Decoding the temporal structures and interactions of multiple face dimensions using optically pumped magnetometer magnetoencephalography (OPM-MEG).

Humans possess a remarkable ability to rapidly access diverse information from others' faces with just a brief glance, which is crucial for intricate social interactions. While previous studies using event-related potentials/fields have explored various face dimensions during this process, the interplay between these dimensions remains unclear. Here, by applying multivariate decoding analysis to neural signals recorded with optically pumped magnetometer magnetoencephalography (OPM-MEG), we systematically investigated the temporal interactions between invariant and variable aspects of face stimuli, including race, gender, age and expression. First, our analysis revealed unique temporal structures for each face dimension with high test-retest reliability. Notably, expression and race exhibited a dominant and stably maintained temporal structure according to temporal generalization analysis. Further exploration into the mutual interactions among face dimensions uncovered age effects on gender and race, as well as expression effects on race, during the early stage (around 200-300 ms post face presentation). Additionally, we observed a relatively late effect of race on gender representation, peaking around 350 ms after stimulus onset. Taken together, our findings provide novel insights into the neural dynamics underlying the multi-dimensional aspects of face perception and illuminate the promising future of utilizing OPM-MEG for exploring higher-level human cognition.Significance statement In everyday social activities, people can quickly interpret a wide range of information from others' faces. Although converging evidence has shed light upon the neural substrates underpinning the perception of invariant and variable aspects of faces, such as race, gender, age and expression, it is still not fully understood how the information of one face dimension alters the perception of another. In this study, we utilized multivariate decoding analysis on neural activity captured through OPM-MEG during face perception. Our approach enabled a comprehensive exploration of the temporal interactions among different face dimensions, providing an improved understanding of the temporally structured neural dynamics that support the multi-dimensional face perception in the human brain.

Cardiometabolic index is associated with increased bone mineral density: a population-based cross-sectional study.

Background: Osteoporosis is a multifactorial bone disease in which lipid metabolism plays an important role. Bone Mineral Density (BMD) measured by Dual-energy X-ray Absorptiometry (DXA) is a critical indicator for diagnosing osteoporosis. The cardiometabolic index (CMI) is a novel metric that combines two quantitative indicators of blood lipids-triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). This study explores the association between CMI and BMD and seeks to elucidate the role of lipid metabolism in the context of bone health. Methods: Based on the data of the National Health and Nutrition Examination Survey (NHANES) 2017-March 2020-pre-pandemic, weighted multiple linear regression and smooth curve fitting were used to study the relationship between CMI and femoral BMD. Stratified analyses were also conducted for age, gender, BMI, ethnicity, diabetes and hypertension status. And, the saturation threshold effect of CMI was further analyzed using a two-stage linear regression model. Result: This study enrolled a total of 1,650 participants (48.7% males), with an average age of 63.0 ± 8.6 years. After adjusting for multiple confounding factors, CMI was positively correlated with total femur BMD, trochanter BMD, and intertrochanter BMD, while the correlation with femur neck BMD was not statistically significant. In the fully adjusted model, each unit increase in CMI was associated with a 0.026 (g/cm2) increase in total femur BMD, a 0.022 (g/cm2) increase in trochanter BMD, and a 0.034 (g/cm2) increase in intertrochanter BMD. Subjects in the highest quartile of CMI had a 0.034 (g/cm2) increase in total femur BMD, a 0.035 (g/cm2) increase in trochanter BMD, and a 0.039 (g/cm2) increase in intertrochanter BMD in the fully-adjusted model compared to those in the lowest quartile. In addition, saturation was observed between CMI and total femur BMD, trochanter BMD and intertrochanter BMD, with saturation thresholds of 1.073, 1.431 and 1.073, respectively. Conclusion: CMI is strongly associated with BMD, indicating its potential relevance in bone metabolism. However, the role of CMI in the context of bone health, especially regarding osteoporosis risk, requires further investigation in large-scale prospective studies.

Improving the activity of an inulosucrase by rational engineering for the efficient biosynthesis of low-molecular-weight inulin.

