A mechanism linking ferroptosis and ferritinophagy in melatonin-related improvement of diabetic brain injury.

Ferroptosis and ferritinophagy play critical roles in various disease contexts. Herein, we observed that ferroptosis and ferritinophagy were induced both in the brains of mice with diabetes mellitus (DM) and neuronal cells after high glucose (HG) treatment, as evidenced by decreases in GPX4, SLC7A11, and ferritin levels, but increases in NCOA4 levels. Interestingly, melatonin administration ameliorated neuronal damage by inhibiting ferroptosis and ferritinophagy both in vivo and in vitro. At the molecular level, we found that not only the ferroptosis inducer p53 but also the ferritinophagy mediator NCOA4 was the potential target of miR-214-3p, which was downregulated by DM status or HG insult, but was increased after melatonin treatment. However, the inhibitory effects of melatonin on ferroptosis and ferritinophagy were blocked by miR-214-3p downregulation. These findings suggest that melatonin is a potential drug for improving diabetic brain damage by inhibiting p53-mediated ferroptosis and NCOA4-mediated ferritinophagy through regulating miR-214-3p in neurons.

J-Aggregate Promoting NIR-II Emission for Fluorescence/ Photoacoustic Imaging-Guided Phototherapy.

J-aggregate is a promising strategy to enhance second near-infrared window (NIR-II) emission, while the controlled synthesis of J-aggregated NIR-II dyes is a huge challenge because of the lack of molecular design principle. Herein, bulk spiro[fluorene-9,9'-xanthene] functionalized benzobisthiadiazole-based NIR-II dyes (named BSFX-BBT and OSFX-BBT) were synthesized with different alkyl chains. The weak repulsion interaction between the donor and acceptor units and the S…N secondary interactions make the dyes to adopt a co-planar molecular conformation and display a peak absorption > 880 nm in solution. Importantly, BSFX-BBT can form a desiring J-aggregate in the condensed state, and femtosecond transient absorption spectra reveal that the excited states of J-aggregate are the radiative states, and J-aggregate can facilitate stimulated emission. Consequently, the J-aggregated nanoparticles (NPs) display a peak emission at 1124 nm with a high relative quantum yield of 0.81%. The efficient NIR-II emission, good photothermal effect and biocompatibility make the J-aggregated NPs demonstrate efficient antitumor efficacy via fluorescence/photoacoustic imaging-guided phototherapy. The paradigm illustrates that tuning the aggregate states of NIR-II dye via spiro-functionalized strategy is an effective approach to enhance photo-theranostic performance. This article is protected by copyright. All rights reserved.

Ultra-processed food consumption and chronic kidney disease risk: a systematic review and dose-response meta-analysis.

Background: High intake of ultra-processed food (UPF) has been associated with increased risk of chronic kidney disease(CKD), but the results remain inconsistent. We therefore performed this systematic review and dose­response meta-analysis of observational studies that shed light on the association between UPF consumption and the risk of CKD. Methods: A systematic literature search of PubMed, Embase, Web of Science, Scopus and China National Knowledge Infrastructure (CNKI) databases was carried out to find the eligible articles published up to October 31, 2023. Random-effects or fixed-effects models were used to pool the relative risks(RRs) and their 95% confidence intervals (CIs).The potential sources of heterogeneity across studies were examined using the Cochran's Q test and I-square(I2). Publication bias was examined using the visual inspection of asymmetry in funnel plots and quantified by Begg's and Egger's tests. Results: Eight studies (six cohort and two cross-sectional studies) exploring the association between UPF consumption and risk of CKD, were included in the final analysis. The pooled analyses revealed that high consumption of UPF was associated with an increased risk of CKD (RR = 1.25; 95%CI: 1.09­1.42, p < 0.0001). Moreover, a 10% increase of UPF consumption was associated with a 7% higher risk of CKD (RR = 1.07; 95%CI: 1.04­1.10, p < 0.001). Dose­response analysis of all included studies showed a linear association between UPF consumption and the risk of CKD (RR = 1.02; 95%CI:0.99­1.05, Pdose­response = 0.178, Pnonlinearity = 0.843). Conclusion: Our findings indicate that high consumption of UPF is significantly associated with an increased risk of CKD. Future research with prospective design is required to confirm this positive association.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023478483, PROSPERO identifier CRD42023478483.

PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. METHODS: RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. RESULTS: PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. CONCLUSIONS: PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

MILIP Binding to tRNAs Promotes Protein Synthesis to Drive Triple-Negative Breast Cancer.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment. SIGNIFICANCE: LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.

Collective decision-making and spatial patterns in orientation of an endemic ungulate on the Tibetan Plateau.

Group living animals form striking aggregation patterns and display synchronization, polarization, and collective intelligence. Though many collective behavioral studies have been conducted on small animals like insects and fish, research on large animals is still rare due to the limited availability of field collective data. We used drones to record videos and analyzed the decision-making and behavioral spatial patterns in orientation of Kiang (Tibetan wild ass, Equus kiang). Leadership is unevenly distributed among Kiang, with the minority initiating majority behavior-shift decisions. Decisions of individual to join are driven by imitation between group members, and are largely dependent on the number of members who have already joined. Kiang respond to the behavior and position of neighbors through different strategies. They strongly polarize when moving, therefore adopting a linear alignment. When vigilant, orientation deviation increases as they form a tighter group. They remain scattered while feeding and, in that context, adopt a side-by-side alignment. This study reveals partially-shared decision-making among Kiang, whereby copying neighbors provides the wisdom to thrive in harsh conditions. This study also suggests that animals' spatial patterns in orientation depend largely on their behavioral states in achieving synchronization.

Genome-Wide Identification, Characterization, and Expression Analysis of the BES1 Family Genes under Abiotic Stresses in Phoebe bournei.

The BRI1 EMS suppressor 1(BES1) transcription factor is a crucial regulator in the signaling pathway of Brassinosteroid (BR) and plays an important role in plant growth and response to abiotic stress. Although the identification and functional validation of BES1 genes have been extensively explored in various plant species, the understanding of their role in woody plants-particularly the endangered species Phoebe bournei (Hemsl.) Yang-remains limited. In this study, we identified nine members of the BES1 gene family in the genome of P. bournei; these nine members were unevenly distributed across four chromosomes. In our further evolutionary analysis of PbBES1, we discovered that PbBES1 can be divided into three subfamilies (Class I, Class II, and Class IV) based on the evolutionary tree constructed with Arabidopsis thaliana, Oryza sativa, and Solanum lycopersicum. Each subfamily contains 2-5 PbBES1 genes. There were nine pairs of homologous BES1 genes in the synteny analysis of PbBES1 and AtBES1. Three segmental replication events and one pair of tandem duplication events were present among the PbBES1 family members. Additionally, we conducted promoter cis-acting element analysis and discovered that PbBES1 contains binding sites for plant growth and development, cell cycle regulation, and response to abiotic stress. PbBES1.2 is highly expressed in root bark, stem bark, root xylem, and stem xylem. PbBES1.3 was expressed in five tissues. Moreover, we examined the expression profiles of five representative PbBES1 genes under heat and drought stress. These experiments preliminarily verified their responsiveness and functional roles in mediating responses to abiotic stress. This study provides important clues to elucidate the functional characteristics of the BES1 gene family, and at the same time provides new insights and valuable information for the regulation of resistance in P. bournei.

Development of a stable genetic transformation system in Erigeron breviscapus: a case study with EbYUC2 in relation to leaf number and flowering time.

MAIN CONCLUSION: A stable genetic transformation system for Erigeron breviscapus was developed. We cloned the EbYUC2 gene and genetically transformed it into Arabidopsis thaliana and E. breviscapus. The leaf number, YUC2 gene expression, and the endogenous auxin content in transgenic plants were significantly increased. Erigeron breviscapus is a prescription drug for the clinical treatment of cardiovascular and cerebrovascular diseases. The rosette leaves have the highest content of the major active compound scutellarin and are an important component in the yield of E. breviscapus. However, little is known about the genes related to the leaf number and flowering time of E. breviscapus. In our previous study, we identified three candidate genes related to the leaf number and flowering of E. breviscapus by combining resequencing data and genome-wide association study (GWAS). However, their specific functions remain to be characterized. In this study, we cloned and transformed the previously identified full-length EbYUC2 gene into Arabidopsis thaliana, developed the first stable genetic transformation system for E. breviscapus, and obtained the transgenic plants overexpressing EbYUC2. Compared with wild-type plants, the transgenic plants showed a significant increase in the number of leaves, which was correlated with the increased expression of EbYUC2. Consistently, the endogenous auxin content, particularly indole-3-acetic acid, in transgenic plants was also significantly increased. These results suggest that EbYUC2 may control the leaf number by regulating auxin biosynthesis, thereby laying a foundation for revealing the molecular mechanism governing the leaf number and flowering time of E. breviscapus.

