Systematic Optimization of Universal Real-Time Hypersensitive Fast Detection Method for HBsAg in Serum Based on SERS.

Hepatitis B virus (HBV) is a major cause of liver cirrhosis and hepatocellular carcinoma, with HBV surface antigen (HBsAg) being a crucial marker in the clinical detection of HBV. Due to the significant harm and ease of transmission associated with HBV, HBsAg testing has become an essential part of preoperative assessments, particularly for emergency surgeries where healthcare professionals face exposure risks. Therefore, a timely and accurate detection method for HBsAg is urgently needed. In this study, a surface-enhanced Raman scattering (SERS) sensor with a sandwich structure was developed for HBsAg detection. Leveraging the ultrasensitive and rapid detection capabilities of SERS, this sensor enables quick detection results, significantly reducing waiting times. By systematically optimizing critical factors in the detection process, such as the composition and concentration of the incubation solution as well as the modification conditions and amount of probe particles, the sensitivity of the SERS immune assay system was improved. Ultimately, the sensor achieved a sensitivity of 0.00576 IU/mL within 12 min, surpassing the clinical requirement of 0.05 IU/mL by an order of magnitude. In clinical serum assay validation, the issue of false positives was effectively addressed by adding a blocker. The final sensor demonstrated 100% specificity and sensitivity at the threshold of 0.05 IU/mL. Therefore, this study not only designed an ultrasensitive SERS sensor for detecting HBsAg in actual clinical serum samples but also provided theoretical support for similar systems, filling the knowledge gap in existing literature.

Palladium-Catalyzed Cascade Heck Coupling and Allylboration of Iododiboron Compounds via Diboryl Radicals.

Geminal bis(boronates) are versatile synthetic building blocks in organic chemistry. The fact that they predominantly serve as nucleophiles in the previous reports, however, has restrained their synthetic potential. Herein we disclose the ambiphilic reactivity of α-halogenated geminal bis(boronates), of which the first catalytic utilization was accomplished by merging a formal Heck cross-coupling with a highly diastereoselective allylboration of aldehydes or imines, providing a new avenue for rapid assembly of polyfunctionalized boron-containing compounds. We demonstrated that this cascade reaction is highly efficient and compatible with various functional groups, and a wide range of heterocycles. In contrast to a classical Pd(0/II) scenario, mechanistic experiments and DFT calculations have provided strong evidence for a catalytic cycle involving Pd(I)/diboryl carbon radical intermediates.

Base-free regio- and stereoselective photochemical synthesis of enol ethers from 1,3-dicarbonyl compounds.

A visible light-induced kinetic controlled regioselective O-alkylation of various 1,3-dicarbonyl compounds with diazoacetates and cyclic ethers has been developed. The protocol provides a green and practical approach to highly stereoselective enol ethers under mild and base-free conditions in good to excellent yields.

Development and evaluation of short-form version of the Constitution in Chinese Medicine Questionnaire: study a new and best brief instrument of Chinese medicine for health management.

BACKGROUND: More efficient instruments for body constitution identification are needed for clinical practice. We aimed to develop the short-form version of the Constitution in Chinese Medicine Questionnaire (CCMQ) and evaluate for health management. METHODS: First, the short forms were developed through expert survey, classical test theory (CTT), and modern item response (IRT) based on the CCMQ. A combination of e-mail and manual methods was used in expert survey. Then, five indexes of CTT including criteria value-critical ratio, correlation coefficient, discrete tendency, internal consistency, and factor loading were used. And, IRT method was used through analyzing the discrimination and difficulty parameters of items. Second, the three top-ranked items of each constitution scale were selected for the simplified CCMQ, based on the three combined methods of different conditions and weights. Third, The psychometric properties such as completion time, validity (Construct, criterion, and divergent validity), and reliability (test-retest and internal consistency reliability) were evaluated. Finally, the diagnostic validity of the best short-form used receiver operating characteristic (ROC) curve. RESULTS: Three short-form editions were developed, and retained items 27, 23 and 27, which are named as WangQi nine body constitution questionnaire of Traditional Chinese Medicine (short-form) (SF-WQ9CCMQ)- A, B, and C, respectively. SF-WQ9CCMQ- A is showed the best psychometric property on Construct validity, Criterion validity, test-retest reliability and internal consistency reliability. The diagnostic validity indicated that the area under the ROC curve was 0.928 (95%CI: 0.924-0.932) for the Gentleness constitution scale, and were 0.895-0.969 and 0.911-0.981 for unbalance constitution scales using the cut-off value of the original CCMQ as 40 ("yes" standard) and 30 ("tendency" standard), respectively. CONCLUSIONS: Our study successfully developed a well short-form which has good psychometric property, and excellent diagnostic validity consistent with the original. New and simplified instrument and opportunity are provided for body constitution identification, health management and primary care implementation.

