Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation.

Cell lineage specification is accomplished by a concerted action of chromatin remodeling and tissue-specific transcription factors. However, the mechanisms that induce and maintain appropriate lineage-specific gene expression remain elusive. Here, we used an unbiased proteomics approach to characterize chromatin regulators that mediate the induction of neuronal cell fate. We found that Tip60 acetyltransferase is essential to establish neuronal cell identity partly via acetylation of the histone variant H2A.Z. Despite its tight correlation with gene expression and active chromatin, loss of H2A.Z acetylation had little effect on chromatin accessibility or transcription. Instead, loss of Tip60 and acetyl-H2A.Z interfered with H3K4me3 deposition and activation of a unique subset of silent, lineage-restricted genes characterized by a bivalent chromatin configuration at their promoters. Altogether, our results illuminate the mechanisms underlying bivalent chromatin activation and reveal that H2A.Z acetylation regulates neuronal fate specification by establishing epigenetic competence for bivalent gene activation and cell lineage transition.

Experimental relativistic zero-knowledge proofs.

Protecting secrets is a key challenge in our contemporary information-based era. In common situations, however, revealing secrets appears unavoidable; for instance, when identifying oneself in a bank to retrieve money. In turn, this may have highly undesirable consequences in the unlikely, yet not unrealistic, case where the bank's security gets compromised. This naturally raises the question of whether disclosing secrets is fundamentally necessary for identifying oneself, or more generally for proving a statement to be correct. Developments in computer science provide an elegant solution via the concept of zero-knowledge proofs: a prover can convince a verifier of the validity of a certain statement without facilitating the elaboration of a proof at all1. In this work, we report the experimental realization of such a zero-knowledge protocol involving two separated verifier-prover pairs2. Security is enforced via the physical principle of special relativity3, and no computational assumption (such as the existence of one-way functions) is required. Our implementation exclusively relies on off-the-shelf equipment and works at both short (60 m) and long distances (≥400 m) in about one second. This demonstrates the practical potential of multi-prover zero-knowledge protocols, promising for identification tasks and blockchain applications such as cryptocurrencies or smart contracts4.

The Quantitative Biotinylproteomics Studies Reveal a WInd-Related Kinase 1 (Raf-Like Kinase 36) Functioning as an Early Signaling Component in Wind-Induced Thigmomorphogenesis and Gravitropism.

Wind is one of the most prevalent environmental forces entraining plants to develop various mechano-responses, collectively called thigmomorphogenesis. Largely unknown is how plants transduce these versatile wind force signals downstream to nuclear events and to the development of thigmomorphogenic phenotype or anemotropic response. To identify molecular components at the early steps of the wind force signaling, two mechanical signaling-related phosphoproteins, identified from our previous phosphoproteomic study of Arabidopsis touch response, mitogen-activated protein kinase kinase 1 (MKK1) and 2 (MKK2), were selected for performing in planta TurboID (ID)-based quantitative proximity-labeling (PL) proteomics. This quantitative biotinylproteomics was separately performed on MKK1-ID and MKK2-ID transgenic plants, respectively, using the genetically engineered TurboID biotin ligase expression transgenics as a universal control. This unique PTM proteomics successfully identified 11 and 71 MKK1 and MKK2 putative interactors, respectively. Biotin occupancy ratio (BOR) was found to be an alternative parameter to measure the extent of proximity and specificity between the proximal target proteins and the bait fusion protein. Bioinformatics analysis of these biotinylprotein data also found that TurboID biotin ligase favorably labels the loop region of target proteins. A WInd-Related Kinase 1 (WIRK1), previously known as rapidly accelerated fibrosarcoma (Raf)-like kinase 36 (RAF36), was found to be a putative common interactor for both MKK1 and MKK2 and preferentially interacts with MKK2. Further molecular biology studies of the Arabidopsis RAF36 kinase found that it plays a role in wind regulation of the touch-responsive TCH3 and CML38 gene expression and the phosphorylation of a touch-regulated PATL3 phosphoprotein. Measurement of leaf morphology and shoot gravitropic response of wirk1 (raf36) mutant revealed that the WIRK1 gene is involved in both wind-triggered rosette thigmomorphogenesis and gravitropism of Arabidopsis stems, suggesting that the WIRK1 (RAF36) protein probably functioning upstream of both MKK1 and MKK2 and that it may serve as the crosstalk point among multiple mechano-signal transduction pathways mediating both wind mechano-response and gravitropism.

