Structurally diverse triterpenoid alkaloids from Buxus rugulosa.

Four new nortriterpenoid alkaloids, namely buxrugulines E-H (1-4), along with five known ones (5-9), were isolated from the twigs and leaves of Buxus rugulosa. Their structures were identified based on extensive NMR data and MS spectroscopic analyses. Our bioassays revealed that compounds 5, 6 and 8 exhibited potent cytotoxicity in vitro against MCF-7 cell lines, with IC50 values ranging from 6.70 to 11.00 µM, respectively.

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer's disease proteopathology for precision medication.

Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer's disease proteopathology for precision medication.

Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects. One-Sentence Summary: A brain-penetrant inhibitor of G9a methylase blocks G9a translational mechanism to reverse Alzheimer's disease related proteome for effective therapy.

The parallel biosynthesis routes of hyperoside from naringenin in Hypericum monogynum.

Hyperoside is a bioactive flavonoid galactoside in both medicinal and edible plants. It plays an important physiological role in the growth of flower buds. However, the hyperoside biosynthesis pathway has not been systematically elucidated in plants, including its original source, Hypericaceae. Our group found abundant hyperoside in the flower buds of Hypericum monogynum, and we sequenced its transcriptome to study the biosynthetic mechanism of hyperoside. After gene screening and functional verification, four kinds of key enzymes were identified. Specifically, HmF3Hs (flavanone 3-hydroxylases) and HmFLSs (flavonol synthases) could catalyze flavanones into dihydroflavonols, as well as catalyzing dihydroflavonols into flavonols. HmFLSs could also convert flavanones into flavonols and flavones with varying efficiencies. HmF3'H (flavonoid 3'-hydroxylase) was found to act broadly on 4'-hydroxyl flavonoids to produce 3',4'-diydroxylated flavanones, dihydroflavonols, flavonols, and flavones. HmGAT (flavonoid 3-O-galactosyltransferase) would transform flavonols into the corresponding 3-O-galactosides, including hyperoside. The parallel hyperoside biosynthesis routes were thus depicted, one of which was successfully reconstructed in Escherichia coli BL21(DE3) by feeding naringenin, resulting in a hyperoside yield of 25 mg/l. Overall, this research not only helped us understand the interior catalytic mechanism of hyperoside in H. monogynum concerning flower development and bioactivity, but also provided valuable insights into these enzyme families.

Hierarchical NiCo@NiOOH@CoMoO4 Core-Shell Heterostructure on Carbon Cloth for High-Performance Asymmetric Supercapacitors.

The fabrication of low-cost, effective, and highly integrated nanostructured materials through simple and reproducible methods for high-energy-density supercapacitors is highly desirable. Herein, an activated carbon cloth (ACC) is designed as the functional scaffold for supercapacitors and treated hydrothermally to deposit NiCo nanoneedles working as internal core, followed by a dip-dry coating of NiOOH nanoflakes core-shell and uniform hydrothermal deposition of CoMoO4 nanosheets serving as an external shell. The structured core-shell heterostructure ACC@NiCo@NiOOH@CoMoO4 electrode resulted in exceptional specific areal capacitance of 2920 mF cm-2 and exceptional cycling stability for 10 000 cycles. Moreover, the fabricated electrode is developed into an asymmetric supercapacitor which demonstrates excellent areal capacitance, energy density, and power density within the broad potential window of 1.7 V with a cycling life of 92.4% after 10 000 charge-discharge cycles, which reflects excellent cycle life. The distinctive core-shell structure, highly conductive substrate, and synergetic effect of coated material results in more electrochemical active sites and flanges for effective electrons and ion transportation. This unique technique provides a new perspective for cost-efficient supercapacitor applications.

