Giant enhancement of fluorescence resonance energy transfer based on nanoporous gold with small amount of residual silver.

Fluorescence resonance energy transfer (FRET) was found strongly enhanced by plasmon resonance. In this work, Nanoporous Gold with small amount of residual silver was used to form nanoporous gold/organic molecular layer compound with PSS and PAH. The ratio of its specific gold and silver content is achieved by controlling the time of its dealloying. Layered films of polyelectrolyte multilayers were assembled between the donor-acceptor pairs and NPG films to control distance. The maximum of FRET enhancement of 80-fold on the fluorescence intensity between the donor-acceptor pairs (CFP-YFP) is observed at a distance of ∼10.5 nm from the NPG film. This Nanoporous Gold with small amount of residual silver not only enhanced FRET 4-fold more than nanoporous gold of only gold content almost, but also effectively realized the regulation of FRET enhancement. The ability to precisely measure and regulate the enhancement of FRET enables the rational selection of plasmonic nanotransducer dimensions for the particular biosensing application.

Synthesis and Broadband Photodetection of a P-Type 1D Van der Waals Semiconductor HfSnS3.

1D van der Waals (vdW) materials have attracted significant interest in recent years due to their giant anisotropic and weak interlayer-coupled characters. More 1D vdW materials are urgently to be exploited for satisfying the practice requirement. Herein, the study of 1D vdW ternary HfSnS3 high-quality single crystals grown via the chemical vapor transport technique is reported. The Raman vibration modes and band structure of HfSnS3 are analyzed via DFT calculations. Its strong in-plane anisotropic is verified by the polarized Raman spectroscopy. The field-effect transistors (FETs) based on the HfSnS3 nanowires demonstrate p-type semiconducting behavior as well as outstanding photoresponse in a broadband range from UV to near-infrared (NIR) with short response times of ≈0.355 ms, high responsivity of ≈11.5 A W-1 , detectivity of ≈8.2 × 1011 , external quantum efficiency of 2739%, excellent environmental stability, and repeatability. Furthermore, a typical photoconductivity effect of the photodetector is illustrated. These comprehensive characteristics can promote the application of the p-type 1D vdW material HfSnS3 in optoelectronics.

Longitudinal Dynamics of the Neutralizing Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing antibodies (NAbs) in patients with COVID-19. METHODS: Blood samples (n = 173) were collected from 30 patients with COVID-19 over a 3-month period after symptom onset and analyzed for SARS-CoV-2-specific NAbs using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines. RESULTS: SARS-CoV-2-specific NAb titers were low for the first 7-10 days after symptom onset and increased after 2-3 weeks. The median peak time for NAbs was 33 days (interquartile range [IQR], 24-59 days) after symptom onset. NAb titers in 93.3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34.8% (IQR, 19.6-42.4%). NAb titers increased over time in parallel with the rise in immunoglobulin G (IgG) antibody levels, correlating well at week 3 (r = 0.41, P < .05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including stem cell factor (SCF), TNF-related apoptosis-inducing ligand (TRAIL), and macrophage colony-stimulating factor (M-CSF). CONCLUSIONS: These data provide useful information regarding dynamic changes in NAbs in patients with COVID-19 during the acute and convalescent phases.

Surface plasmon enhanced THz emission with nanoporous gold supported CdTe.

Terahertz emission by ultrafast excitation of semiconductor/metal interfaces was found strongly enhanced by plasmon resonance. Here, a three-dimensional nanoporous gold (NPG) was used to form semiconductor/metal compound with cadmium telluride (CdTe). We investigated the specific impact of surface plasmon from randomly nanoporous structure in the ultrafast optoelectronic response for THz generation, and observed a THz amplitude enhancement around an order of magnitude from CdTe on NPG compared to that from CdTe on silicon. Moreover, the plasmon enhancement for THz emission from NPG is stronger than that from gold film, indicating that randomly nanoporous structure is also effective for plasmonic enhancement in THz band.

