Multifunctional magnetic tags with photocatalytic and enzyme-mimicking properties for constructing a sensitive dual-readout ELISA.

ELISA has become the gold standard for detecting harmful substances due to its specific antibody recognition and sensitive enzyme-catalyzed reactions. In this study, multifunctional magnetic Prussian blue nanolabels (MPBNs) were synthesized using a simple gentle two-step method to achieve a dual-readout mode. The MPBNs provide a sensitive colorimetric signal by efficiently catalyzing the oxidation of TMB and exhibit prominent photocatalytic degradation activity towards Rhodamine B (RhB). Supplemented by the quenching effect of oxTMB, the fluorescence was enabled to serve as a sensitive second signal. The magnetic property of the labels facilitates the separation and enrichment of the target, thereby improving sensitivity. Utilizing the versatile MPBNs, the visual limit of detection (vLOD) for Staphylococcus aureus is as low as 100 CFU/mL, with a quantitative analysis range of 102-108 CFU/mL. The introduction of photocatalytic reactions into immunoassay has opened up a new signal response system with strong momentum for development and application.

Mitochondria-Targetable Near-Infrared Fluorescent Probe for Visualization of Hydrogen Peroxide in Lung Injury, Liver Injury, and Tumor Models.

Hydrogen peroxide (H2O2) overexpressed in mitochondria has been regarded as a key biomarker in the pathological processes of various diseases. However, there is currently a lack of suitable mitochondria-targetable near-infrared (NIR) probes for the visualization of H2O2 in multiple diseases, such as PM2.5 exposure-induced lung injury, hepatic ischemia-reperfusion injury (HIRI), nonalcoholic fatty liver (NAFL), hepatic fibrosis (HF), and malignant tumor tissues containing clinical cancer patient samples. Herein, we conceived a novel NIR fluorescent probe (HCy-H2O2) by introducing pentafluorobenzenesulfonyl as a H2O2 sensing unit into the NIR hemicyanine platform. HCy-H2O2 exhibits good sensitivity and selectivity toward H2O2, accompanied by a remarkable "turn-on" fluorescence signal at 720 nm. Meanwhile, HCy-H2O2 has stable mitochondria-targetable ability and permits monitoring of the up-generated H2O2 level during mitophagy. Furthermore, using HCy-H2O2, we have successfully observed an overproduced mitochondrial H2O2 in ambient PM2.5 exposure-induced lung injury, HIRI, NAFL, and HF models through NIR fluorescence imaging. Significantly, the visualization of H2O2 has been achieved in both tumor-bear mice as well as surgical specimens of cancer patients, making HCy-H2O2 a promising tool for cancer diagnosis and imaging-guided surgery.

Ultrasensitive monitoring of PCB77 in environmental samples using a visible-driven photoelectrochemical sensing platform coupling with exonuclease I assisted in target recycling.

Due to the urgent need for detecting trace amounts of 3,3',4,4'-tetrachlorobiphenyl (PCB77) in the environment, we have developed an efficient and visible-driven photoelectrochemical (PEC) sensing platform based on carbon quantum dots (CQDs) modified titanium dioxide nanorods (TiO2 NRs), coupling with exonuclease I (Exo I) assisted in target recycling for significant signal amplification. CQDs/TiO2 NRs with high visible-light absorption ability and electron-hole separation efficiency is used as photoactive substrate for anchoring anti-PCB77 aptamer and its complementary DNA (cDNA). With the addition of PCB77, the specific interaction between PCB77 and its aptamer forces aptamer to separate from the electrode surface, resulting in an increase in photocurrent density. Adding Exo I in the test system, a self-catalytic target cycle was motivated, which significantly increased the PEC signal by more than twice, achieving signal amplification. The relationship between the photocurrent density changes and the concentrations of PCB77 are utilized to achieve quantitative detection of PCB77. The designed PEC sensing platform has good analytical performance with a detection limit as low as 0.33 pg L-1, high selectivity and stability. Moreover, the PEC sensor is successfully used to evaluate the content of PBC77 in the environment samples. The established sensing platform provides a simple and efficient method for detecting trace amounts of PCB77 in the environment.

Efficient degradation of tetracycline via peroxymonosulfate activation by phosphorus-doped biochar loaded with cobalt nanoparticles.

