Translations contribute to our knowledge and understanding in various fields of daily life, as they open us to a greater awareness of the world in which we live. The deeper we are delved into the meaning of the transl...Translations contribute to our knowledge and understanding in various fields of daily life, as they open us to a greater awareness of the world in which we live. The deeper we are delved into the meaning of the translation, the more questions are raised, among which, translatable/untranslatable argument strikes the most. In this article, factors including cultural vocabulary vacancy and different image associations leading to temporary untranslatability are presented. Besides, the strategies to change this situation to relatively translatable are given as well.展开更多
AIM To evaluate whether non-steroidal anti-inflammatory drugs(NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODS Gastric ulcer pain was induced by the oral admin...AIM To evaluate whether non-steroidal anti-inflammatory drugs(NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODS Gastric ulcer pain was induced by the oral administration of indomethacin to male,CD1 mice(n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential(TRP),sodium and acid-sensing ion channels(ASICs) as well as opioid receptors and guanylate cyclase C(GC-C). RESULTS Results showed that two opioids and a GC-C agonist,morphine,asimadoline and linaclotide,respectively,the TRP antagonists,AMG9810 and HC-030031 and the sodium channel blocker,carbamazepine,elicited a dose-and/or time-dependent attenuation of referred visceral hypersensitivity,while the ASIC blocker,amiloride,was ineffective at all doses tested. CONCLUSION Together,these findings implicate opioid receptors,GC-C,and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly,these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.展开更多
The lysosomal enzyme β-glucocerebrosidase(GCase) belongs to the family of glycosidases and hydrolyses the glycosphingolipid glucosylceramide(GluCer) into glucose and ceramide. The enzyme is of central importance for ...The lysosomal enzyme β-glucocerebrosidase(GCase) belongs to the family of glycosidases and hydrolyses the glycosphingolipid glucosylceramide(GluCer) into glucose and ceramide. The enzyme is of central importance for two pathologies:(1) the lysosomal storage disorder Gaucher's disease(GD) and(2) the neurodegenerative disorder Parkinson's disease(PD).展开更多
This review comprehensively summarized the potential of artificial intelligence(AI)in the management of esophageal cancer.It highlighted the significance of AI-assisted endoscopy in Japan where endoscopy is central to...This review comprehensively summarized the potential of artificial intelligence(AI)in the management of esophageal cancer.It highlighted the significance of AI-assisted endoscopy in Japan where endoscopy is central to both screening and diagnosis.For the clinical adaptation of AI,several challenges remain for its effective translation.The establishment of high-quality clinical databases,such as the National Clinical Database and Japan Endoscopy Database in Japan,which covers almost all cases of esophageal cancer,is essential for validating multimodal AI models.This requires rigorous external validation using diverse datasets,including those from different endoscope manufacturers and image qualities.Furthermore,endoscopists’skills significantly affect diagnostic accuracy,suggesting that AI should serve as a supportive tool rather than a replacement.Addressing these challenges,along with country-specific legal and ethical considerations,will facilitate the successful integration of multimodal AI into the management of esophageal cancer,particularly in endoscopic diagnosis,and contribute to improved patient outcomes.Although this review focused on Japan as a case study,the challenges and solutions described are broadly applicable to other high-incidence regions.展开更多
GEMIN5 is a predominantly cytoplasmic multifunctional protein, known to be involved in recognizing snRNAs through its WD40 repeats domain placed at the N-terminus. A dimerization domain in the middle region acts as a ...GEMIN5 is a predominantly cytoplasmic multifunctional protein, known to be involved in recognizing snRNAs through its WD40 repeats domain placed at the N-terminus. A dimerization domain in the middle region acts as a hub for protein–protein interaction, while a non-canonical RNA-binding site is placed towards the C-terminus. The singular organization of structural domains present in GEMIN5 enables this protein to perform multiple functions through its ability to interact with distinct partners, both RNAs and proteins. This protein exerts a different role in translation regulation depending on its physiological state, such that while GEMIN5 down-regulates global RNA translation, the C-terminal half of the protein promotes translation of its mRNA. Additionally, GEMIN5 is responsible for the preferential partitioning of mRNAs into polysomes. Besides selective translation, GEMIN5 forms part of distinct ribonucleoprotein complexes, reflecting the dynamic organization of macromolecular complexes in response to internal and external signals. In accordance with its contribution to fundamental cellular processes, recent reports described clinical loss of function mutants suggesting that GEMIN5 deficiency is detrimental to cell growth and survival. Remarkably, patients carrying GEMIN5 biallelic variants suffer from neurodevelopmental delay, hypotonia, and cerebellar ataxia. Molecular analyses of individual variants, which are defective in protein dimerization, display decreased levels of ribosome association, reinforcing the involvement of the protein in translation regulation. Importantly, the number of clinical variants and the phenotypic spectrum associated with GEMIN5 disorders is increasing as the knowledge of the protein functions and the pathways linked to its activity augments. Here we discuss relevant advances concerning the functional and structural features of GEMIN5 and its separate domains in RNA-binding, protein interactome, and translation regulation, and how these data can help to understand the involvement of protein malfunction in clinical variants found in patients developing neurodevelopmental disorders.展开更多