A novel mutation in intron 1 of Wnt1 causes developmental loss of dopaminergic neurons in midbrain and ASD-like behaviors in rats.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic liability. Despite extensive studies, however, the underlying pathogenic mechanism still remains elusive. In the present study, we identified a homozygous mutation in the intron 1 of Wnt1 via large-scale screening of ASD risk/causative genes and verified that this mutation created a new splicing donor site in the intron 1, and consequently, a decrease of WNT1 expression. Interestingly, humanized rat models harboring this mutation exhibited robust ASD-like behaviors including impaired ultrasonic vocalization (USV), decreased social interactions, and restricted and repetitive behaviors. Moreover, in the substantia nigra compacta (SNpc) and the ventral tegmental area (VTA) of mutant rats, dopaminergic (DAergic) neurons were dramatically lost, together with a comparable decrease in striatal DAergic fibers. Furthermore, using single-cell RNA sequencing, we demonstrated that the decreased DAergic neurons in these midbrain areas might attribute to a shift of the boundary of the local pool of progenitor cells from the hypothalamic floor plate to the midbrain floor plate during the early embryonic stage. Moreover, treatments of mutant rats with levodopa could attenuate the impaired USV and social interactions almost completely, but not the restricted and repetitive behaviors. Our results for the first time documented that the developmental loss of DAergic neurons in the midbrain underlies the pathogenesis of ASD, and that the abnormal progenitor cell patterning is a cellular underpinning for this developmental DAergic neuronal loss. Importantly, the effective dopamine therapy suggests a translational significance in the treatment of ASD.

Compact wavemeter incorporating femtosecond laser-induced surface nanostructures enabled by deep learning.

Miniature spectrometers have the advantage of high portability and integration, making them quick and easy to use in various working environments. The speckle patterns produced by light scattering through a disordered medium are highly sensitive to wavelength changes and can be used to design high-precision wavemeters and spectrometers. In this study, we used a self-organized, femtosecond laser-prepared nanostructure with a characteristic size of approximately 30-50 nm on a sapphire surface as a scattering medium to effectively induce spectral dispersion. By leveraging this random scattering structure, we successfully designed a compact scattering wavelength meter with efficient scattering properties. The collected speckle patterns were identified and classified using a neural network, and the variation of speckle patterns with wavelength was accurately extracted, achieving a measurement accuracy of 10 pm in multiple wavelength ranges. The system can effectively suppress instrument and environmental noise with high robustness. This work paves the way for the development of compact high-precision wavemeters.

The application of Aptamer in biomarker discovery.

Biomarkers are detectable molecules that can reflect specific physiological states of cells, organs, and organisms and therefore be regarded as indicators for specific diseases. And the discovery of biomarkers plays an essential role in cancer management from the initial diagnosis to the final treatment regime. Practically, reliable clinical biomarkers are still limited, restricted by the suboptimal methods in biomarker discovery. Nucleic acid aptamers nowadays could be used as a powerful tool in the discovery of protein biomarkers. Nucleic acid aptamers are single-strand oligonucleotides that can specifically bind to various targets with high affinity. As artificial ssDNA or RNA, aptamers possess unique advantages compared to conventional antibodies. They can be flexible in design, low immunogenicity, relative chemical/thermos stability, as well as modifying convenience. Several SELEX (Systematic Evolution of Ligands by Exponential Enrichment) based methods have been generated recently to construct aptamers for discovering new biomarkers in different cell locations. Secretome SELEX-based aptamers selection can facilitate the identification of secreted protein biomarkers. The aptamers developed by cell-SELEX can be used to unveil those biomarkers presented on the cell surface. The aptamers from tissue-SELEX could target intracellular biomarkers. And as a multiplexed protein biomarker detection technology, aptamer-based SOMAScan can analyze thousands of proteins in a single run. In this review, we will introduce the principle and workflow of variations of SELEX-based methods, including secretome SELEX, ADAPT, Cell-SELEX and tissue SELEX. Another powerful proteome analyzing tool, SOMAScan, will also be covered. In the second half of this review, how these methods accelerate biomarker discovery in various diseases, including cardiovascular diseases, cancer and neurodegenerative diseases, will be discussed.

Analysis of the driving role and impact of road construction on carbon stock.

Road construction will have a large impact on the ecosystem in the road area, and carbon stock, as an important indicator to measure the scale and quantity of primary productivity of the ecosystem, will also change, but the specific pattern is not clear. It is important to study the impact of road construction on carbon stock for regional ecosystem protection and sustainable economic and social development. Based on the InVEST model, this paper quantifies the spatial and temporal changes of carbon stocks in Jinhua, Zhejiang Province, from 2002 to 2017, using remote sensing image classification data land cover types as model driving data, geodetector, trend analysis, and buffer zone analysis methods, explores the driving effect of road construction on carbon stocks, and analyzes the spatial and temporal impacts of road construction on carbon stocks within the buffer zone. Results indicate that the total carbon stock in the Jinhua area showed a decreasing trend during the 16 years, decreasing by about 8.58 × 106 t. The spatial changes in the areas with higher carbon stocks were not significant. The explanatory power of road network density on carbon stock reaches 37%, and the anisotropic effect of road construction on carbon stock is strong and had a significant driving effect on carbon storage reduction. The new highway construction will accelerate the rate of carbon stock decline in the buffer zone, and the spatial situation is generally "the farther away from the highway, the higher the carbon stock."