The accumulation of tetracycline hydrochloride (TCH) threatens human health because of its potential biological toxicity. Carbon -based materials with easy isolation and excellent performance that can activate peroxymonosulfate (PMS) to generate reactive oxygen species for TCH degradation are essential, but the development of such materials remains a significant challenge. In this study, based on the idea of treating waste, tricobalt tetraoxide loaded P-doped biochar (Co NP-PBC) was synthesised to activate PMS for the degradation of TCH. Possible degradation pathways and intermediate products of TCH were identified using High performance liquid chromatography tandem mass spectrometry (HPLC-MS) detection and density functional theory analysis. Toxicity analysis software was used to predict the toxicity of the intermediate products. Compared to catalysts loaded with Fe and Mn and other Co-based catalysts, Co NP-PBC exhibited an optimal performance (with a kinetic constant of 0.157 min-1 for TCH degradation), and over 99.0% of TCH can be degraded within 20 min. This mechanism demonstrates that the non-free radical oxidation of 1O2 plays a major role in the degradation of TCH. This study provides insights into the purification of wastewater using BC-based catalysts.

Bovine Serum Albumin Template-Mediated Fabrication of Ruthenium Dioxide/Multiwalled Carbon Nanotubes: High-Performance Electrochemical Dopamine Biosensing in Human Serum.

The presence of abnormal dopamine (DA) levels may cause serious neurological disorders, therefore, the quantitative analysis of DA and its related research are of great significance for ensuring health. Herein, the bovine serum albumin (BSA) template method has been proposed for the preparation of catalytically high-performance ruthenium dioxide/multiwalled carbon nanotube (RuO2/MWCNT) nanocomposites. The incorporation of MWCNTs has improved the active surface area and conductivity while effectively preventing the aggregation of RuO2 nanoparticles. The outstanding electrocatalytic performance of RuO2/MWCNTs has promoted the electro-oxidation of DA at neutral pH. The electrochemical sensing platform based on RuO2/MWCNTs has demonstrated a wide linear range (0.5 to 111.1 µM), low detection limit (0.167 µM), excellent selectivity, long-term stability, and good reproducibility for DA detection. The satisfactory recovery range of 94.7% to 103% exhibited by the proposed sensing podium in serum samples signifies its potential for analytical applications. The aforementioned results reveal that RuO2/MWCNT nanostructures hold promising aptitude in the electrochemical sensor to detect DA in real samples, further offering broad prospects in clinical and medical diagnosis.

Visualization of polarity changes in endoplasmic reticulum (ER) autophagy and rheumatoid arthritis mice with near-infrared ER-targeted fluorescent probe.

The crucial cellular activities for maintaining normal cell functions heavily rely on the polarity of the endoplasmic reticulum (ER). Understanding how the polarity shifts, particularly in the context of ER autophagy (ER-phagy), holds significant promise for advancing knowledge of disorders associated with ER stress. Herein, a polarity-sensitive fluorescent probe CDI was easily synthesized from the condensation reaction of coumarin and dicyanoisophorone. CDI was composed of coumarin as the electron-donating moiety (D), ethylene and phenyl ring as the π-conjugation bridge, and malononitrile as the electron-accepting moiety (A), forming a typical D-π-A molecular configuration that recognition in the near-infrared (NIR) region. The findings suggested that as the polarity increased, the fluorescence intensity of CDI decreased, and it was accompanied by a redshift of emission wavelength at the excitation wavelength of 524 nm, shifting from 641 nm to 721 nm. Significantly, CDI exhibited a notable ability to effectively target ER and enabled real-time monitoring of ER-phagy induced by starvation or drugs. Most importantly, alterations in polarity can be discerned through in vivo imaging in mice model of rheumatoid arthritis (RA). CDI has been proven effective in evaluating the therapeutic efficacy of drugs for RA. ER fluorescent probe CDI can be optically activated in lysosomes, providing a sensitive tool for studying ER-phagy in biology and diseases.

Conjunctive encoding of exploratory intentions and spatial information in the hippocampus.

The hippocampus creates a cognitive map of the external environment by encoding spatial and self-motion-related information. However, it is unclear whether hippocampal neurons could also incorporate internal cognitive states reflecting an animal's exploratory intention, which is not driven by rewards or unexpected sensory stimuli. In this study, a subgroup of CA1 neurons was found to encode both spatial information and animals' investigatory intentions in male mice. These neurons became active before the initiation of exploration behaviors at specific locations and were nearly silent when the same fields were traversed without exploration. Interestingly, this neuronal activity could not be explained by object features, rewards, or mismatches in environmental cues. Inhibition of the lateral entorhinal cortex decreased the activity of these cells during exploration. Our findings demonstrate that hippocampal neurons may bridge external and internal signals, indicating a potential connection between spatial representation and intentional states in the construction of internal navigation systems.

