Chimerization of human ESC-derived extraembryonic cells with the mouse blastocyst.

It has been reported that human embryonic stem cells (hESCs) treated with BMP4 and inhibitors of TGFß signaling (A83-01) and FGF signaling (PD173074), called BAP, can efficiently differentiate to extraembryonic (ExE) cells in vitro. Due to restricted access to human embryos, it is ethically impossible to test the developmental potential of ExE cells in vivo. Here, we demonstrate that most ExE cells expressed molecular markers for both trophoblasts (TBs) and amniotic cells (ACs). Following intra-uterine transplantation, ExE cells contributed to the mouse placenta. More interestingly, ExE cells could chimerize with the mouse blastocyst as, after injection into the blastocyst, they penetrated its trophectoderm. After implantation of the injected blastocysts into surrogate mice, human cells were found at E14 in placental labyrinth, junction zones, and even near the uterine decidua, expressed placental markers, and secreted human chorionic gonadotropin. Surprisingly, ExE cells also contributed to cartilages of the chimeric embryo with some expressing the chondrogenic marker SOX9, consistent with the mesodermal potential of TBs and ACs in the placenta. Deleting MSX2, a mesodermal determinant, restricted the contribution of ExE cells to the placenta. Thus, we conclude that hESC-derived ExE cells can chimerize with the mouse blastocyst and contribute to both the placenta and cartilages of the chimera consistent with their heteogenious nature. Intra-uterus and intra-blastocyst injections are novel and sensitive methods to study the developmental potential of ExE cells.

Multiparametric MRI based deep learning model for prediction of early recurrence of hepatocellular carcinoma after SR following TACE.

BACKGROUND: Surgical resection (SR) following transarterial chemoembolization (TACE) is a promising treatment for unresectable hepatocellular carcinoma (uHCC). However, biomarkers for the prediction of postoperative recurrence are needed. PURPOSE: To develop and validate a model combining deep learning (DL) and clinical data for early recurrence (ER) in uHCC patients after TACE. METHODS: A total of 511 patients who received SR following TACE were assigned to derivation (n = 413) and validation (n = 98) cohorts. Deep learning features were taken from the largest tumor area in liver MRI. A nomogram using DL signatures and clinical data was made to forecast early recurrence risk in uHCC patients. Model performance was evaluated using area under the curve (AUC). RESULTS: A total of 2278 subsequences and 31,346 slices multiparametric MRI including contrast-enhanced T1WI, T2WI and DWI were input in the DL model simultaneously. Multivariable analysis identified three independent predictors for the development of the nomogram: tumor number (hazard ratio [HR]:3.42, 95% confidence interval [CI]: 2.75-4.31, P = 0.003), microvascular invasion (HR: 9.21, 6.24-32.14; P < 0.001), and DL scores (HR: 17.46, 95% CI: 12.94-23.57, P < 0.001). The AUC of the nomogram was 0.872 and 0.862 in two cohorts, significantly outperforming single-subsequence-based DL mode and clinical model (all, P < 0.001). The nomogram provided two risk strata for cumulative overall survival in two cohorts, showing significant statistical results (P < 0.001). CONCLUSIONS: The DL-based nomogram is essential to identify patients with uHCC suitable for treatment with SR following TACE and may potentially benefit personalized decision-making.

Nuclear envelope budding inhibition slows down progerin-induced aging process.

Progerin causes Hutchinson-Gilford progeria syndrome (HGPS), but how progerin accelerates aging is still an interesting question. Here, we provide evidence linking nuclear envelope (NE) budding and accelerated aging. Mechanistically, progerin disrupts nuclear lamina to induce NE budding in concert with lamin A/C, resulting in transport of chromatin into the cytoplasm where it is removed via autophagy, whereas emerin antagonizes this process. Primary cells from both HGPS patients and mouse models express progerin and display NE budding and chromatin loss, and ectopically expressing progerin in cells can mimic this process. More excitingly, we screen a NE budding inhibitor chaetocin by high-throughput screening, which can dramatically sequester progerin from the NE and prevent this NE budding through sustaining ERK1/2 activation. Chaetocin alleviates NE budding-induced chromatin loss and ameliorates HGPS defects in cells and mice and significantly extends lifespan of HGPS mice. Collectively, we propose that progerin-induced NE budding participates in the induction of progeria, highlight the roles of chaetocin and sustained ERK1/2 activation in anti-aging, and provide a distinct avenue for treating HGPS.

