergistic treatment of photodynamic therapy/gas therapy (PDT/GT) in antibacterial and skin cancer. The theoretical calculation results showed that the low dissociation of N-NO in Cy-NMNO enabled it to dissociate effectively under NIR light irradiation, which is conducive to produce Cy and NO. Cy showed better 1O2 generation performance than Cy-NMNO. The cytotoxicity of Cy-NMNO obtained via the synergistic effect of GT and PDT synergistically enhances the effect of photodynamic therapy, thus achieving more effective tumor treatment and sterilization than conventional PDT. Moreover, the nanoplatforms Cy-NMNO@SiO2 realized efficient drug loading and drug delivery. CONCLUSIONS: This work not only offers a promising approach for PDT-GT synergistic drug delivery system, but also provides a valuable reference for the design of its drug molecules.

Evaluating the Effect of Hydrogen Sulfide in the Idiopathic Pulmonary Fibrosis Model with a Fluorescent Probe.

Hydrogen sulfide (H2S), a gaseous signaling molecule, is involved in a wide range of physiological and pathological processes. H2S has been proven to play a beneficial role in lung diseases, and the relationship between perturbations in endogenous H2S synthesis and degree with idiopathic pulmonary fibrosis (IPF) has attacted increasing attention. However, the changes in endogenous lung H2S levels in the pathological progression of chronic pulmonary diseases remain unclear. To this end, we synthesized a fluorescent probe (Bcy-HS) for the selective imaging of H2S in living cells and mice. This probe was mainly used for in situ in vivo and cellular imaging as well as a systematic assessment of intrapulmonary H2S levels at different stages of IPF. In addition, we also discussed the potential of H2S supplementation in the treatment of pulmonary fibrotic diseases. Our results confirmed the key role of H2S in pulmonary fibrosis. In cellular and mice models of pulmonary fibrosis, intracellular H2S levels are reduced. However, the severity of oxidative damage and pulmonary fibrosis decreased after NaSH (H2S donor). Therefore, we concluded that increasing the H2S content in vivo may be a novel strategy for IPF treatment.

Hippocampal subfield morphology in regular hemodialysis patients.

BACKGROUND: Hippocampal alterations have been implicated in the pathophysiology of cognitive impairment in hemodialysis patients. The hippocampus consists of several distinct subfields, and the molecular mechanisms underlying cognition might be associated with specific hippocampal subfield volume changes. However, this has not yet been investigated in hemodialysis patients. This study aimed to explore volumetric abnormalities in hippocampal subfields in regular hemodialysis patients. METHODS: High-resolution T1-weighted structural images were collected in 61 subjects including 36 hemodialysis patients and 25 healthy controls. A state-of-the-art hippocampal segmentation approach was adopted to segment the hippocampal subfields. Group differences in hippocampal subfield volumes were assessed in Python with a statsmodels module using an ordinary least squares regression with age and sex as nuisance effects. RESULTS: Hemodialysis patients had significantly smaller volumes in the bilateral hippocampus (P < .05/2, Bonferroni corrected), cornu ammonis 1 (CA1), CA4, granule cell and molecular layer of the dentate gyrus, hippocampus-amygdala transition area and molecular layer of the hippocampus than healthy controls (P < .05/24, Bonferroni corrected). Hemodialysis patients also had lower volumes in the left hippocampal tail and right fimbria than healthy controls (P < .05/24, Bonferroni corrected). Hippocampal subfield volumes were associated with neuropsychological test scores, the duration of disease and hemoglobin levels. CONCLUSIONS: We found smaller hippocampal subfield volumes in hemodialysis patients, which were associated with impaired cognition, supporting their role in memory disturbance in the hemodialysis population. However, multiple clinical factors may have confounded the results, and therefore, the interpretation of these results needs to be cautious.

MtDNA Copy Number in Oral Epithelial Cells Serves as a Potential Biomarker of Mitochondrial Damage by Neonicotinoid Exposure: A Cross-Sectional Study.

As the mitochondrial DNA copy number (mtDNAcn) has been reported to be a biomarker for mtDNA damage in honeybees when exposed to sublethal neonicotinoids, the feasibility of using human mitochondria as a predictor upon neonicotinoid exposure remains elusive. This study investigated the association between the urinary neonicotinoid and the relative mtDNAcn (RmtDNAcn) of oral epithelial cells collected in a cross-sectional study with repeated measurements over 6 weeks. The molecular mechanism underlying neonicotinoid-caused mitochondrial damage was also examined by in vitro assay. Herein, the average integrated urinary neonicotinoid (IMIRPF) concentration ranged from 8.01 to 13.70 µg/L (specific gravity-adjusted) during the sampling period. Concomitantly, with an increase in the urinary IMIRPF, the RmtDNAcn significantly increased from 1.20 (low group) to 1.93 (high group), indicating potential dose-dependent mitochondrial damage. Furthermore, the linear regression analysis confirmed the significant correlation between the IMIRPF and RmtDNAcn. Results from in vitro assays demonstrated that neonicotinoid exposure led to the inhibition of the genes encoding mitochondrial oxidative phosphorylation (OXPHOS) complexes I and III (e.g., ND2, ND6, CytB, and CYC1), accompanied by increased reactive oxygen species production in SH-SY5Y cells. Conjointly, neonicotinoid exposure led to mitochondrial dysfunction and a resulting increase in the RmtDNAcn, which may serve as a plausible biomarker in humans.

Incidence and risk factors of cognitive dysfunction in hemodialysis patients: A systematic review and meta-analysis.

