Experimental Study on Measuring and Tracking Structural Displacement Based on Surveillance Video Image Analysis.

The digital image method of monitoring structural displacement is receiving more attention today, especially in non-contact structure health monitoring. Some obvious advantages of this method, such as economy and convenience, were shown while it was used to monitor the deformation of the bridge structure during the service period. The image processing technology was used to extract structural deformation feature information from surveillance video images containing structural displacement in order to realize a new non-contact online monitoring method in this paper. The influence of different imaging distances and angles on the conversion coefficient (η) that converts the pixel coordinates to the actual displacement was first studied experimentally. Then, the measuring and tracking of bridge structural displacement based on surveillance video images was investigated by laboratory-scale experiments under idealized conditions. The results showed that the video imaging accuracy can be affected by changes in the relative position of the imaging device and measured structure, which is embodied in the change in η (actual size of individual pixel) on the structured image. The increase in distance between the measured structure and the monitoring equipment will have a significant effect on the change in the η value. The value of η varies linearly with the change in shooting distance. The value of η will be affected by the changes in shooting angle. The millimeter-level online monitoring of the structure displacement can be realized using images based on surveillance video images. The feasibility of measuring and tracking structural displacement based on surveillance video images was confirmed by a laboratory-scale experiment.

Downregulated mitochondrial transcription factor A enhances mycoplasma infection to promote the metastasis of hepatocellular carcinoma.

Mycoplasma is widespread in various hosts and may cause various diseases in animals. Interestingly, the occurrence of mycoplasma infection was observed in many tumor types. However, the mechanism regulating its infection is far from clear. We unexpectedly found that the knockdown of mitochondrial transcription factor A (TFAM) remarkably enhanced mycoplasma infection in hepatocellular carcinoma (HCC) cells. More importantly, we found that mycoplasma infection facilitated by TFAM knockdown significantly promoted HCC cell metastasis. Mycoplasma infection was further found to be positively correlated with poor prognosis in patients with HCC. Mechanistically, the decreased TFAM expression upregulated the transcription factor Sp1 to increase the expression level of Annexin A2 (ANXA2), which was reported to interact with membrane protein of mycoplasma. Moreover, we found that mycoplasma infection enhanced by the TFAM downregulation promoted HCC migration and invasion by activating the nuclear factor-κB signaling pathway. The downregulation of TFAM enhanced mycoplasma infection in HCC cells and promoted HCC cell metastasis. Our study contributes to the understanding of the pathological role of mycoplasma infection and provides supporting evidence that targeting TFAM could be a potential strategy for the treatment of HCC with mycoplasma infection.

In Situ Encapsulation of Graphene Quantum Dots in Highly Stable Porphyrin Metal-Organic Frameworks for Efficient Photocatalytic CO2 Reduction.

Photocatalytic CO2 reduction to valuable hydrocarbon solar fuel is of great significance but still challenging. Strong CO2 enrichment ability and easily adjustable structures make metal-organic frameworks (MOFs) potential photocatalysts for CO2 conversion. Even though pure MOFs have the potential for photoreduction of CO2, the efficiency is still quite low due to rapid photogenerated electron-hole recombination and other drawbacks. In this work, graphene quantum dots (GQDs) were in situ encapsulated into highly stable MOFs via a solvothermal method for this challenging task. The GQDs@PCN-222 with encapsulated GQDs showed similar Powder X-ray Diffraction (PXRD) patterns to PCN-222, indicating the retained structure. The porous structure was also retained with a Brunauer-Emmett-Teller (BET) surface area of 2066 m2/g. After incorporation of GQDs, the shape of GQDs@PCN-222 particles remained, as revealed by the scanning electron microscope (SEM). As most of the GQDs were covered by thick PCN-222, it was hard to observe those GQDs using a transmission electron microscope (TEM) and a high-resolution transmission electron microscope (HRTEM) directly, the treatment of digested GQDs@PCN-222 particles by immersion in a 1 mM aqueous KOH solution can make the incorporated GQDs visible in TEM and HRTEM. The linker, deep purple porphyrins, make MOFs a highly visible light harvester up to 800 nm. The introduction of GQDs inside PCN-222 can effectively promote the spatial separation of the photogenerated electron-hole pairs during the photocatalytic process, which was proved by the transient photocurrent plot and photoluminescence emission spectra. Compared with pure PCN-222, the obtained GQDs@PCN-222 displayed dramatically enhanced CO production derived from CO2 photoreduction with 147.8 µmol/g/h in a 10 h period under visible light irradiation with triethanolamine (TEOA) as a sacrificial agent. This study demonstrated that the combination of GQDs and high light absorption MOFs provides a new platform for photocatalytic CO2 reduction.