Colorectal cancer(CRC)is one of the most molecularly heterogeneous malignancies,with complexity that extends far beyond traditional histopathological classifications.The consensus molecular subtypes(CMS)established in...Colorectal cancer(CRC)is one of the most molecularly heterogeneous malignancies,with complexity that extends far beyond traditional histopathological classifications.The consensus molecular subtypes(CMS)established in 2015 brought a marked advancement in the taxonomy of CRC,consolidating six classification systems into four novel subtypes,which focus on vital gene expression patterns and clinical and prognostic outcomes.However,nearly a decade of clinical experience with CMS classification has revealed fundamental limitations that underscore the inadequacy of any single classification system for capturing the full spectrum of CRC biology.The inherent challenges of the current paradigm are multifaceted.In the CMS classification,mixed phenotypes that remain unclassifiable constitute 13%of CRC cases.This reflects the remarkable heterogeneity that CRC shows.The tumor budding regions reflect the molecular shift due to CMS 2 to CMS 4 switching,causing further heterogeneity.Moreover,the reliance on bulk RNA sequencing fails to capture the spatial organization of molecular signatures within tumors and the critical contributions of the tumor microenvironment.Recent technological advances in spatial transcriptomics,singlecell RNA sequencing,and multi-omic integration have revealed the limitations of transcriptome-only classifications.The emergence of CRC intrinsic subtypes that attempt to remove microenvironmental contributions,pathway-derived subtypes,and stem cell-based classifications demonstrates the field’s recognition that multiple complementary classification systems are necessary.These newer molecular subtypes are not discrete categories but biological continua,thus highlighting that the vast molecular landscape is a tapestry of interlinked features,not rigid subtypes.Multiple technical hurdles cause difficulty in implementing the clinical translation of these newer molecular subtypes,including gene signature complexity,platform-dependent variations,and the difficulty of getting and preserving fresh frozen tissue.CMS 4 shows a poor prognostic outcome among the CMS subtypes,while CMS 1 is associated with poor survival in metastatic cases.However,the predictive value for definitive therapy remains subdued.Looking forward,the integration of artificial intelligence,liquid biopsy approaches,and real-time molecular monitoring promises to enable dynamic,multi-dimensional tumor characterization.The temporal and spatial complexity can only be captured by complementary molecular taxonomies rather than a single,unified system of CRC classification.Such an approach recognizes that different clinical questions–prognosis,treatment selection,resistance prediction–may require different molecular lenses,each optimized for specific clinical applications.This editorial advocates for a revolutionary change from pursuing a single“best”classification system toward a diverse approach that welcomes the molecular mosaic of CRC.Only through such comprehensive molecular characterization can we hope to achieve the promise of precision oncology for the diverse spectrum of patients with CRC.展开更多
Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure pro...Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure proper protein folding,the addition of post-translational modifications,and delivering to intracellular and extracellular destinations.Astrocytes are fundamental homeostatic cells,controlling multiple aspects of the central nervous system physiology,such as ion balance,nutrients,blood flow,neurotransmitters,and responses to insults.Astrocytes are polarized cells,and,such as neurons,extensively use the secretory pathway for secreting factors and exposing functional receptors,channels,and transporters on the plasma membrane.In this review,we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes,based on the possible tight connection between the Golgi apparatus and astrocytes’homeostatic function.Given the topic of this review,we will provide examples mostly about the Golgi apparatus structure,function,localization,and its involvement in astrocytes’homeostatic response,with an insight into congenital glycosylation disorders,as an example of a potential future field in the study of astrocyte homeostatic failure and Golgi apparatus alteration.展开更多
A recently published prospective study marks a breakthrough for congenital olfactory disorders in children.The study provides the first long-term,three-year follow-up data,robustly demonstrating the durable efficacy a...A recently published prospective study marks a breakthrough for congenital olfactory disorders in children.The study provides the first long-term,three-year follow-up data,robustly demonstrating the durable efficacy and safety of autologous nasal epithelial stem cell transplantation.This work reveals immense therapeutic potential for a condition traditionally considered untreatable.However,this milestone achievement also presents new challenges.To translate this pioneering therapy from a single-center success to a global standard,multicenter,controlled clinical trials must be initiated immediately.Only through rigorous validation can we ensure its widespread adoption and ultimately bring hope to millions of children worldwide.展开更多
Stress granules are membraneless organelles that serve as a protective cellular response to external stressors by sequestering non-translating messenger RNAs(mRNAs)and regulating protein synthesis.Stress granules form...Stress granules are membraneless organelles that serve as a protective cellular response to external stressors by sequestering non-translating messenger RNAs(mRNAs)and regulating protein synthesis.Stress granules formation mechanism is conserved across species,from yeast to mammals,and they play a critical role in minimizing cellular damage during stress.Composed of heterogeneous ribonucleoprotein complexes,stress granules are enriched not only in mRNAs but also in noncoding RNAs and various proteins,including translation initiation factors and RNA-binding proteins.Genetic mutations affecting stress granule assembly and disassembly can lead to abnormal stress granule accumulation,contributing to the progression of several diseases.Recent research indicates that stress granule dynamics are pivotal in determining their physiological and pathological functions,with acute stress granule formation offering protection and chronic stress granule accumulation being detrimental.This review focuses on the multifaceted roles of stress granules under diverse physiological conditions,such as regulation of mRNA transport,mRNA translation,apoptosis,germ cell development,phase separation processes that govern stress granule formation,and their emerging implications in pathophysiological scenarios,such as viral infections,cancer,neurodevelopmental disorders,neurodegeneration,and neuronal trauma.展开更多
Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understo...Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.展开更多
Circular RNAs (circRNAs) are a special class of single-stranded RNA molecules with covalently closed loops widely expressed in eukaryotic organisms. CircRNAs have long been considered to play important roles in variou...Circular RNAs (circRNAs) are a special class of single-stranded RNA molecules with covalently closed loops widely expressed in eukaryotic organisms. CircRNAs have long been considered to play important roles in various physiological and pathological processes as non-coding RNAs. However, circRNAs have recently garnered considerable attention due to their ability to be translated into peptides/proteins via internal ribosome entry site- or N6-methyladenosine-mediated pathways or rolling translation mechanisms. Furthermore, dysregulation of translatable circRNAs and their encoded proteins has been associated with developing and progressing diseases such as cancer. This review aims to summarize the driving mechanisms of circRNA translation and the available strategies in circRNA translation research. The main focus is on the emerging biological functions of translatable circRNAs, their regulatory mechanisms, and potential clinical applications in human diseases to provide new perspectives on disease diagnosis, prognosis, and targeted therapy.展开更多
