Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

Reversible Dual Fluorescence-Lifetime Imaging of Mitochondrial GSH and Microviscosity: Real-Time Evaluation of Ferroptosis Status.

Ferroptosis, as a new form of regulated cell death, is implicated in various physiological and pathological processes. Developing a single probe for an independent analysis of multiple analytes related to ferroptosis can provide more accurate information and simplify the detection procedures, but it faces great challenges. In this work, we develop a fluorescent probe for the simultaneous detection of GSH through ratiometric fluorescence response and microviscosity via a fluorescence lifetime model. Based on the reversible Michael addition reaction between GSH and unsaturated C═C bond, the probe responds reversibly to GSH with a ratiometric fluorescence variation and a fast response time (t1/2 = 4.7 s). At the same time, the probe is sensitive to environmental viscosity by changing its fluorescence lifetimes. The probe was applied to monitor the drug-induced ferroptosis process through both the classical Xc-/GSH/GPX4- and DHODH-mediated defense mechanisms. We hope that the probe will provide a useful molecular tool for the real-time live-cell imaging of GSH dynamics, which is benefit to unveiling related physiological and pathological processes.

Structural basis for SARS-CoV-2 neutralizing antibodies with novel binding epitopes.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.

Sncg, Mybpc1, and Parm1 Classify subpopulations of VIP-expressing interneurons in layers 2/3 of the somatosensory cortex.

Neocortical vasoactive intestinal polypeptide-expressing (VIP+) interneurons display highly diverse morpho-electrophysiological and molecular properties. To begin to understand the function of VIP+ interneurons in cortical circuits, they must be clearly and comprehensively classified into distinct subpopulations based on specific molecular markers. Here, we utilized patch-clamp RT-PCR (Patch-PCR) to simultaneously obtain the morpho-electric properties and mRNA profiles of 155 VIP+ interneurons in layers 2 and 3 (L2/3) of the mouse somatosensory cortex. Using an unsupervised clustering method, we identified 3 electrophysiological types (E-types) and 2 morphological types (M-types) of VIP+ interneurons. Joint clustering based on the combined electrophysiological and morphological features resulted in 3 morpho-electric types (ME-types). More importantly, we found these 3 ME-types expressed distinct marker genes: ~94% of Sncg+ cells were ME-type 1, 100% of Mybpc1+ cells were ME-type 2, and ~78% of Parm1+ were ME-type 3. By clarifying the properties of subpopulations of cortical L2/3 VIP+ interneurons, this study establishes a basis for future investigations aiming to elucidate their physiological roles.

Interferon-α2a induces CD4+ T cell apoptosis and suppresses Th1/Th17 responses via upregulating IRF1-mediated PDL1 expression in dendritic cells from Behcet's uveitis.

Recombinant interferon-α2a (IFNα2a) has been widely used in the treatment of Behcet's uveitis (BU). However, the mechanism underlying its effects remains poorly understood. In this study, we investigated its effect on dendritic cells (DCs) and CD4+ T cells, which are essential for the development of BU. Our results showed that the expression of PDL1 and IRF1 was significantly decreased in DCs from active BU patients, and IFNα2a could significantly upregulate PDL1 expression in an IRF1-dependent manner. IFNα2a-treated DCs induced CD4+ T cells apoptosis and inhibited the Th1/Th17 immune response in association with reduced secretion of IFN-γ and IL-17. We also found that IFNα2a promoted Th1 cell differentiation and IL-10 secretion by CD4+ T cells. Finally, a comparison of patients before and after IFNα2a therapy revealed that the frequencies of Th1/Th17 cells significantly decreased in association with remission of uveitis after IFNα2a therapy. Collectively, these results show that IFNα2a could exert its effects by modulating the function of DCs and CD4+ T cells in BU.

Development and validation of a new model for the early diagnosis of tuberculous meningitis in adults based on simple clinical and laboratory parameters.

