RESUMO
Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function1. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11-PIK3R3, found in a CD4+ cutaneous T cell lymphoma2, that augments CARD11-BCL10-MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.
Assuntos
Evolução Molecular , Imunoterapia Adotiva , Linfoma Cutâneo de Células T , Mutação , Linfócitos T , Humanos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/biossíntese , Citocinas/imunologia , Citocinas/metabolismo , Guanilato Ciclase/genética , Guanilato Ciclase/metabolismo , Imunoterapia Adotiva/métodos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/imunologia , Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/terapia , Fosfatidilinositol 3-Quinases , Transdução de Sinais/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplanteRESUMO
N6-methyladenosine (m6A) is the most abundant internal modification in RNAs and plays regulatory roles in a variety of biological and physiological processes. Despite its important roles, the molecular mechanism underlying m6A-mediated gene regulation is poorly understood. Here, we show that m6A-containing RNAs are subject to endoribonucleolytic cleavage via YTHDF2 (m6A reader protein), HRSP12 (adaptor protein), and RNase P/MRP (endoribonucleases). We demonstrate that HRSP12 functions as an adaptor to bridge YTHDF2 and RNase P/MRP, eliciting rapid degradation of YTHDF2-bound RNAs. Transcriptome-wide analyses show that m6A RNAs that are preferentially targeted for endoribonucleolytic cleavage have an HRSP12-binding site and a RNase P/MRP-directed cleavage site upstream and downstream of the YTHDF2-binding site, respectively. We also find that a subset of m6A-containing circular RNAs associates with YTHDF2 in an HRSP12-dependent manner and is selectively downregulated by RNase P/MRP. Thus, our data expand the known functions of RNase P/MRP to endoribonucleolytic cleavage of m6A RNAs.
Assuntos
Adenosina/análogos & derivados , Proteínas de Choque Térmico/genética , Estabilidade de RNA/genética , Proteínas de Ligação a RNA/genética , Ribonuclease P/genética , Ribonucleases/genética , Adenosina/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Sítios de Ligação/genética , Escherichia coli/genética , Regulação da Expressão Gênica/genética , Células HeLa , Humanos , Metiltransferases/genética , RNA/genética , Processamento Pós-Transcricional do RNA/genética , RNA Circular , Transcriptoma/genéticaRESUMO
Sensations of heat and touch produced by receptors in the skin are of essential importance for perceptions of the physical environment, with a particularly powerful role in interpersonal interactions. Advances in technologies for replicating these sensations in a programmable manner have the potential not only to enhance virtual/augmented reality environments but they also hold promise in medical applications for individuals with amputations or impaired sensory function. Engineering challenges are in achieving interfaces with precise spatial resolution, power-efficient operation, wide dynamic range, and fast temporal responses in both thermal and in physical modulation, with forms that can extend over large regions of the body. This paper introduces a wireless, skin-compatible interface for thermo-haptic modulation designed to address some of these challenges, with the ability to deliver programmable patterns of enhanced vibrational displacement and high-speed thermal stimulation. Experimental and computational investigations quantify the thermal and mechanical efficiency of a vertically stacked design layout in the thermo-haptic stimulators that also supports real-time, closed-loop control mechanisms. The platform is effective in conveying thermal and physical information through the skin, as demonstrated in the control of robotic prosthetics and in interactions with pressure/temperature-sensitive touch displays.
Assuntos
Tato , Realidade Virtual , Tecnologia sem Fio , Humanos , Tecnologia sem Fio/instrumentação , Tato/fisiologia , Pele , Robótica/instrumentação , Robótica/métodosRESUMO
Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. In Caenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Longevidade/genética , Chaperonas Moleculares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Intestinos/fisiologia , Chaperonas Moleculares/genética , Ligação Proteica , Transdução de Sinais/genética , Tela Subcutânea/fisiologia , Ativação Transcricional/genéticaRESUMO
The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here, we report that G-quadruplex DNA (G4-DNA) accumulates in neurons, in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory in male C57/BL6 mice. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation.One-Sentence Summary: G4-DNA is a molecular switch that enables the temporal regulation of the gene expression underlying the formation of fear extinction memory.
