Digital quantum simulation of Floquet symmetry-protected topological phases.

Quantum many-body systems away from equilibrium host a rich variety of exotic phenomena that are forbidden by equilibrium thermodynamics. A prominent example is that of discrete time crystals1-8, in which time-translational symmetry is spontaneously broken in periodically driven systems. Pioneering experiments have observed signatures of time crystalline phases with trapped ions9,10, solid-state spin systems11-15, ultracold atoms16,17 and superconducting qubits18-20. Here we report the observation of a distinct type of non-equilibrium state of matter, Floquet symmetry-protected topological phases, which are implemented through digital quantum simulation with an array of programmable superconducting qubits. We observe robust long-lived temporal correlations and subharmonic temporal response for the edge spins over up to 40 driving cycles using a circuit of depth exceeding 240 and acting on 26 qubits. We demonstrate that the subharmonic response is independent of the initial state, and experimentally map out a phase boundary between the Floquet symmetry-protected topological and thermal phases. Our results establish a versatile digital simulation approach to exploring exotic non-equilibrium phases of matter with current noisy intermediate-scale quantum processors21.

Immune cell phenotypes and mortality in the Framingham Heart Study.

BACKGROUND: Global life expectancy is rising, with the 60 + age group projected to hit 2 billion by 2050. Aging impacts the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their importance, links between immune cell phenotypes including ARIPs and mortality are underexplored. We prospectively investigated 16 different immune cell phenotypes using flow cytometry and IL-6 in relation to survival outcome among dementia-free Framingham Heart Study (FHS) offspring cohort participants who attended the seventh exam (1998-2001). RESULTS: Among 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the 19-year survival rate was 65%. Adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR: 0.86 [0.76-0.96], 0.84 [0.74-0.94], respectively), while higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3 +) were associated with increased all-cause mortality risk (HR = 1.17, [1.03-1.32]). Elevated IL-6 levels correlated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26-1.62], 1.70 [1.31-2.21], and 1.36 [1.18-1.57], respectively). However, after adjusting for cardiovascular risk factors and prevalent cancer alongside age, sex, and CMV, immune cell phenotypes were no longer associated with mortality in our cohort. Nonetheless, IL-6 remained significantly associated with all-cause and cardiovascular mortality (HRs: 1.3 [1.13-1.49], 1.5 [1.12-1.99], respectively). CONCLUSIONS: In 19-year follow-up, higher Tc17/CD8 + Treg and CD4/CD8 ratios were associated with lower all-cause mortality, while the CD8 + CD25 + FoxP3 + (CD8 + Treg) phenotype showed increased risk. Elevated IL-6 levels consistently correlated with amplified mortality risks. These findings highlight the links between immune phenotypes and mortality, suggesting implications for future research and clinical considerations.

A Method to Develop the Driver-Adaptive Lane-Keeping Assistance System Based on Real Driver Preferences.

To satisfy the preference of each driver, the development of a Lane-Keeping Assistance (LKA) system that can adapt to individual drivers has become a research hotspot in recent years. However, existing studies have mostly relied on the assumption that the LKA characteristic aligned with the driver's preference is consistent with this driver's naturalistic driving characteristic. Nevertheless, this assumption may not always hold true, causing limitations to the effectiveness of this method. This paper proposes a novel method for a Driver-Adaptive Lane-Keeping Assistance (DALKA) system based on drivers' real preferences. First, metrics are extracted from collected naturalistic driving data using action point theory to describe drivers' naturalistic driving characteristics. Then, the subjective and objective evaluation method is introduced to obtain the real preference of each test driver for the LKA system. Finally, machine learning methods are employed to train a model that relates naturalistic driving characteristics to the drivers' real preferences, and the model-predicted preferences are integrated into the DALKA system. The developed DALKA system is then subjectively evaluated by the drivers. The results show that our DALKA system, developed using this method, can enhance or maintain the subjective evaluations of the LKA system for most drivers.

Inflammatory protein associations with brain MRI measures: Framingham Offspring Cohort.

