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.

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.

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.

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.

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.

Klotho-beta attenuates Rab8a-mediated exosome regulation and promotes prostate cancer progression.

Tumor-secreted exosomes have a wide range of effects on the growth, metastasis, and drug resistance of cancer cells. However, whether and how the molecular mechanisms that regulate the secretion of exosomes could affect tumor progression remains poorly understood. Klotho beta (KLB) has been reported dysregulated in prostate cancer, but its function remains unknown. Herein, we first determined that KLB was upregulated in prostate cancer and its expression level was positively correlated with prostate cancer malignant phenotype both in vitro and in vivo. Intriguingly, KLB overexpression could impair the release of exosomes and cause the intracellular accumulation of multivesicular bodies (MVBs) in prostate cancer cells. Mechanistically, KLB attenuated exosomes secretion through a Rab8a-dependent pathway. Rab8a was downregulated in KLB overexpressing cells whereas overexpression of Rab8a could rescue the impaired release of exosomes and attenuate the KLB-induced malignant phenotype of prostate cancer both in vitro and in vivo. Taken together, this study has unveiled the tumor-promoting role of KLB mediated by its regulation on exosomes secretion through a Rab8a-dependent mechanism. These findings could be exploited to develop novel theranostic targets for prostate cancer.

Reciprocal FGF19-GLI2 signaling induces epithelial-to-mesenchymal transition to promote lung squamous cell carcinoma metastasis.

PURPOSE: Metastatic lung squamous cell carcinoma (LUSC) is one of the most common causes of cancer death worldwide. As yet, however, the molecular mechanism underlying LUSC metastasis remains elusive. In this study, we report a novel mechanism involving signaling interactions between FGF19 and GLI2 that could drive the progression of LUSC. METHODS: The expression of FGF19 in human LUSC samples was assessed by immunohistochemistry. The concentration of FGF19 in serum samples was assessed by ELISA. RNA sequencing, scratch wound-healing, trans-well, GO analysis, GSEA, luciferase reporter, Western blotting, immunofluorescence and immunohistochemistry assays, as well as an animal model were used to investigate the molecular mechanism underlying FGF19 driven LUSC progression. The therapeutic effect of a GLI2 inhibitor was determined using both in vitro cellular and in vivo animal experiments. RESULTS: We found that FGF19, a member of the fibroblast growth factor family, plays a crucial role in the invasion and metastasis of LUSC, and identified GLI2 as an important downstream effector of FGF19 involved in metastasis. Surprisingly, we found that FGF19 and GLI2 could reciprocally induce the expression of each other, and form a positive feedback loop to promote LUSC cell invasion and metastasis. These findings were corroborated by an association between a poor prognosis of LUSC patients and FGF19/GLI2 co-expression. In addition, we found that the GLI inhibitor GANT61 could effectively reduce FGF19-mediated LUSC invasion and metastasis. CONCLUSION: Our data suggest that FGF19 may serve as a novel biomarker for predicting metastatic LUSC. Intervening with the FGF19-GLI2 feedback loop may be a strategy for the treatment of FGF19-driven LUSC metastasis.

Celery (Apium graveolens L.) Exosome-like Nanovesicles as a New-Generation Chemotherapy Drug Delivery Platform against Tumor Proliferation.

Extracellular vesicles (EVs) released from cells have shown robust efficacy in drug delivery compared with traditional synthetic carriers. Hampered by the high production cost and complex purification process, the clinical application of EVs as drug carriers is still limited. Nanoparticles isolated from plants with exosome-like morphology and similar delivery effects could be a new option for drug delivery. The celery exosome-like nanovesicles (CELNs) showed higher cellular uptake efficiency compared to the other three common plant-derived exosome-like nanovesicles, which is an essential advantage for CELNs as a drug carrier. The less toxicity and better tolerance of CELNs as biotherapeutic roles were verified in mice models. Then, doxorubicin (DOX) was encapsulated into CELNs to construct engineered CELNs (CELNs-DOX), which proved to be more efficient in treating tumors than conventional synthetic carriers like liposome both in vitro and in vivo. In conclusion, this study, for the first time, has proposed the emerging role of CELNs as a new-generation drug delivery carrier with distinct advantages.

