Discrete Elemental Distributions inside a Single Mixed-Halide Perovskite Nanocrystal for the Self-Assembly of Multiple Quantum-Light Sources.

An in-depth understanding of the structure-property relationships in semiconductor mixed-halide perovskites is critical for their potential applications in various light-absorbing and light-emitting optoelectronic devices. Here we show that during the crystal growth of mixed-halide CsPbBr1.2I1.8 nanocrystals (NCs), abundant Ruddlesden-Popper (RP) plane stacking faults are formed to release the lattice strain. These RP planes hinder the exchange of halide species across them, resulting in the presence of multiple nanodomains with discrete mixed-halide compositions inside a single CsPbBr1.2I1.8 NC. Photoluminescence peaks from these pre-segregated nanodomains, whose correlated intensity and wavelength variations signify the interactions of coupled quantum dots within a single CsPbBr1.2I1.8 NC, can be simultaneously resolved at cryogenic temperature. Our findings thus point to a fascinating scenario in which a semiconductor nanostructure can be further divided into multiple quantum-light sources, the interaction and manipulation of which will promote novel photophysics to facilitate their potential applications in quantum information technologies.

A Transcriptomic Analysis of Bottle Gourd-Type Rootstock Roots Identifies Novel Transcription Factors Responsive to Low Root Zone Temperature Stress.

The bottle gourd [Lagenaria siceraria (Molina) Standl.] is often utilized as a rootstock for watermelon grafting. This practice effectively mitigates the challenges associated with continuous cropping obstacles in watermelon cultivation. The lower ground temperature has a direct impact on the rootstocks' root development and nutrient absorption, ultimately leading to slower growth and even the onset of yellowing. However, the mechanisms underlying the bottle gourd's regulation of root growth in response to low root zone temperature (LRT) remain elusive. Understanding the dynamic response of bottle gourd roots to LRT stress is crucial for advancing research regarding its tolerance to low temperatures. In this study, we compared the physiological traits of bottle gourd roots under control and LRT treatments; root sample transcriptomic profiles were monitored after 0 h, 48 h and 72 h of LRT treatment. LRT stress increased the malondialdehyde (MDA) content, relative electrolyte permeability and reactive oxygen species (ROS) levels, especially H2O2 and O2-. Concurrently, LRT treatment enhanced the activities of antioxidant enzymes like superoxide dismutase (SOD) and peroxidase (POD). RNA-Seq analysis revealed the presence of 2507 and 1326 differentially expressed genes (DEGs) after 48 h and 72 h of LRT treatment, respectively. Notably, 174 and 271 transcription factors (TFs) were identified as DEGs compared to the 0 h control. We utilized quantitative real-time polymerase chain reaction (qRT-PCR) to confirm the expression patterns of DEGs belonging to the WRKY, NAC, bHLH, AP2/ERF and MYB families. Collectively, our study provides a robust foundation for the functional characterization of LRT-responsive TFs in bottle gourd roots. Furthermore, these insights may contribute to the enhancement in cold tolerance in bottle gourd-type rootstocks, thereby advancing molecular breeding efforts.

Fine mapping of the Ca3GT gene controlling anthocyanin biosynthesis in mature unripe fruit of Capsicum annuum L.