The hydrogen-bonding dynamics of water to a nitrile-functionalized electrode is modulated by voltage according to ultrafast 2D IR spectroscopy.

We report the hydrogen-bonding dynamics of water to a nitrile-functionalized and plasmonic electrode surface as a function of applied voltage. The surface-enhanced two-dimensional infrared spectra exhibit hydrogen-bonded and non-hydrogen-bonded nitrile features in similar proportions, plus cross peaks between the two. Isotopic dilution experiments show that the cross peaks arise predominantly from chemical exchange between hydrogen-bonded and non-hydrogen-bonded nitriles. The chemical exchange rate depends upon voltage, with the hydrogen bond of the water to the nitriles breaking 2 to 3 times slower (>63 vs. 25 ps) under a positive as compared to a negative potential. Spectral diffusion created by hydrogen-bond fluctuations occurs on a ~1 ps timescale and is moderately potential-dependent. Timescales from molecular dynamics simulations agree qualitatively with the experiment and show that a negative voltage causes a small net displacement of water away from the surface. These results show that the voltage applied to an electrode can alter the timescales of solvent motion at its interface, which has implications for electrochemically driven reactions.

Pathogenic bacteria exploit transferrin receptor transcytosis to penetrate the blood-brain barrier.

The human blood-brain barrier (BBB) comprises a single layer of brain microvascular endothelial cells (HBMECs) protecting the brain from bloodborne pathogens. Meningitis is among the most serious diseases, but the mechanisms by which major meningitis-causing bacterial pathogens cross the BBB to reach the brain remain poorly understood. We found that Streptococcus pneumoniae, group B Streptococcus, and neonatal meningitis Escherichia coli commonly exploit a unique vesicle fusion mechanism to hitchhike on transferrin receptor (TfR) transcytosis to cross the BBB and illustrated the details of this process in human BBB model in vitro and mouse model. Toll-like receptor signals emanating from bacteria-containing vesicles (BCVs) trigger K33-linked polyubiquitination at Lys168 and Lys181 of the innate immune regulator TRAF3 and then activate the formation of a protein complex containing the guanine nucleotide exchange factor RCC2, the small GTPase RalA and exocyst subcomplex I (SC I) on BCVs. The distinct function of SEC6 in SC I, interacting directly with RalA on BCVs and the SNARE protein SNAP23 on TfR vesicles, tethers these two vesicles and initiates the fusion. Our results reveal that innate immunity triggers a unique modification of TRAF3 and the formation of the HBMEC-specific protein complex on BCVs to authenticate the precise recognition and selection of TfR vesicles to fuse with and facilitate bacterial penetration of the BBB.

Generation of functional human oligodendrocytes from dermal fibroblasts by direct lineage conversion.

Oligodendrocytes, the myelinating cells of the central nervous system, possess great potential for disease modeling and cell transplantation-based therapies for leukodystrophies. However, caveats to oligodendrocyte differentiation protocols ( Ehrlich et al., 2017; Wang et al., 2013; Douvaras and Fossati, 2015) from human embryonic stem and induced pluripotent stem cells (iPSCs), which include slow and inefficient differentiation, and tumorigenic potential of contaminating undifferentiated pluripotent cells, are major bottlenecks towards their translational utility. Here, we report the rapid generation of human oligodendrocytes by direct lineage conversion of human dermal fibroblasts (HDFs). We show that the combination of the four transcription factors OLIG2, SOX10, ASCL1 and NKX2.2 is sufficient to convert HDFs to induced oligodendrocyte precursor cells (iOPCs). iOPCs resemble human primary and iPSC-derived OPCs based on morphology and transcriptomic analysis. Importantly, iOPCs can differentiate into mature myelinating oligodendrocytes in vitro and in vivo. Finally, iOPCs derived from patients with Pelizaeus Merzbacher disease, a hypomyelinating leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene, showed increased cell death compared with iOPCs from healthy donors. Thus, human iOPCs generated by direct lineage conversion represent an attractive new source for human cell-based disease models and potentially myelinating cell grafts.