Ferroptosis-associated DNA methylation signature predicts overall survival in patients with head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. The aim of this study was to identify a novel ferroptosis-related DNA methylation signature as an alternative diagnosis index for patients with HNSCC. METHODS: Methylome and transcriptome data of 499 HNSCC patients, including 275 oral squamous cell carcinoma (OSCC) samples, were obtained from The Cancer Genome Atlas (TCGA). An additional independent methylation dataset of 50 OSCC patients from the NCBI Gene Expression Omnibus (GEO) database was used for validation. As an index of ferroptosis activity, the ferroptosis score (FS) of each patient was inferred from the transcriptome data using single-sample gene set enrichment analysis. Univariate, multivariate, and LASSO Cox regression analyses were used to select CpG sites for the construction of a ferroptosis-related DNA methylation signature for diagnosis of patients. RESULTS: We initially inferred the FS of each TCGA HNSCC patient and divided the samples into high- and low-FS subgroups. Results showed that the high-FS subgroup displayed poor overall survival. Moreover, 378 differentially methylated CpG sites (DMCs) were identified between the two HNSCC subgroups, with 16 selected to construct a 16-DNA methylation signature for risk prediction in HNSCC patients using the LASSO and multivariate Cox regression models. Relative operating characteristic (ROC) curve analysis showed great predictive efficiency for 1-, 3-, and 5-year HNSCC survival using the 16-DNA methylation signature. Its predictive efficiency was also observed in OSCC patients from the TCGA and GEO databases. In addition, we found that the signature was associated with the fractions of immune types in the tumor immune microenvironment (TIME), suggesting potential interactions between ferroptosis and TIME in HNSCC progression. CONCLUSIONS: We established a novel ferroptosis-related 16-DNA methylation signature that could be applied as an alternative tool to predict prognosis outcome in patients with HNSCC, including OSCC.

Lon protease downregulates phenazine-1-carboxamide biosynthesis by degrading the quorum sensing signal synthase PhzI and exhibits negative feedback regulation of Lon itself in Pseudomonas chlororaphis HT66.

Pseudomonas chlororaphis HT66 exhibits strong antagonistic activity against various phytopathogenic fungi due to its main antibiotic phenazine-1-carboxamide (PCN). PCN gene cluster consists of phzABCDEFG, phzH, phzI, and phzR operons. phzABCDEFG transcription is activated by the PhzI/R quorum sensing system. Deletion of the lon gene encoding an ATP-dependent protease resulted in significant enhancement of PCN production in strain HT66. However, the regulatory pathway and mechanism of Lon on PCN biosynthesis remain unknown. Here, lon mutation was shown to significantly improve antimicrobial activity of strain HT66. The N-acyl-homoserine lactone synthase PhzI mediates the negative regulation of PCN biosynthesis and phzABCDEFG transcription by Lon. Western blot showed that PhzI protein abundance and stability were significantly enhanced by lon deletion. The in vitro degradation assay suggested that Lon could directly degrade PhzI protein. However, Lon with an amino acid replacement (S674 -A) could not degrade PhzI protein. Lon-recognized region was located within the first 50 amino acids of PhzI. In addition, Lon formed a new autoregulatory feedback circuit to modulate its own degradation by other potential proteases. In summary, we elucidated the Lon-regulated pathway mediated by PhzI during PCN biosynthesis and the molecular mechanism underlying the degradation of PhzI by Lon in P. chlororaphis HT66.

Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine.

FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic ß cells with a low risk of hypoglycemia. Many reported FFA1 agonists possessed somewhat pharmacokinetic and/or safety issues. Herein, we describe the identification of 2,3-dihydrobenzo[b][1,4]dioxine as a novel scaffold for FFA1 agonists. Comprehensive structure-activity relationship study based on this scaffold led to the discovery of (S)-3-(4-(((S)-7-(4-methoxyphenyl)-2,3-dihydrobenzo [b][1,4]dioxin-2-yl)methoxy) phenyl)hex-4-ynoic acid (26k), which displayed a potent FFA1 agonistic activity and good pharmacokinetic profiles. Subsequent in vivo studies demonstrated that compound 26k significantly improved the glucose tolerance in ICR mice. In summary, compound 26k is a promising drug candidate for further investigation.

Clinical pharmacodynamics and long-term efficacy of Talcom vs. Plavix in patients undergoing coronary stent implantation: a randomized study with 5-year follow-up.

PURPOSE: Form II clopidogrel bisulfate (Plavix) has been extensively used in patients with acute coronary syndrome. However, the efficacy of form I clopidogrel bisulfate (Talcom) was less investigated. The aim of this study was to investigate the efficacy and safety of Talcom compared with Plavix. METHOD: Two hundred and forty-eight patients were recruited after receiving percutaneous coronary intervention (PCI). Participants were randomly assigned to Talcom or Plavix group, and administered with Talcom or Plavix 75 mg od respectively in combination with aspirin 100 mg od for 12 months. Primary endpoints were set as levels of adenosine diphosphate-induced platelet aggregation (PLADP) on the 5th day and at 1 month after randomization. Patients were followed-up for 5 years. Bleeding events and major adverse cardiovascular events (MACE) including cardiac death, non-fatal myocardial infarction, ischemic stroke, target lesion revascularization (TLR), and cardiogenic re-admission were recorded. RESULTS: On the 5th day and at 1 month after randomization, the antiplatelet effect of Talcom was non-inferior to that of Plavix [PLADP (5th day): 30% (22%, 43%) vs. 33% (22%, 44%), p = 0.007; PLADP (1 month): 29% (19%, 43%) vs. 31% (22%, 43%), p = 0.005]. A total of 208 patients completed the follow-up, the incidences of MACE and bleeding were both comparable, and the MACE-free survival did not differ between the two groups. However, the expenditure was 32% lower for Talcom compared to Plavix during the treatment period. CONCLUSIONS: The antiplatelet effect of Talcom is non-inferior to Plavix, and the clinical efficacy and safety of Talcom and Plavix at 5 years were not significantly different in this study.

Behavioural, physiological and psychological responses of passengers to the thermal environment of boarding a flight in winter.

In practice, passengers actively respond to the thermal environment when they board an aircraft in winter, which is not considered in the current standards. In this study, the behavioural, physiological and psychological responses to the thermal environment were examined at 22 °C (with 68 subjects), 20 °C and 26 °C (with 32 subjects). The results showed that the three air temperature levels had significant effect on nozzle usage and clothing adjustment behaviours, surface skin temperature, and thermal sensation vote (TSV). The walking/waiting states prior to boarding the aircraft cabin had a significant effect on the proportion of jacket removal, TSV and thermal comfort vote. After 10 min in the aircraft cabin, the subjects maintained their comfort in a wider range of the thermal environment when the behavioural adjustments existed compared to when they did not. Thus, a suggestion was made for behavioural adjustments to be provided in aircraft cabins. Practitioner Summary: Experimental investigation of human responses was conducted in an aircraft cabin. Analysis showed that the subjects maintained their comfort in a wider range of the thermal environment when the behavioural adjustments existed compared to when they did not. Thus, a suggestion was made for behavioural adjustments to be provided in aircraft cabins.

Efficacy and safety of cilostazol based triple antiplatelet treatment versus dual antiplatelet treatment in patients undergoing coronary stent implantation: an updated meta-analysis of the randomized controlled trials.

