Cs2CO3 Promoted [4 + 2] Cycloaddition of 1,6-Enynes: An Approach to Tetrahydro-1H-benzo-f-isoindole Isomers.

A Cs2CO3-promoted [4 + 2] cycloaddition of 1,6-enynes under mild reaction conditions has been developed. This protocol provides a facile approach to a series of tetrahydro-1H-benzo[f]isoindole isomerized products promoted by Cs2CO3 with moderate to high yields. By simply switching the reaction solvent and controlling the reaction time, two isomerization products could be obtained, both with good selectivity.

Comprehensive review of drug-mediated ICD inhibition of breast cancer: mechanism, status, and prospects.

The escalating incidence of breast cancer (BC) in women underscores its grave health threat. Current molecular insights into BC's post-adjuvant therapy cure remain elusive, necessitating active treatment explorations. Immunotherapy, notably chemotherapy-induced immunogenic cell death (ICD), has emerged as a promising BC therapy. ICD harnesses chemotherapeutics to activate anti-tumor immunity via DAMPs, fostering long-term T-cell memory and primary BC cure. Besides chemotherapy drugs, Nanodrugs, traditional Chinese medicine (TCM) and ICIs also induce ICD, boosting immune response. ICIs, like PD-1/PD-L1 inhibitors, revolutionize cancer treatment but face limited success in cold tumors. Thus, ICD induction combined with ICIs is studied extensively for BC immunotherapy. This article reviews the mechanism of ICD related drugs in BC and provides reference for the research and development of BC treatment, in order to explore more effective clinical treatment of BC, we hope to explore more ICD inducers and make ICIs more effective vaccines.

Exploring menopausal symptoms, attitudes, and behaviors among menopausal women in China: an online research perspective.

OBJECTIVE: The number of perimenopausal women in China is rising, but the population's concept of menopausal hormone therapy (MHT) is still relatively outdated. METHODS: In this study, we used the Knowledge-Attitude-Practice (KAP) theory and collected online questionnaires from 1,100 women aged 40 to 60 years nationwide to find out their menopausal symptom profiles; to learn about their perceptions, attitudes, and behaviors toward menopause and MHT; to explore the factors influencing the acceptance of hormone treatments; and to look for better ways to promote the dissemination of menopausal knowledge. RESULTS: The results revealed that among women aged 40 to 60 years, 82.36% experienced possible menopausal symptoms, with hot flushes/sweating, sleep disorders, mood disorders, and fatigue being the most prevalent; 55.90% reported moderate to severe symptoms, but only 46.99% of them sought healthcare services. Among those who sought medical care, 16.00% had their first visit to climacteric clinics/gynecological endocrinology, and 5.66% accepted MHT. Furthermore, 77.82% of participants never heard of MHT or were unaware of its existence. The healthcare-seeking behavior of menopausal women in response to symptoms and their willingness to accept MHT were found to be closely associated with their level of self-care. CONCLUSIONS: The prevalence of menopausal symptoms is higher in China than previous research findings, but due to a lack of relevant knowledge, the rate of seeking treatment from the appropriate medical department and accepting MHT is relatively low. Enhancing physicians' knowledge of the menopausal transition and using Internet tools might help improve Chinese women's knowledge of menopause and help them pass through this period smoothly.

GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely (approximately one percent) in PAH patients. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and PAH patients. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor PH but inhibited hypoxia-induced PH. RNA sequencing analysis suggested Endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss of function mutations.

Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)-derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration-approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

A Bio-Inspired Multifunctional Hydrogel Network with Toughly Interfacial Chemistry for Dendrite-Free Flexible Zinc Ion Battery.

Flexible and high-performance aqueous zinc-ion batteries (ZIBs), coupled with low cost and safe, are considered as one of the most promising energy storage candidates for wearable electronics. Hydrogel electrolytes present a compelling alternative to liquid electrolytes due to their remarkable flexibility and clear advantages in mitigating parasitic side reactions. However, hydrogel electrolytes suffer from poor mechanical properties and interfacial chemistry, which limits them to suppressed performance levels in flexible ZIBs, especially under harsh mechanical strains. Herein, a bio-inspired multifunctional hydrogel electrolyte network (polyacrylamide (PAM)/trehalose) with improved mechanical and adhesive properties was developed via a simple trehalose network-repairing strategy to stabilize the interfacial chemistry for dendrite-free and long-life flexible ZIBs. As a result, the trehalose-modified PAM hydrogel exhibits a superior strength and stretchability up to 100 kPa and 5338 %, respectively, as well as strong adhesive properties to various substrates. Also, the PAM/trehalose hydrogel electrolyte provides superior anti-corrosion capability for Zn anode and regulates Zn nucleation/growth, resulting in achieving a high Coulombic efficiency of 98.8 %, and long-term stability over 2400 h. Importantly, the flexible Zn//MnO2 pouch cell exhibits excellent cycling performance under different bending conditions, which offers a great potential in flexible energy-related applications and beyond.

Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α.

In hypoxic and pseudohypoxic rodent models of pulmonary hypertension (PH), hypoxia-inducible factor (HIF) inhibition attenuates disease initiation. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PH in humans, indicating the involvement of other mechanisms. Given the association between endothelial cell dysfunction and PH, the effects of pseudohypoxia and its underlying pathways were investigated in primary human lung endothelial cells. PHD2 silencing or inhibition, while activating HIF2α, induced apoptosis-resistance and IFN/STAT activation in endothelial cells, independent of HIF signaling. Mechanistically, PHD2 deficiency activated AKT and ERK, inhibited JNK, and reduced AIP1 (ASK1-interacting protein 1), all independent of HIF2α. Like PHD2, AIP1 silencing affected these same kinase pathways and produced a similar dysfunctional endothelial cell phenotype, which was partially reversed by AKT inhibition. Consistent with these in vitro findings, AIP1 protein levels in lung endothelial cells were decreased in Tie2-Cre/Phd2 knockout mice compared with wild-type controls. Lung vascular endothelial cells from patients with pulmonary arterial hypertension (PAH) showed IFN/STAT activation. Lung tissue from both SU5416/hypoxia PAH rats and patients with PAH all showed AKT activation and dysregulated AIP1 expression. In conclusion, PHD2 deficiency in lung vascular endothelial cells drives an apoptosis-resistant and inflammatory phenotype, mediated by AKT activation and AIP1 loss independent of HIF signaling. Targeting these pathways, including PHD2, AKT, and AIP1, holds the potential for developing new treatments for endothelial dysfunction in PH.NEW & NOTEWORTHY HIF activation alone does not conclusively lead to human PH, suggesting that HIF-independent signaling may also contribute to hypoxia-induced PH. This study demonstrated that PHD2 silencing-induced pseudohypoxia in human lung endothelial cells suppresses apoptosis and activates STAT, effects that persist despite HIF2α inhibition or knockdown and are attributed to AKT and ERK activation, JNK inhibition, and AIP1 loss. These findings align with observations in lung endothelial cells and tissues from PAH rodent models and patients.

Fluctuation theorem in the quantum Otto engine with long-range interaction.

The fluctuation of the quantum Otto engine has recently received a lot of attention, while applying the many body with a long-range interaction to a quantum heat engine may enhance our ability of controlling it. Using the two-point measurement and its generalization, we explore the fluctuation theorem of work and heat in a single stroke as well as in a cycle. We discover that the fluctuations of work in a cycle as well as fluctuations of heat in a single stroke or cycle can be connected to the fluctuation of work in a single stroke. Then we numerically investigate the effect of a long-range interaction on these fluctuation theorems, and our result shows that the fluctuation can be improved by manipulating the long-range interaction.

Developmental epileptic encephalopathy caused by homozygosity of a c.172+1G>C variant in the WWOX gene.

BACKGROUND: Variations in the WWOX gene have been identified as the leading cause of several central nervous system disorders. However, most previous reports have focused on the description of clinical phenotype, neglecting functional verification. Herein, we presented a case of a patient with developmental epileptic encephalopathy (DEE) caused by WWOX gene variation. CASE PRESENTATION: Our patient was a 13-month-old girl with abnormal facial features, including facial hypotonia, arched eyebrows, a broad nose, and a depressed nasal bridge. She also had sparse and yellow hair, a low anterior hairline, and a short neck. Before the age of 8 months, she was suffering from mild seizures. Her developmental delay gradually worsened, and she suffered infantile spasms. After treatment with vigabatrin, seizures subsided. WWOX gene homozygous variation c.172+1G>C was identified using whole exome sequencing. Further minigene assay confirmed that the variation site affected splicing, causing protein truncation and affecting its function. CONCLUSION: Clinical phenotype and minigene results suggest that WWOX gene homozygous variation c.172+1G>C can cause severe DEE. We also concluded that vigabatrin can effectively treat seizures.

Genome-wide identification of HSP90 gene family in Rosa chinensis and its response to salt and drought stresses.

