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RSPO2 as Wnt signaling enabler: Important roles in cancer development and therapeutic opportunities

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Genes & Diseases 2024年第2期11卷 788-806页

作者： Ankit Srivastava Deeksha Rikhari Sameer Srivastava Department of biotechnology Motilal Nehru National Institute of TechnologyAllahabadUttar Pradesh 211004India

R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway.Among the R-spondin family,RSPO2 has emanated as a novel regulator of Wnt signaling,which has now been acknowledged in numerous in vitro and in vivo studies.Cancer is an abnormal growth of cells that proliferates and spreads uncontrollably due to the accumulation of genetic and epigenetic factors that constitutively activate Wnt signaling in various types of cancer.Colorectal cancer (CRC) begins when cells in the colon and rectum follow an indefinite pattern of division due to aberrant Wnt activation as one of the key hallmarks.Decades-long progress in research on R-spondins has demonstrated their oncogenic function in distinct cancer types,particularly CRC.As a critical regulator of the Wnt pathway,it modulates several phenotypes of cells,such as cell proliferation,invasion,migration,and cancer stem cell properties.Recently,RSPO mutations,gene rearrangements,fusions,copy number alterations,and altered gene expression have also been identified in a variety of cancers,including CRC.In this review,we addressed the recent updates regarding the recurrently altered R-spondins with special emphasis on the RSPO2 gene and its involvement in potentiating Wnt signaling in CRC.In addition to the compelling physiological and biological roles in cellular fate and regulation,we propose that RSPO2 would be valuable as a potential biomarker for prognostic,diagnostic,and therapeutic use in CRC.

关键词： CRC Gene fusion R-Spondins RSPO2 Therapeutics Wnt signaling

Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus

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World Journal of Clinical Cases 2024年第3期12卷 525-537页

作者： Dharmsheel Shrivastav Desh Deepak Singh Amity institute of biotechnology Amity University RajasthanJaipur 303002India

BACKGROUND Type 2 diabetes mellitus(T2DM)is a metabolic disease of impaired glucose utilization.Uncontrolled high sugar levels lead to advanced glycation end products(AGEs),which affects several metabolic pathways by its receptor of advanced glycation end products(RAGE)and causes diabetic complication.MiRNAs are small RNA molecules which regulate genes linked to diabetes and affect AGEs pathogenesis,and target tissues,influencing health and disease processes.AIM To explore miRNA roles in T2DM's metabolic pathways for potential therapeutic and diagnostic advancements in diabetes complications.METHODS We systematically searched the electronic database PubMed using keywords.We included free,full-length research articles that evaluate the role of miRNAs in T2DM and its complications,focusing on genetic and molecular disease mechanisms.After assessing the full-length papers of the shortlisted articles,we included 12 research articles.RESULTS Several types of miRNAs are linked in metabolic pathways which are affected by AGE/RAGE axis in T2DM and its complications.miR-96-5p,miR-7-5p,miR-132,has_circ_0071106,miR-143,miR-21,miR-145-5p,and more are associated with various aspects of T2DM,including disease risk,diagnostic markers,complications,and gene regulation.CONCLUSION Targeting the AGE/RAGE axis,with a focus on miRNA regulation,holds promise for managing T2DM and its complications.MiRNAs have therapeutic potential as they can influence the metabolic pathways affected by AGEs and RAGE,potentially reducing inflammation,oxidative stress,and vascular complications.Additionally,miRNAs may serve as early diagnostic biomarkers for T2DM.Further research in this area may lead to innovative therapeutic strategies for diabetes and its associated complications.

关键词： Type 2 diabetes mellitus MicroRNAs Advanced glycation end products Receptor for advanced glycation end products

Crosstalk between Wnt and bone morphogenetic protein signaling during osteogenic differentiati

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World Journal of Stem Cells 2024年第2期16卷 102-113页

作者： Pakkath Narayanan Arya Iyyappan Saranya Nagarajan Selvamurugan Department of biotechnology School of BioengineeringSRM Institute of Science and TechnologyKattankulathur 603203India

Mesenchymal stem cells(MSCs)originate from many sources,including the bone marrow and adipose tissue,and differentiate into various cell types,such as osteoblasts and adipocytes.Recent studies on MSCs have revealed that many transcription factors and signaling pathways control osteogenic development.Osteogenesis is the process by which new bones are formed;it also aids in bone remodeling.Wnt/β-catenin and bone morphogenetic protein(BMP)signaling pathways are involved in many cellular processes and considered to be essential for life.Wnt/β-catenin and BMPs are important for bone formation in mammalian development and various regulatory activities in the body.Recent studies have indicated that these two signaling pathways contribute to osteogenic differen-tiation.Active Wnt signaling pathway promotes osteogenesis by activating the downstream targets of the BMP signaling pathway.Here,we briefly review the molecular processes underlying the crosstalk between these two pathways and explain their participation in osteogenic differentiation,emphasizing the canonical pathways.This review also discusses the crosstalk mechanisms of Wnt/BMP signaling with Notch-and extracellular-regulated kinases in osteogenic differentiation and bone development.