TRIB3 inhibition by palbociclib sensitizes prostate cancer to ferroptosis via downregulating SOX2/SLC7A11 expression.

Palbociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer by suppressing cell proliferation. However, monotherapy with palbociclib was discouraging in prostate cancer, calling for a mechanism-based effective therapy. In this study, we reported in prostate cancer that palbociclib is a potent sensitizer of ferroptosis, which is worked out by downregulating the expression of TRIB3, a gene highly expressed in prostate cancer. Specifically, TRIB3 knockdown augmented the response of prostate cancer cells to ferroptosis inducers, whereas, TRIB3 overexpression rescued prostate cancer cells from palbociclib-induced ferroptosis. Mechanistically, TRIB3 inhibition by palbociclib resulted in downregulation of SOX2, which subsequently led to compromised expression of SLC7A11, a cystine/glutamate antiporter that counteracts ferroptosis. Functionally, a combined treatment of palbociclib with ferroptosis inducer significantly suppressed prostate cancer growth in a xenograft tumor model. Together, these results uncover an essential role of TRIB3/SOX2/SLC7A11 axis in palbociclib-induced ferroptosis, suggesting palbociclib a promising targeted therapy in combine with ferroptosis induction for the treatment of prostate cancer.

A pH-Sensitive Glucose Oxidase and Hemin Coordination Micelle for Multi-Enzyme Cascade and Amplified Cancer Chemodynamic Therapy.

Chemodynamic therapy (CDT) is an emerging therapeutic paradigm for cancer treatment that utilizes reactive oxygen species (ROS) to induce apoptosis of cancer cells but few biomaterials have been developed to differentiate the cancer cells and normal cells to achieve precise and targeted CDT. Herein, a simple cascade enzyme system is developed, termed hemin-micelles-GOx, based on hemin and glucose oxidase (GOx)-encapsulated Pluronic F127 (F127) micelles with pH-sensitive enzymatic activities. Histidine-tagged GOx can be easily chelated to hemin-F127 micelles via the coordination of histidine and ferrous ions in the center of hemin by simple admixture in an aqueous solution. In tumor microenvironment (TME), hemin-micelles-GOx exhibits enhanced peroxidase (POD)-like activities to generate toxic hydroxyl radicals due to the acidic condition, whereas in normal cells the catalase (CAT)-like, but not POD-like activity is amplified, resulting in the elimination of hydrogen peroxide to generate oxygen. In a murine melanoma model, hemin-micelles-GOx significantly suppresses tumor growth, demonstrating its great potential as a pH-mediated enzymatic switch for tumor management by CDT.

S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients.

Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.

Developmental Validation of the Microreader 23HS Plex ID System: A Novel Supplementary Non-CODIS STR Multiplex Assay for Forensic Application.

A novel supplementary non-CODIS STR multiplex assay designated as the "Microreader 23HS Plex ID System" was developed. The Microreader 23HS Plex ID System enables simultaneous profiling of 23 STR loci and the amelogenin locus. The majority of these loci are non-CODIS STRs (D4S2408, D9S2157, D20S161, D3S2459, D18S1364, D13S305, D1S2142, D19S400, D6S1017, D7S1517, D2S1776, D2S1360, D3S1744, D16S3391, D3S1545, D11S4463, D20S85, D1S549, D10S2325, D21S2055), with the exception of three CODIS STRs (D2S441, D12S391, and D22S1045). Followed the recommendations of Scientific Working Group on DNA Analysis Methods (SWGDAM) and the Chinese validation standards, a comprehensive set of validation studies were conducted, encompassing PCR conditions, stutter ratio and peak height balance, sensitivity, precision and accuracy, reproducibility, species specificity, inhibition, as well as mixture testing. The results demonstrated that the Microreader 23HS Plex ID System is a reliable and robust assay, with well-balanced peak heights, high precision and accuracy, species specificity, and resistance to common inhibitors. The sensitivity of the assay was determined to be 0.125 ng of template DNA. In mixture study, all minor alleles were detected in two-sample mixtures across various ratios (1:19, 1:9, 1:4, 3:7, 2:3, 1:1, 3:2, 4:1, 9:1, and 19:1). In population study, a total of 500 unrelated individuals of Han ethnicity from East China were genotyped. The allele frequencies and forensic population genetic parameters were calculated, with a cumulative random match probability of 7.757 × 10-27, and a total power of discrimination exceeding 0.999,999,999,999,999,999,999,999,99. In conclusion, the Microreader 23HS Plex ID System shows promise as a valuable supplementary tool for forensic applications, particularly in addressing complex kinship testing and challenges posed by STR mutation.

Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.

Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.

Effects of mono- or di-fluoro-substitution on spin crossover behavior in a pair of Schiff base-like FeII-coordination polymers.

Spin crossover (SCO) has long been a hot topic in the field of molecular magnetism owing to its unique bistability character. Rational control of thermal hysteresis and transition temperature (T1/2) is crucial for their practical applications, which rely on precise manipulation of the substituents of SCO coordinating ligands and molecular packing interactions. In this study, we designed two different bridging ligands (2-FDPB: 4,4'-(2-fluoro-1,4-phenylene)dipyridine; 2,3-FDPB: 4,4'-(2,3-difluoro-1,4-phenylene)dipyridine) featuring one and two fluoro substitution on the central benzene ring and applied a Schiff base-like equatorial tetradentate ligand {diethyl(E,E)-2,2'-[4,5-difluoro-1,2-phenyl-bis(iminomethylidyne)]bis(3-oxobutanoate)-(2-)-N,N',O3,O3'} (H2L) to coordinate with the FeII ion. Two FeII-coordination chain polymers [FeII(L)(2,3-FDPB)]·0.25CH2Cl2 (1) and [FeII(L)(2-FDPB)]·0.5CH3OH (2) were obtained. 1 crystallizes in the monoclinic P21/n space group with only one FeII center, while 2 crystallizes in the triclinic P1̄ space group with two independent FeII centers. Unlike the identical 2D layer stacking in 1, 2 exhibited alternating stacking of the extending 2D layers and meshed chains. Magnetic measurements revealed the typical thermally induced spin crossover behavior (SCO): 1 exhibited a 41 K-wide thermal hysteresis with transition temperatures of T1/2↑ = 245 K and T1/2↓ = 204 K, while 2 showed a higher transition temperature (T1/2 = 330 K) with no thermal hysteresis. Magneto-structural correlation studies suggest that the electron-withdrawing effect present in the fluoro substituents does not have a significant impact on the SCO behaviors. Despite the fluoro substituents having a similar atomic radius of hydrogen atoms, variations in the number of these substituents can alter the crystallization behavior of these complexes, which in turn affects the solvents, molecular stacking patterns, and intermolecular interactions, ultimately influencing the SCO behaviors.

Enzyme-Dynamic Extracellular Vesicles for Metalloimmunotherapy of Malignant Pleural Effusions.

Malignant pleural effusions (MPEs) are hard to treat, and their onset usually signals terminal cancer. Immunotherapies hold promise but must overcome the immunosuppressive MPE microenvironment. Herein, we treat MPEs via synergistically combining two emerging cancer therapy modalities: enzyme-dynamic therapy (EDT) and metalloimmunotherapy. To do so, a nanoplatform termed "A-R-SOME" was developed which comprises MPE-targeted M1 type extracellular vesicles (EVs) loaded with (1) a manganese-based superoxide dismutase (SOD) enzyme, (2) stimulator of interferon genes (STING) agonist diABZI-2, and (3) signal transducer and an activator of transcription 3 (STAT3) small interfering RNA. Endogenous reactive oxygen species within tumors induced immunogenic cell death by EDT, along with STING activation by both Mn and diABZI-2, and suppression of the STAT3 pathway. Systemically administered A-R-SOME alleviated the MPE immunosuppressive microenvironment, triggered antitumor systemic immunity, and long-term immune memory, leading to the complete eradication of MPE and pleural tumors with 100% survival rate in an aggressive murine model. A-R-SOME-induced immune effects were also observed in human patient-derived MPE, pointing toward the translation potential of A-R-SOME as an experimental malignancy treatment.