BACKGROUND: The differential diagnosis between tuberculous meningitis (TBM) and viral meningitis (VM) or bacterial meningitis (BM) remains challenging in clinical practice, particularly in resource-limited settings. This study aimed to establish a diagnostic model that can accurately and early distinguish TBM from both VM and BM in adults based on simple clinical and laboratory parameters. METHODS: Patients diagnosed with TBM or non-TBM (VM or BM) between January 2012 and October 2021 were retrospectively enrolled from the General Hospital (derivation cohort) and Branch Hospital (validation cohort) of Ningxia Medical University. Demographic characteristics, clinical symptoms, concomitant diseases, and cerebrospinal fluid (CSF) parameters were collated. Univariable logistic analysis was performed in the derivation cohort to identify significant variables (P < 0.05). A multivariable logistic regression model was constructed using these variables. We verified the performance including discrimination, calibration, and applicability of the model in both derivation and validation cohorts. RESULTS: A total of 222 patients (70 TBM and 152 non-TBM [75 BM and 77 VM]) and 100 patients (32 TBM and 68 non-TBM [31 BM and 37 VM]) were enrolled as derivation and validation cohorts, respectively. The multivariable logistic regression model showed that disturbance of consciousness for > 5 days, weight loss > 5% of the original weight within 6 months, CSF lymphocyte ratio > 50%, CSF glucose concentration < 2.2 mmol/L, and secondary cerebral infarction were independently correlated with the diagnosis of TBM (P < 0.05). The nomogram model showed excellent discrimination (area under the curve 0.959 vs. 0.962) and great calibration (P-value in the Hosmer-Lemeshow test 0.128 vs. 0.863) in both derivation and validation cohorts. Clinical decision curve analysis showed that the model had good applicability in clinical practice and may benefit the entire population. CONCLUSIONS: This multivariable diagnostic model may help clinicians in the early discrimination of TBM from VM and BM in adults based on simple clinical and laboratory parameters.

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

Changes and significance of vascular endothelial injury markers in patients with diabetes mellitus and pulmonary thromboembolism.

BACKGROUND: To investigate the changes and clinical significance of vascular endothelial injury markers in type 2 diabetes mellitus (T2DM) complicated with pulmonary embolism (PE). METHODS: This prospective study enrolled patients with T2DM hospitalized in one hospital from January 2021 to June 2022. Soluble thrombomodulin (sTM) (ELISA), von Willebrand factor (vWF) (ELISA), and circulating endothelial cells (CECs) (flow cytometry) were measured. PE was diagnosed by computed tomography pulmonary angiography (CTPA). RESULTS: Thirty participants were enrolled in each group. The plasma levels of sTM (151.22 ± 120.57 vs. 532.93 ± 243.82 vs. 1016.51 ± 218.00 pg/mL, P < 0.001) and vWF (9.63 ± 2.73 vs. 11.50 ± 2.17 vs. 18.02 ± 3.40 ng/mL, P < 0.001) and the percentage of CECs (0.17 ± 0.46 vs. 0.30 ± 0.08 vs. 0.56 ± 0.18%, P < 0.001) gradually increased from the control group to the T2DM group to the T2DM + PE group. sTM (OR = 1.002, 95%CI: 1.002-1.025, P = 0.022) and vWF (OR = 1.168, 95%CI: 1.168-2.916, P = 0.009) were associated with T2DM + PE. sTM > 676.68 pg/mL for the diagnosis of T2DM + PE achieved an AUC of 0.973, while vWF > 13.75 ng/mL achieved an AUC of 0.954. The combination of sTM and vWF above their cutoff points achieved an AUC of 0.993, with 100% sensitivity and 96.7% specificity. CONCLUSIONS: Patients with T2DM show endothelial injury and dysfunction, which were worse in patients with T2DM and PE. High sTM and vWF levels have certain clinical predictive values for screening T2DM accompanied by PE.

Enantioselective Synthesis of Acyclic Stereotriads Featuring Fluorinated Tetrasubstituted Stereocenters.