A Peptide-Based Magnetic Chemiluminescence Enzyme Immunoassay for Serological Diagnosis of Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel ß-coronavirus, causes severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named coronavirus disease 2019 (COVID-19). To date, real-time reverse-transcription polymerase chain reaction (RT-PCR) is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. METHODS: In this study, we developed a peptide-based luminescent immunoassay that detected immunoglobulin (Ig)G and IgM. The assay cutoff value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. RESULTS: To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. CONCLUSIONS: Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.

Structure-Guided Discovery of a Potent and Selective Cell-Active Inhibitor of SETDB1 Tudor Domain.

SET domain bifurcated protein 1 (SETDB1) is a histone lysine methyltransferase that promotes the silencing of some tumour suppressor genes and is overexpressed in many cancers. SETDB1 contains a unique tandem tudor domain (TTD) that recognizes histone H3 sequences containing both methylated and acetylated lysines. Beginning with the identification of a hit compound (Cpd1), we discovered the first potent and selective small molecule SETDB1-TTD inhibitor (R,R)-59 through stepwise structure-guided optimization. (R,R)-59 showed a KD value of 0.088±0.045 µM in the ITC assay. The high potency of (R,R)-59 was well explained by the cocrystal structure of the (R,R)-59-TTD complex. (R,R)-59 is an endogenous binder competitive inhibitor. Evidence has also demonstrated its cellular target engagement. Interestingly, the enantiomer (S,S)-59 did not show activity in all the assays, highlighting the potential of (R,R)-59 as a tool compound in exploring the biological functions of SETDB1-TTD.

Prevalence characteristics of cervical human papillomavirus (HPV) infection in the Zhoupu District, Shanghai City, China.

BACKGROUND: Human papillomavirus (HPV) infection is the leading cause of genital diseases. It can cause a series of cervical lesions. The distribution of HPV genotypes indicates that the increased prevalence of high-risk HPV (HR-HPV) is positively correlated with the severity of cervical lesions. In addition, persistent HR-HPV infection is associated with the risk of cervical cancer. Considering the latest approval of homemade HPV vaccine in China and the prevalence of HPV distribution, this is of great significance for guiding HPV vaccination work. OBJECTIVE: Our study's purpose was to examine trends of cervical HPV infection rate in each 5-year age group from 2011 to 2019. METHODS: Retrospective analysis of human papillomavirus prevalence rate of 59,541 women from 2011 to 2019 in the District Zhoupu of Shanghai City in China. HPV genotype testing is performed using a commercial kit designed to detect 15 high-risk HPV genotypes and 6 low-risk HPV genotypes. Trends were examined for each 5-year age group. RESULTS: In the District Zhoupu of Shanghai City in China, the prevalence rate of cervical HPV increased significantly among women aged 15-34 years. The most prevalent HR-HPV genotypes were 52, 16, 58, 53, 39, and 51. CONCLUSION: Cervical HPV prevalence rate is very high in younger women in suburb Shanghai. Due to significant differences in infection rates between specific age groups and HPV subtypes, timely intervention is required for these vulnerable populations.

Fabrication of large scale uniform copper-island thin film for ultrasensitive surface enhanced Raman scattering.

Nanostructured metals with designable and controllable structures have received increasing attention in surface enhanced Raman scattering (SERS) due to the single molecular detection limit. Great challenges still remain in creating large scale substrates with high-density 'hotspots' to provide a uniform and stable enhancement of Raman signals. Here, we fabricated a copper island thin film over an 80 cm2 scale substrate with tunable particle sizes by combining sputtering with dealloying processes. The island size can be tailored from 150 nm to 370 nm by controlling parameters and etching conditions and possesses an optimized surface morphology structure. The detection limit of crystal violet (CV) molecules reached 0.1 pM. Meanwhile, the copper island thin film presents good homogeneity and stability. Our method is promising to repeatedly fabricate novel metal SERS substrates on a large scale with standard properties for sensing applications.

Discovery of 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one derivatives as new potent PB2 inhibitors.

