Pivot Axis Research Articles

P0037 ATF7 Deficiency Exacerbates Mitochondrial Dysfunction and Intestinal Inflammation in Ulcerative Colitis

Abstract Background Ulcerative colitis (UC), a chronic inflammatory bowel disease, is marked by sustained inflammation and excessive apoptosis of intestinal epithelial cells (IECs). Despite progress in understanding UC pathogenesis, the role of activating transcription factors (ATFs) in disease progression remains elusive. Here, we profile the expression of ATF family members (ATF1–ATF8) in the colonic mucosa of UC patients and identify ATF7 as a critical regulator of mitophagy through its control of PTEN-induced kinase 1 (PINK1). Methods Expression levels of ATF1–ATF8 were quantified in colonic mucosal samples from UC patients (n = 200) and healthy controls (n = 100) via quantitative PCR and immunohistochemistry. Using IEC-specific ATF7 and PINK1 knockout mouse models and human CCD 841 CoN colonic epithelial cells, we employed ChIP-seq, dual-luciferase assays, transmission electron microscopy, and immunofluorescence to elucidate their roles in mitophagy and disease progression. Clinical correlation between ATF7 expression and disease severity was assessed using the Mayo score. Results ATF7 expression was significantly reduced in UC patients and inversely correlated with disease severity. Mechanistically, ATF7 was identified as a direct transcriptional activator of PINK1, a key mitophagy regulator. Loss of ATF7 or PINK1 disrupted mitophagy, exacerbating mitochondrial dysfunction, IEC apoptosis, and colonic inflammation in vivo and in vitro. Conclusion Our findings uncover a pivotal ATF7-PINK1 axis that governs mitophagy and limits UC progression. The inverse correlation between ATF7 expression and UC severity highlights its potential as a therapeutic target, offering new avenues for intervention in this debilitating disease.

Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies.

Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4-6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance.

Turbulence and flapping pivot axis effects on torsional flutter harvester efficiency by closed-form formula

This “Short Communication” investigates the dynamics of a torsional-flutter energy harvester in atmospheric winds with stationary turbulence. This apparatus is an example of a flutter mill, which operates by exploiting aeroelastic instability as a competitive alternative and as a renewable energy supply for one or few housing units. The apparatus has a rigid blade-airfoil that rotates about a pivot to generate flapping motion. Contrary to recent studies by the second author, the effect of random stationary turbulence on flutter onset is examined by an analytical approach, employed by Scanlan (1997) for bridge flutter analysis. Turbulence effect is simulated by suitably modifying the span-wise coherence equation of the aeroelastic load. The incipient flutter threshold is found as a function of turbulence properties. Various configurations are studied, i.e., pivot position, aspect ratio, turbulence coherence decay parameter and structural damping. The objective is to perform a thorough sensitivity analysis as the necessary premise for the planned, future examination of post-critical instability and operational efficiency of the harvester by suitable modeling and wind tunnel tests.

The connection between aging, cellular senescence and gut microbiome alterations: A comprehensive review.

The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age-associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence-associated secretory phenotype, exacerbate the aging process through pro-inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging-associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging-related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population.

The role of cGAS-STING signaling in rheumatoid arthritis: from pathogenesis to therapeutic targets.

Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily characterized by erosive and symmetric polyarthritis. As a pivotal axis in the regulation of type I interferon (IFN-I) and innate immunity, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has been implicated in the pathogenesis of RA. This pathway mainly functions by regulating cell survival, pyroptosis, migration, and invasion. Therefore, understanding the sources of cell-free DNA and the mechanisms underlying the activation and regulation of cGAS-STING signaling in RA offers a promising avenue for targeted therapies. Early detection and interventions targeting the cGAS-STING signaling are important for reducing the medical burden on individuals and healthcare systems. Herein, we review the existing literature pertaining to the role of cGAS-STING signaling in RA, and discuss current applications and future directions for targeting the cGAS-STING signaling in RA treatments.

PARK2 suppresses the proliferation of high-grade serous ovarian carcinoma via inducing the proteasomal degradation of ZNF703.