Analysis of the impact of expressway construction on soil moisture in road areas.

To reveal the effect pattern of expressways on regional soil moisture, in this study, using trend analysis and buffer zone analysis methods, the data of VSWI (vegetation supply water index) in central Zhejiang Province from 2005 to 2016 were extracted from landsat7 satellite data using a single window algorithm, and spatial analysis was used to investigate the law of its differentiation. The results show that the multi-year average is 0.01879, between 0.01035-0.02774, showing a gentle decreasing trend, and there are obvious regional variations in space. We found that the impact of the new expressway and interchange on the VSWI in the buffer zone lasted for more than two years, and the VSWI increased in space farther away from the road, and this trend returned to normal at 8 km. Finally, the development patterns of the VSWI in the buffer zone of the newly established expressway and the interchange are approximately the same.

Rare noreudesmane sesquiterpenoids from the fruits of Dysoxylum densiflorum.

Seven rare noreudesmane sesquiterpenoids (dysoxydenones M-S, 1-7), including three 11,12,13-trinoreudesmanes, three 13-noreudesmanes and one spirovetivane-type sesquiterpenoid, along with two known analogues were isolated from the fruits of Dysoxylum densiflorum. The planar structures were elucidated by a combination of 1D, 2D NMR and HRESIMS analyses. Their absolute configurations were determined by combination of single-crystal X-ray diffraction, CD exciton chirality method and ECD calculation. All compounds were screened for anti-inflammatory activity on LPS-induced RAW 264.7 cells and IL-1ß inhibitory activity.

Survival outcome among patients with out-of-hospital cardiac arrest who received cardiopulmonary resuscitation in China: a systematic review and meta-analysis.

BACKGROUND: This study aimed to assess the survival outcomes among patients with out-of-hospital cardiac arrest (CA) who received cardiopulmonary resuscitation (CPR) in China. METHODS: Relevant studies, published between January 1, 2010 and September 5, 2022, were retrieved from databases, including EMBASE, PubMed, Cochrane Library, the China Biology Medicine disk, China National Knowledge Infrastructure, and Wanfang databases. We included clinical studies in which all patients were diagnosed with CA and underwent out-of-hospital CPR, and the outcome variables were at least one of the following: return of spontaneous circulation (ROSC), survival to admission, survival to hospital discharge, 1-month survival, achieved good neurological outcomes, and 1-year survival. Two investigators independently extracted the study data and assessed its quality using a modified Newcastle-Ottawa Scale tool. The data were pooled using random-effects models. RESULTS: Of the 3620 identified studies, 49 (63,378 patients) were included in the meta-analysis. The pooled ROSC rate was 9.0% (95% confidence interval [CI] 7.5-10.5%, I2 = 97%), the pooled survival to admission rate was 5.0% (95% CI 2.7-8.0%, I2 = 98%), and the pooled survival to discharge rate was 1.8% (95% CI 1.2-2.5%, I2 = 95%). Additionally, the ROSC rate of patients with bystander CPR was significantly higher than that of those without bystander CPR, and the pooled odds ratio (OR) was 7.92 (95% CI 4.32-14.53, I2 = 85%). The ROSC rate of participants who started CPR within 5 min was significantly higher than that of those who started CPR after 5 min, and the pooled OR was 5.92 (95% CI 1.92-18.26, I2 = 85%). The ROSC rate of participants with defibrillation was significantly higher than that of those without defibrillation, and the pooled OR was 8.52 (95% CI 3.72-19.52, I2 = 77%). CONCLUSION: The survival outcomes of out-of-hospital CPR in China are far below the world average. Therefore, the policy of providing automated external defibrillators (AEDs) in public places and strengthening CPR training for healthcare providers and public personnel should be encouraged and disseminated nationwide. Trial registration This study was registered in PROSPERO (CRD42022326165) on 29 April 2022.

In Situ Probing and Identification of Electrochemical Reaction Intermediates by Floating Electrolytic Electrospray Mass Spectrometry.