The aim of this study was to obtain best estimates of the efficacy and safety of cilostazol-based triple antiplatelet therapy (TAPT: aspirin, clopidogrel and cilostazol) compared with dual antiplatelet therapy (DAPT: aspirin and clopidogrel) in patients undergoing coronary stent implantation. We searched the literature to identify all randomized clinical trials examining efficacy and safety of TAPT versus DAPT in patients undergoing coronary stent implantation. Major efficacy outcomes were death, non-fatal myocardial infarction (MI), ischemic stroke and stent thrombosis (ST) and the safety outcome was bleeding. Data were analyzed using the Review Manager 5.0.0 software. A total of 19 trials involving 7,464 patients were included. TAPT and DAPT were associated with similar rates of death, non-fatal MI, ischemic stroke and ST, but compared with DAPT, TAPT had lower rates of target lesion revascularization (TLR) (RR 0.67, 95 % CI 0.56-0.82, P < 0.0001) and target vessel revascularization (TVR) (RR 0.65, 95 % CI 0.55-0.77, P < 0.00001), as well as less late loss of minimal lumen diameter (mean difference -0.14, 95 % CI -0.17--0.11, P < 0.00001), and less binary angiographic restenosis (RR 0.54, 95 % CI 0.45-0.65, P < 0.00001). TAPT and DAPT had similar rates of bleeding, but TAPT had significantly higher rates of headache, palpitation, rash and gastrointestinal side-effects. Cilostazol-based TAPT compared with DAPT is associated with improved angiographic outcomes and decreased risk of TLR and TVR but does not reduce major cardiovascular events and is associated with an increase in minor adverse events.

Exploring the importance of m5c in the diagnosis and subtype classification of COPD using the GEO database.

BACKGROUND: 5-Methylcytosine (m5C) is an mRNA modifier that is associated with the occurrence and development of viral infection, pulmonary fibrosis, lung cancer, and other diseases. However, the role of m5C regulators in chronic obstructive pulmonary disease (COPD) remains unknown. METHODS: In this study, by analysing the GSE42057 dataset, the differential expression of m5c regulators in the COPD group and control group was obtained, and a correlation analysis was conducted. The random forest model and support vector machine model were used to predict the occurrence of COPD. A nomogram model was also constructed to predict the prevalence of COPD. The COPD patients were divided into subtypes by consistent cluster analysis based on m5c methylation regulators. Immune cell infiltration was performed on the m5c methylation subtypes. Differentially expressed genes (DEGs) between m5c methylation subtypes were screened, and the DEGs were analysed by Gene Ontology (GO) Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, we verified the expression of several m5C regulators and related pathways using a COPD cell model. RESULTS: Seven m5c methylation regulators were differentially expressed. The random forest model based on the above genes was the most accurate for predicting the occurrence of COPD. A nomogram model based on the above genes could also accurately predict the prevalence of COPD, and the implementation of these models could benefit COPD patients. The consistent cluster analysis divided the COPD patients into two subtypes (Cluster A and Cluster B). The main component analysis algorithm determined the m5c methylation subtypes and found that patients in Cluster A had a higher m5c score than those in Cluster B. GO analysis of the DEGs between the m5c methylation COPD patient subtypes revealed that DEGS were mainly enriched in leukocyte-mediated immunity and regulation of T-cell activation. KEGG analysis revealed that DEGS were mainly enriched in Th1 and Th2 cell differentiation, neutrophil extracellular trap formation, and the NF-κB signalling pathway. Immunocyte correlation analysis revealed that Cluster B was associated with neutrophil- and macrophage-mediated immunity, while Cluster A was associated with CD4 + T-cell- and CD8 + T-cell-mediated immunity. Cell experiments have also verified some of the above research results. CONCLUSION: The diagnosis and subtype classification of COPD patients based on m5c regulators may provide a new strategy for the diagnosis and treatment of COPD.

Discovery of Novel Macrocyclic MERTK/AXL Dual Inhibitors.

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar activity against both MERTK and AXL and good selectivity over TYRO3 and FLT3. Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.

[Initial experience of percutaneous coronary intervention guided by computed tomography coronary angiography derived roadmap and magnetic navigation system].