Correction: Mononuclear-macrophages but not neutrophils act as major infiltrating anti-leptospiral phagocytes during leptospirosis.

[This corrects the article DOI: 10.1371/journal.pone.0181014.].

Etiological Survey and Traceability Analysis of a Foodborne Disease Outbreak of Salmonella Senftenberg in Guizhou Province.

To conduct a study that examined the molecular epidemiology and pathogenesis of Salmonella Senftenberg isolates associated with an outbreak of foodborne disease in Guizhou Province and to provide a reference basis for the traceability of foodborne salmonellosis outbreaks and clinical diagnosis and treatment in the province. Fourteen strains of suspected Salmonella isolated from patient stool and food samples were used for pathogenic identification and serotyping by biochemical and mass spectrometry methods. Fourteen types of antibiotics were tested for drug sensitivity by the microbroth dilution method, and molecular typing was performed by pulsed-field gel electrophoresis (PFGE) and whole genome sequencing (WGS). After the sequencing data were spliced by SPAdes, the gene protein sequences were compared with the Comprehensive Antibiotic Research Database and Virulence Factor Database, drug resistance and virulence genes were predicted, and whole genome multilocus sequence typing (wgMLST) was performed. The results were compared with those for Salmonella strains of the same serotype from the past 5 years in China detailed on the TraNet website. All 14 strains were identified as Salmonella Senftenberg (with the antigenic formula 1,3,19:g,s,t:-), and in the PFGE cluster tree, the strains were divided into two band types, with a similarity of 88.9%. The 14 strains were sensitive to the 14 antibiotics. WGS analysis showed that the 14 strains carried the same drug resistance and virulence genes and that all strains carried 3 aminoglycoside and lipopeptide drug resistance genes, including 114 virulence genes. The wgMLST results showed that the strains were distributed on the same small branch as those obtained from previous outbreaks of infection in Tianjin and Jilin. Salmonella Senftenberg, which caused the outbreak, carries a variety of virulence genes, which suggests that the strain is highly pathogenic. These pathogenic bacteria may be associated with the Salmonella strain in Tianjin, Jilin, and other places and have caused foodborne disease outbreaks as a result of imported contamination.

Exploratory study of autophagy inducer sirolimus for childhood cerebral adrenoleukodystrophy.

Objectives: X-linked adrenoleukodystrophy (ALD) is a peroxisomal disease caused by mutations in the ABCD1 gene. Childhood cerebral ALD (CCALD) is characterized by inflammatory demyelination, rapidly progressing, often fatal. Hematopoietic stem cell transplant only delays disease progression in patients with early-stage cerebral ALD. Based on emergency humanitarianism, this study aims to investigate the safety and efficacy of sirolimus in the treatment of patients with CCALD. Methods: This was a prospective, single-center, one-arm clinical trial. We enrolled patients with CCALD, and all enrolled patients received sirolimus treatment for three months. Adverse events were monitored and recorded to evaluate the safety. The efficacy was evaluated using the neurologic function scale (NFS), Loes score, and white matter hyperintensities. Results: A total of 12 patients were included and all presented with CCALD. Four patients dropped out and a total of eight patients in the advanced stage completed a 3-month follow-up. There were no serious adverse events, and the common adverse events were hypertonia and oral ulcers. After sirolimus treatment, three of the four patients with an initial NFS > 10 showed improvements in their clinical symptoms. Loes scores decreased by 0.5-1 point in two of eight patients and remained unchanged in one patient. Analysis of white matter hyperintensities revealed a significant decrease in signal intensity (n = 7, p = 0.0156). Conclusions: Our study suggested that autophagy inducer sirolimus is safe for CCALD. Sirolimus did not improve clinical symptoms of patients with advanced CCALD significantly. Further study with larger sample size and longer follow-up is needed to confirm the drug efficacy.Clinical Trial registration: https://www.chictr.org.cn/historyversionpuben.aspx, identifier ChiCTR1900021288.

