Total Synthesis of (±)-Simonsol C.

Total synthesis of simonsol C has been achieved, focusing on the postdearomatization transformations. Our methodology integrates an efficient combination of dearomatization and Zn/AcOH reduction to introduce an allyl group, followed by oxo-Michael addition, to construct the 6/5/6 benzofuran skeleton. It offers a novel method for synthesizing allyl-containing quaternary carbon atoms in a straightforward manner.

Aza-Prilezhaev Aziridination-Enabled Multidimensional Analysis of Isomeric Lipids via High-Resolution U-Shaped Mobility Analyzer-Mass Spectrometry.

Unsaturated lipids constitute a significant portion of the lipidome, serving as players of multifaceted functions involving cellular signaling, membrane structure, and bioenergetics. While derivatization-assisted liquid chromatography tandem mass spectrometry (LC-MS/MS) remains the gold standard technique in lipidome, it mainly faces challenges in efficiently labeling the carbon-carbon double bond (C═C) and differentiating isomeric lipids in full dimension. This presents a need for new orthogonal methodologies. Herein, a metal- and additive-free aza-Prilezhaev aziridination (APA)-enabled ion mobility mass spectrometric method is developed for probing multiple levels of unsaturated lipid isomerization with high sensitivity. Both unsaturated polar and nonpolar lipids can be efficiently labeled in the form of N-H aziridine without significant side reactions. The signal intensity can be increased by up to 3 orders of magnitude, achieving the nM detection limit. Abundant site-specific fragmentation ions indicate C═C location and sn-position in MS/MS spectra. Better yet, a stable monoaziridination product is dominant, simplifying the spectrum for lipids with multiple double bonds. Coupled with a U-shaped mobility analyzer, identification of geometric isomers and separation of different lipid classes can be achieved. Additionally, a unique pseudo MS3 mode with UMA-QTOF MS boosts the sensitivity for generating diagnostic fragments. Overall, the current method provides a comprehensive solution for deep-profiling lipidomics, which is valuable for lipid marker discovery in disease monitoring and diagnosis.

Silver-Catalyzed Decarboxylative Remote Fluorination via a Zwitterion-Promoted 1,4-Heteroaryl Migration.

A silver-catalyzed decarboxylative remote fluorination via a zwitterion-promoted 1,4-heteroaryl migration has been developed. A variety of heteroaryl-tethered benzyl fluorides have been readily synthesized with good regioselectivity under mild conditions. The zwitterion of the substrate is suggested to accelerate the 1,4-heteroaryl migration, which determines the regioselectivity of this transformation.

I-scan combined with laryngovideostroboscopy for predicting malignancy in vocal fold leukoplakia.

OBJECTIVE: This study evaluated vocal fold leukoplakia using i-scan combined with laryngovideostroboscopy for risk assessment prediction. METHODS: A total of 141 patients with 218 lesions were enrolled in this study. Morphological characteristics of leukoplakia, assessment of the vascular pattern using i-scan, and vocal fold vibratory function were analyzed. RESULTS: The number of patients with no, mild, moderate, severe dysplasia, and invasive carcinoma were 68, 40, 17, 46 and 47, respectively. The sensitivity of morphological characteristic, vascular pattern, vibratory function and predictive model were 77.4%, 72%, 69.9%, and 82.8%, respectively. Receiver operating characteristic curve analysis of morphological characteristic, vascular pattern, vibratory function and predictive model were 0.771, 0.824, 0.769, and 0.923, respectively. The results of logistic regression analysis showed that rough morphological types, perpendicular vascular pattern, severe decrease and absence of mucosal waves increased the risk of malignancy (OR = 5.531, 4.973, and 16.992, respectively; P < 0.001). CONCLUSIONS: I-scan combined with laryngovideostroboscopy can improve the differential diagnosis of low-risk and high-risk vocal fold leukoplakia.

Photoinduced Copper-Catalyzed Enantioconvergent Remote Alkynylation via 1,4-Heteroaryl Migration.

A photoinduced copper-catalyzed enantioconvergent remote alkynylation of N-hydroxyphthalimide esters with terminal alkynes via 1,4-heteroaryl migration has been developed. A broad scope of heteroaryl-tethered chiral alkynes has been synthesized with good regio- and enantioselectivities. The chiral-ligand-coordinated copper species plays a dual role as both the photoredox and cross-coupling catalyst. This methodology provides a new platform for enantioconvergent remote alkynylations.