Zinc Coordination Lipid Nanoparticles Co-Delivering Calcium Peroxide and Chelating STING agonist for Enhanced Cancer Metalloimmunotherapy.

Metalloimmunotherapy has achieved great preclinical success against malignant tumors. Nonetheless, the limited immune cell infiltration and impaired immunogenicity within the tumor microenvironment (TME) significantly hinder its translation to clinical applications. In this study, a zinc coordination lipid nanoparticle is developed loaded with calcium peroxide hydrate (CaO2) nanoparticles and the STING agonist diABZI-2, which is termed A-CaO2-Zn-LNP. The release of Zn2+ from the A-CaO2-Zn-LNP and the calcium overload synergistically induced immunogenic cell death (ICD). In addition, CaO2 nanoparticles can consume H+ and release oxygen (O2) under acidic conditions. This treatment increased the pH and alleviated the hypoxia of the TME. Along with cGAS-STING activation by diABZI-2, A-CaO2-Zn-LNP ultimately results in enhanced anti-tumor systemic immunity and long-term immune memory via alleviating the immunosuppressive microenvironment. Taken together, A-CaO2-Zn-LNP offers a new nanoplatform that expands its application for cancer treatment by metalloimmunotheray.

A novel optimization rainfall coupling model based on stepwise decomposition technique.

Traditional decomposition integration models decompose the original sequence into subsequences, which are then proportionally divided into training and testing periods for modeling. Decomposition may cause data aliasing, then the decomposed training period may contain part of the test period data. A more effective method of sample construction is sought in order to accurately validate the model prediction accuracy. Semi-stepwise decomposition (SSD), full stepwise decomposition (FSD), single model semi-stepwise decomposition (SMSSD), and single model full stepwise decomposition (SMFSD) techniques were used to create the samples. This study integrates Variational Mode Decomposition (VMD), African Vulture Optimization Algorithm (AVOA), and Least Squares Support Vector Machine (LSSVM) to construct a coupled rainfall prediction model. The influence of different VMD parameters α is examined, and the most suitable stepwise decomposition machine learning coupled model algorithm for various stations in the North China Plain is selected. The results reveal that SMFSD is relatively the most suitable tool for monthly precipitation forecasting in the North China Plain. Among the predictions for the five stations, the best overall performance is observed at Huairou Station (RMSE of 18.37 mm, NSE of 0.86, MRE of 107.2%) and Jingxian Station (RMSE of 24.74 mm, NSE of 0.86, MRE of 51.71%), while Hekou Station exhibits the poorest performance (RMSE of 25.11 mm, NSE of 0.75, MRE of 173.75%).

Identification and Validation of JAM-A as a Novel Prognostic and Immune Factor in Human Tumors.

Junctional adhesion molecule-A (JAM-A), also known as F11 receptor (F11R), is a transmembrane glycoprotein that is involved in various biological processes, including cancer initiation and progression. However, the functional characteristics and significance of JAM-A in pan-cancer remain unexplored. In this study, we used multiple databases to gain a comprehensive understanding of JAM-A in human cancers. JAM-A was widely expressed in various tissues, mainly located on the microtubules and cell junctions. Aberrant expression of JAM-A was detected in multiple cancers at both mRNA and protein levels, which can be correlated with poorer prognosis and may be attributed to genetic alterations and down-regulated DNA methylation. JAM-A expression was also associated with immune infiltration and may affect immunotherapy responses in several cancers. Functional enrichment analysis indicated that JAM-A participated in tight junction and cancer-related pathways. In vitro experiments verified that JAM-A knockdown suppressed the proliferation and migration abilities of breast cancer cells and liver cancer cells. Overall, our study suggests that JAM-A is a pan-cancer regulator and a potential biomarker for predicting prognosis and immune-therapeutic responses for different tumors.

HnRNPAB promotes pancreatic ductal adenocarcinoma extravasation and liver metastasis by stablizing MYC mRNA.

Heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) is considered a cancer-promoting heterogeneous nuclear ribonucleoprotein in many cancers, but its function in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. HnRNPAB was highly expressed in PDAC tissues compared to normal pancreatic tissues, and high expression of hnRNPAB was associated with poor overall survival and recurrence-free survival in PDAC patients. HnRNPAB promotes migration and invasion of PDAC cells in vitro. In xenograft tumor mouse models, hnRNPAB deprivation significantly attenuated liver metastasis. HnRNPAB mRNA and protein levels are positively associated with MYC in PDAC cells. Mechanistically, hnRNPAB bound to MYC mRNA and prolonged its half-life of MYC mRNA. HnRNPAB induced PDAC cells to secret CXCL8 via MYC, which promoted neutrophils recruitment and facilitated tumor cells entrancing into the hepatic parenchyma. These findings point to a novel regulatory mechanism via which hnRNPAB promotes PDAC metastasis. Implications: Hnrnpab participates in the post-transcriptional regulation of the oncogene MYC by binding and stabilizing MYC mRNA, thereby promoting liver metastasis in PDAC.

[EMP3 inhibits the formation of heterotypic cell-in-cell structures in hepatocellular carcinoma].

Heterotypic cell-in-cell (heCIC) structures represent a unique intercellular interaction where tumor cells internalize immune cells to enhance the killing efficiency of immune cells. However, the mechanism of heCIC structure formation remains to be fully elucidated. In this study, we explored the role of epithelial membrane protein 3 (EMP3), a PMP-22/EMP/MP20 protein family member highly expressed in the patients with hepatocellular carcinoma and poor prognosis, in the formation of the heCIC structure formed by natural killer cells and hepatocellular carcinoma cells. The analysis of monoclonal hepatocellular carcinoma cell lines revealed that EMP3 presented low expression in the cells with high capability to form heCIC structure and high expression in those with low capability. Knocking down the expression of EMP3 by gene editing promoted the formation of heCIC structures, while overexpression of EMP3 significantly inhibited this process. Additionally, the expression of factors involved in the heCIC structure formation suggested that EMP3 inhibited the formation of heCIC structures by modulating the adhesion ability and cytoskeleton of tumor cells. The findings lay a foundation for enhancing the heCIC-mediated tumor immunotherapy by targeting EMP3.

A bibliometric study of the intellectual base and global research hotspots for single-cell sequencing [2009-2022] in breast cancer.

Background: Breast cancer is the most widespread malignant tumor worldwide. Single-cell sequencing technology offers novel insights and methods to understand the onset, progression, and treatment of tumors. Nevertheless, there is currently an absence of a thorough and unbiased report on the comprehensive research status of single-cell sequencing in breast cancer. This study seeks to summarize and quantify the dynamics and trends of research on breast cancer single-cell sequencing by bibliometric analysis. Methods: Research articles and reviews related to breast cancer single-cell sequencing were selected from the WoSCC database. Visualization of data regarding countries, institutions, authors, references, and keywords was performed by CiteSpace and VOSviewer software. Results: 583 articles and reviews were analyzed in this study. The quantity of publications related to breast cancer single-cell sequencing has been increasing annually. These studies originate from 302 institutions in 46 countries, with YMAX S WICHA producing the most publications and WANG Y being the most cited author. Nature Communications is the most researched journal, while Nature holds the highest number of citations. These journals predominantly cover topics in the molecular/biological/immunological fields. Moreover, an analysis of reference and keyword bursts revealed that current research trends in this area are primarily centered on "clonal evolution," "tumor microenvironment," and "immunotherapy." Conclusion: Breast cancer single-cell sequencing is a rapidly growing area of scientific interest. Future research requires more frequent and in-depth collaborations among countries, institutions, and authors. Furthermore, "clonal evolution," "tumor microenvironment," and "immunotherapy" are likely to become major focal points in upcoming research on breast cancer single-cell sequencing.

Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism.

