Integrating Mendelian randomization and single-cell RNA sequencing to identify therapeutic targets of baicalin for type 2 diabetes mellitus.

Background: Alternative and complementary therapies play an imperative role in the clinical management of Type 2 diabetes mellitus (T2DM), and exploring and utilizing natural products from a genetic perspective may yield novel insights into the mechanisms and interventions of the disorder. Methods: To identify the therapeutic target of baicalin for T2DM, we conducted a Mendelian randomization study. Druggable targets of baicalin were obtained by integrating multiple databases, and target-associated cis-expression quantitative trait loci (cis-eQTL) originated from the eQTLGen consortium. Summary statistics for T2DM were derived from two independent genome-wide association studies available through the DIAGRAM Consortium (74,124 cases vs. 824,006 controls) and the FinnGen R9 repository (9,978 cases vs. 12,348 controls). Network construction and enrichment analysis were applied to the therapeutic targets of baicalin. Colocalization analysis was utilized to assess the potential for the therapeutic targets and T2DM to share causative genetic variations. Molecular docking was performed to validate the potency of baicalin. Single-cell RNA sequencing was employed to seek evidence of therapeutic targets' involvement in islet function. Results: Eight baicalin-related targets proved to be significant in the discovery and validation cohorts. Genetic evidence indicated the expression of ANPEP, BECN1, HNF1A, and ST6GAL1 increased the risk of T2DM, and the expression of PGF, RXRA, SREBF1, and USP7 decreased the risk of T2DM. In particular, SREBF1 has significant interaction properties with other therapeutic targets and is supported by strong colocalization. Baicalin had favorable combination activity with eight therapeutic targets. The expression patterns of the therapeutic targets were characterized in cellular clusters of pancreatic tissues that exhibited a pseudo-temporal dependence on islet cell formation and development. Conclusion: This study identified eight potential targets of baicalin for treating T2DM from a genetic perspective, contributing an innovative analytical framework for the development of natural products. We have offered fresh insights into the connections between therapeutic targets and islet cells. Further, fundamental experiments and clinical research are warranted to delve deeper into the molecular mechanisms of T2DM.

[Analysis of Heavy Metal Sources in Farmland Soil of Sewage Irrigation and Industrial Complex Area Based on APCS-MLR and PMF].

The contents of eight heavy metals （Cr, Ni, Cu, Zn, Cd, Pb, As, and Hg） were determined based on the surface soil samples of sewage irrigation and industrial complex in Kaifeng City. The absolute factor analysis-multiple linear regression （APCS-MLR） model and positive matrix factorization （PMF） model were used to analyze the sources and contribution rates of heavy metals in soil combined with correlation analysis and systematic cluster analysis. The results showed that： ① The average values of ω（Cr）, ω（Ni）, ω（Cu）, ω（Zn）, ω（Cd）, ω（Pb）, ω（As）, and ω（Hg） in the study area were 52.19, 25.00, 42.03, 323.53, 1.79, 53.45, 9.43, and 0.20 mg·kg-1, respectively, and Cr, Ni, and As are lower than the background values of tidal soil. Cu, Zn, Cd, Pb, and Hg are higher than the background values of the tidal soil. ② There were four sources of the eight heavy metals： natural sources, agricultural sewage irrigation sources, industrial atmospheric sedimentation sources, and transportation sources. Cr and Ni were mainly from natural sources； Cu, Zn, Cd, and Pb were mainly from agricultural sewage irrigation and transportation sources； As was mainly from natural sources and agricultural sewage irrigation； and Hg was mainly from industrial atmospheric sedimentation. ③ The APCS-MLR and PMF source analysis results indicated that industrial and agricultural activities were the main sources of heavy metals in the soil of the study area. The average contribution rates of APCS-MLR in the nine sampling areas of the research area were 76.01% （natural sources and agricultural sewage irrigation sources）, 22.71% （industrial atmospheric sedimentation sources and transportation sources）, and 1.28% （unknown sources）. The average contribution rates of PMF were 59.66% （natural sources and agricultural sewage irrigation sources） and 40.34% （industrial atmospheric sedimentation sources and transportation sources）. The source analysis results of the LZ, XZ, NLT, PT, YLZ, and BC models were basically consistent, and WL was better in the APCS-MLR model, whereas SG and QT were better in the PMF model. The research results can provide a scientific basis for the prevention and control of soil heavy metal pollution and environmental remediation.