Causal effects of circulating vitamin levels on the risk of heart failure: a Mendelian randomization study.

BACKGROUND: Observational studies suggest inverse associations between serum vitamin levels and the risk of heart failure (HF). However, the causal effects of vitamins on HF have not been fully elucidated. Here, we conducted a Mendelian randomization (MR) study to investigate the causal associations between genetically determined vitamin levels and HF. METHODS: Genetic instrumental variables for circulating vitamin levels, including vitamins A, B, C, D, and E, which were assessed as either absolute or metabolite levels were obtained from public genome-wide association studies. Summary statistics for single-nucleotide-polymorphisms and HF associations were retrieved from the HERMES Consortium (47,309 cases and 930,014 controls) and FinnGen Study (30,098 cases and 229,612 controls). Two-sample MR analyses were implemented to assess the causality between vitamin levels and HF per outcome database, and the results were subsequently combined by meta-analysis. RESULTS: Our MR study did not find significant associations between genetically determined circulating vitamin levels and HF risk. For absolute vitamin levels, the odds ratio for HF ranged from 0.97 (95% confidence interval [CI]: 0.85-1.09, P = 0.41) for vitamin C to 1.05 (95% CI: 0.61-1.82, P = 0.85) for vitamin A. For vitamin metabolites, the odds ratio ranged between 0.94 (95% CI: 0.75-1.19, P = 0.62) for α-tocopherol and 1.11 (95% CI: 0.98-1.26, P = 0.09) for γ-tocopherol. CONCLUSION: Evidence from our study does not support the causal effects of circulating vitamin levels on HF. Therefore, there may be no direct beneficial effects of vitamin intake on the prevention of primary HF.

UV light-driven late-stage skeletal reorganization to diverse limonoid frameworks: A proof of concept for photobiosynthesis.

Late-stage skeletal reorganization (LSSR) is a type of fascinating organic transformation processes in natural product total synthesis. However, few facile and effective LSSR methodologies have hitherto been developed. Here, LSSR of limonoid natural products via photochemical cascades is first reported. Starting from xyloelves A and B, nine distinct limonoid products with five unprecedented scaffolds are generated. The photocascade pathways of these natural products and mechanistic rationale via intramolecular triplet energy transfer are revealed by quantum mechanical calculations. Most notably, ultraviolet light-driven transannular and stereoselective C â†’ C 1,4-acyl migration is first found as a photochemical approach, particularly for LSSR of natural products. This approach holds promise for designing LSSR strategies to access bioactive cage-like molecules. Besides that, our findings provide a clear proof of concept for natural product photobiosynthesis. Xyloelf A, substantially ameliorating concanavalin A-induced liver injury in mice, could be used as a unique molecular template for hepatoprotective drug discovery.

Formyl Radical Generation from α-Chloro N-Methoxyphthalimides Enables Selective Aldehyde Synthesis.

The aldehydes installation by radical formylation constitutes an attractive synthetic strategy. However, the generation of formyl radicals for organic synthesis applications remains unknown. Herein we report the first formyl radical generation from α-chloro N-methoxyphthalimides, which selectively synthesize aldehydes by alkene hydroformylation under mild photoredox conditions. The aldehydes can be installed on acrylates, acrylamides, vinyl sulfones, vinyl ketones, and complex steroids by radical hydroformylation in excellent chemoselectivity and regioselectivity. The concerted hydrochloride elimination for the formyl radical generation from α-chloro methoxy radicals is established by experimental and computational approaches.