A polarization scheme that resolves cross-peaks with transient absorption and eliminates diagonal peaks in 2D spectroscopy.

Two-dimensional (2D) optical spectroscopy contains cross-peaks that are helpful features for determining molecular structure and monitoring energy transfer, but they can be difficult to resolve from the much more intense diagonal peaks. Transient absorption (TA) spectra contain transitions similar to cross-peaks in 2D spectroscopy, but in most cases they are obscured by the bleach and stimulated emission peaks. We report a polarization scheme, <0°,0°,+θ2(t2),-θ2(t2)>, that can be easily implemented in the pump-probe beam geometry, used most frequently in 2D and TA spectroscopy. This scheme removes the diagonal peaks in 2D spectroscopies and the intense bleach/stimulated emission peaks in TA spectroscopies, thereby resolving the cross-peak features. At zero pump-probe delay, θ2 = 60° destructively interferes two Feynman paths, eliminating all signals generated by field interactions with four parallel transition dipoles, and the intense diagonal and bleach/stimulated emission peaks. At later delay times, θ2(t2) is adjusted to compensate for anisotropy caused by rotational diffusion. When implemented with TA spectroscopy or microscopy, the pump-probe spectrum is dominated by the cross-peak features. The local oscillator is also attenuated, which enhances the signal two times. This overlooked polarization scheme reduces spectral congestion by eliminating diagonal peaks in 2D spectra and enables TA spectroscopy to measure similar information given by cross-peaks in 2D spectroscopy.

A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease.

SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.

MXene-Fiber Composite Membranes for Permeable and Biocompatible Skin-Interfaced Iontronic Mechanosensing.

Artificial ionic sensory systems, bridging the divide between biological systems and electronics, mimic human skin functions but face critical challenges with biocompatibility, comfort, signal stability, and simplifying packaging. Here, we present a simple and permeable skin-interfaced iontronic mechanosensing (SIIM) architecture that integrates human skin as natural ionic material and hierarchically porous MXene-fiber composite membranes as sensing electrodes. The SIIM system eliminates complex ionic material design and multilayer matrix, exhibiting ultrahigh pressure sensitivities (5.4 kPa-1, <75 Pa), a low detection limit (6 Pa), excellent output stability along with high permeability to minimize the impact of sweating on sensing. The noncytotoxic nature of SIIM electrodes ensures excellent biocompatibility (>97% cell coincubational viability), facilitating long-term wearability and high biosafety. Furthermore, the scalable SIIM configuration integrated with matrix smart gloves, effectively monitors human physical movements. This SIIM-based sensor with marked sensing capabilities, structural simplicity, and scalability, holds promising potential in diverse wearable applications.

MEOX1 triggers myofibroblast apoptosis resistance, contributing to pulmonary fibrosis in mice.

The apoptosis resistance of myofibroblasts is a hallmark in the irreversible progression of pulmonary fibrosis (PF). While the underlying molecular mechanism remains elusive. In this study, we unveiled a previously unrecognized mechanism underlying myofibroblast apoptosis resistance during PF. Our investigation revealed heightened expression of mesenchyme homeobox 1 (MEOX1) in the lungs of idiopathic pulmonary fibrosis (IPF) patients and bleomycin-induced PF mice. Silencing MEOX1 significantly attenuated PF progression in mice. In vitro, we found a notable increase in MEOX1 expression in transforming growth factor-ß1 (TGF-ß1)-induced myofibroblasts. Silencing MEOX1 enhanced apoptosis of myofibroblasts. Mechanistically, we identified G-protein signaling pathway regulatory factor 4 (RGS4) as a critical downstream target of MEOX1, as predicted by bioinformatics analysis. MEOX1 enhanced apoptosis resistance by upregulating RGS4 expression in myofibroblasts. In conclusion, our study highlights MEOX1 as a promising therapeutic target for protecting against PF by modulating myofibroblast apoptosis resistance.