Aim:Ovine models for osseointegrated prosthetics research are well established,but do not consider neural control of advanced prostheses.The validity of interfacing technologies,such as the Osseointegrated Neural Inte...Aim:Ovine models for osseointegrated prosthetics research are well established,but do not consider neural control of advanced prostheses.The validity of interfacing technologies,such as the Osseointegrated Neural Interface(ONI),in their ability to provide communication between native nerves and advanced prosthetics is required,necessitating a stable,longitudinal large animal model for testing.The objective of this study is to provide a detailed anatomic description of the major nerves distal to the carpal and tarsal joints,informing the creation of a chronic ONI for prosthetic control in sheep.Methods:Six pelvic and six thoracic cadaveric limbs from mature female,non-lactating sheep were utilized.Radiographs were obtained to determine average bone length,medullary canal diameter,and cortical bone thickness.Microsurgical dissection was performed to discern topographical neuroanatomy and average circumferences of the major nerves of the pelvic and thoracic limbs.Histologic analysis was performed.A surgical approach for the creation of ONI was designed.Results:Average metacarpal and metatarsal length was 15.0 cm(±0.0)and 19.7 cm(±1.0),respectively.Average intramedullary canal diameter was 12.91 mm(±3.69)for forelimbs and 12.60 mm(±3.69)for hindlimbs.The thoracic limb nerves consisted of one dorsal and three ventral nerves,with an average circumference of 5.14 mm(±2.00)and 5.05 mm(±1.06),respectively.Pelvic limb nerves consisted of two dorsal and one ventral nerve with an average circumference of 6.27 mm(±1.79)and 5.40 mm(±0.53),respectively.Conclusions:These anatomic data inform the surgical approach and manufacture of a sensory ONI for chronic testing in awake,freely ambulating animals for future clinical translation.展开更多
Traditional Chinese medicine(TCM) is increasingly recognized worldwide as a valuable complementary and alternative medicine. To facilitate global research and collaboration in this field, the World Health Organization...Traditional Chinese medicine(TCM) is increasingly recognized worldwide as a valuable complementary and alternative medicine. To facilitate global research and collaboration in this field, the World Health Organization(WHO) introduced the International Standard Terminologies on Traditional Chinese Medicine in 2022. This international terminology translation standard, IST 2022, goes beyond conventional translation by embracing three innovative features: 1) It reflects TCM's foundational philosophy of unity and opposition, emphasizing the interconnectedness among TCM terms during translation. This approach transcends individual term translations to explore the interrelationships among them. 2) It preserves the integrity of TCM theory by retaining transliterations for unique TCM terms that possess distinct features. 3) It employs innovative xiang(image) cognition, a concept rooted in traditional Chinese thought by helping readers grasp visual and mental imagery associated with each term. This study presents a qualitative analysis based on interviews with 11 TCM translation experts, examining their perspectives on these features and their translational preferences across the IST 2007 and 2022 versions. These findings contribute to the standardization and global harmonization of TCM terminology, advocating for clarity, precision, and the advancement of TCM in the international healthcare arena.展开更多
Hepatocellular carcinoma(HCC)recurrence after liver transplantation(LT)presents a significant challenge,with recurrence rates ranging from 8%to 20%globally.Current biomarkers,such as alpha-fetoprotein(AFP)and des-gamm...Hepatocellular carcinoma(HCC)recurrence after liver transplantation(LT)presents a significant challenge,with recurrence rates ranging from 8%to 20%globally.Current biomarkers,such as alpha-fetoprotein(AFP)and des-gamma-carboxy prothrombin(DCP),lack specificity,limiting their utility in risk strati-fication.YKL-40,a glycoprotein involved in extracellular matrix remodeling,hepatic stellate cell activation,and immune modulation,has emerged as a promising biomarker for post-LT surveillance.Elevated serum levels of YKL-40 are associated with advanced liver disease,tumor progression,and poorer post-LT outcomes,highlighting its potential to address gaps in early detection and personalized management of HCC recurrence.This manuscript synthesizes clinical and mechanistic evidence to evaluate YKL-40’s predictive utility in post-LT care.While preliminary findings demonstrate its specificity for liver-related pathologies,challenges remain,including assay standardization,lack of pro-spective validation,and the need to distinguish between malignant and non-malignant causes of elevated levels.Integrating YKL-40 into multi-biomarker panels with AFP and DCP could enhance predictive accuracy and enable tailored therapeutic strategies.Future research should focus on multicenter studies to validate YKL-40’s clinical utility,address confounding factors like graft rejection and systemic inflammation,and explore its role in predictive models driven by emerging technologies such as artificial intelligence.YKL-40 holds transformative potential in reshaping post-LT care through precision medicine,providing a pathway for better outcomes and improved management of high-risk LT recipients.展开更多
Edge structures are ubiquitous in the processing and fabrication of various optoelectronic devices.Novel physical properties and enhanced light–matter interactions are anticipated to occur at crystal edges due to the...Edge structures are ubiquitous in the processing and fabrication of various optoelectronic devices.Novel physical properties and enhanced light–matter interactions are anticipated to occur at crystal edges due to the broken spatial translational symmetry.However,the intensity of first-order Raman scattering at crystal edges has been rarely explored,although the mechanical stress and edge characteristics have been thoroughly studied by the Raman peak shift and the spectral features of the edge-related Raman modes.Here,by taking Ga As crystal with a well-defined edge as an example,we reveal the intensity enhancement of Raman-active modes and the emergence of Raman-forbidden modes under specific polarization configurations at the edge.This is attributed to the presence of a hot spot at the edge due to the redistributed electromagnetic fields and electromagnetic wave propagations of incident laser and Raman signal near the edge,which are confirmed by the finite-difference time-domain simulations.Spatially-resolved Raman intensities of both Raman-active and Raman-forbidden modes near the edge are calculated based on the redistributed electromagnetic fields,which quantitatively reproduce the corresponding experimental results.These findings offer new insights into the intensity enhancement of Raman scattering at crystal edges and present a new avenue to manipulate light–matter interactions of crystal by manufacturing various types of edges and to characterize the edge structures in photonic and optoelectronic devices.展开更多