Sensitive detections for three kinds of vitamin B in aqueous solution and on test paper by fluorescent dual-emission carbon dots.

Although a few of fluorescent probes based on carbon dots (CDs) for vitamin B (VB) determination have been emerged, none of them can realize the detection of different kinds of VB. In this paper, nitrogen, chlorine co-doped dual-emission CDs (N, Cl-CDs) with emissions at 404 nm and 595 nm have been easily synthesized. VB2, VB9 and VB12 can all induce obvious fluorescence turn-off response toward the N, Cl-CDs. Based on that, three types of VBs are quantitatively and sensitively evaluated in aqueous solution with wide concentration ranges of 14.9-135.0 µM, 34.7-89.8 µM and 29.8-79.8 µM, respectively. Importantly, visual semiquantitative detection of VBs on a test strip are also proposed. Moreover, the current N, Cl-CDs have been successfully applied to the detection of VBs in real samples. The N, Cl-CDs are sensitively multifunctional sensors for three kinds of VBs in aqueous solution and the visual semiquantitative detection by test paper assay is simple, portable and inexpensive.

Bridging biological and food monitoring: A colorimetric and fluorescent dual-mode sensor based on N-doped carbon dots for detection of pH and histamine.

Rapid and sensitive monitoring of pH and histamine is crucial for bridging biological and food systems and identifying corresponding abnormal situations. Herein, N-doped carbon dots (CDs) are fabricated by a hydrothermal method employing dipicolinic acid and o-phenylenediamine as precursors. The CDs exhibit colorimetric and fluorescent dual-mode responses to track pH and histamine variations in living cells and food freshness, respectively. The aggregation-induced emission enhancement and intramolecular charge transfer result in a decrease in absorbance and an increase in fluorescence, which become readily apparent as the pH changes from acidic to neutral. This property enables precise differentiation between normal and cancerous cells. Furthermore, given the intrinsic basicity of histamine, pH-responsive CDs are advantageous for additional colorimetric and fluorescent monitoring of histamine in food freshness, achieving linearities of 25-1000 µM and 30-1000 µM, respectively, which are broader than those of alternative nanoprobes. Interestingly, the smartphone-integrated sensing platform can portably and visually evaluate pH and histamine changes due to sensitive color changes. Therefore, the sensor not only establishes a dynamic connection between pH and histamine for the purposes of biological and food monitoring, but also presents a novel approach for developing a multifunctional biosensor that can accomplish environmental monitoring and biosensing simultaneously.

Hydrophobic carbon quantum dots with red fluorescence: An optical dual-mode and smartphone imaging sensor for identifying Chinese Baijiu quality.

Chinese Baijiu (Liquor) is a popular alcoholic beverage, and the ethanol content in Baijiu is closely related to its quality; therefore, it is of great significance to explore a facile, sensitive, and rapid method to detect ethanol content in Baijiu. Hydrophobic carbon quantum dots (H-CQDs) with bright red fluorescence (24.14 %) were fabricated by hydrothermal method using o-phenylenediamine, p-aminobenzoic acid, manganese chloride, and hydrochloric acid as reaction precursors. After the introduction of ultrapure water into the ethanol solution dissolved with H-CQDs, the aggregated H-CQDs resulted in significant changes in fluorescence intensity and absorbance. On this basis, a sensor for detecting ethanol by optical dual-mode and smartphone imaging was constructed. More importantly, the sensor can be used for detecting ethanol content in Chinese Baijiu with satisfactory results. This sensing platform has great potential for quality identification in Chinese Baijiu, broadening the application scope of CQDs in food safety detection.

Design of a dual-mode ratiometric fluorescent probe via MOF-on-MOF strategy for Al (III) and pH detection.