关键词： Bone Mesenchymal stem cells Osteogenic differentiation Wnt/β-catenin Bone morphogenetic proteins

Carrimycin inhibits coronavirus replication by decreasing the efficiency of programmed–1 ribosomal frameshifting through directly binding to the RNA pseudoknot of viral frameshift-stimulatory element

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2567-2580页

作者： Hongying Li Jianrui Li Jiayu Li Hu Li Xuekai Wang Jing Jiang Lei Lei Han Sun Mei Tang Biao Dong Weiqing He Shuyi Si Bin Hong Yinghong Li Danqing Song Zonggen Peng Yongsheng Che Jian-Dong Jiang CAMS Key Laboratory of Antiviral Drug Research Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Beijing Key Laboratory of Antimicrobial Agents Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Key Laboratory of biotechnology of Antibiotics the National Health and Family Planning Commission(NHFPC)Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity.Here,we show that carrimycin,a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials,decreases the efficiency of programmed–1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion.Carrimycin binds directly to the coronaviral frameshift-stimulatory element(FSE)RNA pseudoknot,interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes.Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses.Because the FSE mechanism is essential in all coronaviruses,carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA.This finding may open a new direction in antiviral drug discovery for coronavirus variants.

关键词： Carrimycin Coronavirus Broad-spectrum antiviral activity Programmed-1 ribosomal frameshifting RNA pseudoknot Antiviral agent RNA target Synergistic inhibitory effect

Unveiling the early stage evolution of local atomic structures in the crystallization process of a metallic glass

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Chinese Physics B 2024年第3期33卷 58-64页

作者：马琳杨晓东杨锋周鑫嘉武振伟 institute of Nonequilibrium systems School of Systems ScienceBeijing Normal UniversityBeijing 100875China

The early stage evolution of local atomic structures in a multicomponent metallic glass during its crystallization process has been investigated via molecular dynamics simulation.It is found that the initial thermal stability and earliest stage evolution of the local atomic clusters show no strong correlation with their initial short-range orders,and this leads to an observation of a novel symmetry convergence phenomenon,which can be understood as an atomic structure manifestation of the ergodicity.Furthermore,in our system we have quantitatively proved that the crucial factor for the thermal stability against crystallization exhibited by the metallic glass is not the total amount of icosahedral clusters,but the degree of global connectivity among them.

关键词： metallic glass crystallization molecular dynamics simulation local atomic clusters

A novel non-intrusive load monitoring technique using semi-supervised deep learning framework for smart grid

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Building Simulation 2024年第3期17卷 441-457页

作者： Mohammad Kaosain Akbar Manar Amayri Nizar Bouguila Concordia institute for Information systems Engineering Concordia UniversityMontrealCanada

Non-intrusive load monitoring(NILM)is a technique which extracts individual appliance consumption and operation state change information from the aggregate power consumption made by a single residential or commercial unit.NILM plays a pivotal role in modernizing building energy management by disaggregating total energy consumption into individual appliance-level insights.This enables informed decision-making,energy optimization,and cost reduction.However,NILM encounters substantial challenges like signal noise,data availability,and data privacy concerns,necessitating advanced algorithms and robust methodologies to ensure accurate and secure energy disaggregation in real-world scenarios.Deep learning techniques have recently shown some promising results in NILM research,but training these neural networks requires significant labeled data.Obtaining initial sets of labeled data for the research by installing smart meters at the end of consumers’appliances is laborious and expensive and exposes users to severe privacy risks.It is also important to mention that most NILM research uses empirical observations instead of proper mathematical approaches to obtain the threshold value for determining appliance operation states(On/Off)from their respective energy consumption value.This paper proposes a novel semi-supervised multilabel deep learning technique based on temporal convolutional network(TCN)and long short-term memory(LSTM)for classifying appliance operation states from labeled and unlabeled data.The two thresholding techniques,namely Middle-Point Thresholding and Variance-Sensitive Thresholding,which are needed to derive the threshold values for determining appliance operation states,are also compared thoroughly.The superiority of the proposed model,along with finding the appliance states through the Middle-Point Thresholding method,is demonstrated through 15%improved overall improved F1micro score and almost 26%improved Hamming loss,F1 and Specificity score for the performance of individual appliance when compared

