Cooperative Rh/Achiral Phosphoric Acid-Enabled [3+3] Cycloannulation of Carbonyl Ylides with Quinone Monoimines: Synthesis of Benzofused Dioxabicyclo[3.2.1]octane Scaffolds.

A cooperative Rh/achiral phosphoric acid-enabled [3+3] cycloaddition of in situ-generated carbonyl ylides with quinone monoimines has been developed. With the ability to build up the molecular complexity rapidly and efficiently, this method furnishes highly functionalized oxa-bridged benzofused dioxabicyclo[3.2.1]octane scaffolds bearing two quaternary centers in good to excellent yields under mild conditions. Moreover, the utility of the current method was demonstrated by gram-scale synthesis and elaboration of the products into various functionalized oxa-bridged heterocycles.

Mechanisms by which silencing long-stranded noncoding RNA KCNQ1OT1 alleviates myocardial ischemia/reperfusion injury (MI/RI)-induced cardiac injury via miR-377-3p/HMOX1.

BACKGROUND: The key complication of myocardial infarction therapy is myocardial ischemia/reperfusion injury (MI/RI), and there is no effective treatment. The present study elucidates the mechanism of action of lncRNA KCNQ1OT1 in alleviating MI/RI and provides new perspectives and therapeutic targets for cardiac injury-related diseases. METHODS: An ischemia/reperfusion (I/R) injury model of human adult cardiac myocytes (HACMs) was constructed, and the expression of KCNQ1OT1 and miR-377-3p was determined by RT‒qPCR. The levels of related proteins were detected by western blot analysis. Cell proliferation was detected by a CCK-8 assay, and cell apoptosis and ROS content were determined by flow cytometry. SOD and MDA expression as well as Fe2+ changes were detected by related analysis kits. The target binding relationships between lncRNA KCNQ1OT1 and miR-377-3p as well as between miR-377-3p and heme oxygenase 1 (HMOX1) were verified by a dual-luciferase reporter gene assay. RESULTS: Myocardial ischemia‒reperfusion caused oxidative stress in HACMs, resulting in elevated ROS levels, increased Fe2+ levels, decreased cell viability, and increased LDH release (a marker of myocardial injury), and apoptosis. KCNQ1OT1 and HMOX1 were upregulated in I/R-induced myocardial injury, but the level of miR-377-3p was decreased. A dual-luciferase reporter gene assay indicated that lncRNA KCNQ1OT1 targets miR-377-3p and that miR-377-3p targets HMOX1. Inhibition of HMOX1 alleviated miR-377-3p downregulation-induced myocardial injury. Furthermore, lncRNA KCNQ1OT1 promoted the level of HMOX1 by binding to miR-377-3p and aggravated myocardial injury. CONCLUSION: LncRNA KCNQ1OT1 aggravates ischemia‒reperfusion-induced cardiac injury via miR-377-3P/HMOX1.

Efficient assembly and anti-tumor evaluation of novel polycyclic [1,2-a]-fused indoles.

Structurally diverse cyclopenta[4,5]pyrrolo[1,2-a]indoles heterocycles were smoothly constructed in good to excellent yields (up to 99 %) with excellent diastereoselectivities (>19:1 dr) through a novel and facile strategy based on BF3-catalyzed Friedel-Crafts alkylation/Aldol/Dehydrative cyclization cascade reaction. The anti-proliferative activity of these newly synthesized polycyclic indoles was screened, and all the functionalized reductive derivatives exhibited favorable anti-tumor activity. Notably, compound 4ae displayed the remarkable inhibitory activity against MCF-7 and HeLa cells with IC50 values of 4.62 µM and 7.71 µM, respectively. Mechanistically, the representative compound 4ae could effectively induce apoptosis of MCF-7 cells in crediting to up-regulate the relative expression of apoptotic protein BAX/Bcl-2, subsequently activate Pro-caspase 9 and cleave PARP, simultaneously block the cell cycle through down- and up-regulate the expression of cyclin B1 and p53, respectively. Moreover, compound 4ae also exhibited promising antineoplastic efficacy in subcutaneous MCF-7 xenograft mice which manifest significant shrunken tumors conspicuous nuclear apoptotic signal and minimal systemic toxicity. This strategy not only established a novel and efficient method for the assembly of structurally complex indole heterocycles, but also provided a series of compounds possessing attractive anti-cancer activity, which holds immense potential for future biomedical applications.