OBJECTIVE: To evaluate the feasibility, efficacy and safety of the percutaneous coronary intervention (PCI)guided by computed tomography (CT) coronary angiography derived roadmap and magnetic navigation system (MNS). METHODS: During June 2011 and May 2012, thirty consecutive patients receiving elective PCI were enrolled, coronary artery disease was primarily diagnosed by dual-source CT coronary angiography (DSCT-CA) at outpatient clinic and successively proved by coronary artery angiography in the hospital. Target vessels from pre-procedure DSCT-CA were transferred to the magnetic navigation system, and consequently edited, reconstructed, and projected onto the live fluoroscopic screen as roadmap. Parameters including characters of the target lesions, time, contrast volume, radiation dosage for guidewire crossing, and complications of the procedure were recorded. RESULTS: Thirty patients with 36 lesions were recruited and intervened by PCI. Among the target lesions, sixteen were classified as type A, 11 as type B1, 8 as type B2, 1 as type C. The average length of the target lesions was (22.0 ± 9.8) mm, and the average stenosis of the target lesions was (81.3 ± 10.3)%. Under the guidance of CT roadmap and MNS, 36 target lesions were crossed by the magnetic guidewires, with a lesion crossing ratio of 100%. The time of placement of the magnetic guidewires was 92.5 (56.6 - 131.3) seconds. The contrast volume and the radiation dosage for guidewire placement were 0.0 (0.0 - 3.0) ml and 235.0 (123.5 - 395.1) µGym(2)/36.5 (21.3 - 67.8) mGy, respectively. Guidewires were successfully placed in 21 (58.3%) lesions without contrast agent. All enrolled vessels were successfully treated, and there were no MNS associated complications. CONCLUSIONS: It is feasible, effective and safe to initiate PCI under the guidance of CT derived roadmap and MNS. This method might be helpful for the guidewire placement in the treatment of total occlusions.

Testing and Analysis Method of Low Remanence Materials for Magnetic Shielding Device.

Magnetic shielding devices with a grid structure of multiple layers of highly magnetically permeable materials (such as permalloy) can achieve remanent magnetic fields at the nanotesla (nT) level or even lower. The remanence of the material inside the magnetic shield, such as the building materials used in the support structure, can cause serious damage to the internal remanence of the magnetic shield. Therefore, it is of great significance to detect the remanence of the materials used inside the magnetic shielding device. The existing test methods do not limit the test environment, the test process is vulnerable to additional magnetic field interference and did not consider the real results of the material in the weak magnetic environment. In this paper, a novel method of measuring the remanence of materials in a magnetic shielding cylinder is proposed, which prevents the interference of the earth's magnetic field and reduces the measurement error. This method is used to test concrete components, composite materials and metal materials commonly applicated in magnetic shielding devices and determine the materials that can be used for magnetic shielding devices with 1 nT, 10 nT and 100 nT as residual magnetic field targets.

Effects of Three-Dimensional Graphene-Carbon Nanotube Hybrid on the Mechanical Properties and Microstructure of Cement Paste.

This work experimentally studies the mechanical properties and microstructure of cementitious composites reinforced with a three-dimensional graphene-carbon nanotube (CNT) hybrid. Firstly, the graphene-CNT (GC) hybrid is dispersed in cement pastes using ultrasonication and surfactant, and then, the effect of the GC hybrid on the early hydration of the cement pastes is investigated. The experimental results show that adding the GC hybrid shortens the setting stage of cement hydration and accelerates the early hydration process. Moreover, the macro- and micro-mechanical properties of each group are evaluated. The 7- and 28-day strength of the cement pastes improves with addition of the GC hybrid. Finally, the microstructural analysis demonstrates that the GC hybrid is reasonably well distributed in cement and forms a spatial network, which could bridge the cracks and compact the cementitious matrix.

The Influence of Fly Ash on the Tensile Creep Prediction of High-Strength Concrete at Early Ages.

In this study, the tensile creep (TC) of high-strength concrete (HSC) containing 30 wt% fly ash was measured at early ages to investigate the applicability of creep prediction models for concrete containing FA, and to provide ideas to study the prediction model of concrete creep containing other SCMs in the future. The TC values obtained from the experiment were compared with the predicted values of six TC models. Then the accuracy of different models was evaluated by the ratio of predicted values to experimental values. Finally, the applicability of these models to the TC of HSC with fly ash was discussed at an early age. By comparison, it was found that when the loading age was 1d, 2d, and 3d, the ZC model (ZC are the initials for the word "Self-developed" in Chinese), which is a rheology-based model for TC, proposed by Yang.Y et al. agreed with the experimental values. The predicted values of the other five models deviated significantly from the tested ones. When the loading age was 5d and 7d, the calculated results of the ACI 2009R model were more accurate. Compared with the other five models, the time dependency of the paste with fly ash was considered in the ZC model, and parameter q of the ZC model was introduced in order to characterize the influence of fly ash on the paste at early ages. Therefore, this paper demonstrated both theoretically and experimentally that the ZC model can better predict the early-age TC of HSC with fly ash.