INTRODUCTION: Brain magnetic resonance imaging (MRI) and inflammatory biomarkers are crucial for investigating preclinical neurocognitive disorders. Current investigations focus on a few inflammatory markers. The study aims to investigate the associations between inflammatory biomarkers and MRI measures and to examine sex differences among the associations in the Framingham Heart Study. METHODS: Dementia and stroke-free participants underwent OLINK Proteomics profiling and MRI measurements within 5 years. Pairwise cross-sectional analysis assessed 68 biomarkers with 13 brain MRI volumes, adjusting for covariates and familial correlations. RESULTS: Elevated CDCP1, IL6, OPG, and 4E.BP1 were related to smaller total cerebral brain volume (TCBV), whereas higher HGF, IL8, and MMP10 were associated with smaller TCBV, total and frontal white matter volumes. Higher SCF and TWEAK were associated with larger TCBV. In sex-stratified analyses, associations were observed exclusively among males. DISCUSSION: We report several associations between inflammatory biomarkers and brain volumes, highlighting different associations within sex subgroups. HIGHLIGHTS: Higher CDCP1, IL6, OPG, and 4E.BP1 levels were associated with smaller TCBV. Higher levels of HGF, IL8 and MMP10 were associated with smaller TCBV, CWV and FWV. Higher levels of SCF and TWEAK, were associated with larger TCBV. Significance diminished in models adjusting for CVD risk factors. Associations were observed exclusively in males.

Evaluating the Impact of Intracranial Volume Correction Approaches on the Quantification of Intracranial Structures in MRI: A Systematic Analysis.

BACKGROUND: In neuroscience, accurately quantifying individual brain regions in large cohorts is a challenge. Differences in intracranial structures can suggest functional differences, but they also reflect the effects of other factors. However, there is currently no standardized method for the correction of intracranial structure measurements. PURPOSE: To identify the optimal method to counteract the influence of total intracranial volume (TIV) and gender on the measurement of intracranial structures. STUDY TYPE: Prospective. POPULATION/SUBJECTS: One hundred forty-one healthy adult volunteers (70 male, mean age 21.8 ± 1.7 years). FIELD STRENGTH/SEQUENCE: T1-weighted 3D gradient-echo sequence at 3.0 T. ASSESSMENT: A radiologist with 5 years of work experience screened the raw images to exclude poor-quality images. Freesurfer then performed automated segmentation to obtain measurements of intracranial structures. Male-only, female-only, and TIV-matched sub-samples were created separately. Comparisons between the original data and these sub-samples were used to assess the effects of gender and TIV. Comparison the consistency between TIV-matched sample and corrected data that corrected by four methods: Proportion method, power-corrected proportion method, covariate regression method, and residual method. STATISTICAL TESTS: Cohen's d for examining group distribution disparities, t-tests for probing mean differences, correlation coefficients to assess the relationships between intracranial substructure measurements and TIV. Multiple comparison corrections were applied to the results. RESULTS: The correlation coefficients between TIV and the volumes of intracranial structures ranged from 0.033 to 0.883, with an average of 0.467. Thirty significant volume differences were found among 36 structures in the original sample, while no differences were observed in the TIV-matched sample. Among the four correction methods, the residual method had highest consistency (similarity 94.4%) with the TIV-matched group. DATA CONCLUSION: The variation in intracranial structure sizes between genders was largely attributable to TIV. The residual method offers a more accurate and effective approach for correcting the effects of TIV on intracranial structures. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

An antioxidative sophora exosome-encapsulated hydrogel promotes spinal cord repair by regulating oxidative stress microenvironment.

Spinal cord injury (SCI) is a severe traumatic disease because of its complications and multi-organ dysfunction. After the injury, the disruption of microenvironment homeostasis in the lesion demolishes the surrounding healthy tissues via various pathways. The microenvironment regulation is beneficial for neural and functional recovery. Sustained release, cellular uptake, and long-term retention of therapeutic molecules at the impaired sites are important for continuous microenvironment improvement. In our study, a local-implantation system was constructed for SCI treatment by encapsulating exosomes derived from Flos Sophorae Immaturus (so-exos) in a polydopamine-modified hydrogel (pDA-Gel). So-exos are used as nanoscale natural vehicles of rutin, a flavonoid phytochemical that is effective in microenvironment improvement and nerve regeneration. Our study showed that the pDA-Gel-encapsulated so-exos allowed rapid improvement of the impaired motor function and alleviation of urination dysfunction by modulating the spinal inflammatory and oxidative conditions, thus illustrating a potential SCI treatment through a combinational delivery of so-exos.

