Hypocretenolides: collective total syntheses and activities toward metastatic colon cancer.

A concise and collective synthetic route to hypocretenolides was developed for the first time. This route features one-pot addition-alkylation and intramolecular 1,3-dipolar cycloaddition to efficiently assemble the 5/7/6 ring system. Our syntheses enabled multigram preparation of hypocretenolide which facilitated further biological evaluation. Preliminary CCK-8 cytotoxic results of hypocretenolide indicated its IC50 values within 1 µM against 4 colon cancer cell lines. Wound healing and transwell assays suggested the promising inhibitory activities of hypocretenolide toward the migratory capabilities of colon cancer cells in vitro. The animal results confirmed that hypocretenolide can inhibit metastasis of colon cancer cells.

Spontaneous multivessel coronary artery spasm: a case report.

A 60-year-old male presented to the emergency department of our hospital with persistent dull pain in the lower and middle sternum with generalized sweating after a heated argument with another person, and his symptoms did not resolve after 3 hours of onset.

Synthesis of melampomagnolide B derivatives as potential anti-Triple Negative Breast Cancer agents.

Triple-negative breast cancer (TNBC) is the most malignant and aggressive subtype of breast cancer. Currently, the treatment options to TNBC are limited and the discovery of new drugs and novel therapeutic strategies for treatment of TNBC is urgently needed. In this study, a series of melampomagnolide B (MMB) derivatives were designed, synthesized, and evaluated for their anti-TNBC activities. Compound 7 and 13a showed highly potent activity against different TNBC cells with IC50 values ranging from 0.37 µM to 1.52 µM, which demonstrated 3.6- to 54-fold improvement comparing to the parent compound MMB. The phenotypic effect revealed that compound 7 and 13a could inhibit metastasis, induce apoptosis and arrest cell cycle distribution of TNBC cells. Furthermore, the mechanism research indicated compounds 7 and 13a bound IKKß and inhibited the IKKß-mediated phosphorylation of IκB and p65, then inhibited the nuclear translocation of p65 and eventually regulated the genes related to metastasis, apoptosis and cell cycle under NF-κB control. Moreover, compound 7 inhibited the tumor growth in vivo, and the weights of spleens and livers were also reduced compared with control group which indicated that compound 7 could inhibit metastasis of TNBC in vivo. These findings indicate that compound 7 may be used as a promising lead compound for ultimate discovery of anti-TNBC drug.

Quantitative Analysis of Super Resolution in Electromagnetic Inverse Scattering for Microwave Medical Sensing and Imaging.

Microwave medical sensing and imaging (MMSI) has been a research hotspot in the past years. Imaging algorithms based on electromagnetic inverse scattering (EIS) play a key role in MMSI due to the super-resolution phenomenon. EIS problems generally employ far-field scattered data to reconstruct images. However, the far-field data do not include information outside the Ewald's sphere, so theoretically it is impossible to achieve super resolution. The reason for super resolution has not been clarified. The majority of the current research focuses on how nonlinearity affects the super-resolution phenomena in EIS. However, the mechanism of super-resolution in the absence of nonlinearity is routinely ignored. In this research, we address a prevalent yet overlooked problem where the image resolution due to scatterers of extended structures is incorrectly analyzed using the model of point scatterers. Specifically, the classical resolution of EIS is defined by the Rayleigh criterion which is only suitable for point-like scatterers. However, the super-resolution in EIS is often observed for general scatterers like cylinders, squares or Austria shapes. Subsequently, we provide theoretical results for the Born approximation framework in EIS, and employ the Sparrow criteria to quantify the resolution for symmetric objects of extended structures. Furthermore, the modified Sparrow criterion is proposed to calculate the resolution of asymmetric scatterers. Numerical examples show that the proposed approach can better explain the super-resolution phenomenon in EIS.

Dual hypoxia-responsive supramolecular complex for cancer target therapy.