Translation regulation is an important layer of gene expression:Generation of genome-wide expression datasets at multi-omics levels in spatial,temporal,and cell-type resolution is essential for deciphering brain compl...Translation regulation is an important layer of gene expression:Generation of genome-wide expression datasets at multi-omics levels in spatial,temporal,and cell-type resolution is essential for deciphering brain complexity.Regulation of gene expression is a highly dynamic process aiming at the production of precise levels of gene products to guarantee optimal cellular function,in response to physiological cues.Speedy advances in next-generation sequencing enabled the understanding of epigenomic and transcriptomic dynamic landscapes of different brain regions along development,aging,and disease progression.However,the correlation of the“transcriptome”with protein levels is poor because numerous mRNAs are subjected to manipulation of their translation efficiency,to warrant a favorable result under certain conditions.Hence,it is widely accepted that regulation at the translation level is a vital layer of gene expression.Quantification of actively translated mRNA populations(i.e.,“translatome”)is a more reliable predictor of the“proteome”(Wang et al.,2020).展开更多
A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity.However,regulatory mechanisms at the translational level under cardiac stress remain poorly und...A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity.However,regulatory mechanisms at the translational level under cardiac stress remain poorly understood.Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction(TAC)and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy(DCM).The results showed that the heart weight to body weight ratio was significantly elevated,and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC.Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle.RNAseq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling,metabolic processes,and signaling cascades associated with pathological cardiomyocyte growth.When combined with ribosome profiling analysis,we revealed that translation efficiency(TE)of 1,495 genes was enhanced,while the TE of 933 genes was inhibited following TAC.In DCM patients,1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level.Although the majority of the genes were not shared between mouse and human,we identified 93 genes,including Nos3,Kcnj8,Adcy4,Itpr1,Fasn,Scd1,etc.,with highly conserved translational regulations.These genes were remarkably associated with myocardial function,signal transduction,and energy metabolism,particularly related to cGMP-PKG signaling and fatty acid metabolism.Motif analysis revealed enriched regulatory elements in the 5′untranslated regions(5′UTRs)of transcripts with differential TE,which exhibited strong cross-species sequence conservation.Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.展开更多
The second near-infrared window(NIR-II,900-1880 nm)overcomes critical limitations of visible(360-760 nm)and NIR-I(760-900 nm)imaging—including restricted penetration depth,low signal-to-back⁃ground ratio,and tissue a...The second near-infrared window(NIR-II,900-1880 nm)overcomes critical limitations of visible(360-760 nm)and NIR-I(760-900 nm)imaging—including restricted penetration depth,low signal-to-back⁃ground ratio,and tissue autofluorescence—establishing its pivotal role for in vivo deep-tissue bioimaging.With exponential growth in NIR-II photodiagnosis and phototherapy research over the past decade,bibliometric analy⁃sis is essential to map the evolving landscape and guide strategic priorities.We systematically analyzed 2,491 NIR-II-related publications(2009-2023)from the Web of Science Core Collection,employing scientometric tools for distinct analytical purposes:(a)VOSviewer,SCImago Graphica,and Gephi for co-authorship and co-occur⁃rence network mapping;(b)the R bibliometrix package for tracking field evolution and identifying high-impact publications/journals.The search retrieved 2491 studies from 359 journals originating from 54 countries.The country with the most published articles is China.Chinese institutions drive>60%of publications,with Stanford University(USA)and Nanyang Technological University(Singapore)ranked as the top two institutions by re⁃search quality.International cooperation is becoming increasingly frequent.Fan Quli,Tang Benzhong and Dai Hongjie are the top 3 productive authors in this field.Keyword evolution identifies"photodynamic therapy"and"immunotherapy"as pivotal future directions.We summarize the most cited literatures and NIR-II imaging clini⁃cal trials.This study delineates the NIR-II research trajectory,highlighting China's leadership,intensifying glob⁃al collaboration,and interdisciplinary convergence.Future efforts should prioritize the novel NIR-II probe devel⁃opment for NIR-II imaging and clinical translation of photodynamic/immunotherapy combinational platforms.展开更多
This paper takes Chinese red culture resources as its research subject and focuses on evaluating the Chinese-English translation quality of three major AI platforms:ChatGPT-4.0,ERNIE Bot,and DeepSeek.Through automatic...This paper takes Chinese red culture resources as its research subject and focuses on evaluating the Chinese-English translation quality of three major AI platforms:ChatGPT-4.0,ERNIE Bot,and DeepSeek.Through automatic quantitative evaluation,it systematically analyzes their performance in translating red culture texts.The study selects a diverse range of corpora,including historical documents,red classic texts,and culturally loaded terms.Three automatic evaluation metrics—GLEU,METEOR,and COMET—are employed for a comprehensive assessment.展开更多
文摘Translations contribute to our knowledge and understanding in various fields of daily life, as they open us to a greater awareness of the world in which we live. The deeper we are delved into the meaning of the translation, the more questions are raised, among which, translatable/untranslatable argument strikes the most. In this article, factors including cultural vocabulary vacancy and different image associations leading to temporary untranslatability are presented. Besides, the strategies to change this situation to relatively translatable are given as well.