BACKGROUND: The construction of ratiometric fluorescent MOF sensors with integrated self-calibration and dual-channel detection can efficiently overcome the deficiencies of single-signal sensing. In this regard, the rational design of structurally functionalized MOFs is paramount for enhancing their performance in ratiometric fluorescent sensors. Lately, the concept of MOF-on-MOF design has garnered notable interest as a potential strategy for regulating the structural parameters of MOFs by integrating two or more distinct MOF types. Great efforts have been dedicated to exploring new MOF-on-MOF hybrids and developing their applications in diverse fields. Even so, these materials are still in the stage of advancement in the sensing field. RESULTS: Herein, a Zr-based metal-organic framework anchored on a rare-earth metal-organic framework (UiO-66(OH)2@Y-TCPP) was prepared for the ratiometric fluorescence detection toward Al (III) and pH. In this probe, the UiO-66(OH)2 featured hydroxyl active sites for Al (III), leading to a significant enhancement in fluorescence intensity upon the addition of Al (III), while the signal emitted by the red-emitting Y-TCPP, serving as the reference, remained constant. UiO-66(OH)2@Y-TCPP exhibited excellent selectivity for Al (III) sensing with a wider linear range of 0.1-1000 µM, and a lower detection limit of 0.06 µM. This probe has also been utilized for the quantitative determination of Al (III) in hydrotalcite chewable tablets with satisfactory results. In addition, the probe realized ratiometric pH sensing in the range of 7-13 using UiO-66(OH)2 as an interior reference. The paper-based probe strip was developed for visual pH sensing. By installing color recognition and processing software on a smartphone, real-time and convenient pH sensing could be achieved. SIGNIFICANCE: This is the first ratiometric fluorescent sensor for Al (III) and pH detection based on a MOF-on-MOF composite probe, which yields two different response modes. The detection results of Al (III) in hydrotalcite chewable tables and smartphone imaging for pH test paper demonstrate the practicability of the probe. This work opens up a new outlook on constructing a multi-functional application platform with substantial potential for employment in environmental and biological analysis tasks.

A specific dual-locked fluorescence probe to visualize the dynamic changes of lipid droplets and hypochlorous acid in inflammation.

Inflammation is a key factor leading to the occurrence and development of many diseases, both lipid droplets (LDs) and hypochlorous acid (HClO/ClO-) are regarded as the important biomarkers of inflammation. Therefore, it is of great significance to develop an efficient single chemical sensor that can simultaneously detect these two biomarkers. To achieve the goal, we developed a dual-locked fluorescence probe (TPA-DNP) by fusing two targets activated reporting system, its implementation was achieved by turning-on the fluorescence of TPA-DNP through LDs and HClO/ClO- simultaneously. In simulated LDs environment, TPA-DNP displayed excellent selectivity to HClO/ClO-, high sensitivity (LOD = 0.527 µM) and strong anti-interference ability. In addition, cell and zebrafish imaging experiments showed that TPA-DNP could be utilized to visualize exogenous/endogenous HClO/ClO- in LDs environment, and could also be used to observe the impact of LDs changes on the HClO/ClO- detection. On the basis, TPA-DNP served as a favorable tool to achieve visualization of inflammatory dynamic changes.

Sodium tanshinone IIA sulfonate suppresses microglia polarization and neuroinflammation possibly via regulating miR-125b-5p/STAT3 axis to ameliorate neuropathic pain.

The spinal cord microglia play a pivotal role in neuroinflammation and neuropathic pain (NP). Sodium tanshinone IIA sulfonate (STS), a derivative of tanshinone IIA, has anti-inflammatory and anti-hyperalgesic effects. However, its underlying mechanism in NP remains unclear. This study aimed to investigate the effect of STS and elucidate possible mechanisms in a rat model of spared nerve injury. In vivo experiments, STS and AG490 were administered intraperitoneally once daily for 14 consecutive days after surgery. The results showed that the expression of miR-125b-5p in the spinal dorsal horn was substantially reduced, whereas signal transducer and activator of transcription 3 (STAT3) signaling was increased. After treatment with STS, the mechanical thresholds, expression of miR-125b-5p, and microglial M2 marker such as Arg-1 in the spinal cord horn increased significantly, whereas multiple pro-inflammatory cytokines and apoptosis were significantly reduced. Moreover, STAT3 pathway-related proteins and expression of the microglial M1 marker, CD68, were appreciably inhibited. In vitro, lipopolysaccharide (LPS) was used to induce an inflammatory response in BV-2 microglial cells. STS pretreatment inhibited LPS-stimulated pro-inflammatory cytokine secretion, reduced STAT3 pathway related-proteins and apoptosis, increased miR-125b-5p and proopiomelanocortin expression, and enhanced microglia transformation from M1 to M2 phenotype in BV-2 cells. These effects were reversed after the inhibition of miR-125b-5p expression in BV-2 cells. A dual-luciferase reporter assay confirmed that STAT3 binds to miR-125b-5p. In summary, these results suggest that STS exerts anti-hyperalgesic and anti-neuroinflammatory effects in rats with NP possibly via the miR-125b-5p/STAT3 axis.