The prognosis with pancreatic cancer is among the poorest of any human cancer. One of the important factors is the tumor hypoxia. Targeting tumor hypoxia is considered a desirable therapeutic option. However, it has not been translated into clinical success in the treatment of pancreatic cancer. With enhanced cytotoxicities against hypoxic pancreatic cancer cells, BE-43547A2 (BE) may serve as a promising template for hypoxia target strategy. Here, based on rational modification, a BE prodrug (NMP-BE) is encapsulated into sulfonated azocalix[5]arene (SAC5A) to generate a supramolecular dual hypoxia-responsive complex NMP-BE@SAC5A. Benefited from the selective load release within cancer cells, NMP-BE@SAC5A markedly suppresses tumor growth at low dose in pancreatic cancer cells xenograft murine model without developing systemic toxicity. This research presents a strategy for the modification of covalent compounds to achieve efficient delivery within tumors, a horizon for the realization of safe and reinforced hypoxia target therapy using a simple approach.

No causal genetic relationships between atrial fibrillation and vascular dementia: A bidirectional Mendelian randomization study.

Background: Numerous observational studies have suggested that atrial fibrillation (AF) was associated with an increased risk of vascular dementia (VaD). However, the causal genetic relationships between AF and VaD remains unclear. To evaluate the effect of AF on VaD, we performed the Mendelian randomization (MR) analysis to investigate the causal genetic relationships between AF and VaD. Methods: The bidirectional MR analysis was conducted to explore the causal relationships between exposure and disease. We applied a series of quality assessments to select significantly and independently single nucleotide polymorphisms (SNPs) from publicly available large-scale genome-wide association studies (GWAS) databases. Three methods [Inverse variance weighted method (IVW), MR-Egger method, and weighted median (WM)method] were used to derive MR estimates. In order to ensure reliable MR results, sensitivity analyses were performed to evaluate the horizontal pleiotropy and heterogeneity. Results: Our MR analyses revealed no significant genetic relationships between AF and the risk of VaD (IVW: OR = 1.10, 95%CI = 0.95-1.28, P = 0.20). In the reverse direction analysis, there was no evidence to support a significant genetic relationship of VaD with AF risk (IVW: OR = 1.00, 95% CI = 0.99-1.01, P = 0.52). Consistent results were obtained using different MR methods. Sensitivity analyses suggested no significant horizontal pleiotropy and heterogeneity in the study. Conclusion: This MR analysis did not provide evidence to support the causal genetic relationships between AF on VaD risk and the causal effect of VaD on AF risk.

Genome-wide exploration of the GDSL-type esterase/lipase gene family in rapeseed reveals several BnGELP proteins active during early seedling development.

The Gly-Asp-Ser-Leu (GDSL)-type esterase/lipase proteins (GELP) are one of the most important families of lipolytic enzymes and play prominent roles in seed germination and early seedling establishment through mobilizing the lipids stored in seeds. However, there are no comprehensive studies systematically investigating the GELP gene family in Brassica napus (BnGELP), and their biological significance to these physiological processes are far from understood. In the present study, a total of 240 BnGELP genes were identified in B. napus cultivar "Zhongshuang 11" (ZS11), which is nearly 2.3-fold more GELP genes than in Arabidopsis thaliana. The BnGELP genes clustered into 5 clades based on phylogenetic analysis. Ten BnGELPs were identified through zymogram analysis of esterase activity followed by mass spectrometry, among which five clustered into the clade 5. Gene and protein architecture, gene expression, and cis-element analyses of BnGELP genes in clade 5 suggested that they may play different roles in different tissues and in response to different abiotic stresses. BnGELP99 and BnGELP159 were slightly induced by cold, which may be attributed to two low-temperature responsive cis-acting regulatory elements present in their promoters. An increased activity of esterase isozymes by cold was also observed, which may reflect other cold inducible esterases/lipases in addition to the ten identified BnGELPs. This study provides a systemic view of the BnGELP gene family and offers a strategy for researchers to identify candidate esterase/lipase genes responsible for lipid mobilization during seed germination and early seedling establishment.

Atrial fibrillation episode status and incidence of coronary slow flow: A propensity score-matched analysis.