Measurements of the gravitational constant using two independent methods.

The Newtonian gravitational constant, G, is one of the most fundamental constants of nature, but we still do not have an accurate value for it. Despite two centuries of experimental effort, the value of G remains the least precisely known of the fundamental constants. A discrepancy of up to 0.05 per cent in recent determinations of G suggests that there may be undiscovered systematic errors in the various existing methods. One way to resolve this issue is to measure G using a number of methods that are unlikely to involve the same systematic effects. Here we report two independent determinations of G using torsion pendulum experiments with the time-of-swing method and the angular-acceleration-feedback method. We obtain G values of 6.674184 × 10-11 and 6.674484 × 10-11 cubic metres per kilogram per second squared, with relative standard uncertainties of 11.64 and 11.61 parts per million, respectively. These values have the smallest uncertainties reported until now, and both agree with the latest recommended value within two standard deviations.

Prevalence of asthma and allergic rhinitis in children exposed to pets: a meta-analysis.

PURPOSE: Pet exposure has always been controversial with childhood asthma and allergic rhinitis. We aimed to understand the prevalence of asthma and allergic rhinitis in children exposed to pets by meta-analysis. METHODS: We searched articles published from Jan 1, 2012 to Dec 31, 2022 in the Embase, PubMed, Cochrane Library, and Web of Science databases. We included a cross-sectional study that reported the prevalence of asthma and allergic rhinitis in children exposed to pets. Furthermore, we performed subgroup analyses according to pet type and age. RESULTS: In 14 selected studies, the meta-analysis results showed that the pooled prevalence of asthma in children exposed to pets was 19.0% (95% CI 13.3-24.7%), and the pooled prevalence of allergic rhinitis in children exposed to pets was 25.5% (95% CI 12.4-38.5%). The prevalence of asthma in children exposed to cats and dogs was 16.4% (95% CI 9.9-22.8%) and 12.5% (95% CI 8.7-16.2%), respectively. The prevalence of allergic rhinitis was 24.9% (95% CI 2.9-47.0%) and 24.1% (95% CI 2.6-45.6%), respectively. The prevalence of asthma in pet-exposed children was 17.1% (95% CI 12.3-22.0%) in the adolescence group (> 10 years) and 26.3% (95% CI 12.2-40.3%) in the childhood group (0-10 years). The prevalence of allergic rhinitis was 8.6% (95% CI 7.2-10.0%) in the adolescence group and 46.3% (95% CI 44.0-48.6%) in the childhood age group. CONCLUSIONS: The prevalence of asthma and allergic rhinitis in children exposed to pets is different. Exposure to pet cats is more prone to illness, and younger children are more susceptible to disease than older children.

Joint-GWAS, Linkage Mapping, and Transcriptome Analysis to Reveal the Genetic Basis of Plant Architecture-Related Traits in Maize.

Plant architecture is one of the key factors affecting maize yield formation and can be divided into secondary traits, such as plant height (PH), ear height (EH), and leaf number (LN). It is a viable approach for exploiting genetic resources to improve plant density. In this study, one natural panel of 226 inbred lines and 150 family lines derived from the offspring of T32 crossed with Qi319 were genotyped by using the MaizeSNP50 chip and the genotyping by sequence (GBS) method and phenotyped under three different environments. Based on the results, a genome-wide association study (GWAS) and linkage mapping were analyzed by using the MLM and ICIM models, respectively. The results showed that 120 QTNs (quantitative trait nucleotides) and 32 QTL (quantitative trait loci) related to plant architecture were identified, including four QTL and 40 QTNs of PH, eight QTL and 41 QTNs of EH, and 20 QTL and 39 QTNs of LN. One dominant QTL, qLN7-2, was identified in the Zhangye environment. Six QTNs were commonly identified to be related to PH, EH, and LN in different environments. The candidate gene analysis revealed that Zm00001d021574 was involved in regulating plant architecture traits through the autophagy pathway, and Zm00001d044730 was predicted to interact with the male sterility-related gene ms26. These results provide abundant genetic resources for improving maize plant architecture traits by using approaches to biological breeding.