High-grade serous ovarian cancer (HGSC) is an aggressive disease with poor prognosis. The oncoprotein ZNF703 is implicated in driving HGSC pathogenesis, but factors regulating its abundance remain unclear. In this study, we aim to investigate the potential connection between ZNF703 dysregulation and ubiquitin-mediated protein degradation in HGSC. Bioinformatics prediction was performed using BioGRID database. HGSC representative cell lines were utilized for in vitro and in vivo studies. Results showed that ZNF703 protein was stabilized upon proteasome inhibition, suggesting a regulation via ubiquitination. The ubiquitin E3 ligase PARK2 was found to interact with ZNF703 in a dose-dependent manner, promoting its polyubiquitination and subsequent proteasomal degradation. Re-expression of PARK2 in HGSC cells led to reduced ZNF703 levels together with decreased Cyclin D1/E1 abundance and G1 cell cycle arrest. ZNF703 overexpression alone increased S phase cells, Cyclin D1/E1 levels, and xenograft tumor growth, while co-expression with PARK2 mitigated these oncogenic effects. Collectively, our findings identify ZNF703 as a bona fide substrate of PARK2, reveal a tumor suppressive function for PARK2 in attenuating ZNF703-mediated G1/S transition and HGSC growth through instigating its degradation. This study elucidates a pivotal PARK2-ZNF703 axis with therapeutic implications for targeted intervention in HGSC.

Gut microbiota and epigenetic choreography: Implications for human health: A review.

The interwoven relationship between gut microbiota and the epigenetic landscape constitutes a pivotal axis in understanding human health and disease. Governed by a myriad of dietary, genetic, and environmental influences, the gut microbiota orchestrates a sophisticated metabolic interplay, shaping nutrient utilization, immune responses, and defenses against pathogens. Recent strides in genomics and metabolomics have shed light on the intricate connections between these microbial influencers and the host's physiological dynamics, presenting a dynamic panorama across diverse disease spectra. DNA methylation and histone modifications, as key players in epigenetics, intricately align with the dynamic orchestration of the gut microbiota. This seamless collaboration, notably evident in conditions like inflammatory bowel disease and obesity, has captured the attention of researchers, prompting an exploration of its nuanced choreography. Nevertheless, challenges abound. Analyzing data is intricate due to the multifaceted nature of the gut microbiota and the limitations of current analytical methods. This underscores the need for a multidisciplinary approach, where diverse disciplines converge to pave innovative research pathways. The integration of insights from microbiome and epigenome studies assumes paramount importance in unraveling the complexities of this intricate partnership. Deciphering the synchronized interactions within this collaboration offers a deeper understanding of these delicate interplays, potentially heralding revolutionary strides in treatment modalities and strategies for enhancing public health.

Multispectral Imaging and Single-Cell Analysis with Genetically Encoded Biosensors Unveil Complex Interactions between Extracellular ATP and Intracellular Calcium

The dynamic interplay between extracellular ATP (eATP) and intracellular calcium ([Ca2+]i) serves as a pivotal signaling axis in cellular physiology, influencing a myriad of cellular processes. Traditionally recognized as an energy currency within the cell, ATP has emerged as a multifunctional signaling molecule that orchestrates diverse cellular responses through activation of purinergic receptors. The complex link between ATP signaling and calcium dynamics plays a central role in cellular communication and homeostasis. Advancements in imaging technologies such as development of genetically encoded biosensors have revolutionized the study of cellular signaling dynamics, enabling visualization of the spatiotemporal aspects of eATP and [Ca2+]i in real-time. The convergence of eATP signaling and [Ca2+]i dynamics serves as a central hub in cellular communication. In this study, utilizing bicistronic construct biosensors for multispectral imaging of [Ca2+]i responses to eATP, we show that distinct concentrations of eATP administration reveal complex intracellular [Ca2+]i responses, potentially attributed to receptor desensitization. Single-cell co-imaging uncovers [Ca2+]i heterogeneity, emphasizing the significance of individual cell dynamics in eATP-induced calcium signaling. Therefore, this study sheds light on the intricacies of eATP-induced calcium signaling, providing insights valuable for basic research and therapeutic applications.