Topotactic Conversion of Titanium-Oxo Clusters to a Stable TOC-Based Metal-Organic Framework with the Selective Adsorption of Cationic Dyes.

Titanium-oxo cluster (TOC)-based metal-organic frameworks (MOFs) have received considerable attention in recent years due to their ability to expand the application of TOCs to fields that require highly stable frameworks. Herein, a new cyclic TOC formulated as [Ti6O6(OiPr)8(TTFTC)(phen)2]2 (1, where TTFTC = tetrathiafulvalene tetracarboxylate and phen = phenanthroline) was crystallographically characterized. TOC 1 takes a rectangular ring structure with two phen-modified Ti6 clusters as the width and two TTFTC ligands as the length. An intracluster ligand-to-ligand (TTF-to-phen) charge transfer in 1 was found for TOCs for the first time. Compound 1 undergoes topotactic conversion to generate stable TOC-MOF P1, in which the rectangular framework in 1 formed by a TOC core and ligands is retained, as verified by comprehensive characterization. P1 shows an efficient and rapid selective adsorption capacity for cationic dyes. The experimental adsorption capacity (qex) of P1 reaches a value of up to 789.2 mg/g at 298 K for the crystal violet dye, which is the highest among those of various adsorbents. The calculated models are first used to reveal the structure-property relationship of the cyclic host to different guest dyes. The results further confirmed the host MOF structure of P1.

A new phenolic compound from Persicaria capitata.

Persicaria capitata was a frequently used Hmong medicinal flora in China. In this study, one new phenolic compound, capitaone A (1) together with 20 known ones, were isolated from the whole herb of P. capitata. Among them, 7 components (4, 9-11, 15-16, 20-21) were discovered from P. capitata for the first time. Their chemical structures were elucidated on the basis of extensive NMR and MS spectrum. Furthermore, three compounds (15, 20, 21) displayed remarkable cytotoxic activities against two human cancer cell lines (A549 and HepG2).

Challenges and opportunities in human dimensions behind cat-wildlife conflict.

Because global anthropogenic activities cause vast biodiversity loss, human dimensions research is essential to forming management plans applicable to biodiversity conservation outside wilderness areas. Engaging public participation is crucial in this context to achieve social and environmental benefits. However, knowledge gaps remain in understanding how a balance between conservation and public demands can be reached and how complicated sociocultural contexts in the Anthropocene can be incorporated in conservation planning. We examined China's nationwide conflict between free-ranging cats (owned cats that are allowed to go outdoors or homeless cats living outdoors) and wildlife to examine how a consensus between compassion and biodiversity conservation can help in decision-making. We surveyed a random sample of people in China online. Over 9000 questionnaires were completed (44.2% response). In aggregate, respondents reported approximately 29 million free-ranging owned cats and that over 5 million domestic cats per year become feral in mainland China. Respondents who were cat owners, female, and religious were more likely to deny the negative impacts of cats on wildlife and ongoing management strategies and more supportive of stray cat shelters, adoption, and community-based fund raising than nonowners, male, and nonreligious respondents (p < 0.05). Free-ranging cat ownership and abandonment occurred less with owners with more knowledge of biodiversity and invasive species than with respondents with less knowledge of these subjects (p < 0.05). We recommend that cat enthusiasts and wildlife conservationists participate in community-based initiatives, such as campaigns to keep cats indoors. Our study provides a substantially useful framework for other regions where free-ranging cats are undergoing rapid expansion.