KEY MESSAGE: The anthocyanin biosynthesis gene Ca3GT was fine-mapped in a 110.5-kb region through a map-based cloning strategy. Gene expression and promoter analyses confirmed the strong candidate gene Capana10g001978. Pepper (Capsicum annum L.) fruit can be dark green, green, light green, purple, yellow, or ivory at the juvenile stage. Anthocyanins are responsible for fruit color formation in mature unripe pepper fruit, and transient accumulation of anthocyanins is the main problem in breeding pepper plants with mature purple fruit. Only a few genes controlling this trait have been cloned. The present study aimed to map and identify an anthocyanin biosynthesis gene from pepper using an F2 population derived from a cross between line '17C3808' (purple mature unripe fruit) and line '17C3807' (green mature unripe fruit). The trait was mapped on a 110.5-kb interval between markers SSR18213 and SSR18228 on chromosome 10. There were three open reading frames in this region; Capana10g001978 was predicted in this region as markers CAPS-78-708 and InDel146 co-segregated with it. Capana10g001978 is a structural gene encoding the GTB transcription factor involved in the biosynthesis of anthocyanins. Comparing parental sequences, two base mutations were identified in the exon of Capana10g001978, at positions + 528 bp and + 708 bp, which resulted in changes in the 176th and 236th amino acid residues, from glutamine (CAA) to histidine (CAC), causing a nonsense mutation (from CAG to CAA). Additionally, Capana10g001978 was highly expressed in the pericarp of mature, unripe pepper fruit. There were four single nucleotide polymorphisms, three sequence deletions, and one sequence insertion in the promoter region of purple, mature, and unripe pepper fruit, leading to the formation of a W-box and a GT1-motif. Thus, Capana10g001978 is a strong candidate gene of Ca3GT involved in anthocyanin biosynthesis in mature unripe pepper fruit. These results provide important information regarding the isolation and characterization of Ca3GT, and they are the starting point for studying the regulatory pathway responsible for anthocyanin biosynthesis in pepper.

Phenotypic, genetic, and molecular function of msc-2, a genic male sterile mutant in pepper (Capsicum annuum L.).

KEY MESSAGE: Bulked segregant analysis and fine mapping delimited the pepper genic male sterile (msc-2) locus into a 336 kb region on chromosome 5. A strong candidate gene, Capana05g000766, a homolog of AtMS1, was indentified in this region. Genic male sterility (msc-2) is used to produce hybrid seeds in Northern China. However, no co-segregated markers have been reported or candidate genes controlling this trait have been cloned. Here, bulked segregant analysis and genotyping of an F2 population and a 18Q5431AB line were employed to fine map msc-2, which was delimited to a 336 kb region. In this region, Capana05g000766 was a homolog of AtMS1, which encodes a plant homeodomain finger involved in tapetum development. A "T" deletion in the Capana05g000766 locus leads to a premature stop codon, which may cause a loss-of-function mutation. Real-time PCR analysis revealed that Capana05g000766 was an anther-specific gene and down-regulation of the gene resulted in male sterility. Therefore, Capana05g000766 was identified as the strongest candidate gene for the msc-2 locus. Allelism tests showed that msc-1 and msc-2 were nonallelic, and bimolecular fluorescence complementation analysis indicated that the two genes did not interact directly with each other at the protein level. As msc-1 and msc-2 are homologs of AtDYT1 and AtMS1 in Arabidopsis, they may play similar roles in tapetum development in genic male sterile peppers, and Msc-1 might be up stream of Msc-2 in the regulation of other genes involved in tapetum development.

Candidate Gene Selection for Cytoplasmic Male Sterility in Pepper (Capsicum annuum L.) through Whole Mitochondrial Genome Sequencing.

Cytoplasmic male sterility (CMS), which is controlled by mitochondrial genes, is an important trait for commercial hybrid seed production. So far, genes controlling this trait are still not clear in pepper. In this study, complete mitochondrial genomes were sequenced and assembled for the CMS line 138A and its maintainer line 138B. The genome size of 138A is 504,210 bp, which is 8618 bp shorter than that of 138B. Meanwhile, more than 214 and 215 open reading frames longer than 100 amino acids (aas) were identified in 138A and 138B, respectively. Mitochondrial genome structure of 138A was quite different from that of 138B, indicating the existence of recombination and rearrangement events. Based on the mitochondrial genome sequence and structure variations, mitochondrion of 138A and FS4401, a Korean origin CMS line, may have inherited from a common female ancestor, but their CMS traits did originate separately. Candidate gene selection was performed according to the published characteristics of the CMS genes, including the presence SNPs and InDels, located in unique regions, their chimeric structure, co-transcription, and transmembrane domain. A total of 35 ORFs were considered as potential candidate genes and 14 of these were selected, with orf300a and 0rf314a as strong candidates. A new marker, orf300a, was developed which did co-segregate with the CMS trait.

Genome-Wide Correlation of 36 Agronomic Traits in the 287 Pepper (Capsicum) Accessions Obtained from the SLAF-seq-Based GWAS.