关键词： semi-supervised learning non-intrusive load monitoring middle-point thresholding deep learning TCN LSTM

Classification of knowledge graph completeness measurement techniques

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Journal of systems Engineering and Electronics 2024年第1期35卷 154-162页

作者： ZHANG Ying XIAO Gang institute of systems Engineering Academy of Military SciencesBeijing 100107China

At present,although knowledge graphs have been widely used in various fields such as recommendation systems,question and answer systems,and intelligent search,there are always quality problems such as knowledge omissions and errors.Quality assessment and control,as an important means to ensure the quality of knowledge,can make the applications based on knowledge graphs more complete and more accurate by reasonably assessing the knowledge graphs and fixing and improving the quality problems at the same time.Therefore,as an indispensable part of the knowledge graph construction process,the results of quality assessment and control determine the usefulness of the knowledge graph.Among them,the assessment and enhancement of completeness,as an important part of the assessment and control phase,determine whether the knowledge graph can fully reflect objective phenomena and reveal potential connections among entities.In this paper,we review specific techniques of completeness assessment and classify completeness assessment techniques in terms of closed world assumptions,open world assumptions,and partial completeness assumptions.The purpose of this paper is to further promote the development of knowledge graph quality control and to lay the foundation for subsequent research on the completeness assessment of knowledge graphs by reviewing and classifying completeness assessment techniques.

关键词： quality assessment completeness assessment closed world assumptions open world assumption partial completeness assumption

Emergence of machine language: towards symbolic intelligence with neural networks

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National Science Review 2024年第4期11卷 27-30页

作者： Yuqi Wang Xu-Yao Zhang Cheng-Lin Liu Tieniu Tan Zhaoxiang Zhang State Key Laboratory of Multimodal Artificial Intelligence systems Institute of AutomationChinese Academy of Sciences

Representation learning is a core issue in artificial intelligence (AI). Currently,there exists a disparity in the choice of representation between humans and machines. Humans rely on discrete language for communicati...

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Constructing a biofunctionalized 3D-printed gelatin/sodium alginate/chitosan tri-polymer complex scaffold with improvised biological andmechanical properties for bone-tissue engineering

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Bio-Design and Manufacturing 2024年第1期7卷 57-73页

作者： Amit Kumar Singh Krishna Pramanik Amit Biswas Centre of Excellence in Tissue Engineering Department of Biotechnology and Medical EngineeringNational Institute of TechnologyRourkela 769008India

Sodium alginate(SA)/chitosan(CH)polyelectrolyte scaffold is a suitable substrate for tissue-engineering application.The present study deals with further improvement in the tensile strength and biological properties of this type of scaffold to make it a potential template for bone-tissue regeneration.We experimented with adding 0%–15%(volume fraction)gelatin(GE),a protein-based biopolymer known to promote cell adhesion,proliferation,and differentiation.The resulting tri-polymer complex was used as bioink to fabricate SA/CH/GEmatrices by three-dimensional(3D)printing.Morphological studies using scanning electron microscopy revealed the microfibrous porous architecture of all the structures,which had a pore size range of 383–419μm.X-ray diffraction and Fourier-transform infrared spectroscopy analyses revealed the amorphous nature of the scaffold and the strong electrostatic interactions among the functional groups of the polymers,thereby forming polyelectrolyte complexes which were found to improve mechanical properties and structural stability.The scaffolds exhibited a desirable degradation rate,controlled swelling,and hydrophilic characteristics which are favorable for bone-tissue engineering.The tensile strength improved from(386±15)to(693±15)kPa due to the increased stiffness of SA/CH scaffolds upon addition of gelatin.The enhanced protein adsorption and in vitro bioactivity(forming an apatite layer)confirmed the ability of the SA/CH/GE scaffold to offer higher cellular adhesion and a bone-like environment to cells during the process of tissue regeneration.In vitro biological evaluation including the MTT assay,confocal microscopy analysis,and alizarin red S assay showed a significant increase in cell attachment,cell viability,and cell proliferation,which further improved biomineralization over the scaffold surface.In addition,SA/CH containing 15%gelatin designated as SA/CH/GE15 showed superior performance to the other fabricated 3D structures,demonstrating its potential for use in bone-tissue engineering.

关键词： Scaffold Biomaterial Sodium alginate Chitosan Gelatin 3D printing Tissue engineering