Heat shock protein 90 (HSP90) is important for many organisms, including plants. Based on the whole genome information, the gene number, gene structure, evolutionary relationship, protein structure, and active site of the HSP90 gene family in Rosa chinensis and Rubus idaeus were determined, and the expression of the HSP90 gene under salt, and drought stresses in two rose varieties Wangxifeng and Sweet Avalanche were analyzed. Six and eight HSP90 genes were identified from R. chinensis and Ru. idaeus, respectively. Phylogenetic analysis revealed that the analyzed genes were divided into two Groups and four subgroups (Classes 1a, 1b, 2a, and 2b). Although members within the same classes displayed highly similar gene structures, while the gene structures and conserved domains of Group 1 (Class 1a and 1b) and the Group 2 (Class 2a and 2b) are different. Tandem and segmental duplication genes were found in Ru. idaeus, but not in R. chinensis, perhaps explaining the difference in HSP90 gene quantity in the two analyzed species. Analysis of cis-acting elements revealed abundant abiotic stress, photolight-response, and hormone-response elements in R. chinensis HSP90s. qRT-PCR analysis suggested that RcHSP90-1-1, RcHSP90-5-1 and RcHSP90-6-1 in Sweet Avalanche and Wangxifeng varieties played important regulatory roles under salt and drought stress. The analysis of protein structure and active sites indicate that the potential different roles of RcHSP90-1-1, RcHSP90-5-1, and RcHSP90-6-1 in salt and drought stresses may come from the differences of corresponding protein structures and activation sites. These data will provide information for the breeding of rose varieties with high stress resistance. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04052-0.

CPPF++: Uncertainty-Aware Sim2Real Object Pose Estimation by Vote Aggregation.

Object pose estimation constitutes a critical area within the domain of 3D vision. While contemporary state-of-the-art methods that leverage real-world pose annotations have demonstrated commendable performance, the procurement of such real training data incurs substantial costs. This paper focuses on a specific setting wherein only 3D CAD models are utilized as a priori knowledge, devoid of any background or clutter information. We introduce a novel method, CPPF++, designed for sim-to-real category-level pose estimation. This method builds upon the foundational point-pair voting scheme of CPPF, reformulating it through a probabilistic view. To address the challenge posed by vote collision, we propose a novel approach that involves modeling the voting uncertainty by estimating the probabilistic distribution of each point pair within the canonical space. Furthermore, we augment the contextual information provided by each voting unit through the introduction of N-point tuples. To enhance the robustness and accuracy of the model, we incorporate several innovative modules, including noisy pair filtering, online alignment optimization, and a tuple feature ensemble. Alongside these methodological advancements, we introduce a new category-level pose estimation dataset, named DiversePose 300. Empirical evidence demonstrates that our method significantly surpasses previous sim-to-real approaches and achieves comparable or superior performance on novel datasets. Our code is available on https://github.com/qq456cvb/CPPF2.

High-Performance One-Component Epoxy Adhesive Based on the Synergistic Effect of Lignin-Derived Triaryl-Imidazole and Phytic Acid.

Latent curing agents are essential in the formulation of one-component epoxy resins, yet they are seldom derived from fully biobased chemicals. In the present work, a fully biobased latent curing agent for epoxy resins (BIMPA) was produced by synthesizing an ionic complex of lignin-derived triaryl-imidazole (BIM) and phytic acid (PA). Benefiting from the synergistic effect of BIM and PA, the one-component epoxy resin, composed of BIMPA and commercially available E51, exhibits a storage stability of over 90 days. Upon heating, the ionic complex undergoes decomposition, liberating the active imidazole to cure the precursor. The resulting epoxy resins exhibited a flexural modulus of 3.09 GPa, a flexural strength of 107.47 MPa, a notched izod impact strength of 2.47 kJ/m3, and a shear strength of 41.02 MPa. The outcome can provide an effective supplement for the development of biobased epoxy resins.

LAYN Serves as a Prognostic Biomarker and Downregulates Tumor-Infiltrating CD8+ T Cell Function in Hepatocellular Carcinoma.