PB2 is an important subunit of influenza RNA-dependent RNA polymerase (RdRP) and has been recognized as a promising target for the treatment of influenza. We herein report the discovery of a new series of PB2 inhibitors containing the skeleton 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one. Compound 12b is the most potent one, which showed KD values of 0.11 µM and 0.19 µM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In antiviral activity and cellular cytotoxicity assays, compound 12b showed an EC50 value of 1.025 µM and a CC50 value greater than 100 µM. Molecular docking was also used to predict the binding mode of 12b with PB2. Collectively, this study provides a promising lead compound for subsequent anti-influenza drug discovery targeting PB2.

Discovery of New SIRT2 Inhibitors by Utilizing a Consensus Docking/Scoring Strategy and Structure-Activity Relationship Analysis.

SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide (SR86). This compound showed good activity against SIRT2 with an IC50 value of 1.3 µM. SR86 did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, SR86 displayed very good antiviability activity against breast cancer cell line MCF-7. In Western blot assays, SR86 showed considerable activity in blocking the deacetylation of α-tubulin, which is a typical substrate of SIRT2. Collectively, because of the new scaffold structure and good selectivity of SR86, it could serve as a promising lead compound, hence deserving further studies.

IFPTarget: A Customized Virtual Target Identification Method Based on Protein-Ligand Interaction Fingerprinting Analyses.

Small-molecule target identification is an important and challenging task for chemical biology and drug discovery. Structure-based virtual target identification has been widely used, which infers and prioritizes potential protein targets for the molecule of interest (MOI) principally via a scoring function. However, current "universal" scoring functions may not always accurately identify targets to which the MOI binds from the retrieved target database, in part due to a lack of consideration of the important binding features for an individual target. Here, we present IFPTarget, a customized virtual target identification method, which uses an interaction fingerprinting (IFP) method for target-specific interaction analyses and a comprehensive index (Cvalue) for target ranking. Evaluation results indicate that the IFP method enables substantially improved binding pose prediction, and Cvalue has an excellent performance in target ranking for the test set. When applied to screen against our established target library that contains 11,863 protein structures covering 2842 unique targets, IFPTarget could retrieve known targets within the top-ranked list and identified new potential targets for chemically diverse drugs. IFPTarget prediction led to the identification of the metallo-ß-lactamase VIM-2 as a target for quercetin as validated by enzymatic inhibition assays. This study provides a new in silico target identification tool and will aid future efforts to develop new target-customized methods for target identification.

Engineering P450 Peroxygenase to Catalyze Highly Enantioselective Epoxidation of cis-ß-Methylstyrenes.

P450 119 peroxygenase and its site-directed mutants are discovered to catalyze the enantioselective epoxidation of methyl-substituted styrenes. Two new site-directed P450 119 mutants, namely T213Y and T213M, which were designed to improve the enantioselectivity and activity for the epoxidation of styrene and its methyl substituted derivatives, were studied. The T213M mutant is found to be the first engineered P450 peroxygenase that shows highly enantioselective epoxidation of cis-ß-methylstyrenes, with up to 91 % ee. Molecular modeling studies provide insights into the different catalytic activity of the T213M mutant and the T213Y mutant in the epoxidation of cis-ß-methylstyrene. The results of the calculations also contribute to a better understanding of the substrate specificity and configuration control for the regio- and stereoselective peroxygenation catalyzed by the T213M mutant.

O-GlcNAcylation of E3 ubiquitin ligase SKP2 promotes hepatocellular carcinoma proliferation.

O-linked-ß-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC.

PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma.

Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program. Phosphoenolpyruvate carboxylase 1 (PCK1), a gluconeogenic metabolic enzyme, is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis. The oncogenesis and progression of tumors are closely related to cancer stem cells. It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma. Herein, the results showed that PCK1 inhibited the self-renewal property of hepatoma cells, reduced the mRNA level of cancer stem cell markers, and inhibited tumorigenesis. Moreover, PCK1 increased the sensitivity of hepatocellular carcinoma cells to sorafenib. Furthermore, we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation. Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib. Thus, combined treatment with verteporfin and sorafenib may be a potential anti-tumor strategy in hepatocellular carcinoma.

EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL.

BACKGROUND: Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness is deemed inadequate, and the range of therapeutic targets is limited. The aim of this study was to identify early growth response 1 (EGR1) as a transcription factor target in HCC and to explore its role and assess the potential of gene therapy utilizing EGR1 for the management of HCC. METHODS: In this study, both in vitro and in vivo assays were employed to examine the impact of EGR1 on the growth of HCC. The mouse HCC model and human organoid assay were utilized to assess the potential of EGR1 as a gene therapy for HCC. Additionally, the molecular mechanism underlying the regulation of gene expression and the suppression of HCC growth by EGR1 was investigated. RESULTS: The results of our investigation revealed a notable decrease in the expression of EGR1 in HCC. The decrease in EGR1 expression promoted the multiplication of HCC cells and the growth of xenografted tumors. On the other hand, the excessive expression of EGR1 hindered the proliferation of HCC cells and repressed the development of xenografted tumors. Furthermore, the efficacy of EGR1 gene therapy was validated using in vivo mouse HCC models and in vitro human hepatoma organoid models, thereby providing additional substantiation for the anti-cancer role of EGR1 in HCC. The mechanistic analysis demonstrated that EGR1 interacted with the promoter region of phosphofructokinase-1, liver type (PFKL), leading to the repression of PFKL gene expression and consequent inhibition of PFKL-mediated aerobic glycolysis. Moreover, the sensitivity of HCC cells and xenografted tumors to sorafenib was found to be increased by EGR1. CONCLUSION: Our findings suggest that EGR1 possesses therapeutic potential as a tumor suppressor gene in HCC, and that EGR1 gene therapy may offer benefits for HCC patients.

Ultrafast laser state active controlling based on anisotropic quasi-1D material.

Laser state active controlling is challenging under the influence of inherent loss and other nonlinear effects in ultrafast systems. Seeking an extension of degree of freedom in optical devices based on low-dimensional materials may be a way forward. Herein, the anisotropic quasi-one-dimensional layered material Ta2PdS6 was utilized as a saturable absorber to modulate the nonlinear parameters effectively in an ultrafast system by polarization-dependent absorption. The polarization-sensitive nonlinear optical response facilitates the Ta2PdS6-based mode-lock laser to sustain two types of laser states, i.e., conventional soliton and noise-like pulse. The laser state was switchable in the single fiber laser with a mechanism revealed by numerical simulation. Digital coding was further demonstrated in this platform by employing the laser as a codable light source. This work proposed an approach for ultrafast laser state active controlling with low-dimensional material, which offers a new avenue for constructing tunable on-fiber devices.

Investigation of the Degradation Mechanism of the Tensile Mechanical Properties of Sandstone under the Corrosion of Various pH Solutions.

The research aimed to examine the impact of different pH solutions on the tensile mechanical properties of saturated and natural sandstone specimens. The study utilized the WHY-300/10 microcomputer-controlled pressure testing machine to conduct Brazil splitting tests and employed acoustic emission and local dynamic strain testing techniques. The results indicated the tensile strength and split tensile modulus of the sandstone specimens gradually decreased with the polarisation of the solution pH, and the acoustic emission signal ring number monitoring values showed an increasing trend. The pH of the soaking solution followed an exponential decay pattern over time, eventually tending towards weak alkalinity. A new damage variable based on the cumulative ring count after chemical corrosion was defined to indirectly analyze the degree of corrosion degradation. It was discovered that in acidic or alkaline environments, the internal crystals of the rock are dissolved, weakening the mineral interconnections and causing a deterioration in tensile stress and strength. These findings can provide valuable insights for ensuring the safety and stability of the Denglou Mountain Tunnel in Yunnan Province.

Diagnostic value of chemiluminescence for urinary lipoarabinomannan antigen assay in active tuberculosis: insights from a retrospective study.

