Is the Risk of Diabetes Lower in Patients With Atrial Fibrillation Treated With Direct Oral Anticoagulant Compared to Warfarin?

Liu, Xuyang; Feng, Shenghui; Chen, Zhuohui; Zhou, Yue; Yin, Kang; Xue, Zhengbiao; Zhu, Wenzhen

doi:10.3389/fcvm.2022.874795

Cited by 4 publications

(3 citation statements)

References 34 publications

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“…Therefore, we could speculate that lower vitamin K intake or diminished γ-carboxylation activity could be a risk factor for the development of diabetes when combined with nutrient excess. In line with our findings, two recent large observational studies in humans indicate that treatment with warfarin compared to direct anticoagulant not targeting carboxylation does significantly increase the risk of new-onset diabetes in male and female patients with atrial fibrillation (Cheung et al, 2021; Liu et al, 2022).…”

Section: Discussionsupporting

confidence: 92%

Vitamin K-dependent γ-carboxylation regulates calcium flux and adaptation to metabolic stress in β-cells

Lacombe

Guo

Bonneau

et al. 2022

Preprint

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SUMMARYVitamin K (VK) is a micronutrient necessary for the γ-carboxylation of glutamic acids. This post- translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Clinical studies have recently implicated VK in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that β-cells lacking γ-carboxylation fail to adapt their insulin secretion in response to glucose in the context of age-related insulin resistance or diet-induced β-cell stress. Conversely, VK supplementation protects β-cells from ER stress-induced apoptosis. We identified junctate as a γ-carboxylated ER-resident protein expressed in β-cells, whose carboxylation is dysregulated in diabetic mouse models. Mechanistically, γ-carboxylation of junctate maintains basal cytosolic calcium levels and restrains store-operated calcium entry, by diminishing STIM1 and Orai1 puncta formation at the plasma membrane. These results reveal a critical role for γ- carboxylation in the regulation of calcium flux in β-cells and in their capacity to adapt to metabolic stress.

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Section: Discussionsupporting

confidence: 92%

Vitamin K-dependent γ-carboxylation regulates calcium flux and adaptation to metabolic stress in β-cells

Lacombe

Guo

Bonneau

et al. 2022

Preprint

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“…On the other hand, deep learning models require extremely large datasets to train and are difficult to interpret owing to their "black box" nature. While tools like mCSM-AB2 32 have employed classical ML to determine the impact of mutations on antibody binding, this represents the first study (to the best of our knowledge) to show that antibodies having improved properties (e.g., affinity) can be generated within a small experimental screen space using classical ML. The classical MLguided platform presented here is distinct in the following aspects.…”

Section: Discussionmentioning

confidence: 99%

Machine Learning-Guided Antibody Engineering That Leverages Domain Knowledge To Overcome The Small Data Problem

Clark¹,

Subramanian²,

Jayaraman³

et al. 2023

Preprint

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The application of Machine Learning (ML) tools to engineer novel antibodies having predictable functional properties is gaining prominence. Herein, we present a platform that employs an ML-guided optimization of the complementarity-determining region (CDR) together with a CDR framework (FR) shuffling method to engineer affinity-enhanced and clinically developable monoclonal antibodies (mAbs) from a limited experimental screen space (order of 10^2 designs) using only two experimental iterations. Although high-complexity deep learning models like graph neural networks (GNNs) and large language models (LLMs) have shown success in protein folding with large dataset sizes, the small and biased nature of the publicly available antibody-antigen interaction datasets is not sufficient to capture the diversity of mutations virtually screened using these models in an affinity enhancement campaign. To address this key gap, we introduced inductive biases learned from extensive domain knowledge of protein-protein interactions through feature engineering and selected model hyperparameters to reduce the overfitting of the limited interaction datasets. Notably, we show that this platform performs better than GNNs and LLMs on an in-house validation dataset that is enriched in diverse CDR mutations that go beyond alanine-scanning. To illustrate the broad applicability of this platform, we successfully solved a challenging problem of redesigning two different anti-SARS-COV-2 mAbs to enhance affinity (up to 2 orders of magnitude) and neutralizing potency against the dynamically evolving SARS-COV-2 Omicron variants.

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“…In line with our findings, two recent large observational studies indicate that treatment with warfarin compared with a direct anticoagulant not targeting carboxylation does significantly increase the risk of new-onset diabetes in male and female patients with atrial fibrillation. 53 , 54 …”

Section: Discussionmentioning

confidence: 99%

Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in β cells

et al. 2023

View full text Add to dashboard Cite

Is the Risk of Diabetes Lower in Patients With Atrial Fibrillation Treated With Direct Oral Anticoagulant Compared to Warfarin?

Cited by 4 publications

References 34 publications

Vitamin K-dependent γ-carboxylation regulates calcium flux and adaptation to metabolic stress in β-cells

Vitamin K-dependent γ-carboxylation regulates calcium flux and adaptation to metabolic stress in β-cells

Machine Learning-Guided Antibody Engineering That Leverages Domain Knowledge To Overcome The Small Data Problem

Vitamin K-dependent carboxylation regulates Ca2+ flux and adaptation to metabolic stress in β cells

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