Lq-based robust analytics on ultrahigh and high dimensional data.

Ultrahigh and high dimensional data are common in regression analysis for various fields, such as omics data, finance, and biological engineering. In addition to the problem of dimension, the data might also be contaminated. There are two main types of contamination: outliers and model misspecification. We develop an unique method that takes into account the ultrahigh or high dimensional issues and both types of contamination. In this article, we propose a framework for feature screening and selection based on the minimum Lq-likelihood estimation (MLqE), which accounts for the model misspecification contamination issue and has also been shown to be robust to outliers. In numerical analysis, we explore the robustness of this framework under different outliers and model misspecification scenarios. To examine the performance of this framework, we conduct real data analysis using the skin cutaneous melanoma data. When comparing with traditional screening and feature selection methods, the proposed method shows superiority in both variable identification effectiveness and parameter estimation accuracy.

Transplantation of Human Mesenchymal Stem-Cell-Derived Exosomes Immobilized in an Adhesive Hydrogel for Effective Treatment of Spinal Cord Injury.

Spinal cord injury is among the most fatal diseases. The complicated inhibitory microenvironment requires comprehensive mitigation. Exosomes derived from mesenchymal stem cells (MSCs) are natural biocarriers of cell paracrine secretions that bear the functions of microenvironment regulation. However, the effective retention, release, and integration of exosomes into the injured spinal cord tissue are poorly defined. Herein, an innovative implantation strategy is established using human MSC-derived exosomes immobilized in a peptide-modified adhesive hydrogel (Exo-pGel). Unlike systemic admistration of exosomes, topical transplantation of the Exo-pGel provides an exosome-encapsulated extracellular matrix to the injured nerve tissue, thereby inducing effecient comprehensive mitigation of the SCI microenvironment. The implanted exosomes exhibit efficient retention and sustained release in the host nerve tissues. The Exo-pGel elicits significant nerve recovery and urinary tissue preservation by effectively mitigating inflammation and oxidation. The Exo-pGel therapy presents a promising strategy for effective treatment of central nervous system diseases based on exosome implantation.

Development of Ferrocene-Based Diamine-Phosphine-Sulfonamide Ligands for Iridium-Catalyzed Asymmetric Hydrogenation of Ketones.

A series of air-stable, easily accessible tridentate ferrocene-based diamine-phosphine sulfonamide (f-diaphos) ligands were successfully developed for iridium-catalyzed asymmetric hydrogenation of ketones. The f-diaphos ligands exhibited excellent enantioselectivity and superb reactivity in Ir-catalyzed asymmetric hydrogenation of ketones (for arylalkyl ketones, ( S)-selectivity, up to 99.4% ee, and 100 000 TON; for diaryl ketones, ( R)-selectivity, up to 98.2% ee, and 10 000 TON). This protocol could be easily conducted on gram scale, thereby providing a chance to various drugs.

Nod1 Limits Colitis-Associated Tumorigenesis by Regulating IFN-γ Production.

Chronic intestinal inflammation is a major risk factor for the development of colorectal cancer. Nod1, a member of the Nod-like receptor (NLR) family of pattern recognition receptors, is a bacterial sensor that has been previously demonstrated to reduce susceptibility of mice to chemically induced colitis and subsequent tumorigenesis, but the mechanism by which it mediates its protection has not been elucidated. In this study, we show that Nod1 expression in the hematopoietic cell compartment is critical for limiting inflammation-induced intestinal tumorigenesis. Specifically, Nod1-deficient T cells exhibit impaired IFN-γ production during dextran sulfate sodium (DSS)-induced acute inflammation in vivo, and administration of the Nod1 ligand KF1B enhances IFN-γ responses by anti-CD3-activated T cells in vitro. Absence of IFN-γ signaling results in increased inflammation-associated tumors in mice, and adoptive transfer of Nod1(-/-) or IFNγ(-/-) T cells into T cell-deficient mice results in increased tumorigenesis as compared with T cell-deficient mice that were adoptively transferred with wild-type T cells. Collectively, these results suggest a previously unappreciated role for the innate immune receptor Nod1 in suppressing colitis-associated tumorigenesis through a T cell-mediated mechanism.