The in-depth study of electrochemical (EC) synthesis can require a powerful mass spectrometry (MS) analytical platform which can discover and identify fleeting intermediates in EC reactions. Here we report a floating electrolytic electrospray ionization (FE-ESI) strategy that can perform EC processes in a floating electrolytic cell and monitor intermediates by high-resolution MS. Compared with previous EC-MS methods, a significant advantage of FE-ESI-MS is that it allows one to modulate the electrolytic and electrospray process individually, ensuring its high sensitivity in discovering intermediates and universality to investigate redox reactions in different scenarios. This powerful platform has been successfully used to investigate the EC reductive coupling of p-tolylboronic acid and p-nitrotoluene. A series of nitrene intermediates were discovered and identified by FE-ESI-MS, indicating that a hidden mechanism involving nitrene formation might play a key role in EC reductive coupling process.

Cellular vimentin promotes the nuclear transport of the HBoV1 structural protein VP1u.

Human bocavirus 1 (HBoV1) is an important pathogen causing lower respiratory tract infection. The VP1 unique region (VP1u), consisting of 129 amino acids at the N-terminus of the HBoV1 structural protein VP1, is an important component of virus infection. Bioinformatics analysis predicted that HBoV1 VP1u exhibits two bipartite nuclear localization signals (NLS) and contains four basic regions (BRs). The two potential bipartite NLSs consist of BR2 and 3 and BR3 and 4, respectively. In this study, we inserted the truncated vp1u sequences into a double EGFP fusion expression vector and confirmed the vimentin (VIM)-HBoV1 VP1u interaction by mass spectrometry and immunoprecipitation. The results of our IFA analysis showed that all four VP1u BRs displayed strong nuclear transport functions. We further demonstrated that VP1u interacted with VIM and that they colocalized in the cytoplasm. VP1u expression in the cells enhanced the VIM expression, and the VP1u expression also increased upon VIM overexpression, although it was not affected by VIM knockdown. Upon VIM overexpression, VP1u nucleation was significantly enhanced, but was inhibited by VIM downregulation. These results indicate that the VP1u-VIM interaction could be involved in the nuclear transport of VP1u. VP1u nucleation might further affect HBoV1 replication and infection. This study could potentially help clarify the function of VP1u by further revealing the HBoV1 nuclear transport mechanism and provide a new approach for elucidating the molecular mechanism of HBoV1 replication.

Rapid identification of stigmastane-type steroid saponins from Vernonia amygdalina leaf based on α-glucosidase inhibiting activity and molecular networking.

Steroid saponins are secondary metabolites with multiple medicinal values that are found in large quantities in natural medicines, especially Vernonia amygdalina, a famous nature medicine for the treatment of tonsillitis, diabetes, pneumonia. The current study was designed to combine molecular networking (MN) with diagnostic ions for rapid identification of Δ7,9(11) stigmastane-type saponins which were the α-glucosidase inhibitory active substances in V. amygdalina. First, the α-glucosidase inhibitory activities of five Δ7,9(11) stigmastane-type steroid saponins that were previously isolated were screened, which indicated that the Δ7,9(11) stigmastane-type steroid saponin was one of the active constituents responsible for ameliorating diabetes. Furthermore, a strategy was proposed to identify stigmastane-type steroid saponins and verify the plausibility of derived fragmentation pathways by applying MN, MolNetEnhancer and unsupervised substructure annotation (MS2LDA). Based on this strategy, other seven Δ7,9(11) stigmastane-type steroid saponins were identified from this plant. Our research provide scientific evidence for the antidiabetic potential of the steroid saponin-rich extract of V. amygdalina leaf.

Characterizing the Phase-Structure and Rheological Response-Behavior of Multi-Walled Carbon Nanotubes Modified Asphalt-Binder.

In this study, the phase-structure and rheological response-behavior of multi-walled carbon nanotube (MWCNTs) modified asphalt-binder (MWCNTs-MA) were measured and quantified in the laboratory. The changes in the molecular dynamics due to MWCNTs modification were simulated and quantified based on the intermolecular interaction energy computations, electrostatic potential surface analyses and phase-structure modeling of the asphalt-binder matrix. The rheological properties such as the asphalt-binder viscosity and complex modulus, of both the base and modified asphalt-binders, were determined using the standard Brookfield viscometer (BV) and dynamic shear rheology (DSR) test devices, respectively. In comparison to the base asphalt-binder, the corresponding BV-DSR test results exhibited higher viscosity and complex modulus for the MWCNTs modified asphalt-binder, with reduced sensitivity and susceptibility to temperature variations. From the study results, it was observed that MWCNTs significantly improved the rheological properties and high-temperature performance of the asphalt-binder. Overall, the study has demonstrated that MWCNT modified asphalt-binder has great promising potential for application and usage as a road-pavement material, particularly with respect to mitigating the high temperature related distresses such as rutting.