Background: Previous studies have shown that patients with a history of atrial fibrillation (AF) have a higher risk of developing coronary slow flow (CSF). However, whether AF episode status affects the incidence of CSF has not been confirmed. This study investigated the correlation between AF episode status and the incidence of CSF. Methods: We enrolled patients with AF who underwent coronary angiography for symptoms of myocardial ischemia between January 1, 2017, and April 30, 2022, at our institution and classified them according to whether they had an episode of AF in the perioperative period. The outcomes were defined the occurrence of CSF overall and in each of the three coronary arteries. The analysis was repeated after adjusting the baseline information by the propensity score matching method in a 1:1 ratio. Results: 214 patients who met the inclusion and exclusion criteria were included in the study (AF episode group: 100 patients, AF non-episode group: 114 patients). Before matching, age, left atrial size, ejection fraction, heart rate, CSF incidence, and mean corrected thrombolysis in myocardial infarction frame counts were higher in patients with intraoperative AF episodes than in patients without episodes. To prevent the dependent variable (CSF incidence) from being confounded by confounding factors, we matched the two groups for age, left atrial size, and ejection fraction. In the logistic regression analysis, the incidence of CSF was significantly higher in the intraoperative AF episode group (P = 0.010, OR = 2.327, 95% CI: 1.226-4.416) than in the non-episode group. Conclusion: In patients with AF, AF episode status is significantly correlated with an increased overall incidence of CSF.

Cytotoxic Terpenes from the Flowers of Inula japonica against Human Hepatocarcinoma Cells.

Two new 1,10-seco-eudesmanolides (1 and 2) were isolated from the flowers of Inula japonica together with two eudesmanolide analogs (3 and 4) and two monoterpene derivatives (5 and 6). Their structures were established on the basis of detailed spectroscopic analyses and electronic circular dichroism data. All isolates were evaluated for their antiproliferative activities against human hepatocarcinoma HepG2 and SMMC-7721 cells. Japonipene B (3) exhibited the most potent effect with the IC50 values of 14.60±1.62 and 22.06±1.34 µM against HepG2 and SMMC-7721 cells, respectively. Furthermore, japonipene B (3) showed significant efficacies of arresting the cell cycle at the S/G2-M stages, inducing mitochondria-mediated apoptosis, and inhibiting cell migration in HepG2 cells.

ACT001 inhibited CD133 transcription by targeting and inducing Olig2 ubiquitination degradation.

Lung cancer is the most lethal malignancies with high aggressive and poor prognosis. Until now, the five-year survival rate has not been improved which brings serious challenge to human health. Lung cancer stem cells (LCSCs) serve as the root of cancer occurrence, progression, recurrence, and drug resistance. Therefore, effective anti-cancer agents and molecular mechanisms which could specifically eliminate LCSCs are urgently needed for drug design. In this article, we discovered Olig2 was overexpressed in clinical lung cancer tissues and acted as a transcription factor to regulate cancer stemness by regulating CD133 gene transcription. The results suggested Olig2 could be a promising target in anti-LCSCs therapy and new drugs targeted Olig2 may exhibit excellent clinical results. Furthermore, we verified ACT001, a guaianolide sesquiterpene lactone in phase II clinical trial with excellent glioma remission, inhibited cancer stemness by directly binding to Olig2 protein, inducing Olig2 ubiquitination degradation and inhibiting CD133 gene transcription. All these results suggested that Olig2 could be an excellent druggable target in anti-LCSCs therapy and lay a foundation for the further application of ACT001 in the treatment of lung cancer in clinical.

Analysis of the Development Status and Prospect of China's Agricultural Sensor Market under Smart Agriculture.

Agricultural sensors are essential technologies for smart agriculture, which can transform non-electrical physical quantities such as environmental factors. The ecological elements inside and outside of plants and animals are converted into electrical signals for control system recognition, providing a basis for decision-making in smart agriculture. With the rapid development of smart agriculture in China, agricultural sensors have ushered in opportunities and challenges. Based on a literature review and data statistics, this paper analyzes the market prospects and market scale of agricultural sensors in China from four perspectives: field farming, facility farming, livestock and poultry farming and aquaculture. The study further predicts the demand for agricultural sensors in 2025 and 2035. The results reveal that China's sensor market has a good development prospect. However, the paper garnered the key challenges of China's agricultural sensor industry, including a weak technical foundation, poor enterprise research capacity, high importation of sensors and a lack of financial support. Given this, the agricultural sensor market should be comprehensively distributed in terms of policy, funding, expertise and innovative technology. In addition, this paper highlighted integrating the future development direction of China's agricultural sensor technology with new technologies and China's agricultural development needs.