Elaboration of enantioenriched complex acyclic stereotriads represents a challenge for modern synthesis even more when fluorinated tetrasubstituted stereocenters are targeted. We have been able to develop a simple strategy in a sequence of two unprecedented steps combining a diastereoselective aldol-Tishchenko reaction and an enantioselective organocatalyzed kinetic resolution. The aldol-Tishchenko reaction directly generates a large panel of acyclic 1,3-diols possessing a fluorinated tetrasubstituted stereocenter by condensation of fluorinated ketones with aldehydes under very mild basic conditions. The anti 1,3-diols featuring three contiguous stereogenic centers are generated with excellent diastereocontrol (typically >99 : 1 dr). Depending upon the precursors both diastereomers of stereotriads are accessible through this flexible reaction. Furthermore, from the obtained racemic scaffolds, development of an organocatalyzed kinetic resolution enabled to generate the desired enantioenriched stereotriads with excellent selectivity (typically er >95 : 5).

The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.

BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.

Catalytic Reversible (De)hydrogenation To Rotate a Chemically Fueled Molecular Switch.

We report here the development of a rotating molecular switch based on metal-catalyzed reversible (de)-hydrogenation. Under an argon atmosphere, acceptorless dehydrogenation induces a switch from an alcohol to a ketone, while reversing to a hydrogen pressure switches back the system to the alcohol. Based on a tolane scaffold, such reversible (de)-hydrogenation enables 180° rotation. The absence of waste accumulation in a switch relying on chemical stimuli is of great significance and could potentially be applied to the design of efficient complex molecular machines.

Exosomal circ_PIP5K1A regulates the progression of non-small cell lung cancer and cisplatin sensitivity by miR-101/ABCC1 axis.

Circular RNAs (circRNAs) play vital roles in various types of cancer and chemosentivity. In the progression of carcinogenesis, exosomes are messengers for intercellular communication. The aim of this study was to explore the role of exosomal circRNA phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (circ_PIP5K1A) in non-small cell lung cancer (NSCLC) progression and cisplatin sensitivity. The expression levels of circ_PIP5K1A, miR-101 and ATP binding cassette subfamily C member 1 (ABCC1) were detected by quantitative real-time polymerase chain reaction or western blot assay. Cell Counting Kit-8 assay was used to detect cell viability and 50% inhibitory concentration value of cisplatin. Cell migration, invasion, proliferation, and apoptosis were determined by wound healing assay, transwell assay, colony formation assay, and flow cytometry, respectively. A xenograft tumor model was established to explore the role of circ_PIP5K1A in vivo. Exosomes were detected using transmission electron microscopy analysis. The interaction between miR-101 and circ_PIP5K1A or ABCC1 was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay and RNA pull-down assay. Circ_PIP5K1A and ABCC1 were overexpressed and miR-101 was downregulated in NSCLC tissues, serum samples, and cells. Knockdown of exosomal circ_PIP5K1A inhibited NSCLC cell proliferation, migration, and invasion and promoted apoptosis and cisplatin sensitivity. Likewise, circ_PIP5K1A downregulation inhibited tumor growth. MiR-101 was a direct target of circ_PIP5K1A, and its knockdown reversed the effects of circ_PIP5K1A silence on inhibition of NSCLC progression and promotion of cisplatin sensitivity. Moreover, ABCC1 was a downstream target of miR-101, and miR-101 overexpression inhibited the progression of NSCLC cells and increased cisplatin sensitivity by targeting ABCC1. Besides, circ_PIP5K1A positively regulated ABCC1 expression by sponging miR-101. Exosomal circ_PIP5K1A knockdown inhibited NSCLC progression and promoted cisplatin sensitivity by regulating miR-101/ABCC1 axis, providing a novel avenue for treatment of NSCLC.

Serum Soluble ST2 Correlated with Symptom Severity and Clinical Response of Sublingual Immunotherapy for House Dust Mite-Induced Allergic Rhinitis Patients.