Inulin, a widely recognized prebiotic, has diverse applications across various industrial sectors. Although inulin is primarily produced through plant extraction, there is growing interest in enzymatic synthesis as an alternative. The enzymatic production of inulin from sucrose, which yields polymers with degrees of polymerization similar to those of plant-derived inulin, shows potential as a viable replacement for traditional extraction methods. In this study, an inulosucrase from Neobacillus bataviensis was identified, demonstrating a non-processive mechanism specifically tailored for synthesizing inulin with polymerization degrees ranging from 3 to approximately 40. The enzyme exhibited optimal activity at pH 6.5 and 55 °C, efficiently producing inulin with a yield of 50.6%. Ca2+ can improve the activity and thermostability of this enzyme. To enhance catalytic total activity, site-directed and truncated mutagenesis techniques were applied, resulting in the identification of a mutant, T149S, displaying a significant 57% increase in catalytic total activity. Molecular dynamics simulations unveiled that the heightened flexibility observed in three surface regions positively influenced enzymatic activity. This study not only contributes to the theoretical foundation for inulosucrase engineering but also presents a potential avenue for the production of inulin.

IL-11-Engineered Macrophage Membrane-Coated Reactive Oxygen Species-Responsive Nanoparticles for Targeted Delivery of Doxorubicin to Osteosarcoma.

Osteosarcoma (OS) is a lethal malignant orthotopic bone tumor that primarily affects children and adolescents. Biomimetic nanocarriers have attracted wide attention as a new strategy for delivering chemotherapy agents to the OS. However, challenges such as rapid clearance and limited targeting hinder the effectiveness of OS chemotherapy. In this study, we designed reactive oxygen species (ROS)-responsive nanoparticles (NPs) coated with an interleukin (IL)11-engineered macrophage membrane (MM). The camouflage by MMs prevents clearance of IL-11-engineered MM-coated NPs loaded with doxorubicin (IL-11/MM@NPs/Dox) by the immune system. Moreover, the macrophage membrane combined with surface-expressed IL-11 not only directed IL-11/MM@NPs/Dox to OS tissues but also selectively identified IL-11 receptor alpha (IL-11Rα)-enriched OS cells. Within these cells, elevated levels of ROS triggered the controlled release of Dox from the ROS-responsive NPs. The synergistic modification of targeted ligand conjugation and cell membrane coating on the ROS-responsive NPs enhanced drug availability and reduced toxic side effects, thereby boosting the efficacy of OS chemotherapy. In summary, our findings suggest that IL-11/MM@NPs/Dox represents a promising approach to improving OS chemotherapy efficacy while ensuring excellent biocompatibility.

An Adenosine Analogue Library Reveals Insights into Active Sites of Protein Arginine Methyltransferases and Enables the Discovery of a Selective PRMT4 Inhibitor.

Protein arginine methyltransferases (PRMTs) represent promising drug targets. However, the lack of isoform-selective chemical probes poses a significant hurdle in deciphering their biological roles. To address this issue, we devised a library of 100 diverse adenosine analogues, enabling a detailed exploration of the active site of PRMTs. Despite their close homology, our analysis unveiled specific chemical trends unique to the individual members. Notably, compound YD1130 demonstrated over 1000-fold selectivity for PRMT4 (IC50 < 0.5 nM) over a panel of 38 methyltransferases, including the other PRMTs. Its prodrug YD1342 exhibited potent inhibition on cellular substrate methylation, breast cancer cell colony formation, and tumor growth in the animal model, surpassing or matching known PRMT4-specific inhibitors. In summary, our focused library not only illuminates the intricate active sites of PRMTs to facilitate the discovery of highly potent and isoform-selective probes but also offers a versatile blueprint for identifying chemical probes for other methyltransferases.

Perylene-Embedded Helical Nanographenes with Emission up to 1010 nm: Synthesis, Structures, and Chiroptical Properties.