A Novel Analysis of Super-Resolution for Born-Iterative-Type Algorithms in Microwave Medical Sensing and Imaging.

Microwave medical sensing and imaging (MMSI) is a highly active research field. In MMSI, electromagnetic inverse scattering (EIS) is a commonly used technique that infers the internal characteristics of the diseased area by measuring the scattered field. It is worth noting that the image formed by EIS often exhibits the super-resolution phenomenon, which has attracted much research interest over the past decade. A classical perspective is that multiple scattering leads to super-resolution, but this is subject to debate. This paper aims to analyze the super-resolution behavior for Born-iterative-type algorithms for the following three aspects. Firstly, the resolution defined by the traditional Rayleigh criterion can only be applied to point scatterers. It does not suit general scatterers. By using the Sparrow criterion and the generalized spread function, the super-resolution condition can be derived for general scatterers even under the Born approximation (BA) condition. Secondly, an iterative algorithm results in larger coefficients in the high-frequency regime of the optical transfer function compared to non-iterative BA. Due to the anti-apodization effect, the spread function of the iterative method becomes steeper, which leads to a better resolution following the definition of the Sparrow criterion mentioned above. Thirdly, the solution from the previous iteration, as the prior knowledge for the next iteration, will cause changes in the total field, which provides additional information outside the Ewald sphere and thereby gives rise to super-resolution. Comprehensive numerical examples are used to verify these viewpoints.

Influence of Stent Length on Periprocedural Outcomes After Primary Percutaneous Coronary Intervention in Patients with ST Segment Elevation Myocardial Infarction.

Purpose: A longer stent is associated with adverse events after percutaneous coronary intervention (PCI). However, little information is available on the relationship between stent length and periprocedural prognosis in patients with ST segment elevation myocardial infarction (STEMI). We aimed to assess the target vessel stent length influence on angiographic outcomes and in-hospital major adverse cardiovascular event (MACE) during primary PCI in patients with STEMI. Patients and Methods: This single-center retrospective observational study included 246 patients with STEMI admitted to the Zhejiang Provincial People's Hospital between January 2019 and December 2021, who underwent primary PCI and successful stent implantation. The exclusion criteria included left main lesion, multiple diseased vessel-stenting, bleeding disorders, contrast allergy, and incomplete data. Patients were divided into two groups based on the median stents length: group A (≤29 mm, n=125) and group B (>29mm, n=121). Periprocedural outcomes were slow flow/no-reflow (SF-NR) and in-hospital MACE, which included acute heart failure, malignant arrhythmia, cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, and urgent revascularization. Multivariate logistic analyses were used to explore the correlation between stent length and SF-NR. Results: A total of 246 patients (82.9% males) with a mean age of 59.9±12.6 years were included in the analysis. The incidence of SF-NR was significantly higher in group B than in group A (36.4% vs 23.2%, p=0.024). However, the in-hospital MACE incidence rate was similar between the two groups (7.2% vs 7.4%, p=0.943). Multivariate logistic regression analysis showed that stent length and diameter, and peak troponin I level were independent risk factors for SF-NR. Conclusion: Excessive stent length is an independent risk factor for SF-NR, without any significant influence on the risk of MACE during hospitalization.

Apatite nanosheets inhibit initial smooth muscle cell proliferation by damaging cell membrane.