Transient solution of stochastic oscillators with both odd and even nonlinearity under modulated Gaussian white noise.

This study presents an improved solution procedure for determining the transient probability density function (PDF) solutions of the nonlinear oscillators with both odd and even nonlinearity under modulated random stimulation, which is an extension of the exponential-polynomial-closure approach. An evolutionary exponential-polynomial function with time-varying undetermined variables is considered as the transient probabilistic solution. By selecting a set of independent evolutionary base functions spanning a R^{n} space as weight functions, a set of ordinary differential equations can be formulated by integrating the weighted residual error. The undetermined variables can be determined numerically by solving those ordinary differential equations. Three numerical examples illustrate that the improved solution procedure can acquire the transient probabilistic responses of the stochastic dynamic systems effectively and efficiently even in the PDF solution tails when compared with Monte Carlo simulation. Moreover, the results indicate that the PDF solutions of the oscillators are asymmetrical at their nonzero means due to the influence of even nonlinearity. The nonstationary behaviors of the system responses are also investigated along with the behavior of modulated Gaussian white noise.

A combined radiomic model distinguishing GISTs from leiomyomas and schwannomas in the stomach based on endoscopic ultrasonography images.

BACKGROUND: Endoscopic ultrasonography (EUS) is recommended as the best tool for evaluating gastric subepithelial lesions (SELs); nonetheless, it has difficulty distinguishing gastrointestinal stromal tumors (GISTs) from leiomyomas and schwannomas. GISTs have malignant potential, whereas leiomyomas and schwannomas are considered benign. PURPOSE: This study aimed to establish a combined radiomic model based on EUS images for distinguishing GISTs from leiomyomas and schwannomas in the stomach. METHODS: EUS images of pathologically confirmed GISTs, leiomyomas, and schwannomas were collected from five centers. Gastric SELs were divided into training and testing datasets based on random split-sample method (7:3). Radiomic features were extracted from the tumor and muscularis propria regions. Principal component analysis, least absolute shrinkage, and selection operator were used for feature selection. Support vector machine was used to construct radiomic models. Two radiomic models were built: the conventional radiomic model included tumor features alone, whereas the combined radiomic model incorporated features from the tumor and muscularis propria regions. RESULTS: A total of 3933 EUS images from 485 cases were included. For the differential diagnosis of GISTs from leiomyomas and schwannomas, the accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve were 74.5%, 72.2%, 78.7%, and 0.754, respectively, for the EUS experts; 76.8%, 74.4%, 81.0%, and 0.830, respectively, for the conventional radiomic model; and 90.9%, 91.0%, 90.6%, and 0.953, respectively, for the combined radiomic model. For gastric SELs <20 mm, the accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of the combined radiomic model were 91.4%, 91.6%, 91.1%, and 0.960, respectively. CONCLUSIONS: We developed and validated a combined radiomic model to distinguish gastric GISTs from leiomyomas and schwannomas. The combined radiomic model showed better diagnostic performance than the conventional radiomic model and could assist EUS experts in non-invasively diagnosing gastric SELs, particularly gastric SELs <20 mm.

A long-acting recombinant FSH supports high-quality mouse follicle development and oocyte maturation in vitro by coordinating somatic and germ cell transcriptomes.

Strategies to maximize individual fertility chances are constant requirements of ART. In vitro folliculogenesis may represent a valid option to create a large source of immature ovarian follicles in ART. Efforts are being made to set up mammalian follicle culture protocols with suitable FSH stimuli. In this study, a new type of recombinant FSH (KN015) with a prolonged half-life is proposed as an alternative to canonical FSH. KN015 supports the in vitro development of mouse follicles from primary to preovulatory stage with higher efficiency than canonical FSH and enhanced post-fertilization development rates of the ovulated oocytes. The use of KN015 also allows us to compare the dynamic transcriptome changes in oocytes and granulosa cells at different stages, in vivo and in vitro. In particular, KN015 facilitates mRNA accumulation in growing mouse oocytes and prevents spontaneous luteinization of granulosa cells in vitro. Novel analyses of transcriptome changes in this study reveal that the in vivo oocytes were more efficient than in vitro oocytes in terms of maternal mRNA clearing during meiotic maturation. KN015 promotes the degradation of maternal mRNA during in vitro oocyte maturation, improves cytoplasmic maturation and, therefore, enhances embryonic developmental potential. These findings establish new transcriptome data for oocyte and granulosa cells at the key stages of follicle development, and should help to widen the use of KN015 as a valid and commercially available hormonal support enabling optimized in vitro development of follicles and oocytes.