There are many agronomic traits of pepper (Capsicum L.) with abundant phenotypes that can benefit pepper growth. Using specific-locus amplified fragment sequencing (SLAF-seq), a genome-wide association study (GWAS) of 36 agronomic traits was carried out for 287 representative pepper accessions. To ensure the accuracy and reliability of the GWAS results, we analyzed the genetic diversity, distribution of labels (SLAF tags and single nucleotide polymorphisms (SNPs)) and population differentiation and determined the optimal statistical model. In our study, 1487 SNPs were highly significantly associated with 26 agronomic traits, and 2126 candidate genes were detected in the 100-kb region up- and down-stream near these SNPs. Furthermore, 13 major association peaks were identified for 11 key agronomic traits. Then we examined the correlations among the 36 agronomic traits and analyzed SNP distribution and found 37 SNP polymerization regions (total size: 264.69 Mbp) that could be selected areas in pepper breeding. We found that the stronger the correlation between the two traits, the greater the possibility of them being in more than one polymerization region, suggesting that they may be linked or that one pleiotropic gene controls them. These results provide a theoretical foundation for future multi-trait pyramid breeding of pepper. Finally, we found that the GWAS signals were highly consistent with those from the nuclear restorer-of-fertility (Rf) gene for cytoplasmic male sterility (CMS), verifying their reliability. We further identified Capana06g002967 and Capana06g002969 as Rf candidate genes by functional annotation and expression analysis, which provided a reference for the study of cytoplasmic male sterility in Capsicum.

Identification of candidate genes underlying genic male-sterile msc-1 locus via genome resequencing in Capsicum annuum L.

KEY MESSAGE: Based on genome resequencing, a strong candidate gene Capana02g002096 was identified in this study. Capana02g002096 encodes a homolog of AtDYT1 which is a bHLH transcription factor and involves in the early tapetal development. Genic male-sterile line is an efficient tool for commercial hybrid seed production in pepper; however, so far, only few genes controlling this trait have been cloned. A spontaneous genic male-sterile mutant, msc-1, had been identified and widely used in China, of which the male-sterile trait was proved to be controlled by a single recessive locus. For cloning the gene(s) underlying the msc-1 locus, genome resequencing and comparison analyses were performed between male-sterile and male-fertile lines. According to the genomic variations and genes' annotations, Capana02g002096 was selected as a candidate gene underlying the msc-1 locus. Capana02g002096 encodes a homolog of AtDYT1, which is a bHLH transcription factor and involves in the early tapetal development. Moreover, a 7-bp deletion was identified in the exon of Capana02g002096, which led to a premature stop codon and may cause a loss-of-function mutation. Further genotyping in the 16C1369AB population containing 1110 plants, a F2 population consisting of 510 plants and 46 inbreed lines revealed that the male-sterile phenotype was co-segregated with the 7-bp deletion. Additionally, real-time PCR analysis revealed that Capana02g002096 was an anther-specific gene and repression of the gene's expression through VIGS led to male-sterile phenotype. Therefore, based on the evidence at genetic, genomic, transcriptional and posttranscriptional levels, Capana02g002096 was considered as a strong candidate gene underlying the msc-1 locus in pepper and was renamed Msc-1.

A New Formula for Estimating the True QT Interval in Left Bundle Branch Block.

INTRODUCTION: QT prolongation is an independent risk factor for cardiac mortality. Left bundle branch block (LBBB) is more common in patients as they age. Widening of the QRS in LBBB causes false QT prolongation and thus makes true QT assessment difficult. We aimed to develop a simple formula to achieve a good estimate of the QT interval in the presence of LBBB. METHODS AND RESULTS: To determine the effect of QRS duration on the QT interval, QRS and QT were measured in sinus rhythm and during right ventricular apical pacing in 62 patients (age 55 ± 11 years, 60% male) undergoing electrophysiology studies. A QT formula for LBBB (QT-LBBB) was derived based on the effect of increased QRSLBBB on QTLBBB . The predictive accuracy of the QT-LBBB formula was then tested in 22 patients (age 66 ± 13 years, 64% male) with intermittent LBBB with comparisons to prior QT formulae and JT index. On average, the net increase in QRSLBBB constituted 92% of the net increase in QTLBBB . A new formula, QT-LBBB = QTLBBB - (0.86 * QRSLBBB - 71), which takes the net increase in QRSLBBB into account, best predicted the QT interval with heart rate corrected QTc in the test set of LBBB ECGs when compared to the baseline value and prior formulae. CONCLUSION: The QT-LBBB formula developed in this study best estimates the true QT interval in the presence of LBBB. It is simple and therefore can be easily utilized in clinical practice.