Improving hydrological modeling to close the gap between elevated CO2 concentration and crop response: Implications for water resources.

Rising atmospheric carbon dioxide concentrations ([CO2]) affect crop growth and the associated hydrological cycle through physiological forcing, which is mainly regulated by reducing stomatal conductance (gs) and increasing leaf area index (LAI). However, reduced gs and increased LAI can affect crop water consumption, and the overall effects need to be quantified under elevated [CO2]. Here we develop a SWAT-gs-LAI model by incorporating a nonlinear gs-CO2 equation and a missing LAI-CO2 relationship to investigate the responses of water consumption of grain maize, maize yield, and losses of water and soil to elevated [CO2] in the Upper Mississippi River Basin (UMRB; 492,000 km2). Results exhibited enhanced maize yield with decreased water consumption for increases in [CO2] from 495 ppm to 825 ppm during the historical period (1985-2014). Elevated [CO2] promoted surface runoff but suppressed sediment loss as the predominant impact of LAI-CO2 leading to enhanced surface cover. A comprehensive analysis of future climate change showed increased maize water consumption in comparison to the historical period, driven by the more pronounced effects of overall climate change rather than solely elevated [CO2]. Generally, future climate change promoted maize yield in most regions of the UMRB for three Shared Socioeconomic Pathway (SSP) scenarios. Surface runoff was shown to increase generally in the future with sediment loss increasing by an average of 0.39, 0.42, and 0.66 ton ha-1 for SSP1-2.6, SSP2-4.5, and SSP5-8.5, respectively. This was due to negative climatic change effects largely surpassing the positive effect of elevated [CO2], particularly in zones near the middle and lower stream. Our results underscore the crucial role of employing a physically-based model to represent crop physiological processes under elevated [CO2] conditions, improving the reliability of predictions related to crop growth and the hydrological cycle.

Response of hydrology and nutrient losses to different extreme rainfall conditions in a coastal watershed influenced by orchards.

Global warming is altering the frequency of extreme rainfall events and introducing uncertainties for non-point source pollution (NPSP). This research centers on orchard-influenced planting areas (OIPA) in the Wulong River Watershed of Shandong Province, China, which are known for their heightened nitrogen (N) and phosphorus (P) pollution. Leveraging meteorological data from both historical (1989-2018) and projected future periods (2041-2100), this research identified five extreme rainfall indices (ERI): R10 (moderate rain), R20 (heavy rain), R50 (rainstorm), R95p (Daily rainfall between the 95th and 99th percentile of the rainfall), and R99p (>99th percentile). Utilizing an advanced watershed hydrological model, SWAT-CO2, this study carried out a comparison between ERI and average conditions and evaluated the effects of ERI on the hydrology and nutrient losses in this coastal watershed. The findings revealed that the growth multiples of precipitation in the OIPA for five ERI varied between 16 and 59 times for the historical period and 14 to 65 times for future climate scenarios compared to the average conditions. The most pronounced increases in surface runoff and total phosphorus (TP) loss were observed with R50, R95p, and R99p, showing growth multiples as high as 352 and 330 times, and total nitrogen (TN) growth multiples varied between 4.6 and 30.3 times. The contribution rates of R50 and R99p for surface runoff and TP loss in the OIPA during all periods exceeded 55%, however, TN exhibited the opposite trend, primarily due to the dominated NO3-N leaching in the sandy soil. This research revealed how the OIPA reacts to different ERI and pinpointed essential elements influencing water and nutrient losses.

Disulfide-stabilized trimeric hemagglutinin ectodomains provide enhanced heterologous influenza protection.