Assuntos
Quadruplex G , Masculino , Animais , Camundongos , Extinção Psicológica , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Medo , DNA/metabolismoRESUMO
V-ATPase, which comprises 13-14 subunits, is essential for pH homeostasis in all eukaryotes, but its proper function requires a regulator to assemble its subunits. While RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown. In this study, we identified two RAVE complex components, Rav1 and Wdr1, in the fungal meningitis pathogen Cryptococcus neoformans, and analyzed their roles. Rav1 and Wdr1 are orthologous to yeast RAVE and human Rabconnectin-3 counterparts, respectively, forming the hybrid RAVE (hRAVE) complex. Deletion of RAV1 caused severe defects in growth, cell cycle control, morphogenesis, sexual development, stress responses, and virulence factor production, while the deletion of WDR1 resulted in similar but modest changes, suggesting that Rav1 and Wdr1 play central and accessary roles, respectively. Proteomics analysis confirmed that Wdr1 was one of the Rav1-interacting proteins. Although the hRAVE complex generally has V-ATPase-dependent functions, it also has some V-ATPase-independent roles, suggesting a unique role beyond conventional intracellular pH regulation in C. neoformans. The hRAVE complex played a critical role in the pathogenicity of C. neoformans, and RAV1 deletion attenuated virulence and impaired blood-brain barrier crossing ability. This study provides comprehensive insights into the pathobiological roles of the fungal RAVE complex and suggests a novel therapeutic strategy for controlling cryptococcosis.
Assuntos
Criptococose , Cryptococcus neoformans , Proteínas de Saccharomyces cerevisiae , ATPases Vacuolares Próton-Translocadoras , Humanos , Proteínas de Saccharomyces cerevisiae/metabolismo , Cryptococcus neoformans/genética , Cryptococcus neoformans/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , Saccharomyces cerevisiae/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismoRESUMO
Proper regulation of replication fork progression is important for genomic maintenance. Subverting the transcription-induced conflicts is crucial in preserving the integrity of replication forks. Various chromatin remodelers, such as histone chaperone and histone deacetylases are known to modulate replication stress, but how these factors are organized or collaborate are not well understood. Here we found a new role of the OTUD5 deubiquitinase in limiting replication stress. We found that OTUD5 is recruited to replication forks, and its depletion causes replication fork stress. Through its C-terminal disordered tail, OTUD5 assembles a complex containing FACT, HDAC1 and HDAC2 at replication forks. A cell line engineered to specifically uncouple FACT interaction with OTUD5 exhibits increases in FACT loading onto chromatin, R-loop formation, and replication fork stress. OTUD5 mediates these processes by recruiting and stabilizing HDAC1 and HDAC2, which decreases H4K16 acetylation and FACT recruitment. Finally, proteomic analysis revealed that the cells with deficient OTUD5-FACT interaction activates the Fanconi Anemia pathway for survival. Altogether, this study identified a new interaction network among OTUD5-FACT-HDAC1/2 that limits transcription-induced replication stress.
Assuntos
Cromatina , Replicação do DNA , Humanos , Linhagem Celular , Cromatina/genética , Instabilidade Genômica , ProteômicaRESUMO
An RNA structure or modified RNA sequences can provide a platform for ribosome loading and internal translation initiation. The functional significance of internal translation has recently been highlighted by the discovery that a subset of circular RNAs (circRNAs) is internally translated. However, the molecular mechanisms underlying the internal initiation of translation in circRNAs remain unclear. Here, we identify eIF3g (a subunit of eIF3 complex) as a binding partner of eIF4A3, a core component of the exon-junction complex (EJC) that is deposited onto spliced mRNAs and plays multiple roles in the regulation of gene expression. The direct interaction between eIF4A3-eIF3g serves as a molecular linker between the eIF4A3 and eIF3 complex, thereby facilitating internal ribosomal entry. Protein synthesis from in vitro-synthesized circRNA demonstrates eIF4A3-driven internal translation, which relies on the eIF4A3-eIF3g interaction. Furthermore, our transcriptome-wide analysis shows that efficient polysomal association of endogenous circRNAs requires eIF4A3. Notably, a subset of endogenous circRNAs can express a full-length intact protein, such as ß-catenin, in an eIF4A3-dependent manner. Collectively, our results expand the understanding of the protein-coding potential of the human transcriptome, including circRNAs.