CERS4 predicts positive anti-PD-1 response and promotes immunomodulation through Rhob-mediated suppression of CD8+Tim3+ exhausted T cells in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the main malignant tumors with high mortality and short survival time. Immunotherapy has become the standard treatment for advanced NSCLC, but it has the problems of drug resistance and low response rate. Therefore, obtaining effective biomarkers to predict and enhance immune checkpoint inhibitors (ICIs) efficacy in NSCLC is important. Sphingolipid metabolism is recently found to be closely involved in tumor immunotherapy. CERS4, an important sphingolipid metabolizing enzyme, is positively correlated with the efficacy of anti-PD-1 therapy for NSCLC. Upregulation of CERS4 expression could improve the efficacy of anti-PD-1 therapy for NSCLC. High expression of CERS4 could downregulate the expression of Rhob in tumor. Significantly, the ratio of CD4+/CD8+ T cell increased and the ratio of Tim-3+/CD8+ T cell decreased in spleen and peripheral blood cells. When Rhob was knocked out, the efficacy of PD-1 mAb treatment increased, and the frequency of Tim-3+ CD8+ T cell decreased. This finding further confirmed the role of sphingolipid metabolites in regulating the immunotherapeutic function of NSCLC. These metabolites may improve the efficacy of PD-1 mAb in NSCLC by regulating the CERS4/Rhob/Tim-3 axis. Overall, this study provided a potential and effective target for predicting and improving the efficacy of ICIs for NSCLC. It also provided a new perspective for the study on the mechanisms of ICIs resistance for NSCLC.

Integrated IBD Analysis, GWAS Analysis and Transcriptome Analysis to Identify the Candidate Genes for White Spot Disease in Maize.

Foundation parents (FPs) play an irreplaceable role in maize breeding practices. Maize white spot (MWS) is an important disease in Southwest China that always seriously reduces production. However, knowledge about the genetic mechanism of MWS resistance is limited. In this paper, a panel of 143 elite lines were collected and genotyped by using the MaizeSNP50 chip with approximately 60,000 single nucleotide polymorphisms (SNPs) and evaluated for resistance to MWS among 3 environments, and a genome-wide association study (GWAS) and transcriptome analysis were integrated to reveal the function of the identity-by-descent (IBD) segments for MWS. The results showed that (1) 225 IBD segments were identified only in the FP QB512, 192 were found only in the FP QR273 and 197 were found only in the FP HCL645. (2) The GWAS results showed that 15 common quantitative trait nucleotides (QTNs) were associated with MWS. Interestingly, SYN10137 and PZA00131.14 were in the IBD segments of QB512, and the SYN10137-PZA00131.14 region existed in more than 58% of QR273's descendants. (3) By integrating the GWAS and transcriptome analysis, Zm00001d031875 was found to located in the region of SYN10137-PZA00131.14. These results provide some new insights for the detection of MWS's genetic variation mechanisms.

2.4 ng/√Hz low-noise fiber-optic MEMS seismic accelerometer.

This paper introduces a fiber-optic microelectromechanical system (MEMS) seismic-grade accelerometer that is fabricated by bulk silicon processing using photoresist/silicon dioxide composite masking technology. The proposed sensor is a silicon flexure accelerometer whose displacement transduction system employs a light intensity detection method based on Fabry-Perot interference (FPI). The FPI cavity is formed between the end surface of the cleaved optical fiber and the gold-surfaced sidewall of the proof mass. The proposed MEMS accelerometer is fabricated by one-step silicon deep reactive ion etching with different depths using the composite mask, among which photoresist is used as the etching-defining mask for patterning the etching area while silicon dioxide is used as the depth-defining mask. Noise evaluation experiment results reveal that the overall noise floor of the fiber-optic MEMS accelerometer is 2.4 ng/H z at 10 Hz with a sensitivity of 3165 V/g, which is lower than that of most reported micromachined optical accelerometers, and the displacement noise floor of the optical displacement transduction system is 208 fm/H z at 10 Hz. Therefore, the proposed MEMS accelerometer is promising for use in high-performance seismic exploration applications.