BACKGROUND: Suppressor of tumorigenicity 2 (ST2) is a key biomarker in inflammation and cardiovascular diseases, but limited data is available on its role in allergic rhinitis (AR). OBJECTIVE: The aim of this study is to explore the role of serum soluble ST2 (sST2) in evaluating disease severity and predicting the efficacy of sublingual immunotherapy (SLIT) in house dust mite- (HDM-) induced AR patients. METHODS: Eighty healthy controls (HC group) and 160 HDM-induced AR patients, including 40 mild patients (MAR group) and 120 moderate-severe patients (MSAR group), were recruited in this study. Serum was collected from all participants and levels of sST2 were determined by ELISA and the relationship between sST2 levels and disease severity was assessed. In the MSAR group, 109 patients received 3 years of SLIT, and the relationship between serum levels of sST2 and efficacy of SLIT was exampled. RESULTS: Serum sST2 levels were increased in HDM-induced AR patients compared to the HC group (P < 0.001), and the concentrations were higher in the MSAR group than in the MAR group and HC group (all P < 0.05). Moreover, sST2 levels positively correlated with the total nasal symptom score (TNSS), visual analogue scale (VAS), and specific IgE levels (P < 0.05). Seventy-eight MSAR patients accomplished SLIT, and they were divided into an effective group (n = 40) and an ineffective group (n = 38). The serum sST2 levels in the effective group were lower than those in the ineffective group (P < 0.001). In addition, patients in the effective group levels exhibited significantly lower sST2 levels post-SLIT than pre-SLIT (P < 0.001), but no statistic difference was observed in the ineffective group (P > 0.05). Receiver operating characteristic (ROC) curve showed promising accuracy for predicting clinical efficacy of SLIT in AR patients (area under the curve = 0.839, P < 0.001). CONCLUSION: Serum sST2 is a potential biomarker for assessing disease severity and may serve as a sensitive biomarker for predicting the therapeutic response of SLIT in HDM-induced AR patients.

BODIPY-Based Fluorescent Probe for Dual-Channel Detection of Nitric Oxide and Glutathione: Visualization of Cross-Talk in Living Cells.

Nitric oxide (NO) and glutathione (GSH) have interplaying roles in oxidant-antioxidant balance. In this work, we developed the first example of a single fluorescent probe that displayed a turn-on fluorescence response toward NO and GSH from dual emission channels. The probe was synthesized by introducing 4-amino-3-(methylamino)-phenol to a BODIPY scaffold. Specifically, the NO-mediated transformation of diamine into a triazole triggered the fluorescence in the green channel, and the GSH-induced SNAr substitution reaction led to the red-shifted emission in the red channel. The probe was successfully applied to detect the exogenous and endogenous NO and GSH in macrophage cells. More importantly, the probe revealed that NO induced by interferon-γ (IFN-γ), lipopolysaccharide (LPS), and l-arginine (l-Arg) could also elicit the augmentation of intracellular GSH. We anticipate the probe would hold great potential for investigating the redox balance in biological processes.

Seizure characteristics, treatment, and outcome in autoimmune synaptic encephalitis: A long-term study.

OBJECTIVES: The objective of this study was to report seizure characteristics, long-term outcome, and potential factors associated with persistent seizures in patients with autoimmune synaptic encephalitis (ASE). METHOD: Clinical data and courses of 52 patients with ASE who presented with seizures at the Department of Neurology of the First Hospital of Jilin University from January 2015 to August 2017 were reviewed. Seizure outcomes were assessed with a median follow-up duration of 30 months (8-40 months). RESULTS: Most patients (71.2%) presented with seizure at initial consultation; focal to bilateral tonic-clonic seizures (50.0%) were the most common type. The temporal lobe (73.5%) was the prominent region of seizure origin, which was incident with hippocampal lesions on magnetic resonance imaging (MRI) in 62.1% of the patients. Status epilepticus, subclinical seizures, and nonepileptic events were observed in 28.9%, 36.8%, and 28.9% of the patients, respectively. Twenty-seven out of the 43 followed-up patients (62.8%) exhibited seizure remission after initial immunotherapy. Others (37.2%) developed persistent seizures to different extents. Six out of 9 patients experienced additional seizure freedom because of antiepileptic drugs (AEDs); however, the seizures of the other three patients, with serious conditions, showed poor response. Patients with anti-N-methyl-d-aspartate receptor antibodies had a lower risk of developing persistent seizures than those with anti-leucine-rich glioma-inactivated 1 (LGI1) or anti-γ-aminobutyric acid receptor type B receptor (GABABR) antibodies (P = 0.001). CONCLUSIONS: A complex of clinical and subclinical seizures, and nonepileptic events characterize ASE. Patients with anti-LGI1 or anti-GABABR antibodies have a higher risk of developing persistent seizures; AEDs are suitable for achieving additional seizure freedom, but not for patients with serious conditions. A few patients present with super-refractory epilepsy despite multiple treatments.