Assuntos
Fator de Iniciação 3 em Eucariotos , Fator de Iniciação 4A em Eucariotos , RNA Circular , Humanos , Fator de Iniciação 3 em Eucariotos/genética , Fator de Iniciação 3 em Eucariotos/metabolismo , Fator de Iniciação 4A em Eucariotos/metabolismo , Proteínas , Ribossomos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND & AIMS: Weight loss and exercise intervention have been reported to increase the interaction between Bacteroides spp and Akkermansiamuciniphila (Am), although the underlying mechanisms and consequences of the interaction remain unknown. METHODS: Using a healthy Korean twin cohort (n = 582), we analyzed taxonomic associations with host body mass index. B vulgatus strains were isolated from mice and human subjects to investigate the strain-specific effect of B vulgatus SNUG 40005 (Bvul) on obesity. The mechanisms underlying Am enrichment by Bvul administration were investigated by multiple experiments: (1) in vitro cross-feeding experiments, (2) construction of Bvul mutants with the N-acetylglucosaminidase gene knocked out, and (3) in vivo validation cohorts with different metabolites. Finally, metabolite profiling in mouse and human fecal samples was performed. RESULTS: An interaction between Bvul and Am was observed in lean subjects but was disrupted in obese subjects. The administration of Bvul to mice fed a high-fat diet decreased body weight, insulin resistance, and gut permeability. In particular, Bvul restored the abundance of Am, which decreased significantly after a long-term high-fat diet. A cross-feeding analysis of Am with cecal contents or Bvul revealed that Am enrichment was attributed to metabolites produced during mucus degradation by Bvul. The metabolome profile of mouse fecal samples identified N-acetylglucosamine as contributing to Am enrichment, which was confirmed by in vitro and in vivo experiments. Metabolite network analysis of the twin cohort found that lysine serves as a bridge between N-acetylglucosamine, Bvul, and Am. CONCLUSIONS: Strain-specific microbe-microbe interactions modulate the mucosal environment via metabolites produced during mucin degradation in the gut.
Assuntos
Acetilglucosamina , Akkermansia , Humanos , Camundongos , Animais , Bacteroides/genética , Obesidade/metabolismo , Dieta HiperlipídicaRESUMO
Psoriasis is a chronic inflammatory skin disorder with various subtypes, including psoriasis vulgaris (PV) and palmoplantar pustulosis (PPP). Metabolomics studies have provided insights into psoriasis pathogenesis. However, research on metabolomic alterations in PV and PPP patients is limited. We aimed to explore and compare the metabolic profiles of patients with PV and PPP to those of healthy volunteers (HVs). A single-centre retrospective cohort was constructed, comprising Korean patients with psoriasis and HVs matched by age and sex. Clinical information including demographics, disease severity, and comorbidities were collected. Plasma samples were subjected to targeted metabolic analysis using an Absolute IDQ®p180 kit, which quantified 188 metabolites, including amino acids and carnitines. Statistical significance was assessed using an independent t-test and chi-square test, with p-values adjusted by the Benjamini-Hochberg procedure. Pathway analyses were employed to gain a comprehensive understanding of the metabolite profile. This study included 93 patients (73 PV and 20 PPP) and an equal number of HVs. PV patients showed increased levels of sarcosine, serotonin, propionylcarnitine, proline, aspartic acid, tyrosine, taurine, spermine and ornithine, but exhibited a decreased level of acetylcarnitine than matched HVs. Notably, sarcosine levels were significantly elevated in PPP patients. Furthermore, the sarcosine/glycine ratio was significantly higher in both PV and PPP patients than in HVs. Pathway analysis showed significant increases in metabolites involved in amino acid metabolism and the urea cycle in PV patients. In conclusion, this study demonstrated distinct metabolic profiles in PV and PPP patients compared to HVs, suggesting sarcosine as a potential biomarker for psoriasis.
Assuntos
Psoríase , Humanos , Psoríase/sangue , Psoríase/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Metabolômica , Idoso , Estudos de Casos e Controles , Metaboloma , Sarcosina/sangue , Carnitina/sangue , Carnitina/análogos & derivados , Carnitina/metabolismo , Aminoácidos/sangue , Aminoácidos/metabolismo , Índice de Gravidade de DoençaRESUMO
Transposon-associated transposase B (TnpB) is deemed an ancestral protein for type V, Cas12 family members, and the closest ancestor to UnCas12f1. Previously, we reported a set of engineered guide RNAs supporting high indel efficiency for Cas12f1 in human cells. Here we suggest a new technology whereby the engineered guide RNAs also manifest high-efficiency programmable endonuclease activity for TnpB. We have termed this technology TaRGET (TnpB-augment RNA-based Genome Editing Technology). Having this feature in mind, we established TnpB-based adenine base editors (ABEs). A Tad-Tad mutant (V106W, D108Q) dimer fused to the C terminus of dTnpB (D354A) showed the highest levels of A-to-G conversion. The limited targetable sites for TaRGET-ABE were expanded with engineered variants of TnpB or optimized deaminases. Delivery of TaRGET-ABE also ensured potent A-to-G conversion rates in mammalian genomes. Collectively, the TaRGET-ABE will contribute to improving precise genome-editing tools that can be delivered by adeno-associated viruses, thereby harnessing the development of clustered regularly interspaced short palindromic repeats (CRISPR)-based gene therapy.