Stability of Hydroxylated α-Fe2O3(0001) Surfaces.

The stability of hydroxylated terminations of the 0001 surface of α-Fe2O3 (hematite) is investigated computationally using PBE + U calculations with dispersion corrections. Hydroxylated surfaces with low OH concentrations are found to be most stable in a range of the chemical potential of water of -0.95 eV > µH2O > -2.22 eV. These surfaces can be described as isolated Fe(OH)3 groups adsorbed on the dry hematite surface and are predicted to be the exposed termination of the 0001 surface in a wide range of relevant experimental conditions. Most investigated reduced surfaces, containing Fe in oxidation state +2, are only stable in a range of the chemical potential of oxygen µO < -2.44 eV, where bulk hematite is less than magnetite. The only reduced surface stable at a higher µO is derived from the most stable nonreduced hydroxylated surfaces by removing a single OH group per unit cell.

SurgNet: Self-Supervised Pretraining With Semantic Consistency for Vessel and Instrument Segmentation in Surgical Images.

Blood vessel and surgical instrument segmentation is a fundamental technique for robot-assisted surgical navigation. Despite the significant progress in natural image segmentation, surgical image-based vessel and instrument segmentation are rarely studied. In this work, we propose a novel self-supervised pretraining method (SurgNet) that can effectively learn representative vessel and instrument features from unlabeled surgical images. As a result, it allows for precise and efficient segmentation of vessels and instruments with only a small amount of labeled data. Specifically, we first construct a region adjacency graph (RAG) based on local semantic consistency in unlabeled surgical images and use it as a self-supervision signal for pseudo-mask segmentation. We then use the pseudo-mask to perform guided masked image modeling (GMIM) to learn representations that integrate structural information of intraoperative objectives more effectively. Our pretrained model, paired with various segmentation methods, can be applied to perform vessel and instrument segmentation accurately using limited labeled data for fine-tuning. We build an Intraoperative Vessel and Instrument Segmentation (IVIS) dataset, comprised of ~3 million unlabeled images and over 4,000 labeled images with manual vessel and instrument annotations to evaluate the effectiveness of our self-supervised pretraining method. We also evaluated the generalizability of our method to similar tasks using two public datasets. The results demonstrate that our approach outperforms the current state-of-the-art (SOTA) self-supervised representation learning methods in various surgical image segmentation tasks.

Enhanced quantum state transfer by circumventing quantum chaotic behavior.

The ability to realize high-fidelity quantum communication is one of the many facets required to build generic quantum computing devices. In addition to quantum processing, sensing, and storage, transferring the resulting quantum states demands a careful design that finds no parallel in classical communication. Existing experimental demonstrations of quantum information transfer in solid-state quantum systems are largely confined to small chains with few qubits, often relying upon non-generic schemes. Here, by using a superconducting quantum circuit featuring thirty-six tunable qubits, accompanied by general optimization procedures deeply rooted in overcoming quantum chaotic behavior, we demonstrate a scalable protocol for transferring few-particle quantum states in a two-dimensional quantum network. These include single-qubit excitation, two-qubit entangled states, and two excitations for which many-body effects are present. Our approach, combined with the quantum circuit's versatility, paves the way to short-distance quantum communication for connecting distributed quantum processors or registers, even if hampered by inherent imperfections in actual quantum devices.

An integrated long-acting implant of clinical safe cells, drug and biomaterials effectively promotes spinal cord repair and restores motor functions.