Development of a three-degree-of-freedom piezoelectric actuator.

Multi-degree of freedom piezoelectric actuators are strongly needed for industrial applications, especially when manipulating a large and heavy mirror or lens in an optical system. A novel three-degree-of-freedom piezoelectric actuator, which is driven by two pairs of piezo-stack actuator with spatial compliant mechanisms designed to guide the motion and preload the piezo-stack actuators, is herein proposed. The structure and working principle of the proposed actuator are illustrated and its kinematic characteristic is analyzed. The stiffness of the spatial compliant mechanisms is modeled, and the dynamic characteristics are analyzed, Finite Element method is utilized to validate the correctness of the stiffness modeling and the free vibration analysis of the proposed actuator. A prototype actuator is fabricated and its output performances have been tested. Working space of X ranging from -7.1 to 5.6 µm, Y ranging from -6.2 to 8.2 µm and Z ranging from -2.3 to 2.1 µm, displacement resolutions of 15/16/21 nm along X-/Y-/Z-axis and average velocities of 52.3, 82.8 and 29.5 µm/s along X-axis, Y-axis, and Z-axis with carrying load up to 2 kg and driving frequency of 500 Hz have been achieved by the prototype actuator. The method of waveform generating for the proposed actuator has been developed with the inverse hysteresis compensation, and test results indicate that the positioning accuracy of the prototype actuator in the open loop has been improved from 0.94 to 0.23 µm for a circular trajectory tracking, from 0.48 to 0.29 µmm for an elliptical trajectory tracking, and from 0.61 to 0.32 µm for a rectangular trajectory tracking with the compensated waveform of driving voltage.

The process of hypertension induced by high-salt diet: Association with interactions between intestinal mucosal microbiota, and chronic low-grade inflammation, end-organ damage.

Inflammation and immunity play a major role in the development of hypertension, and a potential correlation between host mucosal immunity and inflammatory response regulation. We explored the changes of intestinal mucosal microbiota in hypertensive rats induced by high-salt diet and the potential link between the intestinal mucosal microbiota and inflammation in rats. Therefore, we used PacBio (Pacific Bioscience) SMRT sequencing technology to determine the structure of intestinal mucosal microbiota, used enzyme-linked immunosorbent assay (ELISA) to determined the proinflammatory cytokines and hormones associated with hypertension in serum, and used histopathology methods to observe the kidney and vascular structure. We performed a potential association analysis between intestinal mucosal characteristic bacteria and significantly different blood cytokines in hypertensive rats induced by high-salt. The results showed that the kidney and vascular structures of hypertensive rats induced by high salt were damaged, the serum concentration of necrosis factor-α (TNF-α), angiotensin II (AngII), interleukin-6 (IL-6), and interleukin-8 (IL-8) were significantly increased (p < 0.05), and the coefficient of immune organ spleen was significantly changed (p < 0.05), but there was no significant change in serum lipids (p > 0.05). From the perspective of gut microbiota, high-salt diet leads to significant changes in intestinal mucosal microbiota. Bifidobacterium animalis subsp. and Brachybacterium paraconglomeratum were the dominant differential bacteria in intestinal mucosal, with the AUC (area under curve) value of Bifidobacterium animalis subsp. and Brachybacterium paraconglomeratum were 1 and 0.875 according to ROC (receiver operating characteristic) analysis. Correlation analysis showed that Bifidobacterium animalis subsp. was correlated with IL-6, IL-8, TNF-α, and Ang II. Based on our results, we can speculated that high salt diet mediated chronic low-grade inflammation through inhibited the growth of Bifidobacterium animalis subsp. in intestinal mucosa and caused end-organ damage, which leads to hypertension.