Global trends in research of mitophagy in liver diseases over past two decades: A bibliometric analysis.

Increasing evidence indicated that mitophagy might play a crucial role in the occurrence and progression of liver diseases. In order to enhance our understanding of the intricate relationship between mitophagy and liver diseases, a comprehensive bibliometric analysis of the existing literature in this field was conducted. This analysis aimed to identify key trends, potential areas of future research, and forecast the development of this specific field. We systematically searched the Web of Science Core Collection (WoSCC) for publications related to mitophagy in liver diseases from 2000 to 2022. We conducted the bibliometric analysis and data visualization through VOSviewer and CiteSpace. The analysis of publication growth revealed a substantial increase in articles published in this field over the past years, indicating mitophagy's growing interest and significance in liver diseases. China and USA emerged as the leading contributors in the number of papers, with 294 and 194 independent papers, respectively. Exploring the mechanism of mitophagy in the initiation and procession of liver diseases was the main content of studies in this field, and Parkin-independent mediated mitophagy has attracted much attention recently. "Lipid metabolism," "cell death," "liver fibrosis" and "oxidative stress" were the primary keywords clusters. Additionally, "nlrp3 inflammasome", "toxicity" and "nonalcoholic steatohepatitis" were emerging research hotspots in this area and have the potential to continue to be focal areas of investigation in the future. This study represents the first systematic bibliometric analysis of research on mitophagy in liver diseases conducted over the past 20 years. By providing an overview of the existing literature and identifying current research trends, this analysis sheds light on the critical areas of investigation and paves the way for future studies in this field.

Circulating immune cell phenotypes are associated with age, sex, CMV, and smoking status in the Framingham Heart Study offspring participants.

Understanding the composition of circulating immune cells with aging and the underlying biologic mechanisms driving aging may provide molecular targets to slow the aging process and reduce age-related disease. Utilizing cryopreserved cells from 996 Framingham Heart Study (FHS) Offspring Cohort participants aged 40 and older (mean 62 years, 48% female), we report on 116 immune cell phenotypes including monocytes, T-, B-, and NK cells and their subtypes, across age groups, sex, cytomegalovirus (CMV) exposure groups, smoking and other cardiovascular risk factors. The major cellular differences with CMV exposure were higher Granzyme B+ cells, effector cells, and effector-memory re-expressing CD45RA (TEMRA) cells for both CD4+ and CD8+. Older age was associated with lower CD3+ T cells, lower naïve cells and naïve/memory ratios for CD4+ and CD8+. We identified many immune cell differences by sex, with males showing lower naïve cells and higher effector and effector memory cells. Current smokers showed lower pro-inflammatory CD8 cells, higher CD8 regulatory type cells and altered B cell subsets. No significant associations were seen with BMI and other cardiovascular risk factors. Our cross-sectional observations of immune cell phenotypes provide a reference to further the understanding of the complexity of immune cells in blood, an easily accessible tissue.

Aging-Related Immune Cell Phenotypes and Mortality in the Framingham Heart Study.

Background: The global increase in human life expectancy is evident. The total number of individuals aged 60 or above is anticipated to reach 2 billion by 2050. Aging, an inherently complex process, manifests prominently in the changes observed in the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their significance, the connections between various ARIPs and mortality have not been thoroughly investigated. We prospectively investigated 16 different ARIPs using flow cytometry, namely, CD4/CD8 ratio, Granzyme B + CD8/Granyzme B + CD4, TN/TM = Tn / (Teff + Tem + Tcm) for TN/TM CD4 + and TN/TM CD8 + ratios, Th17/CD4 + Treg, Tc17/CD8 + Treg, Th17, Tc17, CD4 + Temra, CD8 + Temra, CD4 + CD25 + FoxP3+ (CD4 + Treg), CD8 + CD25 + FoxP3+ (CD8 + Treg) CD4 + CD27-, CD4 + CD28-CD27-, CD8 + CD27-, CD8 + CD28-CD27- 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 survival rate was 65% during 19 years of follow-up. For the model 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) and higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3+) were associated with higher all-cause mortality (HR = 1.17, [1.03-1.32]). Higher IL-6 levels were associated 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).