Influenza virus infection poses a continual menace to public health. Here, we developed soluble trimeric HA ectodomain vaccines by establishing interprotomer disulfide bonds in the stem region, which effectively preserve the native antigenicity of stem epitopes. The stable trimeric H1 ectodomain proteins exhibited higher thermal stabilities in comparison with unmodified HAs and showed strong binding activities towards a panel of anti-stem cross-reactive antibodies that recognize either interprotomer or intraprotomer epitopes. Negative stain transmission electron microscopy (TEM) analysis revealed the stable trimer architecture of the interprotomer disulfide-stapled WA11#5, NC99#2, and FLD#1 proteins as well as the irregular aggregation of unmodified HA molecules. Immunizations of mice with those trimeric HA ectodomain vaccines formulated with incomplete Freund's adjuvant elicited significantly more potent cross-neutralizing antibody responses and offered broader immuno-protection against lethal infections with heterologous influenza strains compared to unmodified HA proteins. Additionally, the findings of our study indicate that elevated levels of HA stem-specific antibody responses correlate with strengthened cross-protections. Our design strategy has proven effective in trimerizing HA ectodomains derived from both influenza A and B viruses, thereby providing a valuable reference for designing future influenza HA immunogens.

A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/ß-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.

Engineering a Ce Promoter into a Three-Dimensional Porous Mo2C@NC Heterostructure for Hydrogen Evolution Electrocatalysis via Weakening the Mo-H Bond Strength.

The pursuit of highly efficient electrocatalysts for the alkaline hydrogen evolution reaction (HER) is of paramount importance for water splitting. However, it is still a formidable task in Mo2C-based materials because of the agglomeration and strong Mo-H binding of Mo2C units. Herein, a novel CeOCl-CeO2/Mo2C heterostructure nesting within a three-dimensional porous nitrogen-doped carbon matrix has been designed and used for catalyzing HER via simultaneous morphology and heterointerface engineering. As expected, the optimal CeOCl-CeO2(0.2)/Mo2C@3DNC exhibits impressive HER activity, with a low overpotential of 156 mV at a current density of 10 mA cm-2 coupled with a slight Tafel slope of 62.20 mV dec-1. Introducing a Ce promoter, that is CeOCl and CeO2, would endow the interface with an internal electric field and electron redistribution between CeOCl-CeO2 and Mo2C induced by the heterogeneous work function difference. Moreover, experimental investigation and density functional calculations confirm that the CeOCl-CeO2/Mo2C heterointerface can downshift the d-band center of the active Mo center, weakening the strength of the Mo-H coupling. This proposed concept, engineering Ce-based promoters into active entities involved in the heterostructure to modulate intermediate adsorption, offers a great opportunity for the design of superior electrocatalysts for energy conversion.

Combination Therapy Consisting of Transarterial Chemoembolization, Lenvatinib, and Programmed Cell Death Protein 1 Blockade for Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus: A Case Series Study and Literature Review.

INTRODUCTION: Patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) have poor prognosis. Combination therapy involving the blockade of programmed cell death protein 1 (PD-1) and tyrosine kinase inhibitors is an efficient treatment strategy for advanced HCC. However, surgical treatment after a combination of systemic therapy and transarterial chemoembolization (TACE) for HCC with IVCTT has not been widely reported, and the efficacy and safety of this treatment have not been studied. METHODS: In the 21 cases reported herein, the patients were treated with TACE, lenvatinib, and PD-1 blockade. The treatment responses, progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities were evaluated, and the related literature was reviewed. RESULTS: The overall response and disease control rates were 66.7% and 85.7%, respectively. The median PFS time was 16.0 months, with a 1-year PFS rate of 55.60%. The median OS was not reached, with a 1-year OS rate of 66.70%. Four patients underwent hepatectomy without serious complications and survived for 29.1, 24.7, 14.2, and 13.8 months. Three patients survived tumor-free, and 1 patient experienced intrahepatic recurrence. Pathological complete response and major pathological responses were observed in 1 and 3 patients, respectively. Treatment-related adverse events of any grade occurred in 8/9 patients (88.9%), and grade 3 treatment-related adverse events occurred in 1 patient. CONCLUSION: The combination of TACE, lenvatinib, and PD-1 is effective for HCC with IVCTT and has acceptable adverse effects.

Enhancing homology-directed repair efficiency with HDR-boosting modular ssDNA donor.