Polyp detection and false-positive rates by computer-aided analysis of withdrawal-phase videos of colonoscopy of the right-sided colon segment in a randomized controlled trial comparing water exchange and air insufflation.

BACKGROUND AND AIMS: Water exchange (WE) improves lesion detection but misses polyps because of human limitations. Computer-aided detection (CADe) identifies additional polyps overlooked by the colonoscopist. Additional polyp detection rate (APDR) is the proportion of patients with at least 1 additional polyp detected by CADe. The number of false positives (because of feces and air bubble) per colonoscopy (FPPC) is a major CADe limitation, which might be reduced by salvage cleaning with WE. We compared the APDR and FPPC by CADe between videos of WE and air insufflation in the right-sided colon. METHODS: CADe used a convolutional neural network with transfer learning. We edited and coded withdrawal-phase videos in a randomized controlled trial that compared right-sided colon findings between air insufflation and WE. Two experienced blinded endoscopists analyzed the CADe-overlaid videos and identified additional polyps by consensus. An artifact triggered by CADe but not considered a polyp by the reviewers was defined as a false positive. The primary outcome was APDR. RESULTS: Two hundred forty-five coded videos of colonoscopies inserted with WE (n = 123) and air insufflation (n = 122) methods were analyzed. The APDR in the WE group was significantly higher (37 [30.1%] vs 15 [12.3%], P = .001). The mean [standard deviation] FPPC related to feces (1.78 [1.67] vs 2.09 [2.09], P = .007) and bubbles (.53 [.89] vs 1.25 [2.45], P = .001) in the WE group were significantly lower. CONCLUSIONS: CADe showed significantly higher APDR and lower number of FPPC related to feces and bubbles in the WE group. The results support the hypothesis that the strengths of CADe and WE complement the weaknesses of each other in optimizing polyp detection.

Andrographolide suppresses non-small-cell lung cancer progression through induction of autophagy and antitumor immune response.

Despite recent advances in diagnosis and therapeutic strategies, treatment of non-small-cell lung cancer (NSCLC) remains unsatisfactory in terms of prognosis. Andrographolide (AD), a principal active component of Andrographis paniculata (Burm.f.) Nees, exerts anti-cancer therapeutic properties. AD has been used for centuries in China for clinical treatment of viral infections. However, the pharmacological biology of AD in NSCLC remains unknown. In this study, AD regulated autophagy and PD-L1 expression in NSCLC. Molecular dynamics simulations indicated that AD bound directly to signal transducer and activator of transcription-3 (STAT3) with high affinity. Proteomics analysis indicated that AD reduced the expression of tumour PD-L1 in NSCLC by suppressing JAK2/STAT3 signalling. AD modulated the P62-dependent selective autophagic degradation of PD-L1 by inhibiting STAT3 phosphorylation. In vivo study revealed that AD suppressed tumour growth in H1975 xenograft mice and Lewis lung carcinoma cell models, and better efficacy was obtained at higher concentrations. AD prolonged the survival time of the mice and enhanced the treatment efficacy of anti-PD-1 mAb immunotherapy by stimulating CD8+ T cell infiltration and function. This work elucidated the specific mechanism by which AD inhibited NSCLC. Treatment with the combination of AD and anti-PD-1 mAb immunotherapy could be a potential strategy for patients with NSCLC.

Substrate-Switched Chemodivergent Pyrazole and Pyrazoline Synthesis: [3 + 2] Cycloaddition/Ring-Opening Rearrangement Reaction of Azadienes with Nitrile Imines.

By virtue of a fundamentally new reaction model of benzofuran-derived azadienes (BDAs), an unprecedented synthesis of biologically important pyrazoles has been achieved through a tandem [3 + 2] cycloaddition/ring-opening rearrangement reaction of BDAs with nitrile imines. The nature and type of substrates are found to act as a chemical switch to trigger two distinct reaction pathways. A minor modification to the substrates allows the access to spiro-pyrazolines.