Azoarene activation for Schmidt-type reaction and mechanistic insights.

The Schmidt rearrangement, a reaction that enables C-C or C-H σ bond cleavage and nitrogen insertion across an aldehyde or ketone substrate, is one of the most important and widely used synthetic tools for the installation of amides and nitriles. However, such a reaction frequently requires volatile, potentially explosive, and highly toxic azide reagents as the nitrogen donor, thus limiting its application to some extent. Here, we show a Schmidt-type reaction where aryldiazonium salts act as the nitrogen precursor and in-situ-generated cyclopenta-1,4-dien-1-yl acetates serve as pronucleophiles from gold-catalyzed Nazarov cyclization of 1,3-enyne acetates. Noteworthy is that cycloketone-derived 1,3-enyne acetates enabled ring-expansion relay to access a series of 2-pyridone-containing fused heterocycles, in which nonsymmetric cycloketone-derived counterparts demonstrated high regioselectivity. Aside from investigating the scope of this Schmidt-type reaction, mechanistic details of this transformation are provided by performing systematic theoretical calculations.

Catalytic Multicomponent Synthesis of C-Acyl Glycosides by Consecutive Cross-Electrophile Couplings.

C-Acyl glycosides are versatile intermediates to natural products and medicinally relevant entities. Conventional cross-coupling strategies to secure these molecules often relied on two-component manifolds in which a glycosyl precursor is coupled with an acyl donor (pre-synthesized or generated in situ) under transition metal or dual catalysis to forge a C-C bond. Here, we disclose a three-component Ni-catalyzed reductive regime that facilitates the chemoselective union of glycosyl halides, organoiodides and commercially available isobutyl chloroformate as a CO surrogate. The method tolerates multiple functionalities and the resulting products are obtained in high diastereoselectivities. Theoretical calculations provide a mechanistic rationale for the unexpectedly high chemoselectivity of sequential cross-electrophile couplings. This approach enables the expeditious assembly of difficult-to-synthesize C-acyl glycosides, as well as late-stage keto-glycosylation of oligopeptides.

Iminyl radical-triggered relay annulation for the construction of bridged aza-tetracycles bearing four contiguous stereogenic centers.

Bridged tetracyclic nitrogen scaffolds are found in numerous biologically active molecules and medicinally relevant structures. Traditional methods usually require tedious reaction steps, and/or the use of structurally specific starting materials. We report an unprecedented, iminyl radical-triggered relay annulation from oxime-derived peresters and azadienes, which shows good substrate scope and functional group compatibility, and can deliver various bridged aza-tetracyclic compounds with complex molecular topology and four contiguous stereogenic centers (dr > 19 : 1) in a single operation. This transformation represents the first example of trifunctionalization of iminyl radicals through simultaneous formation of one C-N and two C-C bonds. DFT calculation studies were conducted to obtain an in-depth insight into the reaction pathways, which revealed that the reactions involved an interesting 1,6-hydrogen atom transfer process.

Design and synthesis of stable four-coordinated benzotriazole-borane with tunable fluorescence emission.

A new class of stable four-coordinated benzotriazole-borane compounds was developed via gold-catalyzed alkyne hydroboration. The application of polymeric (BH2CN) n reagent gave the formation of cyano-amine-boranes (CAB) complexes with less basic N-heterocyclic amines and anilines. Various new CABs were investigated in catalytic hydroboration to synthesize N-B cycles. The 1,2,3-benzotriazoles were identified as the only feasible N-source, giving the four coordinated borane N-B cycles (BTAB) in excellent yields (up to 90%) with good functional group tolerability. This new class of polycyclic N-B compounds showed excellent stability toward acid, base, high temperature, and photo-irradiation. The facile synthesis, excellent stability, strong and tunable fluorescence emission make BTAB interesting new fluorescent probes for future chemical and biological applications.