Background: Layilin (LAYN) represents a valuable prognostic biomarker across various tumor types, while also serving as an innovative indicator of dysfunctional or exhausted CD8+ T cells and exhibiting correlation with immune context. However, the immune function and prognostic significance of LAYN in hepatocellular carcinoma (HCC) remain unexplored. Therefore, our objective is to investigate the role of LAYN in CD8+ T cell exhaustion, clinical prognosis, and the tumor microenvironment within HCC. Methods: TIMER or GEPIA databases were used to analyze LAYN expression level and its correlation with immune infiltration in HCC. Bioinformatics analysis was conducted on TCGA and scRNA-seq cohorts. The evaluation of LAYN expression level in fresh specimens was performed through IF, IHC, and ELISA assays. Flow cytometry and mRNA-seq were employed to investigate co-expressed genes of LAYN, the LAYN+CD8+ T cell exhaustion signature and immune function. Cell proliferation ability and killing activity were assessed using CCK8 and CFSE/PI. Results: The expression level of LAYN in HCC tumors was significantly higher compared to peri-tumors. Patients with high levels of LAYN exhibited poorer OS. GO or KEGG analysis confirmed that LAYN was involved in immune response and was positively associated with CD8+ T cell immune infiltration levels. Furthermore, LAYN negatively regulated the immune function of CD8+ T cells, leading to dysfunctional phenotypes characterized by elevated levels of CD39, TIM3 and reduced levels of perforin, TNF-α, Ki-67. CFSE/PI assays demonstrated that LAYN+CD8+ T cells displayed decreased cytotoxic activity. Additionally, there was a positive correlation between LAYN and CD146 levels, which are involved in adhesion and localization processes of CD8+ T cells. Interestingly, blocking LAYN partially restored the exhaustion properties of CD8+ T cells. Conclusion: LAYN exhibits a strong correlation with immune infiltration in the TME and represents a novel biomarker for predicting clinical prognosis in HCC. Moreover, targeting LAYN may hold promise as an effective strategy for HCC immunotherapy.

Human impacts overwhelmed climate as the dominant factor controlling lacustrine organic matter accumulation in Erhai Lake 2000 years ago, Southwest China.

Climate and human activity are two important factors in regulating organic matter (OM) accumulation in the lake environment. However, when and how anthropogenic impacts have affected lacustrine OM accumulation in southwest China during the late Holocene have not yet been well defined. Here, a 16.3-kyr n-alkane record derived from Erhai Lake was used to trace OM sources and explore their connections to climate and human activity. The n-alkane distributions indicated that the dominant sediment sources shifted from terrestrial and aquatic plants to algae in the late Holocene. OM accumulation was closely related to catchment soil erosion, sediment transport, and deposition processes regulated by climate conditions before 5.0 cal. kyr B.P., following the patterns that stronger monsoon precipitation favoured more terrestrial and less aquatic OM input, and vice versa. From 5.0 to 2.0 cal. kyr B.P., the synchronous downwards trends in terrestrial OM input and precipitation intensity indicated that climate remained a major driving force for OM accumulation. However, sediment sources experienced large-magnitude and centennial-scale oscillations between allochthonous and autochthonous inputs, reflecting early human impacts appeared and lake ecosystems retained the self-regulated ability to recover from the basin-wide early moderate human disturbances. Afterwards, the increased (decreased) OM contributions from terrestrial (aquatic) plants contradicted the weakening monsoon precipitation since 2.0 cal. kyr B.P., indicating a dominant effect of human activities on OM accumulation. This change was accompanied by highly improved algae productivity and gradually elevated lacustrine trophic status, and the lake ecosystem eventually shifted into another state largely deviating from its climate-driven background due to intensified deforestation and agricultural cultivation. Regional comparison indicated that anthropogenic disturbances have temporal differences in southwest China. This study will further improve our understanding of past climate-human-environment interactions in southwest China.

Ratiometric Fluorescence Probes for In Situ Imaging of Membrane Tension in Live Cells.

Membrane tension is an important physical parameter of describing cellular homeostasis, and it is widely used in the study of cellular processes involving membrane deformation and reorganization, such as cell migration, cell spreading, and cell division. Despite the importance of membrane tension, direct measurement remains difficult. In this work, we developed a ratiometric fluorescent probe sensitive to membrane tension by adjusting the carbon chain structure based on polarity-sensitive fluorophores. The probe is sensitive to changes in membrane tension after cells were subjected to physical or chemical stimuli, such as osmotic shock, lipid peroxidation, and mechanical stress. When the polarity of the plasma membrane increases (the green/red ratio decreases) and the membrane tension increases, the relative magnitude of the membrane tension can be quantitatively calculated by fluorescence ratio imaging. Thus, the probe proved to be an efficient and sensitive membrane tension probe.

Ligand-Enabled ortho-Selective C-H Olefination of Tertiary Aniline Derivatives.