Understanding how nanostructured coatings interact with cells is related to how they manipulate cell behaviors and is therefore critical for designing better biomaterials. The apatite nanosheets were deposited on metallic substrates via biomimetic precipitation. Cell viability of apatite nanosheets towards to smooth muscle cells (SMCs) were investigated, and the underlying mechanism was proposed. Apatite nanosheets presented inhibitory activity on SMC growth, and caused rupture of cell membranes. On the basis of measuring changes in intracellular calcium ([Ca2+]i), observing cell contraction and apatite nanosheets - SMC interaction, it was found that calcium ions released from apatite led to rises in [Ca2+]i, which induced vigorous SMC contraction on apatite nanosheets. Consequently, the cell membrane of individual SMCs was cut/penetrated by the sharp edges of apatite nanosheets, resulting in cell inactivation. This damage of cell membranes suggests a novel mechanism to manipulate cell viability, and may offer insights for the better design of calcium-based nanostructured coatings or other biomedical applications.

Probe Synthesis Reveals Eukaryotic Translation Elongation Factor†1 Alpha†1 as the Anti-Pancreatic Cancer Target of BE-43547A2.

The natural product, BE-43547A2 , decreases pancreatic cancer cell stemness. However, its anticancer molecular mechanisms have not been fully established. Based on structure-activity relationships of BE-43547A2 , we synthesized a probe and investigated its potential targets using an in situ click reaction. We found that BE-43547A2 exerts its anticancer effects by covalently binding the cysteine234 (C234) residue of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1). This binding mode was confirmed by a series of experiments including a xenograft mouse model. We also determined that eEF1A1 plays an important role in regulating pancreatic cancer cell stemness. Analyses of 99 clinical pancreatic cancer samples revealed that eEF1A1 expressions are closely correlated with clinicopathological grade and patient survival. In conclusion, eEF1A1 is involved in pancreatic cancer progression and is therefore, a promising novel covalent target for pancreatic cancer treatment.

Total synthesis and stereochemical assignment of rakicidin F.

Total synthesis of rakicidin F was accomplished in 20 linear steps (0.68% overall yield), which enabled the configural determination of its six stereogenic centers as 2R, 15R, 16R, 17S, 19S, and 21S. The macrolactonization of the rakicidin linear precursor was investigated and the unsuccessful results might be attributed to the steric hindrance near C16-OH.

Levistilide A Promotes Expansion of Human Umbilical Cord Blood Hematopoietic Stem Cells by Enhancing Antioxidant Activity.

Several approaches to expand human hematopoietic stem cells (hHSCs) clinically along with retainable capability of multipotential differentiation have been reported, but only a few have advanced to evaluation in clinical trials, which limits the application of HSC-based therapy. Here we show a phthalide derivative, Levistilide A (LA), can serve as a promising molecule to expand functional human umbilical cord blood (UCB) HSCs ex vivo. An in-house screen identified LA out of nine natural products as an outstanding candidate for hHSCs expansion. Additionally, our data indicated that LA treatment not only increased the numbers of phenotype-defined HSCs, but also enhanced their colony formation ability. Xenotransplantation assays showed that LA treatment could maintain unaffected engraftment of hHSCs with multilineage differentiation capacity. Further experiments revealed that LA enhanced the antioxidant activity of hHSCs by reducing intracellular and mitochondrial reactive oxygen species (ROS) levels. The identification of LA provides a new strategy in solving the clinical issue of limited numbers of UCB HSCs.

A Two-Phase Approach to Fusicoccane Synthesis To Uncover a Compound That Reduces Tumourigenesis in Pancreatic Cancer Cells.

Alterbrassicicene D (1) and 3(11)-epoxyhypoestenone (2) were synthesised via a two-phase approach featuring concise construction of the 5-8-5 tricyclic intermediate and a tandem base-mediated epoxide opening-transannular oxa-Michael addition cascade to forge the complex skeleton of 2. The route is scalable and we generated 15 g of the tricyclic intermediate in 8 steps from (R)-limonene and 720 mg of the penultimate bioactive intermediate in a protecting-group-free manner. Our synthesis enabled the structural determination of 2 and provided materials for preliminary anticancer evaluation. The penultimate intermediate showed therapeutic potential in terms of its ability to dramatically reduce the tumourigenic potential of PANC-1 pancreatic cancer cells according to a limiting dilution tumour-initiating assay. Our synthetic approach will facilitate unified access to naturally occurring fusicoccanes and their derivatives for anticancer evaluation.