Fucoxanthin and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Synergistically Promotes Apoptosis of Human Cervical Cancer Cells by Targeting PI3K/Akt/NF-κB Signaling Pathway.

BACKGROUND Fucoxanthin is a carotenoid present in the chloroplasts of brown seaweeds. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively induces apoptosis in many tumor cells and is an attractive candidate for antitumor therapies. MATERIAL AND METHODS After human cervical cancer cell lines HeLa, SiHa, and CaSki were treated with fucoxanthin or TRAIL. Cell viability was determined by 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2-tetrazolium 5-carboxanilide (XTT) method. Apoptosis was measured by flow cytometry (FCM). Protein expression of phosphatidylinositol 3 kinase (PI3K), protein kinase B (Akt), phosphated Akt (p-Akt), NF-κB nuclear factor-k-gene binding (NF-κB). Phosphated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (p-IκBα), was measured by Western blot analysis. mRNA expression of Bax and Bcl2 was measured by RNA preparation and quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS In the present study, the effectiveness in terms of apoptosis was as follows: TRAIL plus fucoxanthin>fucoxanthin>TRAIL, indicating the combination of fucoxanthin and TRAIL, produced a strong synergistic effect on apoptosis in human cervical cancer cells. Additionally, we found that upstream signaling PI3K/Akt and NF-κB pathways-mediated cell apoptosis was activated by TRAIL and suppressed by fucoxanthin. By using PI3K and NF-κB inhibitors LY49002 and PDTC, we found that fucoxanthin- or TRAIL-induced apoptosis of human cervical cancer cells was obviously down-regulated. CONCLUSIONS Taken together, these findings suggest that fucoxanthin and TRAIL increased the apoptosis in human cervical cancer cells by targeting the PI3K/Akt/NF-κB signaling pathway.

Association of toll-like receptor gene polymorphisms and its interaction with HPV infection in determining the susceptibility of cervical cancer in Chinese Han population.

The aim of the study is to investigate the association of several single-nucleotide polymorphisms (SNPs) within Toll-like receptors (TLRs) gene and additional gene-gene and gene-human papillomavirus (HPV) infection interaction with cervical cancer risk. A total of 1262 participants are selected, including 420 cervical cancer patients and 842 control participants. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among five SNPs within TLR gene and HPV infection. Logistic regression was performed to calculate the ORs (95 %CI) for association of five SNPs within TLR gene and additional gene-HPV infection interaction with cervical cancer risk. Cervical cancer risk was significantly higher in carriers of the T allele of rs3775290 within TLR2 gene, the G allele of rs7873784 within TLR4 gene, and the A allele of rs352140 within TLR9 gene than those with wild genotype; adjusted ORs (95 %CI) were 1.78 (1.20-2.24), 1.65 (1.23-2.12), and 1.70 (1.16-2.31). However, we did not find any significant association of rs4986791 and rs11536889 with cervical cancer risk. GMDR analysis suggested a significant two-locus model (p = 0.0107) involving rs352140 and HPV infection. Subjects with HPV infection and rs352140-GA + AA genotype within TLR9 gene have the highest cervical cancer risk, compared to no HPV infection participants with rs352140-GG genotype, OR (95 %CI) = 3.22 (1.68-4.81). Pairwise LD analysis did not find any significant haplotype combination associated with cervical cancer risk. The minor alleles of TLR2-rs3775290, TLR4-rs7873784, and TLR9-rs352140, and interaction between rs352140 and HPV infection were all associated with increased cervical cancer risk.