文摘AIM To evaluate whether non-steroidal anti-inflammatory drugs(NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODS Gastric ulcer pain was induced by the oral administration of indomethacin to male,CD1 mice(n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential(TRP),sodium and acid-sensing ion channels(ASICs) as well as opioid receptors and guanylate cyclase C(GC-C). RESULTS Results showed that two opioids and a GC-C agonist,morphine,asimadoline and linaclotide,respectively,the TRP antagonists,AMG9810 and HC-030031 and the sodium channel blocker,carbamazepine,elicited a dose-and/or time-dependent attenuation of referred visceral hypersensitivity,while the ASIC blocker,amiloride,was ineffective at all doses tested. CONCLUSION Together,these findings implicate opioid receptors,GC-C,and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly,these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.
基金supported by the Michael J Fox Foundation (to PA and FZ)。
文摘The lysosomal enzyme β-glucocerebrosidase(GCase) belongs to the family of glycosidases and hydrolyses the glycosphingolipid glucosylceramide(GluCer) into glucose and ceramide. The enzyme is of central importance for two pathologies:(1) the lysosomal storage disorder Gaucher's disease(GD) and(2) the neurodegenerative disorder Parkinson's disease(PD).
基金Supported by Japan Society for the Promotion of Science,No.24K11935.
文摘This review comprehensively summarized the potential of artificial intelligence(AI)in the management of esophageal cancer.It highlighted the significance of AI-assisted endoscopy in Japan where endoscopy is central to both screening and diagnosis.For the clinical adaptation of AI,several challenges remain for its effective translation.The establishment of high-quality clinical databases,such as the National Clinical Database and Japan Endoscopy Database in Japan,which covers almost all cases of esophageal cancer,is essential for validating multimodal AI models.This requires rigorous external validation using diverse datasets,including those from different endoscope manufacturers and image qualities.Furthermore,endoscopists’skills significantly affect diagnostic accuracy,suggesting that AI should serve as a supportive tool rather than a replacement.Addressing these challenges,along with country-specific legal and ethical considerations,will facilitate the successful integration of multimodal AI into the management of esophageal cancer,particularly in endoscopic diagnosis,and contribute to improved patient outcomes.Although this review focused on Japan as a case study,the challenges and solutions described are broadly applicable to other high-incidence regions.
基金partially supported by grants PID2020-115096RB-I00 and PID2023-148273NB-I00 from Ministerio de Ciencia y Universidad (MICIU/AEI)(to EMS)。
文摘GEMIN5 is a predominantly cytoplasmic multifunctional protein, known to be involved in recognizing snRNAs through its WD40 repeats domain placed at the N-terminus. A dimerization domain in the middle region acts as a hub for protein–protein interaction, while a non-canonical RNA-binding site is placed towards the C-terminus. The singular organization of structural domains present in GEMIN5 enables this protein to perform multiple functions through its ability to interact with distinct partners, both RNAs and proteins. This protein exerts a different role in translation regulation depending on its physiological state, such that while GEMIN5 down-regulates global RNA translation, the C-terminal half of the protein promotes translation of its mRNA. Additionally, GEMIN5 is responsible for the preferential partitioning of mRNAs into polysomes. Besides selective translation, GEMIN5 forms part of distinct ribonucleoprotein complexes, reflecting the dynamic organization of macromolecular complexes in response to internal and external signals. In accordance with its contribution to fundamental cellular processes, recent reports described clinical loss of function mutants suggesting that GEMIN5 deficiency is detrimental to cell growth and survival. Remarkably, patients carrying GEMIN5 biallelic variants suffer from neurodevelopmental delay, hypotonia, and cerebellar ataxia. Molecular analyses of individual variants, which are defective in protein dimerization, display decreased levels of ribosome association, reinforcing the involvement of the protein in translation regulation. Importantly, the number of clinical variants and the phenotypic spectrum associated with GEMIN5 disorders is increasing as the knowledge of the protein functions and the pathways linked to its activity augments. Here we discuss relevant advances concerning the functional and structural features of GEMIN5 and its separate domains in RNA-binding, protein interactome, and translation regulation, and how these data can help to understand the involvement of protein malfunction in clinical variants found in patients developing neurodevelopmental disorders.