Near-infrared (NIR) circularly polarized absorbing or emitting materials offer distinct advantages over their visible-light counterparts and have attracted considerable interest across various fields. Materials exhibiting NIR chiroptical properties with high fluorescence quantum yields (ΦF) are particularly rare. In this study, we report the synthesis of a series of helical nanographenes (1, 2, 3, and 4), where perylene is fused with one to four hexa-peri-hexabenzocoronene (sub)units via a strategy involving Diels-Alder cycloaddition followed by Scholl reaction. X-ray crystallographic analysis confirmed their structures, revealing helicene moieties integrated into a highly contorted framework. Benefiting from a similar distribution pattern of frontier molecular orbitals to perylene and extended π-conjugation, compounds 1-4 demonstrate respectable ΦF values of 31.9%, 15.0%, 13.7%, and 6.5%, respectively, with emission maxima reaching up to 1010 nm. Their enantiopure forms, isolated by preparative chiral HPLC, exhibit distinct circular dichroism signals and circularly polarized luminescence across a broad spectral range, extending from the ultraviolet to the NIR.

Role of the screening with coronary computed tomography angiography on lipid management and risk factors control in an asymptomatic Chinese population: a community-based, parallel-group, open-label, randomized clinical trial (RESPECT2).

BACKGROUND: Lipid management based on cardiovascular risk level is the cornerstone of primary prevention of coronary artery disease (CAD), while the accuracy and adherence of traditional cardiovascular risk stratification have been questioned. Prevention strategies based on imaging screening for atherosclerotic plaques are found to be more objective and adherent in recent studies. This trial aims to investigate the role of coronary computed tomography angiography (CCTA) in guiding the primary prevention of CAD in a randomized controlled design. METHODS: Approximately 3400 middle-aged asymptomatic community participants will be recruited and randomized in a 1:1 ratio to a traditional cardiovascular risk score-guided (usual care group) or CCTA-guided (CCTA group) strategy. Participants with cardiovascular disease, prior lipid-lowering therapy, CCTA contraindication, or serious diseases that affect life span will be excluded. The intervention strategy includes blood pressure, blood glucose, and lipid management and lifestyle modifications. Blood pressure and glucose targets and lifestyle modification recommendations keep the same in both strategies, while lipid management is personalized based on traditional risk level or CCTA results, respectively. The primary outcome is the proportion of participants taking lipid-lowering medication regularly at both 6 and 12 months. The secondary outcomes include the proportion of participants achieving low-density lipoprotein cholesterol lowering targets at 12 months, mean changes in lipid levels from baseline to 12 months, barriers to adherence, adverse reactions related to CCTA examination, and cardiovascular events. DISCUSSION: The study is the first randomized clinical trial to examine the effectiveness of a CCTA-guided versus a traditional risk score-guided primary prevention strategy in an asymptomatic community-based population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05725096. Registered on 2 February 2023.

Mass spectrometry-based multi-omics analysis reveals distinct molecular features in early and advanced stages of hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC) is a serious primary solid tumor that is prevalent worldwide. Due to its high mortality rate, it is crucial to explore both early diagnosis and advanced treatment for HCC. In recent years, multi-omics approaches have emerged as promising tools to identify biomarkers and investigate molecular mechanisms of biological processes and diseases. In this study, we performed proteomics, phosphoproteomics, metabolomics, and lipidomics to reveal the molecular features of early- and advanced-stage HCC. The data obtained from these omics were analyzed separately and then integrated to provide a comprehensive understanding of the disease. The multi-omics results unveiled intricate biological pathways and interaction networks underlying the initiation and progression of HCC. Moreover, we proposed specific potential biomarker panels for both early- and advanced-stage HCC by overlapping our data with CPTAC database for HCC diagnosis, and deduced novel insights and mechanisms related to HCC origination and development, such as glucose depletion during tumor progression, ROCK1 deactivation and GSK3A activation.

Regulating the 3d-orbital occupancy on Ni sites enables high-rate and durable Ni(OH)2 cathode for alkaline Zn batteries.