Despite the potential of small molecules and recombinant proteins to enhance the efficiency of homology-directed repair (HDR), single-stranded DNA (ssDNA) donors, as currently designed and chemically modified, remain suboptimal for precise gene editing. Here, we screen the biased ssDNA binding sequences of DNA repair-related proteins and engineer RAD51-preferred sequences into HDR-boosting modules for ssDNA donors. Donors with these modules exhibit an augmented affinity for RAD51, thereby enhancing HDR efficiency across various genomic loci and cell types when cooperated with Cas9, nCas9, and Cas12a. By combining with an inhibitor of non-homologous end joining (NHEJ) or the HDRobust strategy, these modular ssDNA donors achieve up to 90.03% (median 74.81%) HDR efficiency. The HDR-boosting modules targeting an endogenous protein enable a chemical modification-free strategy to improve the efficacy of ssDNA donors for precise gene editing.

Pathways to identify and reduce uncertainties in agricultural climate impact assessments.

Both climate and impact models are essential for understanding and quantifying the impact of climate change on agricultural productivity. Multi-model ensembles have highlighted considerable uncertainties in these assessments, yet a systematic approach to quantify these uncertainties is lacking. We propose a standardized approach to attribute uncertainties in multi-model ensemble studies, based on insights from the Agricultural Model Intercomparison and Improvement Project. We find that crop model processes are the primary source of uncertainty in agricultural projections (over 50%), excluding unquantified hidden uncertainty that is not explicitly measured within the analyses. We propose multidimensional pathways to reduce uncertainty in climate change impact assessments.

The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway.

BACKGROUND: This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS: LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS: LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS: Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.

The response of non-point source pollution to climate change in an orchard-dominant coastal watershed.

China is the largest global orchard distribution area, where high fertilization rates, complex terrain, and uncertainties associated with future climate change present challenges in managing non-point source pollution (NPSP) in orchard-dominant growing areas (ODGA). Given the complex processes of climate, hydrology, and soil nutrient loss, this study utilized an enhanced Soil and Water Assessment Tool model (SWAT-CO2) to investigate the impact of future climate on NPSP in ODGA in a coastal basin of North China. Our investigation focused on climate-induced variations in hydrology, nitrogen (N), and phosphorus (P) losses in soil, considering three Coupled Model Intercomparison Project phase 6 (CMIP6) climate scenarios: SSP1-2.6, SSP2-4.5, and SSP5-8.5. Research results indicated that continuous changes in CO2 levels significantly influenced evapotranspiration (ET) and water yield in ODGA. Influenced by sandy soils, nitrate leaching through percolation was the principal pathway for N loss in the ODGA. Surface runoff was identified as the primary pathway for P loss. Compared to the reference period (1971-2000), under three future climate scenarios, the increase in precipitation of ODGA ranged from 15% to 28%, while the growth rates of P loss and surface runoff were the most significant, both exceeding 120%. Orchards in the northwest basin proved susceptible to nitrate leaching, while others were more sensitive to N and P losses via surface runoff. Implementing targeted strategies, such as augmenting organic fertilizer usage and constructing terraced fields, based on ODGA's response characteristics to future climate, could effectively improve the basin's environment.

Testing the ectomycorrhizal-dominance hypothesis for ecosystem multifunctionality in a subtropical mountain forest.

Mycorrhizal associations are key mutualisms that shape the structure of forest communities and multiple ecosystem functions. However, we lack a framework for predicting the varying dominance of distinct mycorrhizal associations in an integrated proxy of multifunctionality across ecosystems. Here, we used the datasets containing diversity of mycorrhizal associations and 18 ecosystem processes related to supporting, provisioning, and regulating services to examine how the dominance of ectomycorrhiza (EcM) associations affects ecosystem multifunctionality in subtropical mountain forests in Southwest China. Meanwhile, we synthesized the prevalence of EcM-dominant effects on ecosystem functioning in forest biomes. Our results demonstrated that elevation significantly modified the distributions of EcM trees and fungal dominance, which in turn influenced multiple functions simultaneously. Multifunctionality increased with increasing proportion of EcM associations, supporting the ectomycorrhizal-dominance hypothesis. Meanwhile, we observed that the impacts of EcM dominance on individual ecosystem functions exhibited different relationships among forest biomes. Our findings highlight the importance of ectomycorrhizal dominance in regulating multifunctionality in subtropical forests. However, this ectomycorrhizal feedback in shaping ecosystem functions cannot necessarily be generalized across forests. Therefore, we argue that the predictions for ecosystem multifunctionality in response to the shifts of mycorrhizal composition could vary across space and time.