文摘Colorectal cancer(CRC)is one of the most molecularly heterogeneous malignancies,with complexity that extends far beyond traditional histopathological classifications.The consensus molecular subtypes(CMS)established in 2015 brought a marked advancement in the taxonomy of CRC,consolidating six classification systems into four novel subtypes,which focus on vital gene expression patterns and clinical and prognostic outcomes.However,nearly a decade of clinical experience with CMS classification has revealed fundamental limitations that underscore the inadequacy of any single classification system for capturing the full spectrum of CRC biology.The inherent challenges of the current paradigm are multifaceted.In the CMS classification,mixed phenotypes that remain unclassifiable constitute 13%of CRC cases.This reflects the remarkable heterogeneity that CRC shows.The tumor budding regions reflect the molecular shift due to CMS 2 to CMS 4 switching,causing further heterogeneity.Moreover,the reliance on bulk RNA sequencing fails to capture the spatial organization of molecular signatures within tumors and the critical contributions of the tumor microenvironment.Recent technological advances in spatial transcriptomics,singlecell RNA sequencing,and multi-omic integration have revealed the limitations of transcriptome-only classifications.The emergence of CRC intrinsic subtypes that attempt to remove microenvironmental contributions,pathway-derived subtypes,and stem cell-based classifications demonstrates the field’s recognition that multiple complementary classification systems are necessary.These newer molecular subtypes are not discrete categories but biological continua,thus highlighting that the vast molecular landscape is a tapestry of interlinked features,not rigid subtypes.Multiple technical hurdles cause difficulty in implementing the clinical translation of these newer molecular subtypes,including gene signature complexity,platform-dependent variations,and the difficulty of getting and preserving fresh frozen tissue.CMS 4 shows a poor prognostic outcome among the CMS subtypes,while CMS 1 is associated with poor survival in metastatic cases.However,the predictive value for definitive therapy remains subdued.Looking forward,the integration of artificial intelligence,liquid biopsy approaches,and real-time molecular monitoring promises to enable dynamic,multi-dimensional tumor characterization.The temporal and spatial complexity can only be captured by complementary molecular taxonomies rather than a single,unified system of CRC classification.Such an approach recognizes that different clinical questions–prognosis,treatment selection,resistance prediction–may require different molecular lenses,each optimized for specific clinical applications.This editorial advocates for a revolutionary change from pursuing a single“best”classification system toward a diverse approach that welcomes the molecular mosaic of CRC.Only through such comprehensive molecular characterization can we hope to achieve the promise of precision oncology for the diverse spectrum of patients with CRC.
文摘Cell function has a tight relationship with cell architecture.Distribution of proteins to the correct compartment is one of the functions of the traffic pathway through the Golgi apparatus.The others are to ensure proper protein folding,the addition of post-translational modifications,and delivering to intracellular and extracellular destinations.Astrocytes are fundamental homeostatic cells,controlling multiple aspects of the central nervous system physiology,such as ion balance,nutrients,blood flow,neurotransmitters,and responses to insults.Astrocytes are polarized cells,and,such as neurons,extensively use the secretory pathway for secreting factors and exposing functional receptors,channels,and transporters on the plasma membrane.In this review,we will underline the importance of studying the Golgi apparatus and the secretory pathway in astrocytes,based on the possible tight connection between the Golgi apparatus and astrocytes’homeostatic function.Given the topic of this review,we will provide examples mostly about the Golgi apparatus structure,function,localization,and its involvement in astrocytes’homeostatic response,with an insight into congenital glycosylation disorders,as an example of a potential future field in the study of astrocyte homeostatic failure and Golgi apparatus alteration.
文摘A recently published prospective study marks a breakthrough for congenital olfactory disorders in children.The study provides the first long-term,three-year follow-up data,robustly demonstrating the durable efficacy and safety of autologous nasal epithelial stem cell transplantation.This work reveals immense therapeutic potential for a condition traditionally considered untreatable.However,this milestone achievement also presents new challenges.To translate this pioneering therapy from a single-center success to a global standard,multicenter,controlled clinical trials must be initiated immediately.Only through rigorous validation can we ensure its widespread adoption and ultimately bring hope to millions of children worldwide.
基金supported by a grant from the Merkin Peripheral Neuropathy and Nerve Regeneration Center(to PKS)the Rutgers University Startup Fund(to PKS).
文摘Stress granules are membraneless organelles that serve as a protective cellular response to external stressors by sequestering non-translating messenger RNAs(mRNAs)and regulating protein synthesis.Stress granules formation mechanism is conserved across species,from yeast to mammals,and they play a critical role in minimizing cellular damage during stress.Composed of heterogeneous ribonucleoprotein complexes,stress granules are enriched not only in mRNAs but also in noncoding RNAs and various proteins,including translation initiation factors and RNA-binding proteins.Genetic mutations affecting stress granule assembly and disassembly can lead to abnormal stress granule accumulation,contributing to the progression of several diseases.Recent research indicates that stress granule dynamics are pivotal in determining their physiological and pathological functions,with acute stress granule formation offering protection and chronic stress granule accumulation being detrimental.This review focuses on the multifaceted roles of stress granules under diverse physiological conditions,such as regulation of mRNA transport,mRNA translation,apoptosis,germ cell development,phase separation processes that govern stress granule formation,and their emerging implications in pathophysiological scenarios,such as viral infections,cancer,neurodevelopmental disorders,neurodegeneration,and neuronal trauma.
文摘Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins.Although the consequences of ufmylation on target proteins are not fully understood,its importance is evident from the disorders resulting from its dysfunction.Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders.
基金supported by the National Natural Science Foundation of China(No.81802793 and 82103465)Natural Science Foundation of Shanxi Province(China)(No.201801D221419)+4 种基金Youth Foundation of First Hospital Affiliated with Shanxi Medical University(China)(No.YQ161701)Science Research Start-up Fund for Doctor of Shanxi Medical University(China)(No.XD1801)Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(China)(STIPNo.2021-185)Fund of Shanxi"1331 Project"Key Subjects Construction(China).
文摘Circular RNAs (circRNAs) are a special class of single-stranded RNA molecules with covalently closed loops widely expressed in eukaryotic organisms. CircRNAs have long been considered to play important roles in various physiological and pathological processes as non-coding RNAs. However, circRNAs have recently garnered considerable attention due to their ability to be translated into peptides/proteins via internal ribosome entry site- or N6-methyladenosine-mediated pathways or rolling translation mechanisms. Furthermore, dysregulation of translatable circRNAs and their encoded proteins has been associated with developing and progressing diseases such as cancer. This review aims to summarize the driving mechanisms of circRNA translation and the available strategies in circRNA translation research. The main focus is on the emerging biological functions of translatable circRNAs, their regulatory mechanisms, and potential clinical applications in human diseases to provide new perspectives on disease diagnosis, prognosis, and targeted therapy.