Engineering of Substrate-Binding Domain to Improve Catalytic Activity of Chondroitin B Lyase with Semi-Rational Design.

Dermatan sulfate and chondroitin sulfate are dietary supplements that can be utilized as prophylactics against thrombus formation. Low-molecular-weight dermatan sulfate (LMWDS) is particularly advantageous due to its high absorbability. The enzymatic synthesis of low-molecular-weight dermatan sulfates (LMWDSs) using chondroitin B lyase is a sustainable and environmentally friendly approach to manufacturing. However, the industrial application of chondroitin B lyases is severely hampered by their low catalytic activity. To improve the activity, a semi-rational design strategy of engineering the substrate-binding domain of chondroitin B lyase was performed based on the structure. The binding domain was subjected to screening of critical residues for modification using multiple sequence alignments and molecular docking. A total of thirteen single-point mutants were constructed and analyzed to assess their catalytic characteristics. Out of these, S90T, N103C, H134Y, and R159K exhibited noteworthy enhancements in activity. This study also examined combinatorial mutagenesis and found that the mutant H134Y/R159K exhibited a substantially enhanced catalytic activity of 1266.74 U/mg, which was 3.21-fold that of the wild-type one. Molecular docking revealed that the enhanced activity of the mutant could be attributed to the formation of new hydrogen bonds and hydrophobic interactions with the substrate as well as neighbor residues. The highly active mutant would benefit the utilization of chondroitin B lyase in pharmaceuticals and functional foods.

Better efficacy, lower recurrence rate and decreased CD8+TRM with guselkumab treatment for generalized pustular psoriasis: A prospective cohort study from China.

Generalized pustular psoriasis (GPP) is a severe and uncommon form of psoriasis, for which treatment options are limited. There is an urgent need to expand the treatment options for GPP. Currently, adalimumab, secukinumab, and guselkumab are considered effective for GPP, but there is a lack of prospective direct comparative studies on their efficacy for GPP. We conducted a prospective, single-center, observational study on 50 GPP patients to compare the efficacy, safety, and recurrence rates of these three biologics. Adalimumab, secukinumab, and guselkumab resulted in varying degrees of improvement in patients with GPP, but guselkumab exhibited superior efficacy and a lower recurrence rate than the other two drugs. This enhanced response may be attributed to the significant reduction in CD8+ tissue-resident memory T cells within GPP lesions caused by guselkumab.

PCDH8 is a novel prognostic biomarker in thyroid cancer and promotes cell proliferation and viability.

Protocadherin 8 (PCDH8), a calcium-dependent transmembrane protein in the protocadherin family, regulates cell adhesion and signal transduction. While some studies have provided indirect evidence that PCDH8 has cancer-promoting properties, this association is controversial. In particular, its involvement in thyroid cancer (THCA) remains unclear. We aimed to elucidate the role of PCDH8 in THCA using bioinformatic analysis. Subsequently, the results were experimentally validated. The analysis conducted using the R programming language and online web tools explored PCDH8 expression levels, prognostic, and clinical implications, and its relationship with the tumor immune microenvironment in THCA. Furthermore, we examined the association between PCDH8 and co-expressed genes, highlighting their involvement in several biological processes relevant to THCA. The potential of PCDH8 as a therapeutic target for this pathology was also explored. Immunohistochemical (IHC) staining was performed on samples from 98 patients with THCA, and experimental validation was carried out. PCDH8 was significantly elevated in cancer tissues and associated with poor prognosis, several clinical factors, and immune cell and checkpoint abundance. Cox regression and survival analyses, together with Receiver Operating Curves (ROC) indicated that PCDH8 was an independent prognostic factor for THCA. Furthermore, PCDH8 impacts cell viability and proliferation, promoting tumorigenesis. Also, it influences tumor cell sensitivity to various drugs. Thus, PCDH8 might be a potential therapeutic target for THCA. IHC, cell culture, MTT, and colony formation experiments further confirmed our findings. This analysis provided insights into the potential carcinogenic role of PCDH8 in THCA, as it impacts cell viability and proliferation. Thus, PCDH8 might play an important role in its prognosis, immune infiltration, and diagnosis.