The capacity and cycling stability of ß-Ni(OH)2-based cathodes in aqueous alkaline Ni-Zn batteries are still unsatisfactory due to their undesirable OH- adsorption/desorption dynamics during the electrochemical redox process. To settle this issue, we introduce a new atomic-level strategy to finely modulate the OH- adsorption/desorption of ß-Ni(OH)2 through tailoring the 3d-orbital occupancy of Ni center by Co/Cu co-doping (denoted as Co-Cu-Ni(OH)2). Both experimental outcomes and density functional theory calculations validate that the co-doping of Co and Cu endows the Ni species in Co-Cu-Ni(OH)2 with appropriate proportion of the unoccupied 3d-orbital, leading to optimized adsorption/desorption strength of OH-. As anticipated, the Co-Cu-Ni(OH)2 electrode demonstrates superior performance, achieving an areal capacity of 0.83 mAh cm-2 and a gravimetric capacity of 164.3 mAh g-1 at ∼50 mA cm-2 (10 A g-1). Furthermore, it sustains an impressive capacity of 170.8 mAh g-1 (2.3 mAh cm-2) at a high mass loading of 13.5 mg cm-2, alongside a long-term cycling performance over 1000 cycles. The assembled Co-Cu-Ni(OH)2//Zn cell is able to provide a peak energy density of 0.98 mWh cm-2 and excellent durability. This work highlights the potential of an orbital engineering strategy in the development of next-generation high-capacity and durable energy storage materials.

Edible bird's nest improves hemorheology and immune function in mice with transplanted uterine leiomyomas.

OBJECTIVE: To investigate the effect of edible bird's nest (EBN) on tumor growth, hemorheology and immune function of mice with transplanted uterine myomas. METHODS: A subcutaneous tumor model of human uterus myoma was established in mice, and the mice were randomly divided into a model group, EBN group, estradiol receptor (ER) group and ER+EBN group. Body weight and tumor volume were measured at 2 weeks, 4 weeks and 8 weeks after the uterus myoma transplantation. Eight weeks after transplantation, the tumor weight was assessed, the morphology of different organs was observed, and the pathological changes of the uterus myoma was observed. Besides, the levels of ER and progesterone receptor (PR), various hemorheological parameters (including hematocrit, plasma viscosity and whole blood viscosity under different shearing conditions), and immune functions (CD3 +, CD4 + and CD8 + cells) were also measured. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), nitricoxidesynthase (NOS) and vascular endothelial growth factor (VEGF) in each group. RESULTS: There were no statistical differences in body weight, tumor weight, tumor volume, uterus myoma pathology or the levels of ER and PR between the model group and EBN group, nor between the ER group and ER+EBN group (all P>0.05). Similarly, no notable morphological differences were observed in the heart, liver, spleen, lung, kidney, stomach, intestines and uterus among different groups (all P>0.05). However, in contrast to the model group, the EBN group exhibited significant reductions in hemorheology indicators, the proportion of CD8 + cells, as well as the levels of TNF-α, NOS and VEGF (all P<0.05). Conversely, the proportion of CD3 + and CD4 + cells, the CD4 +/CD8 + ratio and the level of IL-2 in the EBN group were obviously increased (all P<0.05). Compared with the ER group, the proportion of CD8 + cells, the levels of TNF-α, NOS and VEGF in the ER+EBN group were significantly decreased while the proportion of CD3 + and CD4 + cells, the CD4 +/CD8 + ratio and the level of IL-2 in the ER+EBN group were obviously increased. CONCLUSION: For mice with uterine myoma transplantation, EBN does not influence tumor growth but significantly regulates hemorheology and enhances immune function.

Sivelestat Sodium Alleviates Ischemia-Reperfusion-Induced Acute Kidney Injury via Suppressing TLR4/Myd88/NF-κB Signaling Pathway in Mice.