Retos y oportunidades de las dimensiones humanas detrás del conflicto entre gatos y fauna Resumen Debido a que las actividades antropogénicas globales causan una enorme pérdida de la biodiversidad, la investigación sobre las dimensiones humanas es esencial para generar planes de manejo aplicables a la conservación de la biodiversidad fuera de las áreas silvestres. Es muy importante lograr que el público participe en este contexto para obtener los beneficios sociales y ambientales. Sin embargo, todavía existen vacíos en el conocimiento sobre cómo lograr el balance entre la conservación y las demandas públicas y cómo incorporar los contextos socioculturales complejos del Antropoceno a la planeación de la conservación. Analizamos el conflicto nacional entre los gatos libres (gatos callejeros o gatos domésticos que se les permite salir) y la fauna en China para estudiar cómo un consenso entre la compasión y la conservación de la biodiversidad puede ayudar en la toma de decisiones. Encuestamos en línea a una muestra aleatoria de personas en China. Se completaron más de 9000 cuestionarios (44.2% de respuesta). En total, los respondientes reportaron un aproximado de 29 millones de gatos libres y que más de cinco millones de gatos domésticos se vuelven ferales al año en China. Quienes respondieron y son dueños de gatos, mujeres y religiosos tuvieron la mayor probabilidad de negar los impactos negativos de los gatos sobre la fauna y de las estrategias actuales de manejo y de mostrar más apoyo por los refugios de gatos abandonados, la adopción y de la recaudación de fondos comunitaria que quienes no son dueños, no son religiosos y son hombres (p < 0.05). La propiedad de gatos libres y el abandono ocurrieron menos con los dueños con más conocimiento sobre la biodiversidad y las especies invasoras que con los respondientes con menos conocimiento sobre estos temas (p < 0.05). Recomendamos que los aficionados a los gatos y los conservacionistas de la fauna participen en las iniciativas comunitarias; por ejemplo, campañas para mantener a los gatos dentro de casa. Nuestro estudio proporciona un marco sustancialmente útil para otras regiones en donde los gatos libres se encuentran en rápida expansión.

Charge-Localized Retention and Long-Term Memory Enabled by Cooperating Sterically Confined Molecular Crystallization with Spiro[fluorene-9,9'-xanthene]-Based Csp3-Hindrance.

Charge localization of memory materials plays a crucial role in the endurance and retention ability of organic nonvolatile memory, which is completely opposite from the charge delocalization of high-mobility materials. However, charge transfer of both though-space and through-bond based on molecular design principles still faces challenges. Herein, a nonplanar wide-bandgap semiconductor with Csp3-hindrance (DOCH3-DDPA-SFX) has been designed and synthesized. An effective crystallization effect of self-assembled two-dimensional nanosheets on charge trapping dynamics and kinetics is visualized by Kelvin probe force microscopy (KPFM). The trapped charges are localized completely on a single nanosheet, which has better charge trapping and retention properties than an amorphous film. Meanwhile, crystallization also greatly improves structure stability. Combining DFT theoretical calculations, the mechanisms of localization and long-term retention are discussed. The steric crystallization effects on the charge localization will guide the effective design of single-component semiconducting charge-memory materials by molecular assembly and aggregate control for high-performance organic memory.

Comprehensive analysis and experimental verification of the mechanism of action of T cell-mediated tumor-killing related genes in Colon adenocarcinoma.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy of the digestive tract. A new prognostic scoring model for colon adenocarcinoma (COAD) is developed in this study based on the genes involved in tumor cell-mediated killing of T cells (GSTTKs), accurately stratifying COAD patients, thus improving the current status of personalized treatment. METHOD: The GEO and TCGA databases served as the sources of the data for the COAD cohort. This study identified GSTTKs-related genes in COAD through single-factor Cox analysis. These genes were used to categorize COAD patients into several subtypes via unsupervised clustering analysis. The biological pathways and tumor microenvironments of different subgroups were compared. We performed intersection analysis between different subtypes to obtain intersection genes. Single-factor Cox regression analysis and Lasso-Cox analysis were conducted to establish clinical prognostic models. Two methods are used to assess the accuracy of model predictions: ROC and Kaplan-Meier analysis. Next, the prediction model was further validated in the validation cohort. Differential immune cell infiltration between various risk categories was identified via single sample gene set enrichment analysis (ssGSEA). The COAD model's gene expression was validated via single-cell data analysis and experiments. RESULT: We established two distinct GSTTKs-related subtypes. Biological processes and immune cell tumor invasion differed significantly between various subtypes. Clinical prognostic models were created using five GSTTKs-related genes. The model's risk score independently served as a prognostic factor. COAD patients were classified as low- or high-risk depending on their risk scores. Patients in the low-risk category recorded a greater chance of surviving. The outcomes from the validation cohort match those from the training set. Risk scores and several tumor-infiltrating immune cells were strongly correlated, according to ssGSEA. Single-cell data illustrated that the model's genes were linked to several immune cells. The experimental results demonstrated a significant increase in the expression of HOXC6 in colon cancer tissue. CONCLUSION: Our research findings established a new gene signature for COAD. This gene signature helps to accurately stratify the risk of COAD patients and improve the current status of individualized care.