Assuntos
Adenina , RNA , Adenina/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Edição de Genes , Humanos , Mamíferos/genética , RNA/genética , RNA/metabolismo , RNA Guia de Cinetoplastídeos/genética , RNA Guia de Cinetoplastídeos/metabolismo , Transposases/genética , Transposases/metabolismoRESUMO
BACKGROUND: The association between antihypertensive medication and schizophrenia has received increasing attention; however, evidence of the impact of antihypertensive medication on subsequent schizophrenia based on large-scale observational studies is limited. We aimed to compare the schizophrenia risk in large claims-based US and Korea cohort of patients with hypertension using angiotensin-converting enzyme (ACE) inhibitors versus those using angiotensin receptor blockers (ARBs) or thiazide diuretics. METHODS: Adults aged 18 years who were newly diagnosed with hypertension and received ACE inhibitors, ARBs, or thiazide diuretics as first-line antihypertensive medications were included. The study population was sub-grouped based on age (> 45 years). The comparison groups were matched using a large-scale propensity score (PS)-matching algorithm. The primary endpoint was incidence of schizophrenia. RESULTS: 5,907,522; 2,923,423; and 1,971,549 patients used ACE inhibitors, ARBs, and thiazide diuretics, respectively. After PS matching, the risk of schizophrenia was not significantly different among the groups (ACE inhibitor vs. ARB: summary hazard ratio [HR] 1.15 [95% confidence interval, CI, 0.99-1.33]; ACE inhibitor vs. thiazide diuretics: summary HR 0.91 [95% CI, 0.78-1.07]). In the older subgroup, there was no significant difference between ACE inhibitors and thiazide diuretics (summary HR, 0.91 [95% CI, 0.71-1.16]). The risk for schizophrenia was significantly higher in the ACE inhibitor group than in the ARB group (summary HR, 1.23 [95% CI, 1.05-1.43]). CONCLUSIONS: The risk of schizophrenia was not significantly different between the ACE inhibitor vs. ARB and ACE inhibitor vs. thiazide diuretic groups. Further investigations are needed to determine the risk of schizophrenia associated with antihypertensive drugs, especially in people aged > 45 years.
Assuntos
Hipertensão , Esquizofrenia , Adulto , Humanos , Anti-Hipertensivos/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Esquizofrenia/induzido quimicamente , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/diagnóstico , Estudos de CoortesRESUMO
The efficacy of a smartphone app intervention (BabyMind©) in facilitating mind-mindedness was investigated in a randomized controlled trial, assigning mothers and their 6-month-olds (N = 152; 72 girls, 146 White) to intervention or active control conditions. Mothers who had received the BabyMind© app intervention scored higher for appropriate (d = .61, 95% CI .28, .94) and lower for non-attuned (d = -.55, 95% CI -.92, -.18) mind-related comments at follow-up (age 12 months), compared with their control group counterparts. Adjusting for missing data did not alter this pattern of findings. Mothers' baseline parental reflective functioning did not moderate these relations. Results are discussed in terms of the benefits of early intervention and exploring the efficacy of the app in more diverse populations.
Assuntos
Aplicativos Móveis , Feminino , Humanos , Lactente , Relações Mãe-Filho , Mães , Intervenção Educacional PrecoceRESUMO
Alkoxide precursors have been highlighted for depositing carbon-free films, but their use in Atomic Layer Deposition (ALD) often exhibits a non-saturated growth. This indicates no self-limiting growth due to the chain reaction of hydrolysis or ligand decomposition caused by ß-hydride elimination. In the previous study, we demonstrated that self-limiting growth of ALD can be achieved using our newly developed precursor, hafnium cyclopentadienyl tris(N-ethoxy-2,2-dimethyl propanamido) [HfCp(edpa)3]. To elucidate the growth mechanism and the role of cyclopentadienyl (Cp) ligand in a heteroleptic alkoxide precursor, herein, we compare homoleptic and heteroleptic Hf precursors consisting of N-ethoxy-2,2-dimethyl propanamido (edpa) ligands with and without cyclopentadienyl ligand-hafnium tetrakis(N-ethoxy-2,2-dimethyl propanamido) [Hf(edpa)4] and HfCp(edpa)3. We also investigate the role of a Cp ligand in growth characteristics. By substituting an alkoxide ligand with a Cp ligand, we could modify the surface reaction during ALD, preventing undesired reactions. The last remaining edpa after Hf(edpa)4 adsorption can undergo a hydride elimination reaction, resulting in surface O-H generation. In contrast, Cp remains after the HfCp(edpa)3 adsorption. Accordingly, we observe proper ALD growth with self-limiting properties. Thus, a comparative study of different ligands of the precursors can provide critical clues to the design of alkoxide precursors for obtaining typical ALD growth with a saturation behavior.