Phytoremediation as a potential technique for vehicle hazardous pollutants around highways.

With the synchronous development of highway construction and the urban economy, automobiles have entered thousands of households as essential means of transportation. This paper reviews the latest research progress in using phytoremediation technology to remediate the environmental pollution caused by automobile exhaust in recent years, including the prospects for stereoscopic forestry. Currently, most automobiles on the global market are internal combustion vehicles using fossil energy sources as the primary fuel, such as gasoline, diesel, and liquid or compressed natural gas. The composition of vehicle exhaust is relatively complex. When it enters the atmosphere, it is prone to a series of chemical reactions to generate various secondary pollutants, which are very harmful to human beings, plants, animals, and the eco-environment. Despite improving the automobile fuel quality and installing exhaust gas purification devices, helping to reduce air pollution, the treatment costs of these approaches are expensive and cannot achieve zero emissions of automobile exhaust pollutants. The purification of vehicle exhaust by plants is a crucial way to remediate the environmental pollution caused by automobile exhaust and improve the environment along the highway by utilizing the ecosystem's self-regulating ability. Therefore, it has become a global trend to use phytoremediation technology to restore the automobile exhaust pollution. Now, there is no scientific report or systematic review about how plants absorb vehicle pollutants. The screening and configuration of suitable plant species is the most crucial aspect of successful phytoremediation. The mechanisms of plant adsorption, metabolism, and detoxification are reviewed in this paper to address the problem of automobile exhaust pollution.

Merging photoredox with copper catalysis: enantioselective remote cyanation via 1,4-heteroaryl migration.

We have developed a photoredox/Cu dual catalyzed enantioselective remote cyanation via 1,4-heteroaryl migration. Experimental and computational studies have been carried out to reveal the reaction mechanism and explain the origins of the regio- and enantioselectivities of the remote cyanation process. This methodology exhibits mild conditions, a broad substrate scope and good regio- and enantioselectivities, which provides a unique approach for catalyst-controlled asymmetric backbone recombination of molecules via functional group migration.

A new method for studying the mechanism of "Feature Identification based quality assessment" of Traditional Chinese Medicine, taking Gastrodiae Rhizoma as an example.

Aim of the study: The research group proposed that the mechanism of "Feature Identification based Quality Assessment" (FIQA) of Traditional Chinese Medicine (TCM) can be explained according to the relationship between the "Feature" of TCM and the Pharmacodynamic Components representing the holistic effect of TCM. Gastrodiae Rhizoma (GR) was selected as the research object to reveal the close relationship between "Feature" and the quality of TCM. Materials and methods: In this study, the "Feature" such as "Shape", "Color", "Odour" and "Taste" of GR are quantified by the electronic nose, electronic tongue, and other instruments. Then, the Pharmacodynamic Components Group (PCG) of GR was determined which could reflect the holistic effect of GR by spectrum effect relationship analysis. By analyzing the correlation between the "Feature" and the content of PCG, the mechanism of FIQA of GR was determined. Results: The quantitative results of "Shape", "Color", "Odour" and "Taste" of GR from different sources were significantly different. Six components were selected as the PCG, which can represent the holistic effect of GR in the aspect of the neuroprotective effect. There was a good correlation between the components in the PCG and "Feature". Conclusions: The quality of GR can be determined quantitatively according to its "Shape", "Color", "Odour" and "Taste". The mechanism of FIQA of TCM can be explained according to the relationship between the Shape of TCM and the Pharmacodynamic Components representing the quality of TCM. The revelation of this mechanism reflects the holistic characteristics of the multi-component synergistic effect of TCM. This study provides a reference research method for revealing the mechanism of FIQA of TCM.

Ultrasound-triggered drug delivery for glioma therapy through gambogic acid-loaded nanobubble-microbubble complexes.