Purpose: We aim to detect the effects of sivelestat on renal ischemia-reperfusion associated with AKI and also explore the underlying mechanism. Materials and Methods: Mice, aged between 8 and 12 weeks, were randomly allocated among four distinct groups, respectively normal saline sham group(C), normal saline surgery group(I), sivelestat (50 mg/kg) sham group(S), sivelestat (50 mg/kg) surgery group(SI) (n=6, each group). In the surgical groups, the renal pedicles of mice were clamped with non-traumatic micro-aneurysm clamps, resulting in ischemia of the kidneys for 45 minutes. This was followed by a period of reperfusion lasting 24 hours. Sham group mice underwent the identical surgery produced without clamping renal pedicles. Mice blood was obtained from eyeballs, and Serum creatinine and blood urea nitrogen levels were measured. After a 24-hour period of reperfusion, the mice were euthanized, and their kidneys were gathered for various analyses, including Western Blot (WB) analysis, RT-PCR, immunofluorescence (IF), hematoxylin and eosin (H&E) staining, and Tunel assay. Results: Pretreatments with sivelestat decreased renal Neutrophil elastase (NE), serum creatinine, and blood urea nitrogen levels after renal ischemia-reperfusion. Sivelestat also reduced histological damage and cell apoptosis in kidneys following ischemia-reperfusion injury (IRI). In addition, the sivelestat administration diminished the levels of mRNA expression of interleukin 6 (IL-6), Macrophage inflammatory protein-2 (MIP-2), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-α in the kidneys during IRI. The kidney tissues of the SI group had significantly mitigated TLR4, Myd88, and NF-κB p-p65 protein expression levels compared to the I group (all P<0.05). Conclusion: We demonstrated a previously unidentified mechanism that sivelestat effectively attenuates AKI-induced renal dysfunction, possibly through suppressing the TLR4/Myd88/ NF-κB pathway.

Structure-based design of antibodies targeting the EBNA1 DNA-binding domain to block Epstein-Barr virus latent infection and tumor growth.

The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is critically involved in maintaining episomes during latent infection and promoting tumorigenesis. The development of an epitope-specific monoclonal antibody (mAb) for EBNA1 holds great promise due to its high affinity and specificity, offering a new and innovative approach for the treatment of EBV-related diseases. In this proof-of-concept study, we employed a structure-based design strategy to create three unique immunogens specifically targeting the DNA binding state of the EBNA1 DBD. By immunizing mice, we successfully generated a mAb, named 5E2-12, which selectively targets the DNA binding interface of EBNA1. The 5E2-12 mAb effectively disrupts the interaction between EBNA1 and DNA binding, resulting in reduced proliferation of EBV-positive cells and inhibition of xenograft tumor growth in both cellular assays and mouse tumor models. These findings open up new avenues for the development of innovative biological macromolecular drugs that specifically target EBNA1 and provide potential for clinical therapy options for early-stage EBV-positive tumors. The epitope-specific mAb approach demonstrates novelty and innovation in tackling EBV-related diseases and may have broad implications for precision medicine strategies in the field of viral-associated cancers.

ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages.

Hepatocellular carcinoma (HCC) often occurs in the context of fibrosis or cirrhosis. Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis-associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional Ash1l depletion in the hepatocyte cell lineage (Ash1lflox/floxAlbcre) or HSCs (Ash1lflox/floxGFAPcreERT2) are generated, and these mice are challenged in a diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced model of liver fibrosis and HCC. Depleting Ash1l in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single-cell transcriptomic sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L-mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2-like pro-tumorigenic macrophages. The M2-like macrophages further enhance tumor cell proliferation and suppress CD8+ T cell activation. AS-99, a small molecule inhibitor of ASH1L, demonstrates similar anti-fibrosis and tumor-suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small-molecule therapeutic target against fibrosis-related HCC.

Porous starch microspheres loaded with luteolin exhibit hypoglycemic activities and alter gut microbial communities in type 2 diabetes mellitus mice.