Silica nanoparticle design for colorectal cancer treatment: Recent progress and clinical potential.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.

[Source Apportionment and Health Risk Assessment of Heavy Metals in Dust Around Bus Stops in Kaifeng City Based on APCS-MLR Model].

In order to reveal the influence of urban transportation systems on the quality of urban ecological environment, this study selected surface dust from bus stops, which is strongly disturbed by transportation, as the research object. The contents of eight heavy metals (V, Cr, Co, Ni, Cu, Zn, Cd, and Pb) in the dust were determined through inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectroscopy (ICP-ASE). The spatial distribution characteristics and pollution levels of the eight heavy metals in the dust were analyzed using the geo-accumulation index method. A combined qualitative (correlation analysis and principal component analysis) and quantitative (absolute principal component scores-multiple linear regression model (APCS-MLR)) method was used to explore the sources of heavy metals in surface dust near bus stops. The spatial distribution characteristics of heavy metals from different sources were elucidated using the Kriging interpolation method. The health risk assessment model proposed by the United States Environmental Protection Agency was used to evaluate the human health risks. The results showed that the average values of ω(V), ω(Cr), ω(Co), ω(Ni), ω(Cu), ω(Zn), ω(Cd), ω(Pb), and ω(As) in the bus stop surface dust were 68.36, 59.73, 5.81, 19.34, 40.10, 208.32, 1.01, and 49.46 mg·kg-1, respectively. The concentrations of heavy metals (Cd, Zn, Pb, Cu, and Cr) in the dust were all higher than the background values in the surrounding dust, exceeding them by 3.37, 2.70, 2.01, 1.95, and 1.28 times, respectively. The order of the geo-accumulation index for the eight heavy metals was Cd > Zn > Pb > Cu > Cr > V > Ni > Co, with Cd, Zn, Cu, and Pb in the dust indicating mild pollution levels and the others showing no pollution. The source analysis results showed that Cr, Co, and Ni were natural sources, whereas Cu, Zn, Pb, and Cd were traffic sources, and V was derived from a combination of industrial and natural sources. The APCS-MLR results indicated that the average contribution rates of the four sources were as follows:natural source (34.17 %), traffic source (29.84 %), industrial-natural mixed source (14.64 %), and unknown source (21.35 %). The spatial distribution map of the contribution rate of the traffic source was consistent with the trends of traffic volume and bus route density distribution. According to the health risk assessment, the cancer risk and non-cancer risk for children were both higher than those for adults. Cr was the main non-cancer factor, and Cd was the main cancer-causing factor. Natural and traffic sources contributed the most to non-cancer risk and cancer risk, respectively.

Lidar AOD inversion and aerosol extinction profile correction method based on GA-BP neural network.

Lidar is an effective remote sensing method to obtain the vertical distribution of aerosols, and how to select the aerosol extinction-backscattering ratio (AE-BR) during the inversion process is a key step to guarantee the accuracy of the lidar inversion of aerosol optical thickness (AOD) and aerosol extinction coefficient profile (AECP). In this paper, an inversion algorithm for AOD and AECP based on a genetic BP (GA-BP) neural network is proposed. Simultaneous measurements are carried out using CE318 sun photometer and lidar, and the mapping relationship between the lidar echo signal and AOD is established based on the genetic BP (GA-BP) neural network method, which achieves the accurate inversion of AOD with an absolute error mean value of 0.0156. Based on the AOD output from the GA-BP neural network, the real-time best AE- BR to improve the inversion accuracy of AECP. Finally, practical tests show that the method achieves accurate inversion of AOD, determines the range of AE-BR from 20-50sr, realizes real-time dynamic correction of AECP, and has strong generalization ability and applicability in practical situations.