Common Genotypes of Long QT Syndrome in China and the Role of ECG Prediction.

OBJECTIVES: Genetic testing, a gold standard for long QT syndrome (LQTS) diagnosis, is time-consuming and costly when all the 15 candidate genes are screened. Since genotype-specific ECG patterns are present in most LQT1-3 mutation carriers, we tested the utility of ECG-guided genotyping in a large cohort of Chinese LQTS patients. METHODS AND RESULTS: We enrolled 230 patients (26 ± 17 years, 66% female) with a clinical diagnosis of LQTS. Genotypes were predicted as LQT1-3 based on the presence of ECG patterns typical for each genotype in 200 patients (85 LQT1, 110 LQT2 and 5 LQT3). Family-based genotype prediction was also conducted if gene-specific ECG patterns were found in other affected family members. Mutational screening identified 104 mutations (44% novel), i.e. 46 KCNQ1, 54 KCNH2 and 4 SCN5A mutations. The overall predictive accuracy of ECG-guided genotyping was 79% (157/200) and 79% (67/85), 78% (86/110) and 80% (4/5) for LQT1, LQT2 and LQT3, respectively. The predictive accuracy was 98% (42/43) when family-based ECG assessment was performed. CONCLUSIONS: From this large-scale genotyping study, we found that LQT2 is the most common genotype among the Chinese. Family-based ECG-guided genotyping is highly accurate. ECG-guided genotyping is time- and cost-effective. We therefore recommend it as an optimal approach for the genetic diagnosis of LQTS.

Simultaneous quantification of tizoxanide and tizoxanide glucuronide in mouse plasma by liquid chromatography-tandem mass spectrometry.

Nitazoxanide (NTZ) is a broad-spectrum antimicrobial agent. Tizoxanide (T) and tizoxanide glucuronide (TG) are the major circulating metabolites after oral administration of NTZ. A rapid and specific LC-MS/MS method for the simultaneous quantification of T and TG in mouse plasma was developed and validated. A simple acetonitrile-induced protein precipitation method was employed to extract two analytes and the internal standard glipizide from 50 µL of mouse plasma. The purified samples were resolved using a C18 column with a mobile phase consisting of acetonitrile and 5 mm ammonium formate buffer (containing 0.05% formic acid) following a gradient elution. An API 3000 triple quadrupole mass spectrometer was operated under multiple reaction-monitoring mode with electrospray ionization. The precursor-to-product ion transitions m/z 264 → m/z 217 for T and m/z 440 → m/z 264 for TG were used for quantification. The developed method was linear in the concentration ranges of 1.0-500.0 ng/mL for T and 5.0-1000.0 ng/mL for TG. The intra- and inter-day precision and accuracy of the quality control samples at low, medium and high concentrations exhibited an RSD of <13.2% and the accuracy values ranged from -9.6 to 9.3%. We used this validated method to study the pharmacokinetics of T and TG in mice following oral administration of NTZ. Copyright © 2016 John Wiley & Sons, Ltd.

Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001.

Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of "lock-in" can be used to solve these problems. A series of thiamine disulfide prodrugs 7a-7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.

Inhibiting (pro)renin receptor-mediated p38 MAPK signaling decreases hypoxia/reoxygenation-induced apoptosis in H9c2 cells.