c-CBL/LCK/c-JUN/ETS1/CD28 axis restrains childhood asthma by suppressing Th2 differentiation.

BACKGROUND: Asthma is a common immune disease with high morbidity in children. Type 2 inflammation is the center of asthma development, and mainly mediated by a subset of CD4 + T cells, T helper 2 (Th2) cells. Excess Th2 differentiation was generally associated with asthmatic attack. Casitas B-lineage lymphoma (c-CBL) was reported to involved in T cell development and databank showed its decreased expression in CD4 + T cells from peripheral blood of asthmatic children. This study aims to investigate the role of c-CBL in childhood asthma and Th2 differentiation, and explore the underlying mechanism. METHODS: We collected peripheral blood samples from clinical childhood asthma cases and healthy controls, and determined c-CBL expression in CD4 + T cells. Asthma was induced in neonatal mice by ovalbumin (OVA) intraperitoneal injection and aerosol inhalation, and c-CBL expression in CD4 + T cells from peripheral blood and spleen was measured. Gain-of-function experiments was performed to confirm the effects of c-CBL on Th2 differentiation in vitro. Finally, c-CBL was delivered into asthmatic mice via lentivirus infection to verify its effects on experimental asthma. RESULTS: c-CBL was lowly expressed in CD4 + T cells from asthmatic children than those of healthy controls. Similarly, it was downregulated in CD4 + T cells from peripheral blood and spleen of asthma mice. Overexpression of c-CBL restrained lung pathological injury and type 2 inflammation in experimental asthmatic mice. Gain-of-function experiments demonstrated that c-CBL inhibited Th2 differentiation of CD4 + T cells from healthy children, and mediated the ubiquitination of lymphocyte cell-specific protein-tyrosine kinase (LCK). LCK acted as a kinase to phosphorylate and activate c-JUN, which was predicted to bind promoter sequence of CD28 by bioinformatic analysis. Dual-luciferase reporter assay verified that c-JUN and ETS1 synergically enhanced transcription of CD28, and this transcription activation was aggravated by LCK overexpression. CONCLUSION: c-CBL alleviated asthma and suppressed Th2 differentiation by facilitating LCK ubiquitination, interrupting c-JUN activation and CD28 expression in vivo and in vitro. c-CBL/LCK/c-JUN/ETS1/CD28 axis was partially involved in childhood asthma, and may provide novel insights for clinical treatment for asthma.

Wnt5a-mediated autophagy contributes to the epithelial-mesenchymal transition of human bronchial epithelial cells during asthma.