Glioma is one of the most common primary brain tumors. Gambogic acid (GA) is widely used in tumor chemotherapy. However, GA has poor water solubility, low bioavailability, and difficult permeability across the blood-brain barrier (BBB), leading to poor efficacy against brain tumors. In our study, we developed negatively charged GA-loaded PLGA nanobubbles [GA/poly(lactic-co-glycolic acid) (PLGA)] and conjugated them onto the surface of cationic lipid microbubbles (CMBs) through electrostatic interactions. The resulting GA/PLGA-CMB complex was characterized for its particle size, distribution, drug encapsulation efficiency, and ultrasound imaging property, revealing a high drug encapsulation efficiency and excellent contrast imaging capability. Importantly, significantly enhanced GA delivery into the brain could be observed after the intravenous administration of GA/PLGA-CMBs combined with low-intensity focused ultrasound (FUS) due to the cavitation from CMBs, which mediated blood-brain barrier (BBB) opening. Taking advantage of the opened BBB, GA/PLGA nanobubbles could be delivered into the tumor. Then, the second FUS irradiation at higher energy was used to induce the cavitation of GA/PLGA nanobubbles, producing the second cavitation on tumor cells, significantly enhancing the ability of GA to enter tumor cells and inhibit tumor growth inhibition efficacy.

Effectiveness and Safety of Probiotics for Patients with Constipation-Predominant Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of 10 Randomized Controlled Trials.

To perform a systematic review and meta-analysis to evaluate the effectiveness and safety of probiotics in the treatment of constipation-predominant irritable bowel syndrome (IBS-C), we searched for randomized controlled trials (RCTs) comparing probiotic care versus placebos for patients with IBS-C in five comprehensive databases (March 2022). The risk of bias was assessed using the Cochrane Collaboration Risk of Bias Tool. RevMan 5.3 was used to perform a meta-analysis on stool consistency, abdominal pain, bloating, quality of life (QoL), fecal Bifidobacterium and Lactobacillus counts, and adverse events. The GRADE approach was used to evaluate the certainty of the evidence. Ten RCTs involving 757 patients were included. Only three studies were rated as having a low risk of bias. The meta-analysis results show that, compared to the placebo, probiotics significantly improved stool consistency (MD = 0.72, 95% CI (0.18, 1.26), p < 0.05, low quality) and increased the number of fecal Bifidobacteria (MD = 1.75, 95% CI (1.51, 2.00), p < 0.05, low quality) and Lactobacillus (MD = 1.69, 95% CI (1.48, 1.89), p < 0.05, low quality), while no significant differences were found in abdominal pain scores, bloating scores, QoL scores, or the incidence of adverse events (p > 0.05). The low-to-very low certainty evidence suggests that probiotics might improve the stool consistency of patients with IBS-C and increase the number of Bifidobacteria and Lactobacilli in feces with good safety. However, more high-quality studies with large samples are needed to verify the findings.

Up-regulation of cell division cycle 20 expression alters the morphology of neuronal dendritic spines in the nucleus accumbens by promoting FMRP ubiquitination.

The nucleus accumbens (NAc) is the key area of the reward circuit, but its heterogeneity has been poorly studied. Using single-cell RNA sequencing, we revealed a subcluster of GABAergic neurons characterized by cell division cycle 20 (Cdc20) mRNA expression in the NAc of adult rats. We studied the coexpression of Cdc20 and Gad1 mRNA in the NAc neurons of adult rats and assessed Cdc20 protein expression in the NAc during rat development. Moreover, we microinjected AAV2/9-hSyn-Cdc20 with or without the dual-AAV system into the bilateral NAc for sparse labeling to observe changes in the synaptic morphology of mature neurons and assessed rat behaviors in open field and elevated plus maze tests. Furthermore, we performed the experiments with a Cdc20 inhibitor, Cdc20 over-expression AAV vector, and Cdc20 conditional knockout primary striatal neurons to understand the ubiquitination-dependent degradation of fragile X mental retardation protein (FMRP) in vitro and in vivo. We confirmed the mRNA expression of Cdc20 in the NAc GABAergic neurons of adult rats, and its protein level was decreased significantly 3 weeks post-birth. Up-regulated Cdc20 expression in the bilateral NAc decreased the dendritic spine density in mature neurons and induced anxiety-like behavior in rats. Cdc20-APC triggered FMRP degradation through K48-linked polyubiquitination in Neuro-2a cells and primary striatal neurons and down-regulated FMRP expression in the NAc of adult rats. These data revealed that up-regulation of Cdc20 in the bilateral NAc reduced dendritic spine density and led to anxiety-like behaviors, possibly by enhancing FMRP degradation via K48-linked polyubiquitination.