The (pro)renin receptor is a new molecular member of the renin-angiotensin system and participates in regulating many physiological and pathological processes. However, the role of (pro)renin receptor-mediated signaling pathways in myocardial ischemic/reperfusion injury remains unclear. In this study, we hypothesized that p38 mitogen-activated protein kinase (MAPK) signaling pathway activation by the (pro)renin receptor had effects on myocardial apoptosis induced by ischemia/reperfusion. This analysis was performed using a hypoxia/reoxygenation model in H9c2 cells to mimic ischemia/reperfusion injury. The H9c2 rat cardiomyocyte cell line was subjected to 2 h of hypoxia followed by 6 h of reoxygenation. The (pro)renin receptor, caspase 3, and phosphorylated p38 MAPK protein expression levels were analyzed by Western blot. After 2 h of hypoxia followed by 6 h of reoxygenation, apoptosis increased in H9c2 cells; the (pro)renin receptor, caspase 3, and phosphorylated p38 MAPK protein expressions were upregulated. siRNA silencing of the (pro)renin receptor significantly decreased p38 MAPK phosphorylation. siRNA silencing of the (pro)renin receptor and treatment with the p38MAPK inhibitor SB203580 significantly decreased the hypoxia/reoxygenation-induced apoptosis and caspase 3 protein expression in H9c2 cells. Furthermore, we found that the role of the (pro)renin receptor was independent of angiotensin II (Ang II). Thus, we concluded that (pro)renin receptor activation could trigger hypoxia/reoxygenation-induced apoptosis in H9c2 cells, partially through the p38 MAPK/caspase 3 signaling pathway, independent of Ang II. Therefore, this study may provide new therapeutic targets for myocardial ischemic/reperfusion injury prevention, and further in vivo studies are needed.

Regulation of CARD8 expression by ANRIL and association of CARD8 single nucleotide polymorphism rs2043211 (p.C10X) with ischemic stroke.

BACKGROUND AND PURPOSE: ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease. However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism. METHODS: Using expression quantitative loci analysis, we identified potential genes whose expression may be influenced by genetic variation in ANRIL. To verify the identified gene(s), knockdown and overexpression of ANRIL were evaluated in human umbilical vein endothelial cells and HepG2 cells. Ischemic stroke and coronary artery disease risk were then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry: 2 ischemic stroke populations consisting of the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls) and 1 coronary artery disease cohort consisting of 772 patients and 873 controls. RESULTS: Expression quantitative loci analysis identified CARD8 among others, with knockdown of ANRIL expression decreasing CARD8 expression and overexpression of ANRIL increasing CARD8 expression. The minor T allele of a previously identified CARD8 variant (rs2043211) was found to be significantly associated with a protective effect of ischemic stroke under the recessive model in 2 independent stroke cohorts. No significant association was found between rs2043211 and coronary artery disease. CONCLUSIONS: CARD8 is a downstream target gene regulated by ANRIL. Single nucleotide polymorphism rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.

Orthogonal reference pattern multiplexing for collinear holographic data storage.

An orthogonal reference pattern multiplexing (ORPM) method for collinear holographic data storage (CHDS) is investigated to increase the data storage density and realize parallel optical image superimposition. Holograms are multiplexed in the same volume of the recording medium with multiple orthogonal reference patterns (RPs). The physical principle of this method is analyzed based on scalar diffraction theory. The orthogonal condition of the RPs is derived in order to suppress the interpage cross talk. The parameters of the radial-line RP have significant influence on the signal-to-noise ratio (SNR) of the reconstructed data page. They are optimized to reduce the intrapage cross talk. With a random binary phase mask (RBPM) located closely before the spatial light modulator, SNR of the reconstructed data page is seven times the SNR without the RBPM. Three data pages are multiplexed in the same volume of the medium using the ORPM method. The reconstructed data pages for the CHDS system show the effectiveness of the RBPM in suppressing the intrapage and interpage cross talk.

Noninvasive assessment of left atrial phasic function in patients with hypertension and diabetes using two-dimensional speckle tracking and volumetric parameters.