G protein-coupled receptor 30 activation inhibits ferroptosis and protects chondrocytes against osteoarthritis.

Background: Osteoarthritis (OA) is the most common joint disease worldwide, but its cause remains unclear. Oestrogen protects against OA, but its clinical use is limited. G protein-coupled receptor 30 (GPR30) is a receptor that binds oestrogen, and GPR30 treatment has benefitted patients with some degenerative diseases. However, its effects on OA prevention and treatment remain unclear. Moreover, several studies have found that activation of estrogen receptors exerting anti-ferroptosis effects, which plays an important role in chondrocyte survival. Therefore, this study explored the general and ferroptosis-related effects and mechanisms of GPR30 in OA. Methods: Genome-wide RNA sequencing, western blotting, and immunohistochemistry were used to evaluate GPR30 expression and ferroptosis-related indicators in cartilage tissues from clinical patients. Next, we investigated the effects of G1 (a GPR30 receptor agonist) on the function and pathology of OA in an animal model. We also treated chondrocytes with erastin (ferroptosis agonist) plus G1, G15 (GPR30 receptor antagonist), GPR30 short hairpin RNA, or ferrostatin-1 (ferroptosis inhibitor), then measured cell viability and ferroptosis-related indices and performed proteomics analyses. Finally, western blotting and reverse transcription-polymerase chain reaction were used to assess the effects of G1 on yes-associated protein 1 (YAP1) and ferritin heavy chain 1 (FTH1) expression. Results: GPR30 expression was lower in the OA cartilage tissues than in the normal tissues, and G1 treatment significantly improved the locomotor ability of mice. Moreover, chondrocyte cell viability significantly decreased after erastin treatment, but G1 treatment concentration-dependently mitigated this effect. Furthermore, G1 treatment decreased phosphorylated YAP1 expression, increased activated YAP1 expression, and increased FTH1 transcription and protein expression, protecting against ferroptosis. Conclusion: GPR30 activation inhibited ferroptosis in chondrocytes by suppressing YAP1 phosphorylation, which regulates FTH1 expression.The Translational Potential of this Article: These results provide a novel potential target for therapeutic OA interventions.

Charge transfer in superbase n-type doping of PCBM induced by deprotonation.

N-type electronic doping of organic semiconductors (OSCs) by using superbase compounds shows high doping efficiency (H. Wei, Z. Cheng, T. Wu, Y. Liu, J. Guo, P.-A. Chen, J. Xia, H. Xie, X. Qiu, T. Liu, B. Zhang, J. Hui, Z. Zeng, Y. Bai and Y. Hu, Adv. Mater. 2023, 35, 2300084). While a deprotonation reaction is believed to trigger the doping process, the detailed mechanism therein is not yet fully understood. In the present work we theoretically study the electronic structure of the deprotonated Phenyl-C61-butyric acid methyl ester (PCBM) molecule, as well as the charge transfer (CT) between PCBM and its deprotonated species. We find that deprotonated PCBM without formation of a new bond between the deprotonated side chain and fullerene induces electronic structure with broken spin symmetry, where an in-gap state is singly occupied by an unpaired electron. A second scenario that we find to be possible is the formation of a new bond between the deprotonated side chain and a fullerene. This leads to a spin symmetric electronic structure with partially localized in-gap state, which is expected to contribute less to the effective doping. These results show that the deprotonated PCBM species without new bond formation predominantly accounts for the effective n-type doping of PCBM, an insight that will be useful for optimization of this recently discovered doping method.

A sensitive sensor based on carbon dots for the determination of Fe3+ and ascorbic acid in foods.

To develop a feasible, sensitive, and essential sensor is important for the identification of Fe3+ ions and ascorbic acid (AA). Herein, highly fluorescent heteroatom co-doped carbon dots (N,S-CDs) with a quantum yield (QY) of 24.6% were synthesized, using hydrothermal treatment of L-cysteine (Cys) and 1-amino-2-naphthol-4-sulfonic acid (ANSA). The fluorescence emission of the as-prepared N,S-CDs was quenched strongly by Fe3+ ions, and this was further recovered by the reduction effect of AA on Fe3+. Based on this, continuous fluorescence sensing of Fe3+ and AA with an "on-off-on" style was developed. The detection of Fe3+ and AA were in relatively wider linear ranges of 5.00-105 µmol L-1 and 4.97-54.8 µmol L-1, with a detection limit of 0.10 µmol L-1 and 2.4 nmol L-1 (S/N = 3), respectively. Then, the N,S-CDs were successfully used to measure Fe3+ ions and AA in some daily food samples, and this method exhibited some advantages over most other reported techniques in the term of response speed, quantum yield, and detection limit.