Altered dynamic amplitude of low-frequency fluctuation in individuals at high risk for Alzheimer's disease.

The brain's dynamic spontaneous neural activity is significant in supporting cognition; however, how brain dynamics go awry in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) remains unclear. Thus, the current study aimed to investigate the dynamic amplitude of low-frequency fluctuation (dALFF) alterations in patients at high risk for Alzheimer's disease and to explore its correlation with clinical cognitive assessment scales, to identify an early imaging sign for these special populations. A total of 152 participants, including 72 SCD patients, 44 MCI patients and 36 healthy controls (HCs), underwent a resting-state functional magnetic resonance imaging and were assessed with various neuropsychological tests. The dALFF was measured using sliding-window analysis. We employed canonical correlation analysis (CCA) to examine the bi-multivariate correlations between neuropsychological scales and altered dALFF among multiple regions in SCD and MCI patients. Compared to those in the HC group, both the MCI and SCD groups showed higher dALFF values in the right opercular inferior frontal gyrus (voxel P < .001, cluster P < .05, correction). Moreover, the CCA models revealed that behavioural tests relevant to inattention correlated with the dALFF of the right middle frontal gyrus and right opercular inferior frontal gyrus, which are involved in frontoparietal networks (R = .43, P = .024). In conclusion, the brain dynamics of neural activity in frontal areas provide insights into the shared neural basis underlying SCD and MCI.

Withanolides from the active extract of Physalis angulate and their anti-hepatic fibrosis effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis angulata L., a traditional Chinese medicine called "Kuzhi" in China, was used traditionally to treat liver diseases (eg. icterus, hepatitis) as well as malaria, asthma, and rheumatism. AIM OF THE STUDY: Our study aimed to investigate the withanolides with anti-hepatic fibrosis effect from P. angulate. MATERIALS AND METHODS: Withanolides were obtained from the EtOH extract of P. angulate by bioassay-molecular networking analysis-guided isolation using column chromatography and normal/reversed-phase semipreparative HPLC. The structures of new withanolides were elucidated by combinations of spectroscopic techniques with NMR and ECD calculations. MTT cell viability assay, AO/EB staining method, cell wound healing assay, ELISA and Western blot experiments were employed to evaluate the anti-hepatic fibrosis activity and to uncover related mechanism. Molecular docking analysis and cellular thermal shift assay were used to evaluate and verify the interaction between the active withanolides and their potential targets. RESULTS: Eight unreported withanolides, withagulides A-H (1-8), along with twenty-eight known ones were obtained from P. angulate. Withanolides 6, 9, 10, 24, 27, and 29-32 showed marked anti-hepatic fibrosis effect with COL1A1 expression inhibition above 50 %. Physalin F (9), the main component in the active fraction, significantly decreased the TGF ß1-stimulated expressions of collagen I and α-SMA in LX-2 cells. Mechanism study revealed that physalin F exerted its anti-hepatic fibrosis effect via the PI3K/AKT/mTOR signaling pathway. CONCLUSION: This study suggested that withanolides were an important class of natural products with marked anti-hepatic fibrosis effect. The main withanolide physalin F might be a promising candidate for hepatic fibrosis treatment. The work provided experimental foundation for the use of P. angulate to treat hepatic fibrosis.

deMULTIplex2: robust sample demultiplexing for scRNA-seq.

Sample multiplexing enables pooled analysis during single-cell RNA sequencing workflows, thereby increasing throughput and reducing batch effects. A challenge for all multiplexing techniques is to link sample-specific barcodes with cell-specific barcodes, then demultiplex sample identity post-sequencing. However, existing demultiplexing tools fail under many real-world conditions where barcode cross-contamination is an issue. We therefore developed deMULTIplex2, an algorithm inspired by a mechanistic model of barcode cross-contamination. deMULTIplex2 employs generalized linear models and expectation-maximization to probabilistically determine the sample identity of each cell. Benchmarking reveals superior performance across various experimental conditions, particularly on large or noisy datasets with unbalanced sample compositions.

The Synergistic Effect between Metal and Sulfur Vacancy to Boost CO2 Reduction Efficiency: A Study on Descriptor Transferability and Activity Prediction.