Zr-doped MgAl-LDH@Au nano-catalysts for selective and efficient oxidation of biomass-derived furfural

Lignocellulosic biomass upgrading is a pivotal axis in the transition from an economy based on fossil resources to one reliant on renewable biomass resources. Within this context, low-cost Zr-doped MgAl-LDH@Aunano-catalysts are reported in this study as efficient catalysts to synthesize bio-based succinic acid. A series of Zr-doped MgAl-LDH and Au/Zr-doped MgAl-LDH catalysts have been successfully prepared. All catalysts have a lamellar double hydroxide structure LDH even after enrichment with Zr and addition of Au.Au NPs have small average sizes ranging from 1.2 to 8.5 nm. The materials under study showed exalted catalytic performances in the direct synthesis of succinic acid from bio based furfural via an aqueous phase oxidation reaction with H2O2. 84 % of furfural conversion and 99 % selectivity towards succinic acid were achieved.A positive synergy between Zr and Au NPs is highlighted and related to this catalytic performances improvement.

Comunidades de alimentos e fazendas de camponeses: estratégias para a sustentabilidade alimentar

Abstract This article shows the results of the study “Virtual Office of 10,000 sustainable peasant farms from the regions of Santander and Magdalena Medio”. The study is framed in a Colombian social movement for the preservation of the peasant farm as pivotal axis for food sustainability in the territories. The study has a principal aim to identify the organization process of fourteen (14) food communities and the participatory design of the peasant farm model as strategies for food security in the Colombian territories of Magdalena Medio and Santander. The study conducted a mixed methodology with both qualitative and descriptive, cross-sectional quantitative analysis with data collected from participant communities. Data collection was done through focus groups with seven (7) communities and fourteen (14) interviews with food community leaders from eleven (11) municipalities in three different Colombian departments. Results show that the peasant organization structure called food community and the peasant farm participatory models for each territory are strategies that have led to the strengthening of the local autonomy of the peasant communities for the defense of food sustainability practices within their contexts.

Potential therapies targeting nuclear metabolic regulation in cancer.

The interplay between genetic alterations and metabolic dysregulation is increasingly recognized as a pivotal axis in cancer pathogenesis. Both elements are mutually reinforcing, thereby expediting the ontogeny and progression of malignant neoplasms. Intriguingly, recent findings have highlighted the translocation of metabolites and metabolic enzymes from the cytoplasm into the nuclear compartment, where they appear to be intimately associated with tumor cell proliferation. Despite these advancements, significant gaps persist in our understanding of their specific roles within the nuclear milieu, their modulatory effects on gene transcription and cellular proliferation, and the intricacies of their coordination with the genomic landscape. In this comprehensive review, we endeavor to elucidate the regulatory landscape of metabolic signaling within the nuclear domain, namely nuclear metabolic signaling involving metabolites and metabolic enzymes. We explore the roles and molecular mechanisms through which metabolic flux and enzymatic activity impact critical nuclear processes, including epigenetic modulation, DNA damage repair, and gene expression regulation. In conclusion, we underscore the paramount significance of nuclear metabolic signaling in cancer biology and enumerate potential therapeutic targets, associated pharmacological interventions, and implications for clinical applications. Importantly, these emergent findings not only augment our conceptual understanding of tumoral metabolism but also herald the potential for innovative therapeutic paradigms targeting the metabolism-genome transcriptional axis.