文摘Aim:Ovine models for osseointegrated prosthetics research are well established,but do not consider neural control of advanced prostheses.The validity of interfacing technologies,such as the Osseointegrated Neural Interface(ONI),in their ability to provide communication between native nerves and advanced prosthetics is required,necessitating a stable,longitudinal large animal model for testing.The objective of this study is to provide a detailed anatomic description of the major nerves distal to the carpal and tarsal joints,informing the creation of a chronic ONI for prosthetic control in sheep.Methods:Six pelvic and six thoracic cadaveric limbs from mature female,non-lactating sheep were utilized.Radiographs were obtained to determine average bone length,medullary canal diameter,and cortical bone thickness.Microsurgical dissection was performed to discern topographical neuroanatomy and average circumferences of the major nerves of the pelvic and thoracic limbs.Histologic analysis was performed.A surgical approach for the creation of ONI was designed.Results:Average metacarpal and metatarsal length was 15.0 cm(±0.0)and 19.7 cm(±1.0),respectively.Average intramedullary canal diameter was 12.91 mm(±3.69)for forelimbs and 12.60 mm(±3.69)for hindlimbs.The thoracic limb nerves consisted of one dorsal and three ventral nerves,with an average circumference of 5.14 mm(±2.00)and 5.05 mm(±1.06),respectively.Pelvic limb nerves consisted of two dorsal and one ventral nerve with an average circumference of 6.27 mm(±1.79)and 5.40 mm(±0.53),respectively.Conclusions:These anatomic data inform the surgical approach and manufacture of a sensory ONI for chronic testing in awake,freely ambulating animals for future clinical translation.
基金financed by the grants from the Research Program of Sichuan TCM Culture Coordinated Development Research Center (No. 2021XT31)National Traditional Chinese Medicine Examination Research Project (No. TC2023019)National Innovation & Entrepreneurship Training Program for College Students (No. 202210633008X)。
文摘Traditional Chinese medicine(TCM) is increasingly recognized worldwide as a valuable complementary and alternative medicine. To facilitate global research and collaboration in this field, the World Health Organization(WHO) introduced the International Standard Terminologies on Traditional Chinese Medicine in 2022. This international terminology translation standard, IST 2022, goes beyond conventional translation by embracing three innovative features: 1) It reflects TCM's foundational philosophy of unity and opposition, emphasizing the interconnectedness among TCM terms during translation. This approach transcends individual term translations to explore the interrelationships among them. 2) It preserves the integrity of TCM theory by retaining transliterations for unique TCM terms that possess distinct features. 3) It employs innovative xiang(image) cognition, a concept rooted in traditional Chinese thought by helping readers grasp visual and mental imagery associated with each term. This study presents a qualitative analysis based on interviews with 11 TCM translation experts, examining their perspectives on these features and their translational preferences across the IST 2007 and 2022 versions. These findings contribute to the standardization and global harmonization of TCM terminology, advocating for clarity, precision, and the advancement of TCM in the international healthcare arena.
文摘Hepatocellular carcinoma(HCC)recurrence after liver transplantation(LT)presents a significant challenge,with recurrence rates ranging from 8%to 20%globally.Current biomarkers,such as alpha-fetoprotein(AFP)and des-gamma-carboxy prothrombin(DCP),lack specificity,limiting their utility in risk strati-fication.YKL-40,a glycoprotein involved in extracellular matrix remodeling,hepatic stellate cell activation,and immune modulation,has emerged as a promising biomarker for post-LT surveillance.Elevated serum levels of YKL-40 are associated with advanced liver disease,tumor progression,and poorer post-LT outcomes,highlighting its potential to address gaps in early detection and personalized management of HCC recurrence.This manuscript synthesizes clinical and mechanistic evidence to evaluate YKL-40’s predictive utility in post-LT care.While preliminary findings demonstrate its specificity for liver-related pathologies,challenges remain,including assay standardization,lack of pro-spective validation,and the need to distinguish between malignant and non-malignant causes of elevated levels.Integrating YKL-40 into multi-biomarker panels with AFP and DCP could enhance predictive accuracy and enable tailored therapeutic strategies.Future research should focus on multicenter studies to validate YKL-40’s clinical utility,address confounding factors like graft rejection and systemic inflammation,and explore its role in predictive models driven by emerging technologies such as artificial intelligence.YKL-40 holds transformative potential in reshaping post-LT care through precision medicine,providing a pathway for better outcomes and improved management of high-risk LT recipients.
基金Project supported by the National Key Research and Development Program of China(Grant No.2023YFA1407000)the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB0460000)+4 种基金the National Natural Science Foundation of China(Grant Nos.12322401,12127807,and 12393832)CAS Key Research Program of Frontier Sciences(Grant No.ZDBS-LY-SLH004)Beijing Nova Program(Grant No.20230484301)Youth Innovation Promotion Association,Chinese Academy of Sciences(Grant No.2023125)CAS Project for Young Scientists in Basic Research(Grant No.YSBR-026)。
文摘Edge structures are ubiquitous in the processing and fabrication of various optoelectronic devices.Novel physical properties and enhanced light–matter interactions are anticipated to occur at crystal edges due to the broken spatial translational symmetry.However,the intensity of first-order Raman scattering at crystal edges has been rarely explored,although the mechanical stress and edge characteristics have been thoroughly studied by the Raman peak shift and the spectral features of the edge-related Raman modes.Here,by taking Ga As crystal with a well-defined edge as an example,we reveal the intensity enhancement of Raman-active modes and the emergence of Raman-forbidden modes under specific polarization configurations at the edge.This is attributed to the presence of a hot spot at the edge due to the redistributed electromagnetic fields and electromagnetic wave propagations of incident laser and Raman signal near the edge,which are confirmed by the finite-difference time-domain simulations.Spatially-resolved Raman intensities of both Raman-active and Raman-forbidden modes near the edge are calculated based on the redistributed electromagnetic fields,which quantitatively reproduce the corresponding experimental results.These findings offer new insights into the intensity enhancement of Raman scattering at crystal edges and present a new avenue to manipulate light–matter interactions of crystal by manufacturing various types of edges and to characterize the edge structures in photonic and optoelectronic devices.