OBJECTIVE: To evaluate the left atrial phasic function of hypertensive patients with or without coexisting diabetes using two-dimensional speckle tracking echocardiography (2DSTE)-based strain and strain rate imaging and volumetric parameters. METHODS: The study included an isolated hypertension group (HT group) comprising 99 patients, a hypertension and diabetes group (HT + DM group) comprising 65 patients, and 26 age-matched healthy controls. The 2DSTE-based strain and strain rate images were studied, and the following parameters were measured: peak left atrial longitudinal strain (LAS-S ), early diastolic (LAS-E ) and late diastolic (LAS-A ) atrial longitudinal strains, and systolic (LASR-S ), early diastolic (LASR-E ) and late diastolic (LASR-A ) strain rates. RESULTS: The LAS-S and LASR-S were lower in the HT group and the HT + DM group compared with the control group (P < 0.001). The LAS-E and LASR-E were lower in the HT group (14.9 ± 5.5% and -1.1 ± 0.4/sec, respectively) than in the control group (22.1 ± 8.3% and -1.7 ± 0.6/sec, respectively) (P < 0.001), and they were further depressed in the HT + DM group (12.3 ± 6.3% and -1.0 ± 0.4/sec, respectively) (P < 0.05). There were no significant differences in LAS-A or LASR-A among the 3 groups (P > 0.05). Multivariate regression analysis revealed that HT and DM were independently related to LAS-E and LASR-E . CONCLUSIONS: Hypertension can lead to abnormal left atrial reservoir and conduit functions, and coexisting diabetes can further impair conduit function. 2DSTE-derived strain and strain rate imaging are sensitive methods for evaluating left atrial phasic function.

Structural elucidation of Sulodexide with multidimensional chromatography and online in-source acid-induced dissociation mass spectrometry.

Sulodexide, a heparinoid medicine, is wildly used in clinic for prophylaxis and treatment of thromboembolic diseases and diabetic nephropathy. Despite its widespread use, the structure of Sulodexide remains poorly understood. It consists of various polysaccharides characterized by differing sugar compositions, linkages, and sulfonation patterns, yet they share common features such as strong hydrophilicity, high native charges, and considerable polydispersity, posing significant challenges for conventional chromatographic and online mass spectrometry (MS) characterization. In this work, a novel analytical method combining multiple-heart cut 2D-LC and in-source acid-induced dissociation (inAID) MS was developed. Three polysaccharides in Sulodexide were separated by high efficient strong-anion-exchange chromatography, followed by desalting with the second dimensional size-exclusion chromatography before MS. A novel MS strategy employing inAID technique was utilized for online analysis, leading to the initial identification of Sulodexide polysaccharide components. The results were validated through disaccharide composition analysis of those three polysaccharide components after offline preparation. This advanced strategy, merging various techniques, enable a comprehensive structural elucidation of such complex drugs and provides a viable tool for potential routine analysis of complex biomolecules.

Association of Preablation Plasma Corin Levels With Atrial Fibrillation Recurrence After Catheter Ablation: A Prospective Observational Study.

BACKGROUND: We assessed the impact of pre- and postprocedural plasma corin levels on the recurrence of atrial fibrillation (AF) after catheter ablation (CA). METHODS AND RESULTS: This prospective, single-center, observational study included patients undergoing their first CA of AF. Corin was measured before and 1 day after CA. The primary end point was recurrent AF between 3 and 12 months after ablation. From April 2019 through May 2021, we analyzed 616 patients with AF (59.09% men) with a mean age of 62.86±9.42 years. Overall, 153 patients (24.84%) experienced recurrent AF. In the recurrence group, the pre- and postprocedure corin concentrations were 539.14 (329.24-702.08) and 607.37 (364.50-753.80) pg/mL, respectively, which were significantly higher than the nonrecurrence group's respective concentrations of 369.05 (186.36-489.28) and 489.12 (315.66-629.05) pg/mL (both P<0.0001). A multivariate Cox regression analysis with confounders found that elevated preablation corin levels were significantly associated with an increased risk of AF recurrence after CA. Receiver operating characteristic curve analysis identified that a preablation corin threshold of >494.85 pg/mL predicted AF recurrence at 1 year. An increase of 1 SD in corin concentrations before CA (264.94 pg/mL) increased the risk of recurrent AF by 54.3% after adjusting for confounding variables (hazard ratio, 1.465 [95% CI, 1.282-1.655]; P<0.0001). CONCLUSIONS: Plasma corin levels at baseline is a valuable predictor of AF recurrence after CA, independent of established conventional risk factors. Risk stratification before ablation for AF may be useful in selecting treatment regimens for patients.

NAD+ metabolic enzyme inhibitor as radiosensitizer for malignant meningioma and its modulation of P53 expression.