AtomNet-Aided OTUD7B Inhibitor Discovery and Validation.

Protein deubiquitinases play critical pathophysiological roles in cancer. Among all deubiquitinases, an oncogenic function for OTUD7B has been established in genetic NSCLC murine models. However, few deubiquitinase inhibitors have been developed due to technical challenges. Here, we report a putative small molecule OTUD7B inhibitor obtained from an AI-aided screen of a 4 million compound library. We validated the effects of the OTUD7B inhibitor (7Bi) in reducing Akt-pS473 signals in multiple NSCLC and HEK293 cells by blocking OTUD7B-governed GßL deubiquitination in cells, as well as inhibiting OTUD7B-mediated cleavage of K11-linked di-ub in an in vitro enzyme assay. Furthermore, we report in leukemia cells, either genetic depletion or 7Bi-mediated pharmacological inhibition of OTUD7B reduces Akt-pS473 via inhibiting the OTUD7B/GßL signaling axis. Together, our study identifies the first putative OTUD7B inhibitor showing activities both in cells and in vitro, with promising applications as a therapeutic agent in treating cancer with OTUD7B overexpression.

Overexpression of circFNDC3B promotes the progression of oral tongue squamous cell carcinoma through the miR-1322/MED1 axis.

BACKGROUND: The potential role of circFNDC3B in regulating oral tongue squamous cell carcinoma development (OTSCC) remains unknown. METHODS: The level of circFNDC3B in OTSCC tissues or cell lines was measured and its function in vitro and in vivo was analyzed. Interactions among circFNDC3B, miR-1322, and MED1 were verified by luciferase reporter and RNA pull-down assays. RESULTS: The level of circFNDC3B in tissues or cell lines of OTSCC was higher than that in control groups. siRNA-mediated circFNDC3B inhibition resulted in weakened proliferation, migration, and invasion, which was reversed by miR-1322. Overexpression of MED1 in OTSCC cells partially reversed the tumor suppression functions of si-circFNDC3B or miR-1322 mimics in vitro. circFNDC3B overexpression dramatically promoted tumor growth in vivo. circFNDC3B directly bound with miR-1322 and consequently promoted the MED1 expression in OTSCC cells. CONCLUSIONS: The circFNDC3B/miR-1322/MED1 axis participates in OTSCC progression, which may provide novel therapeutic targets for OTSCC.

Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability.

Endocrine therapies in the treatment of early and metastatic estrogen receptor α positive (ERα+) breast cancer (BC) are greatly limited by de novo and acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization of LSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led us to identify compound 40 as the preferred candidate. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.

Development of a light-initiated chemiluminescence assay for the quantitative detection of cow's milk allergen-specific IgE.

BACKGROUND: Cow's milk allergy is a common food allergy in children. Clinically, cow's milk-specific IgE (CM-sIgE) antibody test is often used to diagnose milk allergy. An inexpensive light-initiated chemiluminescence assay (LICA), with fast detection speed and small sample volume demand, has application prospects in the field of quantitative detection of CM-sIgE. METHODS: Chemibeads coated with five major milk allergens, serum samples, biotinylated anti-human IgE antibodies, and streptavidin-coated sensibeads constitute a system to establish a LICA method for the quantitative detection of CM-sIgE. A series of experiments were performed to optimize its reaction conditions and evaluated its performance. RESULTS: The optimal conditions for LICA were 10:4 mass ratio of chemibeads to milk allergen, 20 µg/mL chemibeads, 1.0 µg/mL biotinylated anti-human IgE antibodies and a 1/10 dilution of serum for 30-min incubation. The limit of Quantitation (LoQ) was 0.22 kUA/L. For repeatability, the CV ranged from 3.71% to 8.11%. For intermediate precision, the CV ranged from 4.08% to 14.71%. It was linear within 0.20-18.20 kUA/L. This method did not interfere with common interfering substances and total IgE in serum, and there was no obvious cross-reaction with milk-specific IgG and non-milk-specific IgE. CONCLUSION: We have established a method to quantitatively detect CM-sIgE based on light-initiated chemiluminescence assay, which has good analytical performance and could meet the needs of clinical laboratories.

Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity.

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.