Luteolin (LUT), a natural flavonoid known for its hypoglycemic properties, is primarily sourced from vegetables such as celery and broccoli. However, its poor stability and low bioavailability in the upper digestive tract hinder its application in the functional food industry. To address these challenges, this study employed porous starch (PS) as a carrier to develop PS microspheres loaded with luteolin (PSLUT), simulating its release in vitro. The research assessed the hypoglycemic effects of LUT in type 2 diabetes mellitus (T2DM) mice both before and after PS treatment. In vitro findings demonstrated that PS improved LUT's stability in simulated gastric fluids and enhanced its in vivo bioavailability, aligning with experimental outcomes. PSLUT administration significantly improved body weight, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), pancreatic islet function, and other relevant indicators in T2DM mice. Moreover, PSLUT alleviated abnormal liver biochemical indicators and liver tissue injury caused by T2DM. The underlying hypoglycemic mechanism of PSLUT is thought to involve the regulation of protein kinase B (AKT-1) and glucose transporter 2 (GLUT-2). After four weeks of intervention, various PSLUT doses significantly reduced the Firmicutes to Bacteroidetes ratio at the phylum level and decreased the relative abundance of harmful bacteria at the genus level, including Acetatifactor, Candidatus-Arthromitus, and Turicibacter. This microbial shift was associated with improvements in hyperglycemia-related indicators such as FBG, the area under the curve (AUC) of OGTT, and homeostasis model assessment of insulin resistance (HOMA-IR), which are closely linked to these bacterial genera. Additionally, Lachnoclostridium, Parasutterella, Turicibacter, and Papillibacter were identified as key intestinal marker genera involved in T2DM progression through Spearman correlation analysis. In conclusion, PS enhanced LUT's hypoglycemic efficacy by modulating the transcription and protein expression levels of AKT-1 and GLUT-2, as well as the relative abundance of potential gut pathogens in T2DM mice. These results provide a theoretical foundation for advancing luteolin's application in the functional food industry and further investigating its hypoglycemic potential.

Ultrasensitive surface-enhanced Raman scattering sensing of Cr(VI) with a Au@Ag nano-sea urchin paper-tip substrate.

Bimetallic Au@Ag nano-sea urchins (Au@Ag NSUs) functionalized with methimazole were synthesized and combined with paper tips as efficient surface-enhanced Raman scattering (SERS) substrates for ultrasensitive Cr(VI) detection. The redox reaction between methimazole and Cr(VI) ensured the reliability of quantitative Cr(VI) analysis. When droplets were continuously dropped on the tip of the paper, based on the gravity effect, the nanoparticles achieved enrichment at the front end of the tip, which further improved the sensitivity of detection. The detection limit is as low as 0.956 ng L-1, demonstrating its excellent performance in ultrarace Cr(VI) detection. Additionally, the SERS sensor was successfully applied to the detection of Cr(VI) in real water samples, such as lake water and tap water, indicating its wide application potential in environmental monitoring. This study not only provides an efficient and reliable new method for detecting Cr(VI) but also shows the great prospect of paper-based SERS sensors in practical applications.

Dual trigger or hCG alone: A retrospective analysis on patients with diminished ovarian reserve under in vitro fertilization and embryo transfer (IVF-ET) treatment.

OBJECTIVE: With remarkable deficiency in both oocyte stock and competence, the prognosis of IVF-ET in diminished ovarian reserve (DOR) is obstinately poor, underscoring warranted optimization to current procedures. We compared the efficacy of dual-trigger (hCG plus GnRH-a) and hCG alone on the outcomes for DOR patients. STUDY DESIGN: A total of 381 couples and 857 controlled ovarian stimulation (COS) cycles, and 222 couples and 366 frozen embryo transfer (FET) ones were included. The intermediate outcomes during oocyte retrieval and in vitro culture were compared based on COS dataset, while outcomes after embryo transfer analyzed based on FET dataset. The marginal effect of all study factors and covariates were evaluated with a cluster-weighted GEE model. RESULTS AND CONCLUSION: Neither the intermediate nor implantation outcomes were improved by dual-trigger. The OR values were 1.08 (95 % CI: 0.41-2.78) for retrieval cancellation, 1.33 (95 % CI: 0.89-2.00) for oocyte harvest, 1.04(95 %CI: 0.94-1.15) for viable embryo and 1.03(95 %CI: 0.88-1.19) for top-quality embryo. Similarly, the ORs were 0.90 (95 %CI: 0.62-1.30) for implantation and 0.97 (95 %CI: 0.56-1.69) for clinical pregnancy. This equivalence remained unchanged after adjusting for the covariates such as age, BMI, controlled ovarian stimulation protocols, etc. Thus, dual-trigger cannot provide significant advantage over hCG in related to immediate or clinical outcomes of IVF-ET treatments in DOR patients.

Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFß and Hedgehog signal pathway.

PURPOSE: Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug. METHOD: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance. RESULTS: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFß and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC. CONCLUSIONS: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFß, Hedgehog axis.