Long noncoding RNA NONHSAT160169.1 promotes resistance via hsa-let-7c-3p/SOX2 axis in gastric cancer

In clinical trials involving patients with HER2 (ERBB2 receptor tyrosine kinase 2) positive gastric cancer, the efficacy of the HER2-targeted drug lapatinib has proven to be disappointingly poor. Under the persistent pressure exerted by targeted drug therapy, a subset of tumor cells exhibit acquired drug resistance through the activation of novel survival signaling cascades, alongside the proliferation of tumor cells that previously harbored mutations conferring resistance to the drug. This study was undertaken with the aim of elucidating in comprehensive detail the intricate mechanisms behind adaptive resistance and identifying novel therapeutic targets that hold promise in the development of effective lapatinib-based therapies for the specific subset of patients afflicted with gastric cancer. We have successfully established a gastric cancer cell line with acquired lapatinib resistance, designated as HGC-27-LR cells. Utilizing comprehensive coding and noncoding transcriptome sequencing analysis, we have identified key factors that regulate lapatinib resistance in HGC-27 cells. We have compellingly validated that among all the lncRNAs identified in HGC-27-LR cells, a novel lncRNA (long noncoding RNA) named NONHSAT160169.1 was found to be most notably upregulated following exposure to lapatinib treatment. The upregulation of NONHSAT160169.1 significantly augmented the migratory, invasive, and stemness capabilities of HGC-27-LR cells. Furthermore, we have delved into the mechanism by which NONHSAT160169.1 regulates lapatinib resistance. The findings have revealed that NONHSAT160169.1, which is induced by the p-STAT3 (signal transducer and activator of transcription 3) nuclear transport pathway, functions as a decoy that competitively interacts with hsa-let-7c-3p and thereby abrogates the inhibitory effect of hsa-let-7c-3p on SOX2 (SRY-box transcription factor 2) expression. Hence, our study has unveiled the NONHSAT160169.1/hsa-let-7c-3p/SOX2 signaling pathway as a novel and pivotal axis for comprehending and surmounting lapatinib resistance in the treatment of HER2-positive gastric cancer.

Intraoperative imaging with the mobile C-arm : Technique, image creation and radiation protection

Imaging techniques in the discipline of orthopedics and trauma surgery are essential not only for making a diagnosis but also play a central role in the performance, documentation and monitoring of the corresponding treatment. Procedures such as open reduction and internal fixation (ORIF) and closed reduction and internal fixation (CRIF) of fractures, kyphoplasty and vertebroplasty as well as posterior stabilization of spinal fractures are carried out under X‑ray control. In the relevant operating rooms of emergency departments and operating theaters, mobile fluoroscopy devices are available, which due to their appearance are called C‑arms. These devices can be moved horizontally, vertically, and along the pivotal axis, enabling real-time imaging of joints and bones from various angles. This imaging enables minimally invasive surgical techniques as this often eliminates the need for extensive preparation and resulting in smaller wound defects compared to open surgical preparation. Additionally, surgeons can immediately assess and, if necessary, adjust the reduction outcome to achieve the best possible care and reduce the need for corrective interventions. With current C‑arms it is also possible to generate 3‑dimensional datasets, to enhance the assessment of implant positioning, particularly in complex intra-articular fractures. This availability helps avoid subsequent corrective interventions that would otherwise only be identified through postoperative computed tomography [1].

Flexure Hinge Design and Optimization for Compact Anthropomorphic Grippers Made via Metal Additive Manufacturing

Abstract Flexure-based grippers offer an attractive alternative to conventional grippers used in robotics and automation. However, most existing designs appear to suffer from insufficient range of motion, loadability, and support stiffness. This article presents an approach to obtain well-performing flexure hinges for compact anthropomorphic grippers made via metal additive manufacturing. We propose a flexure hinge architecture that achieves a high range of motion despite the challenging combination of a small design space, high Young’s modulus, and limited minimum feature size. Furthermore, we present an optimization procedure to generate suitable tendon-driven designs with high loadability. Using this framework, a flexure hinge with an outer diameter of 21.5 mm and range of motion of ±30 deg is synthesized. For the range of 0–30 deg, simulations show a lateral loadability of 52.5–18.6 N and lateral support stiffness of 12,309–11,130 N/m, determined at a gripper interface located 41.2 mm from the hinge pivot axis. Experiments confirm a loadability of at least 15.4 N and determined a stiffness of 8982 to 9727 N/m for same conditions. The results show that the flexure hinge architecture has large potential for a wide range of applications, while in combination with the optimization procedure, superior designs for tendon-driven grippers can be obtained.