A Gambogic Acid-Loaded Delivery System Mediated by Ultrasound-Targeted Microbubble Destruction: A Promising Therapy Method for Malignant Cerebral Glioma.

Background: The blood-brain barrier (BBB) inhibits the delivery of macromolecular chemotherapeutic drugs to brain tumors, leading to low utilization rates and toxic side effects to surrounding tissues and organs. Ultrasonic targeted microbubble destruction (UTMD) technology can open the BBB, leading to a new type of drug delivery system with particular utility in glioma. Purpose: We have developed a new type of drug-loaded microbubble complex based on poly(lactic-co-glycolic acid) (PLGA) that targets gambogic acid (GA) to the area of brain tumors through UTMD. Methods: GA/PLGA nanoparticles were prepared by the double emulsification method, and cationic microbubbles (CMBs) were prepared by a thin film hydration method. The GA/PLGA-CMB microbubble complex was assembled through electrostatic attractions and was characterized chemically. The anti-glioblastoma effect of GA/PLGA-CMB combined with focused ultrasound (FUS) was evaluated by biochemical and imaging assays in cultured cells and model mice. Results: GA/PLGA-CMB combined with FUS demonstrated a significant inhibitory effect on glioblastoma cell lines U87 and U251 as compared with controls (P<0.05). Tumor access and imaging analyses demonstrated that administration of GA/PLGA-CMBs combined with FUS can open the BBB and target the treatment of glioblastoma in a mouse model, as compared with control groups (P<0.05). Conclusion: The combination of PLGA-CMB with FUS provides an effective and biocompatible drug delivery system, and its application to the delivery of GA in a mouse glioblastoma model was successful.

Dysregulation of LINC00324 associated with methylation facilitates leukemogenesis in de novo acute myeloid leukemia.

INTRODUCTION: LINC00324 was overexpressed and facilitated carcinogenesis in various solid malignant tumors. However, the role of LINC00324 in leukemogenesis remains to be elucidated. METHODS: The relative expression and unmethylation levels of LINC00324 were detected by real-time quantitative PCR (RT-qPCR) and real-time quantitative methylation-specific PCR (RT-qMSP). Cell proliferation experimental and flow cytometer (FCM) was used to detect the change of proliferation and apoptosis in leukemia cell lines after overexpression of LINC00324. RESULTS: The results showed that the expression of LINC00324 and the methylation level of the promoter region were significantly negatively correlated in AML patients. Moreover, patients with lower LINC00324 expression showed more prolonged overall survival (OS). Remarkably, overexpression of LINC00324 in leukemia cell lines promoted the proliferation of target cells and inhibited their apoptosis. CONCLUSION: Our findings firstly identified that the hypomethylation of LINC00324 was a common molecular event in de novo AML patients. The abnormally upregulated LINC00324 promotes proliferation and inhibits apoptosis in leukemia cells.

Nonstoichiometric Molybdenum Trioxide Adjustable Energy Barrier Enabling Ultralong-Life All-Solid-State Lithium Batteries.

The performance of lithium batteries is largely dependent on the ionic conductivity within robust solid electrolytes. Poly(ethylene oxide) (PEO)-based electrolytes, however, have a low lithium ionic conductivity, which limits the hop of Li+. Herein, a novel PEO-based composite electrolyte is prepared that contains nonstoichiometric transition molybdenum trioxide (MoO3-x) nanosheets as fillers to improve the ionic conductivity. The MoO3-x nanosheets containing many oxygen vacancies can cross-link with PEO chains to reduce the energy barrier of Li+ migration and the matrix crystallinity, leading to an increase in the lithium-ion transference number (up to 0.56) and a high ionic conductivity (up to 6 × 10-4 S cm-1) at 60 °C. Meanwhile, the incorporation of MoO3-x nanosheets alleviates the decomposition of the electrolyte, enhancing the tensile strength by ∼4 times compared to PEO. As a result, a LiFePO4/Li cell with PEO/LiTFSI/MoO3-x (PLM3-x) delivers an excellent rate capability, high capacity, and lifespan during high rates (2 C, ≥10 000 cycles), which demonstrates a facile yet effective strategy toward high-performance lithium batteries.