ABSTRACT
Transcription factors specifically bind to their consensus sequence motifs and regulate transcription efficiency. Transcription factors are also able to non-specifically contact the phosphate backbone of DNA through electrostatic interaction. The homeodomain of Meis1 TALE human transcription factor (Meis1-HD) recognizes its target DNA sequences via two DNA contact regions, the L1-α1 region and the α3 helix (specific binding mode). This study demonstrates that the non-specific binding mode of Meis1-HD is the energetically favored process during DNA binding, achieved by the interaction of the L1-α1 region with the phosphate backbone. An NMR dynamics study suggests that non-specific binding might set up an intermediate structure which can then rapidly and easily find the consensus region on a long section of genomic DNA in a facilitated binding process. Structural analysis using NMR and molecular dynamics shows that key structural distortions in the Meis1-HD-DNA complex are induced by various single nucleotide mutations in the consensus sequence, resulting in decreased DNA binding affinity. Collectively, our results elucidate the detailed molecular mechanism of how Meis1-HD recognizes single nucleotide mutations within its consensus sequence: (i) through the conformational features of the α3 helix; and (ii) by the dynamic features (rigid or flexible) of the L1 loop and the α3 helix. These findings enhance our understanding of how single nucleotide mutations in transcription factor consensus sequences lead to dysfunctional transcription and, ultimately, human disease.
Subject(s)
DNA , Molecular Dynamics Simulation , Myeloid Ecotropic Viral Integration Site 1 Protein , Protein Binding , Myeloid Ecotropic Viral Integration Site 1 Protein/metabolism , Myeloid Ecotropic Viral Integration Site 1 Protein/genetics , Humans , DNA/metabolism , DNA/chemistry , DNA/genetics , Binding Sites , Homeodomain Proteins/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/chemistry , Mutation , Consensus Sequence , Base SequenceABSTRACT
The definition of service has evolved from a focus on material value in manufacturing before the 2000s to a customer-centric value based on the significant growth of the service industry. Digital transformation has become essential for companies in the service industry due to the incorporation of digital technology through the Fourth Industrial Revolution and COVID-19. This study utilised Bidirectional Encoder Representations from Transformer (BERT) to analyse 3029 international patents related to the customer service industry and digital transformation registered between 2000 and 2022. Through topic modelling, this study identified 10 major topics in the customer service industry and analysed their yearly trends. Our findings show that as of 2022, the trend with the highest frequency is user-centric network service design, while cloud computing has experienced the steepest increase in the last five years. User-centric network services have been steadily developing since the inception of the Internet. Cloud computing is one of the key technologies being developed intensively in 2023 for the digital transformation of customer service. This study identifies time series trends of customer service industry patents and suggests the effectiveness of using BERTopic to predict future trends in technology.
ABSTRACT
Atrial fibrillation (AF) is associated with an increased risk of thromboembolic events; however, many patients with AF are noncompliant with medication regimens, which increases said risk substantially. Suboptimal health literacy presents significant hurdles to compliance with medical treatment. Here we present a case of an elderly Hispanic woman with AF and several comorbidities, including a history of dementia, who presented with consecutive recurrence of acute limb ischemia in the bilateral lower extremities just 3 days apart. Both events were successfully treated with endovascular thrombectomy. This case study not only showcases the efficacy of the latest endovascular technologies, but also draws attention to the importance of strict patient medication adherence in AF and the effects that health literacy can have on said adherence.
Subject(s)
Endovascular Procedures , Ischemia , Thrombectomy , Humans , Thrombectomy/methods , Female , Ischemia/surgery , Ischemia/therapy , Endovascular Procedures/methods , Lower Extremity/blood supply , Atrial Fibrillation/surgery , Aged , RecurrenceABSTRACT
Lifetime-reconfigurable soft robots have emerged as a new class of robots, emphasizing the unmet needs of futuristic sustainability and security. Trigger-transient materials that can both actuate and degrade on-demand are crucial for achieving life-reconfigurable soft robots. Here, we propose the use of transient and magnetically actuating materials that can decompose under ultraviolet light and heat, achieved by adding photo-acid generator (PAG) and magnetic particles (Sr-ferrite) to poly(propylene carbonate) (PPC). Chemical and thermal analyses reveal that the mechanism of PPC-PAG decomposition occurs through PPC backbone cleavage by the photo-induced acid. The self-assembled monolayer (SAM) encapsulation of Sr-ferrite preventing the interaction with the PAG allowed the transience of magnetic soft actuators. We demonstrate remotely controllable and degradable magnetic soft kirigami actuators using blocks with various magnetized directions. This study proposes novel approaches for fabricating lifetime-configurable magnetic soft actuators applicable to diverse environments and applications, such as enclosed/sealed spaces and security/military devices.
ABSTRACT
Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.
Subject(s)
Microsatellite Instability , Neoplasms , Thiophenes , Humans , Cyclohexanones , Neoplasms/drug therapy , Neoplasms/genetics , Werner Syndrome Helicase/antagonists & inhibitors , Werner Syndrome Helicase/metabolism , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
Iontronic sensors have garnered significant attention as wearable sensors due to their exceptional mechanical performance and the ability to maintain electrical performance under various mechanical stimuli. Iontronic sensors can respond to stimuli like mechanical stimuli, humidity, and temperature, which has led to exploration of their potential as versatile sensors. Here, a comprehensive review of the recent researches and developments on several types of iontronic sensors (e.g., pressure, strain, humidity, temperature, and multi-modal sensors), in terms of their sensing principles, constituent materials, and their healthcare-related applications is provided. The strategies for improving the sensing performance and environmental stability of iontronic sensors through various innovative ionic materials and structural designs are reviewed. This review also provides the healthcare applications of iontronic sensors that have gained increased feasibility and broader applicability due to the improved sensing performance. Lastly, outlook section discusses the current challenges and the future direction in terms of the applicability of the iontronic sensors to the healthcare.