Surgical resection followed by radiotherapy (RT) is recommended for malignant meningioma but poor outcome is unavoidable. To improve the efficacy of RT in malignant meningioma, a targeted radiosensitizer could be added. Nicotinamide phosphoribosyltransferase (NAMPT), highly expressed in high-grade meningiomas may have a role in determining the radioresponse. Here, we evaluated the impact of NAMPT inhibition on radiosensitivity in malignant meningioma in vivo and in vitro. IOMM-Lee and TTMM705 cells were treated with NAMPT inhibition (FK866 or shRNA NAMPT) before irradiation. The subsequent clonogenic assay demonstrated significantly increased radiosensitivity. Combination treatment with FK866 and irradiation significantly increased the number of G2/M-phase cells, the percentage of apoptotic cells and the γ-H2A.X level compared to FK866 or RT alone. We examined the effect of NAMPT inhibition on NMI and p53 expression in IOMM-Lee and TTMM705 cells. NAMPT inhibition by FK866 and shRNA treatment increased NMI, p53, CDKN1A and BAX expression. Additionally, we assessed the efficacy of FK866/RT combination treatment in vivo. The combination treatment exhibited increased antitumor efficacy compared to either treatment alone. The Ki-67 level was significantly lower and the p53 and γ-H2A.X level was significantly higher in the combination treatment group than in any of the other three groups. In conclusion, these results indicate that FK866 improves radiosensitivity in malignant meningioma, an effect that may be attributed to the increase in p53 expression.

Identification of a Kir3.4 mutation in congenital long QT syndrome.

Congenital long QT syndrome (LQTS) is a hereditary disorder that leads to sudden cardiac death secondary to fatal cardiac arrhythmias. Although many genes for LQTS have been described, the etiology remains unknown in 30%-40% of cases. In the present study, a large Chinese family (four generations, 49 individuals) with autosomal-dominant LQTS was clinically evaluated. Genome-wide linkage analysis was performed by using polymorphic microsatellite markers to map the genetic locus, and positional candidate genes were screened by sequencing for mutations. The expression pattern and functional characteristics of the mutated protein were investigated by western blotting and patch-clamp electrophysiology. The genetic locus of the LQTS-associated gene was mapped to chromosome 11q23.3-24.3. A heterozygous mutation (Kir3.4-Gly387Arg) was identified in the G protein-coupled, inwardly rectifying potassium channel subunit Kir3.4, encoded by the KCNJ5 gene. The Kir3.4-Gly387Arg mutation was present in all nine affected family members and absent in 528 ethnically matched controls. Western blotting of human cardiac tissue demonstrated significant Kir3.4 expression levels in the cardiac ventricles. Heterologous expression studies with Kir3.4-Gly387Arg revealed a loss-of-function electrophysiological phenotype resulting from reduced plasma membrane expression. Our findings suggest a role for Kir3.4 in the etiology of LQTS.

Synthetic microbial consortia for the treatment of Clostridioides difficile infection in mice model.

Clostridioides difficile infection (CDI) as of recent has become a great concern to the impact on human health due to its high hazardous risk and rate of recurrence. Live bacterial therapeutics is a promising method to treat or prevent CDI. Here, a synthetic microbial consortia (SMC) B10 was constructed using probiotic strains with antibacterial and anti-quorum sensing activities, and the therapeutic effect of SMC B10 against C. difficile infection was evaluated in vitro. Compared to the model group, the treatment of SMC B10 significantly increased the survival rate. The clinical signs of mice were significantly ameliorated, especially the cecum injury, while the secretion of pro-inflammatory associated cytokines such as IL-1α, IL-6, IL-17A and TNF-α was reduced, the expression of TLR4 was inhibited, which alleviated the inflammatory response, and the expression of the tight junction protein Claudin-1 was increased, ultimately promoting the recovery of host health. The treatment of B10 restored gut microbiota dysbiosis and led to a healthy intestinal microbiota structure, significantly improved alpha diversity, suppressing potentially harmful bacteria and restoring other core bacterial species. In conclusion, SMC B10 can effectively treat CDI through modulate gut microbiota and attenuate the inflammatory response.