Metabolomics and integrated network pharmacology analysis reveal Tricin as the active anti-cancer component of Weijing decoction by suppression of PRKCA and sphingolipid signaling.

Currently, conventional methods of treating non-small cell lung cancer (NSCLC) have many disadvantages. An alternative effective therapy with minimal adverse reactions is urgently needed. Weijing decoction (WJD), which is a classic ancient Chinese herbal prescription, has been used successfully to treat pulmonary system diseases containing lung cancer in the clinic. However, the key active component and target of Weijing decoction are still unexplored. Therefore, for the first time, our study aims to investigate the pharmacological treatment mechanism of Weijing decoction in treating NSCLC via an integrated model of network pharmacology, metabolomics and biological methods. Network pharmacology results conjectured that Tricin is a main bioactive component in this formula which targets PRKCA to suppress cancer cell growth. Metabolomics analysis demonstrated that sphingosine-1-phosphate, which is regulated by sphingosine kinase 1 and sphingosine kinase 2, is a differential metabolite in plasma between the WJD-treated group and the control group, participating in the sphingolipid signaling. In vitro experiments demonstrated that Tricin had vital effects on the proliferation, pro-apoptosis, migration and colony formation of Lewis lung carcinoma cells. Through a series of validation assays, Tricin inhibited the tumor growth mainly by suppressing PRKCA/SPHK/S1P signaling and antiapoptotic signaling. On the other hand, Weijing formula could inhibit the tumor growth and prolong the survival time. A high dosage of Tricin was much more potent in animal experiments. In conclusion, we confirmed that Weijing formula and its primary active compound Tricin are promising alternative treatments for NSCLC patients.

[3 + 2] Cycloaddition of Nitrile Imines with Enamides: An Approach to Functionalized Pyrazolines and Pyrazoles.

An efficient [3 + 2] cycloaddition of in situ generated nitrile imines with enamides has been established. A wide range of functionalized pyrazoline derivatives (53 examples) were obtained in moderate to good yields (up to 96%) under very mild conditions. This protocol features broad substrate scope, good functional group tolerance, and operational simplicity. Practical transformation of the products into useful pyrazoles via a one-pot process and the scalability of this protocol highlight the utility of this synthetic methodology.

Computer-Aided Colon Polyp Detection on High Resolution Colonoscopy Using Transfer Learning Techniques.

Colonoscopies reduce the incidence of colorectal cancer through early recognition and resecting of the colon polyps. However, the colon polyp miss detection rate is as high as 26% in conventional colonoscopy. The search for methods to decrease the polyp miss rate is nowadays a paramount task. A number of algorithms or systems have been developed to enhance polyp detection, but few are suitable for real-time detection or classification due to their limited computational ability. Recent studies indicate that the automated colon polyp detection system is developing at an astonishing speed. Real-time detection with classification is still a yet to be explored field. Newer image pattern recognition algorithms with convolutional neuro-network (CNN) transfer learning has shed light on this topic. We proposed a study using real-time colonoscopies with the CNN transfer learning approach. Several multi-class classifiers were trained and mAP ranged from 38% to 49%. Based on an Inception v2 model, a detector adopting a Faster R-CNN was trained. The mAP of the detector was 77%, which was an improvement of 35% compared to the same type of multi-class classifier. Therefore, our results indicated that the polyp detection model could attain a high accuracy, but the polyp type classification still leaves room for improvement.

Improvement for Testing the Gravitational Inverse-Square Law at the Submillimeter Range.

We improve the test of the gravitational inverse-square law at the submillimeter range by suppressing the vibration of the electrostatic shielding membrane to reduce the disturbance coupled from the residual surface potential. The result shows that, at a 95% confidence level, the gravitational inverse-square law holds (|α|≤1) down to a length scale λ=48 µm. This work establishes the strongest bound on the magnitude α of the Yukawa violation in the range of 40-350 µm, and improves the previous bounds by up to a factor of 3 at the length scale λ≈70 µm. Furthermore, the constraints on the power-law potentials are improved by about a factor of 2 for k=4 and 5.