Both metal center active sites and vacancies can influence the catalytic activity of a catalyst. A quantitative model to describe the synergistic effect between the metal centers and vacancies is highly desired. Herein, we proposed a machine learning model to evaluate the synergistic index, PSyn, which is learned from the possible pathways for CH4 production from CO2 reduction reaction (CO2RR) on 26 metal-anchored MoS2 with and without sulfur vacancy. The data set consists of 1556 intermediate structures on metal-anchored MoS2, which are used for training. The 2028 structures from the literature, comprising both single active site and dual active sites, are used for external test. The XGBoost model with 3 features, including electronegativity, d-shell valence electrons of metal, and the distance between metal and vacancy, exhibited satisfactory prediction accuracy on limiting potential. Fe@Sv-MoS2 and Os@MoS2 are predicted to be promising CO2RR catalysts with high stability, low limiting potential, and high selectivity against hydrogen evolution reactions (HER). Based on some easily accessible descriptors, transferability can be achieved for both porous materials and 2D materials in predicting the energy change in the CO2RR and nitrogen reduction reaction (NRR). Such a predictive model can also be applied to predict the synergistic effect of the CO2RR in other oxygen and tungsten vacancy systems.

Phomopsterone B Alleviates Liver Fibrosis through mTOR-Mediated Autophagy and Apoptosis Pathway.

Liver fibrosis is the initial pathological process of many chronic liver diseases. Targeting hepatic stellate cell (HSC) activation is an available strategy for the therapy of liver fibrosis. We aimed to explore the anti-liver fibrosis activity and potential mechanism of phomopsterone B (PB) in human HSCs. The results showed that PB effectively attenuated the proliferation of TGF-ß1-stimulated LX-2 cells in a concentration-dependent manner at doses of 1, 2, and 4 µM. Quantitative real-time PCR and Western blot assays displayed that PB significantly reduced the expression levels of α-SMA and collagen I/III. AO/EB and Hoechst33342 staining and flow cytometry assays exhibited that PB promoted the cells' apoptosis. Meanwhile, PB diminished the number of autophagic vesicles and vacuolated structures, and the LC3B fluorescent spots indicated that PB could effectively inhibit the accretion of autophagosomes in LX-2 cells. Moreover, rapamycin and MHY1485 were utilized to further investigate the effect of mTOR in autophagy and apoptosis. The results demonstrated that PB regulated autophagy and apoptosis via the mTOR-dependent pathway in LX-2 cells. In summary, this is the first evidence that PB effectively alleviates liver fibrosis in TGF-ß1-stimulated LX-2 cells, and PB may be a promising candidate for the prevention of liver fibrosis.

Adipose-derived stem cell exosomes promote tumor characterization and immunosuppressive microenvironment in breast cancer.

Adipose-derived stem cells (ASC) or autologous fat transplantation could be used to ameliorate breast cancer postoperative deformities. This study aims to explore the action of ASC and ASC-exosomes (ASC-exos) in breast cancer characterization and tumor microenvironment immunity, which provided a new method into the application of ASC-exos. ASC were extracted from human adipose tissue for the isolation and verification of ASC-exos. ASC-exos were co-cultured with CD4+T cells, CD14+ monocytes and MCF-7 cells, respectively. The tumor formation of nude mice was also constructed. Cell characterization was determined by CCK8, scratch assay, and Transwell. Hematoxylin-eosin (HE), immunohistochemistry (IHC) and immunofluorescence (IF) staining were used to observe the histopathology and protein expression. CD4+T cell and CD14+ monocytes differentiation was detected by flow cytometry. Western blot, qRT-PCR and RNAseq were used to detect the action of ASC-exos on gene and protein expression. CD4+T cells could take up ASC-exos. ASC-exos inhibited Th1 and Th17 differentiation and promoted Treg differentiation of CD4+T cells. ASC-exos inhibited M1 differentiation and promoted M2 differentiation of CD14+ monocytes. ASC-exos promoted the migration, proliferation, and invasion, while inhibited apoptosis of MCF-7 cells. ASC-exos promoted the tumor formation of breast cancer. The effect of ASC-exos on tumor microenvironment immunity was in accordance with the above in vitro results. TOX, CD4 and LYZ1 genes were upregulated, while Mettl7b and Serpinb2 genes were downregulated in ASC-exos group. Human T-cell leukemia virus 1 infection pathway was significantly enriched in ASC-exos. Thus, ASC-exos promoted breast cancer characterization and tumor microenvironment immunosuppression by regulating macrophage and T cell differentiation.