Purpose: This study aimed to assess the efficacy of chemiluminescence-based urinary lipoarabinomannan (LAM) antigen assay as a diagnostic tool for identifying active tuberculosis. Methods: A retrospective study was conducted on 166 Tuberculosis (TB), 22 Non-Tuberculous Mycobacteria (NTM), 69 Non-TB cases, and 73 healthy controls from Zhangjiagang First Peoples Hospital between July 2022 and November 2022. Clinical and laboratory data were collected, including urine samples for LAM antigen detection, sputum samples and pleural effusion for GeneXpert, TB-DNA, and culture. Results: TB group exhibited a higher LAM positivity rate (P < 0.001). CD4 count and diabetes as independent factors influencing the diagnostic accuracy of LAM. The LAM assay showed a sensitivity of 50.6% and a specificity of 95.65%. Notably, LAM's sensitivity was superior to TB-DNA (50.60% vs. 38.16%, P < 0.05). LAM's PTB detection rate was 51.7%, superior to TB-DNA (P = 0.047). Moreover, in EPTB cases, the LAM detection rate was 42.11%, surpassing Gene Xpert (P = 0.042), as well as exceeding the detection rates of TB-DNA and sputum culture. Conclusion: LAM antigen detection using chemiluminescence has demonstrated outstanding clinical diagnostic value for active TB, especially in the diagnosis of extrapulmonary TB. The convenience of sample collection in this diagnostic approach allows for widespread application in the clinical diagnosis of active tuberculosis, particularly in cases of EPTB and sputum-negative patients.

SLC27A5 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by downregulating glutathione reductase.

Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), shows a favorable anti-tumor effect while resistance is a barrier impeding patients from benefiting from it. Thus, more efforts are needed to lift this restriction. Herein, we first find that solute carrier family 27 member 5 (SLC27A5/FATP5), an enzyme involved in the metabolism of fatty acid and bile acid, is downregulated in sorafenib-resistant HCC. SLC27A5 deficiency facilitates the resistance towards sorafenib in HCC cells, which is mediated by suppressing ferroptosis. Further mechanism studies reveal that the loss of SLC27A5 enhances the glutathione reductase (GSR) expression in a nuclear factor erythroid 2-related factor 2 (NRF2)-dependent manner, which maintains glutathione (GSH) homeostasis and renders insensitive to sorafenib-induced ferroptosis. Notably, SLC27A5 negatively correlates with GSR, and genetic or pharmacological inhibition of GSR strengthens the efficacy of sorafenib through GSH depletion and the accumulation of lipid peroxide products in SLC27A5-knockout and sorafenib-resistant HCC cells. Based on our results, the combination of sorafenib and carmustine (BCNU), a selective inhibitor of GSR, remarkably hamper tumor growth by enhancing ferroptotic cell death in vivo. In conclusion, we describe that SLC27A5 serves as a suppressor in sorafenib resistance and promotes sorafenib-triggered ferroptosis via restraining the NRF2/GSR pathway in HCC, providing a potential therapeutic strategy for overcoming sorafenib resistance.

Synthesis and evaluation of N-sulfonylpiperidine-3-carboxamide derivatives as capsid assembly modulators inhibiting HBV in vitro and in HBV-transgenic mice.

The hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been developed as effective anti-HBV agents in the treatment of chronic HBV infection by targeting the HBV core protein and inducing the formation of aberrant or morphologically normal capsid. However, some CAMs have been observed adverse events such as ALT flares and rash. Therefore, finding new CAMs is of great importance. In this report, we synthesized N-sulfonylpiperidine-3-carboxamides (SPCs) derivatives and evaluated their anti-HBV activities. Among the SPC derivatives, compound C-49 notably suppressed HBV replication in HepAD38, HepG2-HBV1.3 and HepG2-NTCP cells. Moreover, treatment with C-49 for 12 days exhibited potent anti-HBV activity (100 mg/kg; 2.42 log reduction of serum HBV DNA) in HBV-transgenic mice without apparent hepatotoxicity. Our findings provided a new SPC derivative as HBV capsid assembly modulator for developing safe and efficient anti-HBV therapy.