Combined physical confinement and chemical adsorption on co-doped hollow TiO2 for long-term cycle lithium-sulfur batteries.

Lithium-sulfur (Li-S) batteries have long been expected to be promising high-energy-density secondary batteries because of their high theoretical specific capacity and element abundances. Yet, their poor cyclability and low rate-capacity strongly limited their practical application. Herein, a nitrogen and sulfur dual doped hollow TiO2 sphere is designed and synthesized for the sulfur host. The dual doped hollow TiO2 can enhance the adsorption ability of soluble lithium polysulfides, which effectively promote the conversion reaction of lithium polysulfides from high-order to low-order in Li-S batteries. What is more, the hollow spherical TiO2 host provides a deposition space for lithium polysulfides and blocks polysulfide migration from the cathode to the electrolyte. Both theoretical calculations and experimental studies confirmed that the electrochemical properties of the sulfur electrode are significantly improved by the dual doped hollow TiO2 sphere. The typical as-prepared dual doped hollow TiO2 cathode coated sulfur has a capacity of 1258 mA h g-1 for the first discharge and a capacity decay as low as 0.0648% per cycle during 500 cycles with a sulfur loading of 3.8 mg cm-2.

Automatic MS/MS Data Mining Strategy for Discovering Target Natural Products: A Case of Lindenane Sesquiterpenoids.

Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a widely used method for discovering natural products (NPs); however, automatic MS/MS data mining for the discovery of NPs remains a challenge. In this work, LindenaneExtractor, a program based on characteristic MS/MS ions of lindenane sesquiterpenoids (LSs) was developed to automatically extract the LSs features for target LS discovery in plant extracts. To build this program, fragmentation mechanisms of characteristic ions of LSs were elucidated and confirmed by quantum chemical calculation and deuterium-labeled compounds. Subsequently, the information of characteristic ions was integrated and coded to develop LindenaneExtractor, which was further examined by standards and several public databases. Finally, the target LS features in Sarcandra hainanensis extract were automatically extracted by LindenaneExtractor and visualized by feature-based molecular networking and two-dimensional (2D) retention time-m/z plot, leading to the discovery of 96 target LSs in total, 37 of these compounds were potentially new NPs and one was confirmed by further isolation. This work proposed a new strategy for target NP analysis and discovery based on automatic MS/MS data mining, which could significantly improve the efficiency and accuracy of NP discovery.

Phase-Transfer-Catalyzed Asymmetric Annulations of Alkyl Dihalides with Oxindoles: Unified Access to Chiral Spirocarbocyclic Oxindoles.

A general phase-transfer-catalyzed asymmetric (n+1) (n = 4 or 5) annulation reaction, featuring the direct coupling of simple oxindoles with alkyl dihalides that are allylic/benzylic and non-allylic/benzylic, has been developed to provide previously inaccessible cyclopentane- and cyclohexane-fused spirooxindole scaffolds with high yields and enantioselectivities (88-95% ee). Along with a broad scope and mild conditions, the new protocol also enables a two-step and gram-scale synthesis of the core of the drug ubrogepant.

Integrated molecular networking strategy enhance the accuracy and visualization of components identification: A case study of Ginkgo biloba leaf extract.

Molecular networking (MN) is an efficient tool for natural product research. However, single MN might lead to false annotation due to the limited information, and the importance of combining MN with chromatogram is always ignored. In this study, we proposed a comprehensive MN strategy combining feature-based molecular networking (FBMN) and dual ionization mode MS/MS to improve the annotation accuracy and to achieve structural feature visualization in a chemotaxonomic chromatogram. Three steps were taken: (1) employing FBMN and dual ionization mode MS/MS to distinguish isomers and improve components' identification accuracy. (2) Using a 3-level initiative supported by in-house database to evaluate the annotation confidence. As a result, 95 compounds were successfully identified from Ginkgo biloba leaf extract (GBE) and Ginkgo biloba leaf (GBL), and 70 compounds mainly consisting of flavonoid glycosides, ginkgolides, and lignan glycosides were assigned as high-confidence molecules. (3) Building color-dependent chemotaxonomic chromatograms, to achieve component visualization by connecting FBMN with chromatogram in which the peaks of the same color indicated the compounds with similar structural features. Our research provided a new and efficient strategy for component identification and visualization of herbal medicine.