Molecular Dynamics Mappings of the CCT/TRiC Complex-Mediated Protein Folding Cycle Using Diffracted X-ray Tracking.

The CCT/TRiC complex is a type II chaperonin that undergoes ATP-driven conformational changes during its functional cycle. Structural studies have provided valuable insights into the mechanism of this process, but real-time dynamics analyses of mammalian type II chaperonins are still scarce. We used diffracted X-ray tracking (DXT) to investigate the intramolecular dynamics of the CCT complex. We focused on three surface-exposed loop regions of the CCT1 subunit: the loop regions of the equatorial domain (E domain), the E and intermediate domain (I domain) juncture near the ATP-binding region, and the apical domain (A domain). Our results showed that the CCT1 subunit predominantly displayed rotational motion, with larger mean square displacement (MSD) values for twist (χ) angles compared with tilt (θ) angles. Nucleotide binding had a significant impact on the dynamics. In the absence of nucleotides, the region between the E and I domain juncture could act as a pivotal axis, allowing for greater motion of the E domain and A domain. In the presence of nucleotides, the nucleotides could wedge into the ATP-binding region, weakening the role of the region between the E and I domain juncture as the rotational axis and causing the CCT complex to adopt a more compact structure. This led to less expanded MSD curves for the E domain and A domain compared with nucleotide-absent conditions. This change may help to stabilize the functional conformation during substrate binding. This study is the first to use DXT to probe the real-time molecular dynamics of mammalian type II chaperonins at the millisecond level. Our findings provide new insights into the complex dynamics of chaperonins and their role in the functional folding cycle.

Effects of inertia on the time-averaged propulsive performance of a pitching and heaving foil

The inertia may play an important role in the unsteady behavior of a flapping foil. Of particular relevance in forward flapping locomotion is how the foil inertia may affect its time-averaged propulsive performance. This is the question addressed by the present study from a general, nonlinear formulation of the unsteady interaction with the surrounding fluid of a thin, flexible, two-dimensional and non-uniform foil undergoing prescribed pitching and heaving motion of any amplitude about an arbitrary pivot axis. For a rigid foil it is shown that, although the unsteady inertial forces and moments may be much larger than the unsteady aerodynamic forces and moments if the fluid density is much smaller than the foil density, the inertia does not affect the cycle-averaged propulsive performance for harmonic pitching and heaving motion, independently of their amplitude. Inertia may affect only the cycle-averaged moment if the mean angle of attack is not zero, but without affecting the cycle-averaged power input, and therefore the propulsive efficiency. When a small flexural deflection of the foil is considered, although the cycle-averaged inertial thrust and lift also vanish for any amplitude of the pitching and heaving harmonic motion, the cycle-averaged power input does not. Thus, the foil inertia contributes through the moment and power to the time-averaged propulsive performance for any flexural deflection of the foil, obtained her e analytically in terms of the trailing edge location for general pitching and heaving motion of any amplitude and phase and small flexural deflection amplitude. Simple analytical results are also provided for inertia dominated deflection, characterizing the conditions that minimize the power consumption. The results are valid for arbitrary chord-wise distribution of mass, thickness and (sufficiently large) stiffness of the foil.

Force and torque reactions on a pitching flexible aerofoil

Experimental measurements in a wind tunnel of the unsteady force and moment that a fluid exerts on flexible flapping aerofoils are not trivial because the forces and moments caused by the aerofoil's inertia and others structural tensions at the pivot axis have to be obtained separately and subtracted from the direct measurements with a force/torque sensor. Here we derive from the nonlinear beam equation general relations for the force and torque reactions at the leading edge of a pitching aerofoil in terms of the fluid force and moment on the aerofoil and its kinematics, involving geometric and structural parameters of the flexible aerofoil. These relations are validated by comparing high-resolution numerical simulations of the flow–structure interaction of a two-dimensional flexible aerofoil pitching about its leading edge with direct force and torque measurements in a wind tunnel.