OCIAD2 promotes pancreatic cancer progression through the AKT signaling pathway.

BACKGROUND: OCIAD2（Ovarian carcinoma immunoreactive antigen-like protein 2） is a protein reported in various cancers. However, the role of OCIAD2 has not been explored in pan-cancer datasets. The purpose of this research lies in analyzing the expression level and prognostic-related value of OCIAD2 in different human cancers, as well as revealing the underlying mechanism in specific cancer type (pancreatic adenocarcinoma, PAAD). METHODS: The correlation between OCIAD2 expression level and clinical relevance in different human cancers was investigated from bioinformatical perspective (GTEx and TCGA). The OCIAD2 expression level and clinical significance in PAAD were explored in GEO datasets and tissue microarray. Functional experiments were used to determine the OCIAD2 cell functions in vitro and in vivo. GSEA, western blot and immunohistochemistry were used to uncover the potential mechanism. RESULTS: OCIAD2 expression level was closely correlated with clinical relevance in many cancer types through pan-cancer analysis, and we found OCIAD2 was highly expressed in PAAD and associated with poorer prognosis. OCIAD2 acted as the promotor of Warburg effect and influenced PAAD cells proliferation, migration and apoptosis. Mechanistically, OCIAD2 upregulation may boost glycolysis in PAAD via activating the AKT signaling pathway in PAAD. CONCLUSIONS: In PAAD, OCIAD2 promotes Warburg effect via AKT signaling pathway and targeting cancer cells metabolic reprogramming could be a potential treatment.

Y4 RNA fragments from cardiosphere-derived cells ameliorate diabetic myocardial ischemia‒reperfusion injury by inhibiting protein kinase C ß-mediated macrophage polarization.

The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cß (PKCß) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCß activation. The mechanism by which Y4 RNA affects PKCß by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCß in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCß knockout mice. Our findings indicate that PKCß plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCß expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCß/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.

Asymmetric Dearomatization of Indoles through Cobalt-Catalyzed Enantioselective C-H Functionalization Enabled by Photocatalysis.

Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition-metal-catalyzed asymmetric C-H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt-catalyzed enantioselective C-H activation reaction enabled by visible-light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96 % to >99 % ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.

Disruption of microRNA pathway core genes inhibits molting and reproduction of the cigarette beetle, Lasioderma serricorne.

BACKGROUND: MicroRNA (miRNA) pathway genes have been widely reported to participate in several physiological events in insect lifecycles. The cigarette beetle Lasioderma serricorne is an economically important storage pest worldwide. However, the functions of miRNA pathway genes in L. serricorne remain to be clarified. Herein, we investigated the function of molting and reproduction of the miRNA pathway in L. serricorne. RESULTS: LsDicer-1, LsArgonaute-1, LsLoquacious and LsExportin-5 were universally expressed in adults, whereas LsPasha and LsDrosha were mainly expressed in the pupae. The genes presented different patterns in various tissues. Silencing of LsDicer-1, LsArgonaute-1, LsDrosha and LsExportin-5 resulted in a high proportion of wing deformities and molting defects. Silencing of LsDicer-1, LsArgonaute-1, LsPasha and LsLoquacious affected the development of the ovary and the maturation of oocytes, resulting in a significant decrease in fecundity. Further investigation revealed that the decreases in LsDicer-1 and LsArgonaute-1 expression destroyed follicular epithelia and delayed vitellogenesis and oocyte development. In addition, the expression levels of several miRNAs (let-7, let-7-5p, miR-8-3p, miR-8-5p, miR-9c-5p, miR-71, miR-252-5p, miR-277-3p, miR-263b and Novel-miR-50) were decreased significantly after knockdown of these miRNA pathway core genes, indicating that they played important roles in regulating miRNA-mediated gene expression. CONCLUSION: The results indicate that miRNA pathway genes play important roles in the molting, ovarian development and female fecundity of L. serricorne, and thus are potentially suitable target genes for developing an RNAi strategy against a major pest of stored products. © 2024 Society of Chemical Industry.