Spinal cord injury (SCI) is incurable and raises growing concerns. The main barrier to nerve repair is the complicated inhibitory microenvironment, where single-targeted strategies are largely frustrated. Despite the progress in combinatory therapeutic systems, the development and translation of effective therapies remain a challenge with extremely limited clinical materials. In this study, mesenchymal stem cells are transplanted in combination with sustained release of methylprednisolone through delivery in one composite matrix of a microsphere-enveloped adhesive hydrogel. All the materials used, including the stem cells, drug, and the matrix polymers gelatin and hyaluronan, are clinically approved. The therapeutic effects and safety issues are evaluated on rat and canine SCI models. The implantation significantly promotes functional restoration and nerve repair in a severe long-span rat spinal cord transection model. Distant spinal cord segments and the urinary system are effectively protected against pathologic damage. Moreover, the local sustained drug delivery mitigates the inflammatory microenvironment when overcoming the clinical issue of systemic side effects. The study presents an innovative strategy to achieve safe and efficient combinatory treatment of SCI.

PTPRT loss enhances anti-PD-1 therapy efficacy by regulation of STING pathway in non-small cell lung cancer.

With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti-PD-1/PD-L1 axis therapy. Anti-PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-ß, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti-PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti-PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti-PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.

Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment.

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting. Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults. Design, Setting, and Participants: The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023. Exposure: SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed. Main Outcomes and Measures: Consensus-diagnosed MCI, AD, and all-cause dementia. Results: This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged. Conclusions and Relevance: Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS.

Chemically programmed metabolism drives a superior cell fitness for cartilage regeneration.

The rapid advancement of cell therapies underscores the importance of understanding fundamental cellular attributes. Among these, cell fitness-how transplanted cells adapt to new microenvironments and maintain functional stability in vivo-is crucial. This study identifies a chemical compound, FPH2, that enhances the fitness of human chondrocytes and the repair of articular cartilage, which is typically nonregenerative. Through drug screening, FPH2 was shown to broadly improve cell performance, especially in maintaining chondrocyte phenotype and enhancing migration. Single-cell transcriptomics indicated that FPH2 induced a super-fit cell state. The mechanism primarily involves the inhibition of carnitine palmitoyl transferase I and the optimization of metabolic homeostasis. In animal models, FPH2-treated human chondrocytes substantially improved cartilage regeneration, demonstrating well-integrated tissue interfaces in rats. In addition, an acellular FPH2-loaded hydrogel proved effective in preventing the onset of osteoarthritis. This research provides a viable and safe method to enhance chondrocyte fitness, offering insights into the self-regulatory mechanisms of cell fitness.

Salinomycin, a potent inhibitor of XOD and URAT1, ameliorates hyperuricemic nephropathy by activating NRF2, modulating the gut microbiota, and promoting SCFA production.

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p-NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic.

Resveratrol inhibits K(v)2.2 currents through the estrogen receptor GPR30-mediated PKC pathway.

Resveratrol (REV) is a naturally occurring phytoalexin that inhibits neuronal K⁺ channels; however, the molecular mechanisms behind the effects of REV and the relevant α-subunit are not well defined. With the use of patch-clamp technique, cultured cerebellar granule cells, and HEK-293 cells transfected with the K(v)2.1 and K(v)2.2 α-subunits, we investigated the effect of REV on K(v)2.1 and K(v)2.2 α-subunits. Our data demonstrated that REV significantly suppressed Kv2.2 but not Kv2.1 currents with a fast, reversible, and mildly concentration-dependent manner and shifted the activation or inactivation curve of Kv2.2 channels. Activating or inhibiting the cAMP/PKA pathway did not abolish the inhibition of K(v)2.2 current by REV. In contrast, activation of PKC with phorbol 12-myristate 13-acetate mimicked the inhibitory effect of REV on K(v)2.2 by modifying the activation or inactivation properties of Kv2.2 channels and eliminated any further inhibition by REV. PKC and PKC-α inhibitor completely eliminated the REV-induced inhibition of K(v)2.2. Moreover, the effect of REV on K(v)2.2 was reduced by preincubation with antagonists of GPR30 receptor and shRNA for GPR30 receptor. Western blotting results indicated that the levels of PKC-α and PKC-ß were significantly increased in response to REV application. Our data reveal, for the first time, that REV inhibited K(v)2.2 currents through PKC-dependent pathways and a nongenomic action of the oestrogen receptor GPR30.

Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer.

PURPOSE: PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research. METHODS: The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments. RESULTS: We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission. CONCLUSION: Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.