Islamic Education Update K.H. Hasyim Asy’ari

The characteristic of the Indonesia Islamic education modernism is largely determined by the creativity which the Muslim pointed out. The flexibility of the Islamic education system enable it to easily adapt itself to the surrounding and to create the new and appropriate format of its derivation in line with the new demand of the umma for the field in the modern era. A number of experiments had been performed by the Muslim figures, individually or collectively, to fulfill that demand in the early decades of the 20th century. How did they adopt the elements of modernity to keep the Islamic education remain in its own identity? For this purpose, it is important to understand and to explain the ideas and the efforts of Syaikh Hasyim Asy’ari of Tebuireng in modernizing his pesantren and its main contribution to the development of the new madrasahs in the country. Using the analytical-critical method, this examination is in conclusion that Hasyim’s allegiance to stand on his traditional bases in modernizing his pesantren has created a something useful for directing the orientation and giving the strong foundation of the Indonesia’s Islamic education modernism. His success in harmonizing the elements of modernity with the Islamic traditions under the religious inspection as the pivotal axis is his real contribution to the new madrasah with its own identity to distinct itself with the public school, though the government has “nationalized” the first to be in equivalent to the public school.

Cross-species emotional political ecology in rural Pakistan

This article engages cross-species intersectionality and emotional political ecology to evaluate a dairy extension service that ran in Punjab and Sindh, Pakistan, between 2012 and 2017. The project aimed to mitigate potential negative impacts of implementation, such as the exacerbation of pre-existing social inequality, by applying principles of women’s agency and empowerment in project design. Evidence from the two case study villages reveals how social difference (caste and class) shape women’s access to extension meetings and the resources to implement practices. The evidence also reveals that through cattle work woman cultivate an emotional bond with their animals, given the multiple instrumental and sociocultural values they represent for households. Singh (2013) provides a definition of the agentic potential of this emotional bond as the ‘ability to affect and be affected.’ The higher socioeconomic classes that had good access to the extension service were able to improve animal welfare and milk production through which they cultivated satisfaction, pride and independence. Alternatively, women expressed feelings of longing or boredom in the absence of this invaluable resource in their lives. This article confirms the importance of intersectionality for designing interventions that are sensitive to inter and intra household dynamics and that cross-species relations form pivotal axes for social difference. These cross-species relations cultivate emotions/affect during engagement with the extension service.

Impact of the von Willebrand factor-ADAMTS-13 axis on the risk of future venous thromboembolism

Backgroundvon Willebrand factor (VWF) and its cleaving protease, ADAMTS-13, form a pivotal axis that regulates hemostasis. However, the role of the VWF-ADAMTS-13 axis in the risk of future venous thromboembolism (VTE) is unknown. ObjectivesTo investigate whether plasma ADAMTS-13 levels and an imbalance with VWF levels, assessed as the VWF/ADAMTS-13 ratio, are associated with the risk of future VTE. Patients/MethodsA population-based nested case-control study, comprising 383 incident VTE cases and 780 age- and sex-matched controls, was derived from the Tromsø study cohort (1994-2007). Antigen levels of ADAMTS-13 and VWF were measured in plasma samples obtained at cohort baseline. Odds ratios (ORs) with 95% CIs were estimated according to quartile cutoffs of ADAMTS-13 and VWF/ADAMTS-13 ratio determined in controls. ResultsIn age- and sex-adjusted analysis, ADAMTS-13 levels were inversely associated with the VTE risk, with an OR of 1.40 (95% CI, 0.99-1.99) for the lowest vs highest quartiles. The VWF/ADAMTS-13 ratio was linearly associated with the VTE risk (P for trend = .001), with an OR of 1.70 (95% CI, 1.19-2.43) for the highest vs lowest quartiles, and the association was particularly pronounced for unprovoked VTE (OR, 2.81; 95% CI, 1.65-4.81). The ORs were only slightly attenuated after additional adjustments for body mass index and C-reactive protein. ConclusionsLowered ADAMTS-13 levels and an imbalance between ADAMTS-13 and VWF levels, reflected by an increased VWF/ADAMTS-13 ratio, were associated with an increased risk of future VTE. Our findings suggest that the VWF-ADAMTS-13 axis is involved in the pathogenesis of VTE.