Signaling through the Ras-MAPK pathway can exhibit switch-like activation, which has been attributed to the underlying positive feedback and bimodality in the activation of RasGDP to RasGTP by SOS. SOS contains both catalytic and allosteric Ras binding sites, and a common assumption is that allosteric activation selectively by RasGTP provides the mechanism of positive feedback. However, recent single-molecule studies have revealed that SOS catalytic rates are independent of the nucleotide state of Ras in the allosteric binding site, raising doubt about this as a positive feedback mechanism. Here, we perform detailed kinetic analyses of receptor-mediated recruitment of full-length SOS to the membrane while simultaneously monitoring its catalytic activation of Ras. These results, along with kinetic modeling, expose the autoinhibition release step in SOS, rather than either recruitment or allosteric activation, as the underlying mechanism giving rise to positive feedback in Ras activation.

Quercetin Alleviates LPS-Stimulated Myocardial Injury through Regulating ALOX5/PI3K/AKT Pathway in Sepsis.

Quercetin (QUE) has been found to inhibit the progression of sepsis-related diseases, including sepsis-induced cardiomyopathy (SIC). More information about the role and mechanism of QUE in SIC progression deserves further exploration. Human cardiomyocytes (AC16) were induced with LPS to mimic SIC cell models. Cell proliferation and apoptosis were determined using CCK8 assay, EdU assay, and flow cytometry. Cell inflammation and ferroptosis were evaluated by detecting IL-1ß, TNF-α, Fe2+, ROS, GSH, and GPX4 levels. 5-lipoxygenase (ALOX5) expression was examined by quantitative real-time PCR and western blot. LPS treatment reduced AC16 cell proliferation, while enhanced apoptosis, inflammation, and ferroptosis. QUE repressed LPS-induced AC16 cell apoptosis, inflammation, and ferroptosis. ALOX5 was upregulated in SIC patients, and its expression was reduced by QUE. ALOX5 knockdown restrained LPS-induced apoptosis, inflammation, and ferroptosis in AC16 cells. The inhibitory effect of QUE on LPS-induced myocardial injury could be reversed by ALOX5 overexpression. QUE promoted the activity of PI3K/AKT pathway by reducing ALOX5 expression. QUE could alleviate LPS-induced myocardial injury by regulating ALOX5/PI3K/AKT pathway, suggesting that QUE might be used for treating SIC.

Visualization of transcatheter aortic valve implantation from the perspective of bibliometric analysis.

Transcatheter aortic valve implantation (TAVI) was originally devised as a treatment for patients with aortic stenosis (AS). It has since emerged as a beneficial alternative to surgical aortic valve replacement (SAVR), extending its reach to a broader array of patients. Our objective was to illustrate the developmental trends and focus areas in TAVI research. We sourced a total of 11,480 research papers on TAVI, published between 1994 and 2022, from the Web of Science Core Collection (WoSCC) database. We conducted a bibliometric analysis of these publications, generating cooperation maps, performing co-citation analysis of journals and references, and carrying out a cluster analysis of keywords. Our findings indicate that TAVI research grapples with numerous clinical challenges. We created knowledge maps that highlight contributing countries/institutions, authors, journals with high publication and citation rates, and notable references in this domain. North America and Europe have been at the forefront of research within the TAVI field. The institutions and authors from these regions exert significant influence in this area of study. Beginning in 2009, China has progressively expanded its research on TAVI over the past two decades. We anticipate that future research will increasingly focus on three key areas: implementation scope, lifelong management, outcomes and predicting the risk of TAVI. Research on TAVI is flourishing. Cooperation among different countries and institutions in this field must be strengthened in the future, especially for developing counties.

Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.

Ras is a small GTPase that is central to important functional decisions in diverse cell types. An important aspect of Ras signaling is its ability to exhibit bimodal or switch-like activity. We describe the total reconstitution of a receptor-mediated Ras activation-deactivation reaction catalyzed by SOS and p120-RasGAP on supported lipid membrane microarrays. The results reveal a bimodal Ras activation response, which is not a result of deterministic bistability but is rather driven by the distinct processivity of the Ras activator, SOS. Furthermore, the bimodal response is controlled by the condensation state of the scaffold protein, LAT, to which SOS is recruited. Processivity-driven bimodality leads to stochastic bursts of Ras activation even under strongly deactivating conditions. This behavior contrasts deterministic bistability and may be more resistant to pharmacological inhibition.