BACKGROUND: The study aims to explore the incidence and risk factors of cognitive dysfunction in hemodialysis patients. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were searched for clinical studies on the association between hemodialysis and cognitive dysfunction from the database's inception to 1 December 2022. Two researchers independently completed data extraction and risk of bias assessments for the included studies. All statistical analyses were performed using STATA15.0 software. RESULTS: Ten studies were included in this meta-analysis, with a total of 5535 hemodialysis patients, that is, 2033 patients with cognitive dysfunction and 3502 patients with normal cognitive function. The Newcastle-Ottawa Scale scores of the included studies were greater than 5. Meta-analysis results suggested that the incidence of cognitive dysfunction in hemodialysis patients was (effect size = 51%, 95% confidence interval [CI] [0.33, 0.69]), and hemodialysis patients with cognitive dysfunction were often older than those with normal cognition (standard mean difference [SMD] = 0.49, 95% CI [0.31, 0.68]). Female gender was a risk factor for cognitive dysfunction in hemodialysis patients (relative risk [RR] = 1.21, 95% CI [1.04, 1.41]); diabetes (RR = 1.33, 95% CI [1.04, 1.71]) and stroke (RR = 1.66, 95% CI [1.08, 2.55]) increased the incidence of cognitive dysfunction in hemodialysis patients. CONCLUSIONS: The most important risk factors for cognitive dysfunction associated with hemodialysis might be female gender, old age, diabetes, and stroke. Close attention should be paid to such patients for early prevention.

Relationship between Dialysate Bicarbonate Concentration and All-Cause Mortality in Hemodialysis Patients.

INTRODUCTION: The optimal dialysate bicarbonate concentration (DBIC) for hemodialysis (HD) remains controversial. Herein, we analyzed the effect of dialysate bicarbonate levels on mortality in HD patients. METHODS: Patients undergoing maintenance HD were recruited from the HD unit of the Daping Hospital. Patients were categorized into quartiles according to their DBIC level (quartile 1: <31.25 mmol/L, n = 77; quartile 2: 31.25-32.31 mmol/L, n = 76; quartile 3: 32.31-33.6 mmol/L; n = 81; quartile 4: ≥33.6 mmol/L, n = 79). Demographic and clinical data were collected. Survival curves were estimated using the Kaplan-Meier method. A Cox proportional hazards regression model was used to estimate the association between DBIC and all-cause mortality. RESULTS: We included 313 patients undergoing maintenance HD with a mean DBIC of 32.16 ± 1.59 mmol/L (range, 27.20-34.72 mmol/L). The patients in quartile 4 were more likely to have higher pre- and post-HD serum bicarbonate concentrations than those in other quartiles. The mortality rate was lowest in quartile 2 (10.53%). The survival time was significantly lower in the quartile 4 group than in the other quartiles (p = 0. 008, log-rank test). After full adjustment, the hazard ratio (per 3 mmol/L higher DBIC) for all-cause mortality was 4.29 (95% confidence interval, 2.11-8.47) in all patients, whereas no significant association was observed between DBIC and initial hospitalization. CONCLUSIONS: Our data indicate that DBIC is positively associated with all-cause mortality. A DBIC concentration of 31-32 mmol/L may benefit patient outcomes. This study provides an evidence-based medical basis for optimal dialysis prescription in the future.

Abnormal white matter along fibers by automated fiber quantification in patients undergoing hemodialysis.

BACKGROUND: Abnormal white matter has been reported in patients with end-stage renal disease (ESRD). However, few studies have investigated the relationship between specific damage segments and cognition in ESRD. This study aimed to delineate white matter alterations in ESRD and its relationship with cognition. METHODS: A total of 36 patients undergoing hemodialysis and 25 healthy controls underwent diffusion tensor imaging (DTI) and a series of neuropsychiatric tests. Automated fiber quantification was used to extract distinct DTI indices, and the relationship between the specific segment of the white matter and clinical properties was investigated. Furthermore, a support vector machine was applied to differentiate patients with ESRD from healthy controls. RESULTS: Fractional anisotropy values decreased in multiple fiber bundles, including bilateral thalamic radiata, cingulum cingulate, inferior fronto-occipital fasciculus (IFOF), uncinate, Callosum_Forceps_Major/Callosum_Forceps_Minor (CFMaj/CFMin), and left uncinate from the tract level in patients with ESRD. Specific damaged segments were detected in 8 fiber bundles, including bilateral thalamic radiation, cingulum cingulate, IFOF, CFMin, and left corticospinal tract. Few alterations in these fiber bundles were correlated with cognition impairment and hemoglobin levels. The tract profiles of the left thalamic radiata and left cingulum cingulate could be used to differentiate hemodialysis patients from healthy controls, with an accuracy of 76.9% and 67.6%, respectively. CONCLUSIONS: This study revealed white matter damage in hemodialysis patients. This damage occurred in specific segments of the tract, especially in the left thalamic radiata and left cingulum cingulate, which might become a new biomarker for patients with ESRD and cognition impairment.

Development of QuEChERS coupled with UHPLC-MS/MS for simultaneous determination of eight neonicotinoid pesticides in breast milk.

A speedy and hypersensitive method was built to detect eight neonicotinoid insecticides (neonics) in breast milk by ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The breast milk was extracted with a mixture of acetonitrile and water and purified with primary secondary amine (PSA) and C18. The recovery of the method ranged from 74.3 to 105.9% with relative standard deviations (RSDs) of less than 10%, and the limit of detection ranged from 0.05 to 0.18 ng/mL. Among 32 samples obtained from women 1 month postpartum, thiamethoxam and imidacloprid were the most frequently detected neonics. Moreover, thiacloprid and imidaclothiz were not detected in any samples. The concentrations of neonics in breast milk ranged from 1.90 to 149.95 ng/mL. Considering the toxic effects on mammals and even humans, infants who are exposed to neonics through ingestion of breast milk should receive extensive attention in future studies.

Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.

A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.