基金funded by the Israel Science Foundation(grants No.1036/12 and 1228/20)(to OES).
文摘Translation regulation is an important layer of gene expression:Generation of genome-wide expression datasets at multi-omics levels in spatial,temporal,and cell-type resolution is essential for deciphering brain complexity.Regulation of gene expression is a highly dynamic process aiming at the production of precise levels of gene products to guarantee optimal cellular function,in response to physiological cues.Speedy advances in next-generation sequencing enabled the understanding of epigenomic and transcriptomic dynamic landscapes of different brain regions along development,aging,and disease progression.However,the correlation of the“transcriptome”with protein levels is poor because numerous mRNAs are subjected to manipulation of their translation efficiency,to warrant a favorable result under certain conditions.Hence,it is widely accepted that regulation at the translation level is a vital layer of gene expression.Quantification of actively translated mRNA populations(i.e.,“translatome”)is a more reliable predictor of the“proteome”(Wang et al.,2020).
基金supported by grants from National Natural Science Foundation of China(No.82370392)Shenzhen Medical Research Fund(No.B2302026)+4 种基金Science,Technology and Innovation Commission of Shenzhen Municipality(No.RCJC20210706091947009)National Key R&D Program of China(No.2022YFA1104500)CAMS Innovation Fund for Medical Sciences(No.2023-I2M-1-003 and 2022-I2M-2-001)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2019PT320026)National High Level Hospital Clinical Research Funding(No.2022-GSP-GG-7)。
文摘A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity.However,regulatory mechanisms at the translational level under cardiac stress remain poorly understood.Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction(TAC)and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy(DCM).The results showed that the heart weight to body weight ratio was significantly elevated,and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC.Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle.RNAseq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling,metabolic processes,and signaling cascades associated with pathological cardiomyocyte growth.When combined with ribosome profiling analysis,we revealed that translation efficiency(TE)of 1,495 genes was enhanced,while the TE of 933 genes was inhibited following TAC.In DCM patients,1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level.Although the majority of the genes were not shared between mouse and human,we identified 93 genes,including Nos3,Kcnj8,Adcy4,Itpr1,Fasn,Scd1,etc.,with highly conserved translational regulations.These genes were remarkably associated with myocardial function,signal transduction,and energy metabolism,particularly related to cGMP-PKG signaling and fatty acid metabolism.Motif analysis revealed enriched regulatory elements in the 5′untranslated regions(5′UTRs)of transcripts with differential TE,which exhibited strong cross-species sequence conservation.Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
基金Supported by National Natural Science Foundation of China(81874059 and 82102105)the Natural Science Foundation of Zhejiang Province(LQ22H160017)the China Postdoctoral Science Foundation(2021M702825).
文摘The second near-infrared window(NIR-II,900-1880 nm)overcomes critical limitations of visible(360-760 nm)and NIR-I(760-900 nm)imaging—including restricted penetration depth,low signal-to-back⁃ground ratio,and tissue autofluorescence—establishing its pivotal role for in vivo deep-tissue bioimaging.With exponential growth in NIR-II photodiagnosis and phototherapy research over the past decade,bibliometric analy⁃sis is essential to map the evolving landscape and guide strategic priorities.We systematically analyzed 2,491 NIR-II-related publications(2009-2023)from the Web of Science Core Collection,employing scientometric tools for distinct analytical purposes:(a)VOSviewer,SCImago Graphica,and Gephi for co-authorship and co-occur⁃rence network mapping;(b)the R bibliometrix package for tracking field evolution and identifying high-impact publications/journals.The search retrieved 2491 studies from 359 journals originating from 54 countries.The country with the most published articles is China.Chinese institutions drive>60%of publications,with Stanford University(USA)and Nanyang Technological University(Singapore)ranked as the top two institutions by re⁃search quality.International cooperation is becoming increasingly frequent.Fan Quli,Tang Benzhong and Dai Hongjie are the top 3 productive authors in this field.Keyword evolution identifies"photodynamic therapy"and"immunotherapy"as pivotal future directions.We summarize the most cited literatures and NIR-II imaging clini⁃cal trials.This study delineates the NIR-II research trajectory,highlighting China's leadership,intensifying glob⁃al collaboration,and interdisciplinary convergence.Future efforts should prioritize the novel NIR-II probe devel⁃opment for NIR-II imaging and clinical translation of photodynamic/immunotherapy combinational platforms.
基金Shanxi Normal University Graduate Innovation Project(2024XSY31)。
文摘This paper takes Chinese red culture resources as its research subject and focuses on evaluating the Chinese-English translation quality of three major AI platforms:ChatGPT-4.0,ERNIE Bot,and DeepSeek.Through automatic quantitative evaluation,it systematically analyzes their performance in translating red culture texts.The study selects a diverse range of corpora,including historical documents,red classic texts,and culturally loaded terms.Three automatic evaluation metrics—GLEU,METEOR,and COMET—are employed for a comprehensive assessment.