Palladium-Catalyzed Asymmetric [3 + 2] Annulation of Vinylethylene Carbonates with Alkenes Installed on Cyclic N-Sulfonyl Imines: Highly Enantio- and Diastereoselective Construction of Chiral Tetrahydrofuran Scaffolds Bearing Three Vicinal and Quaternary Stereocenters.

A multisubstituted tetrahydrofuran building block bearing three vicinal chiral carbon centers widely exists in a broad spectrum of bioactive natural products, and the development of efficient and convenient methods to establish this skeleton remains a challenging task. Herein, we have developed an efficient method for the construction of significant tetrahydrofuran scaffolds bearing three vicinal and α-quaternary chiral carbon stereocenters through Pd-catalyzed asymmetric [3 + 2] annulation of vinylethylene carbonates with alkenes installed on cyclic N-sulfonyl imines. A series of multisubstituted tetrahydrofuran derivatives are obtained in high efficiencies with excellent enantioselectivities and diastereoselectivities. Density functional theory (DFT) studies are accomplished to rationalize the stereocontrol of the annulation process and disclose that methanol could be applied to stabilize the reactive zwitterionic π-allylpalladium via the H-bond interaction.

Boryl Radical Activation of Benzylic C-OH Bond: Cross-Electrophile Coupling of Free Alcohols and CO2 via Photoredox Catalysis.

A new strategy for the direct cleavage of the C(sp3)-OH bond has been developed via activation of free alcohols with neutral diphenyl boryl radical generated from sodium tetraphenylborate under mild visible light photoredox conditions. This strategy has been verified by cross-electrophile coupling of free alcohols and carbon dioxide for the synthesis of carboxylic acids. Direct transformation of a range of primary, secondary, and tertiary benzyl alcohols to acids has been achieved. Control experiments and computational studies indicate that activation of alcohols with neutral boryl radical undergoes homolysis of the C(sp3)-OH bond, generating alkyl radicals. After reducing the alkyl radical into carbon anion under photoredox conditions, the following carboxylation with CO2 affords the coupling product.

Photo/Electrochromic Dual Responsive Behavior of a Cage-like Zr(IV)-Viologen Metal-Organic Polyhedron (MOP).

Stable stimulus-responsive materials are highly desirable due to their widespread potential applications and growing demand in recent decades. Despite the fact that viologen derivatives have long been known as excellent photochromic and electrochromic materials, the development of stable viologen-based multifunctional smart materials with short coloration times remains an exciting topic. To obtain photochromic and electrochromic dual responsive materials, embedding the viologen ligand into a robust metal oxide cluster to increase its stability and sensitivity is an effective strategy. Herein, a viologen-based metal-organic polyhedron (MOP) {[Zr6L3(µ3-O)2(µ2-OH)6Cp6]·8Cl·CH3OH·DMF} [Zr-MOP-1; H2L·2Cl = 1,1'-bis(4-carboxyphenyl)-4,4'-bipyridinium dichloride, and Cp = η5-C5H5] was successfully prepared and characterized. It consists of trinuclear Zr-oxygen secondary building units and exhibits reversible photochromic and electrochromic dual responsive behaviors. As expected, the designed robust viologen-based nanocage with a V2E3 (V = vertex, and E = edge) topology can maintain its stability and rapid photo/electrochromic behaviors with an obvious reversible change in color from purple (brown) to green, mainly due to the enclosed cluster structure and the abundant free viologen radicals that originate from the effective Cl → N and O → N electron transfers. Spectroelectrochemistry and theoretical calculations of this Zr-MOP were also performed to verify the chromic mechanism.

Diradical Generation via Relayed Proton-Coupled Electron Transfer.

Diradical generation followed by radical-radical cross-coupling is a powerful synthetic tool, but its detailed mechanism has yet to be established. Herein, we proposed and confirmed a new model named relayed proton-coupled electron transfer (relayed-PCET) for diradical generation, which could open a door for new radical-radical cross-coupling reactions. Quantum mechanics calculations were performed on a selected carbene-mediated diradical cross-coupling reaction model and a designed model, and the exact electronic structural changes during the radical processes have been observed for the first time.