An Integrated Gold-Film Temperature Sensor for In Situ Temperature Measurement of a High-Precision MEMS Accelerometer.

Temperature sensors are one of the most important types of sensors, and are employed in many applications, including consumer electronics, automobiles and environmental monitoring. Due to the need to simultaneously measure temperature and other physical quantities, it is often desirable to integrate temperature sensors with other physical sensors, including accelerometers. In this study, we introduce an integrated gold-film resistor-type temperature sensor for in situ temperature measurement of a high-precision MEMS accelerometer. Gold was chosen as the material of the temperature sensor, for both its great resistance to oxidation and its better compatibility with our in-house capacitive accelerometer micro-fabrication process. The proposed temperature sensor was first calibrated and then evaluated. Experimental results showed the temperature measurement accuracy to be 0.08 °C; the discrepancies among the sensors were within 0.02 °C; the repeatability within seven days was 0.03 °C; the noise floor was 1 mK/√Hz@0.01 Hz and 100 µK/√Hz@0.5 Hz. The integration test with a MEMS accelerometer showed that by subtracting the temperature effect, the bias stability within 46 h for the accelerometer could be improved from 2.15 µg to 640 ng. This demonstrates the capability of measuring temperature in situ with the potential to eliminate the temperature effects of the MEMS accelerometer through system-level compensation.

A Location Privacy Attack Based on the Location Sharing Mechanism with Erroneous Distance in Geosocial Networks.

Geographical social networks (GSN) is an emerging research area. For example, Foursquare, Yelp, and WeChat are all well-known service providers in this field. These applications are also known as location-based services (LBS). Previous studies have suggested that these location-based services may expose user location information. In order to ensure the privacy of the user's location data, the service provider may provide corresponding protection mechanisms for its applications, including spatial cloaking, fuzzy location information, etc., so that the user's real location cannot be easily cracked. It has been shown that if the positioning data provided by the user is not accurate enough, it is still difficult for an attacker to obtain the user's true location. Taking this factor into consideration, our attack method is divided into two stages for the entire attack process: (1) Search stage: cover the area where the targeted user is located with unit discs, and then calculate the minimum dominating set. Use the triangle positioning method to find the minimum precision disc. (2) Inference phase: Considering the existence of errors, an Error-Adjusted Space Partition Attack Algorithm (EASPAA) was proposed during the inference phase. Improved the need for accurate distance information to be able to derive the user's true location. In this study, we focus on the Location Sharing Mechanism with Maximal Coverage Limit to implement the whole attack. Experimental results show that the proposed method still can accurately infer the user's real location even when there is an error in the user's location information.

Access to Imidazolidines via 1,3-Dipolar Cycloadditions of 1,3,5-Triazinanes with Aziridines.

The unprecedented 1,3-dipolar cycloaddition of 1,3,5-triazinanes and aziridines has been described. With readily available starting material, this method offers efficient access to a wide range of functionalized imidazolidine derivatives in moderate to good yields (up to 92%) under mild conditions. Preliminary mechanistic investigations show that the ring opened zwitterionic pathway product dominated over the second-order nucleophilic substitution-like product. This protocol is very promising because the reaction is scalable, and gives versatile transformation of the products into other functionalized imidazolidines.

Test of the Equivalence Principle with Chiral Masses Using a Rotating Torsion Pendulum.

Here we present a new test of the equivalence principle designed to search for the possible violation of gravitational parity using test bodies with different chiralities. The test bodies are a pair of left- and right-handed quartz crystals, whose gravitational acceleration difference is measured by a rotating torsion pendulum. The result shows that the acceleration difference towards Earth Δa_{left-right}=[-1.7±4.1(stat)±4.4(syst)]×10^{-15} m s^{-2} (1-σ statistical uncertainty), correspondingly the Eötvös parameter η=[-1.2±2.8(stat)±3.0(syst)]×10^{-13}. This is the first reported experimental test of the equivalence principle for chiral masses and opens a new way to the search for the possible parity-violating gravitation.