BACKGROUND: The epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBECs) is essential for airway remodeling during asthma. Wnt5a has been implicated in various lung diseases, while its role in the EMT of HBECs during asthma is yet to be determined. This study sought to define whether Wnt5a initiated EMT, leading to airway remodeling through the induction of autophagy in HBECs. METHODS: Microarray analysis was used to investigate the expression change of WNT5A in asthma patients. In parallel, EMT models were induced using 16HBE cells by exposing them to house dust mites (HDM) or interleukin-4 (IL-4), and then the expression of Wnt5a was observed. Using in vitro gain- and loss-of-function approaches via Wnt5a mimic peptide FOXY5 and Wnt5a inhibitor BOX5, the alterations in the expression of the epithelial marker E-cadherin and the mesenchymal marker protein were observed. Mechanistically, the Ca2+/CaMKII signaling pathway and autophagy were evaluated. An autophagy inhibitor 3-MA was used to examine Wnt5a in the regulation of autophagy during EMT. Furthermore, we used a CaMKII inhibitor KN-93 to determine whether Wnt5a induced autophagy overactivation and EMT via the Ca2+/CaMKII signaling pathway. RESULTS: Asthma patients exhibited a significant increase in the gene expression of WNT5A compared to the healthy control. Upon HDM and IL-4 treatments, we observed that Wnt5a gene and protein expression levels were significantly increased in 16HBE cells. Interestingly, Wnt5a mimic peptide FOXY5 significantly inhibited E-cadherin and upregulated α-SMA, Collagen I, and autophagy marker proteins (Beclin1 and LC3-II). Rhodamine-phalloidin staining showed that FOXY5 resulted in a rearrangement of the cytoskeleton and an increase in the quantity of stress fibers in 16HBE cells. Importantly, blocking Wnt5a with BOX5 significantly inhibited autophagy and EMT induced by IL-4 in 16HBE cells. Mechanistically, autophagy inhibitor 3-MA and CaMKII inhibitor KN-93 reduced the EMT of 16HBE cells caused by FOXY5, as well as the increase in stress fibers, cell adhesion, and autophagy. CONCLUSION: This study illustrates a new link in the Wnt5a-Ca2+/CaMKII-autophagy axis to triggering airway remodeling. Our findings may provide novel strategies for the treatment of EMT-related diseases.

Metabolomics analysis of different diameter classes of Taxus chinensis reveals that the resource allocation is related to carbon and nitrogen metabolism.

Taxus chinensis (Taxus cuspidata Sieb. et Zucc.) is a traditional medicinal plant known for its anticancer substance paclitaxel, and its growth age is also an important factor affecting its medicinal value. However, how age affects the physiological and metabolic characteristics and active substances of T. chinensis is still unclear. In this study, carbon and nitrogen accumulation, contents of active substances and changes in primary metabolites in barks and annual leaves of T. chinensis of different diameter classes were investigated by using diameter classes instead of age. The results showed that leaves and barks of small diameter class (D1) had higher content of non-structural carbohydrates and C, which were effective in enhancing defense capacity, while N content was higher in medium (D2) and large diameter classes (D3). Active substances such as paclitaxel, baccatin III and cephalomannine also accumulated significantly in barks of large diameter classes. Moreover, 21 and 25 differential metabolites were identified in leaves and barks of different diameter classes, respectively. The differential metabolites were enhanced the TCA cycle and amino acid biosynthesis, accumulate metabolites such as organic acids, and promote the synthesis and accumulation of active substances such as paclitaxel in the medium and large diameter classes. These results revealed the carbon and nitrogen allocation mechanism of different diameter classes of T. chinensis, and its relationship with medicinal components, providing a guidance for the harvesting and utilization of wild T. chinensis.

Tumor Microenvironment-Induced Drug Depository for Persistent Antitumor Chemotherapy and Immune Activation.

Herein, a drug-loading nanosystem that can in situ form drug depository for persistent antitumor chemotherapy and immune regulation is designed and built. The system (DOX@MIL-LOX@AL) is fabricated by packaging alginate on the surface of Doxorubicin (DOX) and lactate oxidase (LOX) loaded MIL-101(Fe)-NH2 nanoparticle, which can easily aggregate in the tumor microenvironment through the cross-linking with intratumoral Ca2+. Benefiting from the tumor retention ability, the fast-formed drug depository will continuously release DOX and Fe ions through the ATP-triggered slow degradation, thus realizing persistent antitumor chemotherapy and immune regulation. Meanwhile, LOX in the non-aggregated nanoparticles is able to convert the lactic acid to H2O2, which will be subsequently decomposed into ·OH by Fe ions to further enhance the DOX-induced immunogenic death effect of tumor cells. Together, with the effective consumption of immunosuppressive lactic acid, long-term chemotherapy, and oxidation therapy, DOX@MIL-LOX@AL can execute high-performance antitumor chemotherapy and immune activation with only one subcutaneous administration.