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

New genes (or young genes) are structural novelties pivotal in mammalian evolution. Their phenotypic impacts on humans, however, remain elusive due to the technical and ethical complexities in functional studies. Through combining gene age dating with Mendelian disease phenotyping, our research reveals a steady integration of new genes with biomedical phenotypes into the human genome over macroevolutionary timescales (~0.07% per million years). Despite this stable pace, we observe distinct patterns in phenotypic enrichment, pleiotropy, and selective pressures shaped by different gene ages. Notably, young genes show significant enrichment in the male reproductive system, indicating strong sexual selection. Young genes also exhibit functions in tissues and systems potentially linked to human phenotypic innovations, such as increased brain size, musculoskeletal phenotypes, and color vision. Our findings further reveal increasing levels of pleiotropy over evolutionary time, which accompanies stronger selective constraints. We propose a "pleiotropy-barrier" model that delineates different potentials for phenotypic innovation between young and older genes subject to natural selection. Our study demonstrates that evolutionary new genes are critical in influencing human reproductive evolution and adaptive phenotypic innovations driven by sexual and natural selection, with low pleiotropy as a selective advantage.

Synthesis of Yellow Fluorescence Carbon Dots for the Applications of Vitamin B12 Detection and Cell Imaging.

In this work, bright yellow fluorescent and multifunctional carbon dots (N-CDs) were prepared by hydrothermal method from O-phenylenediamine and 4-aminobenzoic acid. The fluorescence characterization showed that the N-CDs possessed good optical properties (QY = 32%) and excitation dependent multi-color emission. By exciting with 390 nm, the strong selective interaction of VB12 with N-CDs could result in a sharp decrease in the luminescence of N-CDs at 567 nm. An efficient fluorescence sensor in aqueous solution was constructed which could linearly respond VB12 in wide concentration ranges of 0-90 µM and 140-250 µM. The linear correlation coefficients of N-CDs and VB12 were 0.9950 and 0.9968, respectively, and the detection limit was 0.119 µM. N-CDs were performed for sensitive determination of VB12 in real samples. Moreover, the N-CDs were exploited to image cell. This N-CDs was a sensitive fluorescence probe to monitor VB12 and presented prospective potential in living cells imaging. Schematic diagram of the synthesis process and application research of N-CDs.

Rare Genomic Copy Number Variants Implicate New Candidate Genes for Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in cohorts with late onset sporadic disease (n = 5040). We identified 34 large and rare (< 1:1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 8% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

A novel multi-functional fluorescent probe for dual-channel detection of SO2 and Hg2+ and dynamic visualization of SO2 fluctuations in vivo upon mercury exposure.

Although there are many drugs used for the treatment of mercury poisoning, it is remains confused that pathological symptoms associated with Hg2+-induced oxidative stress. It is reported that SO2 can be generated as the anti-oxidant, and plays an important role in maintaining redox balance in cells. There has not yet been a study to precisely track the changes in SO2 during mercury ion poisoning. We developed a novel dual-response fluorescence probe (CY-SPH) for respective or successive determination of Hg2+ and SO2 in neutral aqueous media. The nucleophilic addition of HSO3- toward CY-SPH caused a significant fluorescence enhancement at 455 nm while the Hg2+ -triggered desulfurization of CY-SPH to the final phenolic product (CY-OH) elicited a markedly enhanced emission at 760 nm, allowing for two-color visualization of Hg2+ and SO2 with good selectivity (detection limit: 67.2 nM for Hg2+ and 34.7 nM for SO2). Moreover, CY-OH could undergo further nucleophilic addition reaction with HSO3- and resulted in a decrease in emission at 760 nm and an increase in emission at 438 nm, enabling the ratiometric determination of SO2 with better sensitivity (detection limit, 3.50 nM). Significantly, CY-SPH can monitor the endogenous SO2 fluctuations upon mercury exposure by means of confocal fluorescence imaging, which may prove valuable for deciphering the relationship between SO2 levels and the mercury induced oxidative stress. We anticipated that this research will promote to understand the functions of SO2 under the oxidative stress by Hg2+.