Azetidine-derived dinuclear zinc catalyzed asymmetric phospha-Michael addition of dialkyl phosphite to α,ß-unsaturated carbonyl compounds.

The asymmetric phospha-Michael addition of dialkyl phosphite to α,ß-unsaturated carbonyl compounds by using an azetidine-derived dinuclear zinc catalyst was described. The catalyst was proved to be general and efficient for a broad spectrum of enones and α,ß-unsaturated N-acylpyrroles. A series of phosphonate-containing compounds were generated with excellent enantioselectivities (up to 99% ee) and chemical yields (up to 99%) under mild conditions without using additives. The products were obtained with more than 95% ee for 23 examples of α,ß-unsaturated carbonyl compounds. A positive nonlinear effect was observed and the possible mechanism was proposed.

Core-shell structured CdTe/CdS@SiO2 @CdTe@SiO2 composite fluorescent spheres: Synthesis and application for Cd2+ detection.

Core-shell structured quantum dot (QD)-silica fluorescent nanoparticles have attracted a great deal of attention due to the excellent optical properties of QDs and the stability of silica. In this study, core-shell structured CdTe/CdS@SiO2 @CdTe@SiO2 fluorescent nanospheres were synthesized based on the Stöber method using multistep silica encapsulation. The second silica layer on the CdTe QDs maintained the optical stability of nanospheres and decreased adverse influences on the probe during subsequent processing. Red-emissive CdTe/CdS QDs (630 nm) were used as a built-in reference signal and green-emissive CdTe QDs (550 nm) were used as a responding probe. The fluorescence of CdTe QDs was greatly quenched by added S2- , owing to a S2- -induced change in the CdTe QDs surface state in the shell. Upon addition of Cd2+ to the S2- -quenched CdTe/CdS@SiO2 @CdTe@SiO2 system, the responding signal at 550 nm was dramatically restored, whereas the emission at 630 nm remained almost unchanged; this response could be used as a ratiometric 'off-on' fluorescent probe for the detection of Cd2+ . The sensing mechanism was suggested to be: the newly formed CdS-like cluster with a higher band gap facilitated exciton/hole recombination and effectively enhanced the fluorescence of the CdTe QDs. The proposed probe shows a highly sensitive and selective response to Cd2+ and has potential application in the detection of Cd2+ in environmental or biological samples.

Ratiometric Fluorescent Biosensing of Hydrogen Peroxide and Hydroxyl Radical in Living Cells with Lysozyme-Silver Nanoclusters: Lysozyme as Stabilizing Ligand and Fluorescence Signal Unit.

Construction of facile ratiometric fluorescent probes which possess sensitive and selective sensing ability for bioactive small molecules is highly desirable and challenging. Herein, silver nanoclusters capped with denatured lysozyme (dLys-AgNCs) were synthesized and proved to be dual emissive. The facility of the dLys-AgNCs ratiometric probe was attributed to the finding that the lysozyme acted not only as stabilizing ligand but also as fluorescence signal unit. In the presence of Fenton reagents, the emission of dLys-AgNCs at 640 nm was quenched by •OH, whereas the emission at 450 was enhanced due to •OH-induced oxidation of tyrosine in the lysozyme. This probe could be used for highly sensitive detection of H2O2. The fluorescence changes of F450/F640 had fantastic linearity to H2O2 concentrations in the range of 0.8-200 µmol/L (R2 = 0.9993), with a limit of detection (LOD) as low as 0.2 µmol/L. Additionally, this probe was also applied to H2O2-generated oxidase-based biosensing. As a proof-of-concept, glucose and acetylcholine chloride were detected with benefical LOD values of 0.6 µmol/L and 0.8 µmol/L, respectively. Furthermore, fluorescence confocal imaging demonstrated dLys-AgNCs had a sensitive response to fluctuation of •OH levels in living cells, which might have promising application in study of •OH-induced oxidative damage to proteins.