Comprehensive assessment of cellular senescence in the tumor microenvironment.

Cellular senescence (CS), a state of permanent growth arrest, is intertwined with tumorigenesis. Due to the absence of specific markers, characterizing senescence levels and senescence-related phenotypes across cancer types remain unexplored. Here, we defined computational metrics of senescence levels as CS scores to delineate CS landscape across 33 cancer types and 29 normal tissues and explored CS-associated phenotypes by integrating multiplatform data from ~20 000 patients and ~212 000 single-cell profiles. CS scores showed cancer type-specific associations with genomic and immune characteristics and significantly predicted immunotherapy responses and patient prognosis in multiple cancers. Single-cell CS quantification revealed intra-tumor heterogeneity and activated immune microenvironment in senescent prostate cancer. Using machine learning algorithms, we identified three CS genes as potential prognostic predictors in prostate cancer and verified them by immunohistochemical assays in 72 patients. Our study provides a comprehensive framework for evaluating senescence levels and clinical relevance, gaining insights into CS roles in cancer- and senescence-related biomarker discovery.

Long non-coding RNA Linc00657 up-regulates Skp2 to promote the progression of cervical cancer through lipid reprogramming and regulation of immune microenvironment.

More and more evidence shows that long non-coding RNA (lncRNA) plays an important role in the biological behavior of many kinds of malignant tumors, but the specific function of lncRNA Linc00657 in cervical cancer is still unknown. The purpose of this study is to explore the effect of Linc00657 on the malignant progression of cervical cancer and its potential mechanism. In two kinds of cervical cancer cell lines and normal cervical epithelial cells, qRT-PCR showed increased expression of Linc00657 in cervical cancer cells. Through MTT, clone formation test, flow cytometry, wound healing test and Transwell test, it has been found that overexpression of Linc00657 could promote the proliferation,migration and invasion of cervical cancer cells，and inhibit apoptosis. Through the StarBase database, it was found that there may be a mutual regulatory relationship between Linc00657 and Skp2, and Skp2 may be the downstream target of Linc00657. QRT-PCR detection confirmed that the expression of Skp2 was increased in cervical cancer cells with overexpression of Linc00657. TIMER2 database found that Skp2 was associated with lipid metabolic enzymes and immune cell infiltration. It was found that Linc00657 knockdown inhibited tumor growth and metastasis and inhibited the expression of Skp2 in vivo. In short, our research shows that Linc00657 has carcinogenic properties in cervical cancer, and LINC00657 promotes the occurrence of cervical cancer by up-regulating the expression of Skp2. We predict that Linc00657/mir30s/Skp2 axis plays a role in the malignant progression of cervical cancer. In addition, Skp2 may participate in cancer immune response and promote lymph node metastasis of cervical cancer through lipid reprogramming. These findings also provide promising targets for the diagnosis and treatment of cervical cancer.

Susceptibility to Attentional Capture by Target-Matching Distractors Predicts High Visual Working Memory Capacity.

Recent event-related potential (ERP) studies showed that individuals with low visual working memory (VWM) capacity are more susceptible to salience-driven attentional capture than high-capacity individuals are, with the latter being able to proactively suppress salient but irrelevant distractors. However, it remains unclear whether and how contingent attentional capture by distractors that possess a task-relevant (target) feature is related to VWM capacity. Here, we adopted a central focused-attention task that contained peripheral target-matching distractors to investigate this issue (N = 51 adults). Surprisingly, we revealed that target-matching distractors elicited both a larger N2-posterior-contralateral (N2pc) and a larger post-N2pc distractor positivity (PD) component in high-capacity individuals than in low-capacity ones, meaning that high-capacity individuals are less able to ignore such distractors initially, though they could call on a stronger reactive suppression mechanism afterward. These findings illustrate that high-capacity individuals are more (rather than less or equally) susceptible to contingent attention capture compared with low-capacity ones.