A highly ortho-selective CAr-H olefination of tertiary anilines without a directing group was developed. This reaction tolerated various substituted arenes and olefin coupling partners, affording ortho-olefination products in moderate to good yields. Preliminary mechanistic studies showed that N-Ac-d-Ala, Ag2CO3, and BQ were the key factors for tuning the regioselectivity from para to ortho. Density functional theory was used to achieve a theoretical understanding of the ortho selectivity.

Single-extracellular vesicle (EV) analyses validate the use of L1 Cell Adhesion Molecule (L1CAM) as a reliable biomarker of neuron-derived EVs.

Isolation of neuron-derived extracellular vesicles (NDEVs) with L1 Cell Adhesion Molecule (L1CAM)-specific antibodies has been widely used to identify blood biomarkers of CNS disorders. However, full methodological validation requires demonstration of L1CAM in individual NDEVs and lower levels or absence of L1CAM in individual EVs from other cells. Here, we used multiple single-EV techniques to establish the neuronal origin and determine the abundance of L1CAM-positive EVs in human blood. L1CAM epitopes of the ectodomain are shown to be co-expressed on single-EVs with the neuronal proteins ß-III-tubulin, GAP43, and VAMP2, the levels of which increase in parallel with the enrichment of L1CAM-positive EVs. Levels of L1CAM-positive EVs carrying the neuronal proteins VAMP2 and ß-III-tubulin range from 30% to 63%, in contrast to 0.8%-3.9% of L1CAM-negative EVs. Plasma fluid-phase L1CAM does not bind to single-EVs. Our findings support the use of L1CAM as a target for isolating plasma NDEVs and leveraging their cargo to identify biomarkers reflecting neuronal function.

Introduction of Cellulolytic Bacterium Bacillus velezensis Z2.6 and Its Cellulase Production Optimization.

Enzyme-production microorganisms typically occupy a dominant position in composting, where cellulolytic microorganisms actively engage in the breakdown of lignocellulose. Exploring strains with high yields of cellulose-degrading enzymes holds substantial significance for the industrial production of related enzymes and the advancement of clean bioenergy. This study was inclined to screen cellulolytic bacteria, conduct genome analysis, mine cellulase-related genes, and optimize cellulase production. The potential carboxymethylcellulose-hydrolyzing bacterial strain Z2.6 was isolated from the maturation phase of pig manure-based compost with algae residuals as the feedstock and identified as Bacillus velezensis. In the draft genome of strain Z2.6, 31 related cellulolytic genes were annotated by the CAZy database, and further validation by cloning documented the existence of an endo-1,4-ß-D-glucanase (EC 3.2.1.4) belonging to the GH5 family and a ß-glucosidase (EC 3.2.1.21) belonging to the GH1 family, which are predominant types of cellulases. Through the exploration of ten factors in fermentation medium with Plackett-Burman and Box-Behnken design methodologies, maximum cellulase activity was predicted to reach 2.98 U/mL theoretically. The optimal conditions achieving this response were determined as 1.09% CMC-Na, 2.30% salinity, and 1.23% tryptone. Validation under these specified conditions yielded a cellulose activity of 3.02 U/mL, demonstrating a 3.43-fold degree of optimization. In conclusion, this comprehensive study underscored the significant capabilities of strain Z2.6 in lignocellulolytic saccharification and its potentialities for future in-depth exploration in biomass conversion.

Peri-coronary fat attenuation index combined with high-risk plaque characteristics quantified from coronary computed tomography angiography for risk stratification in new-onset chest pain individuals without acute myocardial infarction.

This study aims to evaluate the role of the peri-coronary Fat Attenuation Index (FAI) and High-Risk Plaque Characteristics (HRPC) in the assessment of coronary heart disease risk. By conducting coronary CT angiography and coronary angiography on 217 patients with newly developed chest pain (excluding acute myocardial infarction), their degree of vascular stenosis, FAI, and the presence and quantity of HRPC were assessed. The study results demonstrate a correlation between FAI and HRPC, and the combined use of FAI and HRPC can more accurately predict the risk of major adverse cardiovascular events (MACE). Additionally, the study found that patients with high FAI were more prone to exhibit high-risk plaque characteristics, severe stenosis, and multiple vessel disease. After adjustment, the combination of FAI and HRPC improved the ability to identify and reclassify MACE. Furthermore, the study identified high FAI as an independent predictor of MACE in patients undergoing revascularization, while HRPC served as an independent predictor of MACE in patients not undergoing revascularization. These findings suggest the potential clinical value of FAI and HRPC in the assessment of coronary heart disease risk, particularly in patients with newly developed chest pain excluding acute myocardial infarction.