RESUMO
BACKGROUND: This study aimed to develop and evaluate the validity and reliability of a self-management self-efficacy for premature birth prevention (SMSE-PBP) in women of childbearing age (WCA). METHODS: Instrument development and validation were undertaken in three phases: conceptualization, item generation and evaluation of content validity, and evaluation of construct and concurrent validity and reliability. Data were analyzed using exploratory and second-order confirmatory factor analyses, and concurrent validity was examined using Pearson's correlation coefficients. The reliability was analyzed using omega hierarchical and Cronbach's âº. RESULTS: Content validity was assessed by experts and cognitive interviews of WCA. The SMSE-PBP consists of a second-order 3-dimension and 10-factor scale with 60 items; therefore, the construct and concurrent validity of the SMSE-PBP were supported. The omega values were 0.93 for pre-pregnancy SMSE-PBP, 0.92 for pregnancy SMSE-PBP, and 0.94 for hospital SMSE-PBP. Cronbach's ⺠was 0.88 for pre-pregnancy SMSE-PBP, 0.96 for pregnancy SMSE-PBP, and 0.96 for hospital SMSE-PBP. CONCLUSIONS: The SMSE-PBP scale is valid and reliable for WCA; it is helpful for WCA and health professionals to assess women's SMSE-PBP and pre-pregnancy, pregnancy, or hospital SMSE-PBP. The next steps should include assessing the relationship with pregnancy health behaviors.
Assuntos
Nascimento Prematuro , Autogestão , Gravidez , Humanos , Feminino , Autoeficácia , Reprodutibilidade dos Testes , Nascimento Prematuro/prevenção & controle , Inquéritos e Questionários , Psicometria/métodosRESUMO
PURPOSE: Large language models continue to dramatically change the medical landscape. We aimed to explore the utility of ChatGPT in providing accurate, actionable, and understandable generative medical translations in English, Spanish, and Mandarin pertaining to Otolaryngology. METHODS: Responses of GPT-4 to commonly asked patient questions listed on official otolaryngology clinical practice guidelines (CPG) were evaluated with the Patient Education materials Assessment Tool-printable (PEMAT-P.) Additional critical elements were identified a priori to evaluate ChatGPT's accuracy and thoroughness in its responses. Multiple fluent speakers of English, Mandarin, and Spanish evaluated each response generated by ChatGPT. RESULTS: Total PEMAT-P scores differed between English, Mandarin, and Spanish GPT-4 generated responses depicting a moderate effect size of language, Eta-Square 0.07 with scores ranging from 73 to 77 (P-value = 0.03). Overall understandability scores did not differ between English, Mandarin, and Spanish depicting a small effect size of language, Eta-Square 0.02 scores ranging from 76 to 79 (P-value = 0.17), nor did overall actionability scores Eta-Square 0 score ranging 66-73 (P-value = 0.44). Overall a priori procedure-specific responses similarly did not differ between English, Spanish, and Mandarin Eta-Square 0.02 scores ranging 61-78 (P-value = 0.22). CONCLUSION: GPT-4 produces accurate, understandable, and actionable outputs in English, Spanish, and Mandarin. Responses generated by GPT-4 in Spanish and Mandarin are comparable to English counterparts indicating a novel use for these models within Otolaryngology, and implications for bridging healthcare access and literacy gaps. LEVEL OF EVIDENCE: IV.
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Bioluminescence, the light produced by biochemical reactions involving luciferases in living organisms, has been extensively investigated for various applications. It has attracted particular interest as an internal light source for theranostic applications due to its safe and efficient characteristics that overcome the limited penetration of conventional external light sources. Recent advancements in protein engineering technologies and protein delivery platforms have expanded the application of bioluminescence to a wide range of theranostic areas, including bioimaging, biosensing, photodynamic therapy, and optogenetics. This comprehensive review presents the fundamental concepts of bioluminescence and explores its recent applications across diverse fields. Moreover, it discusses future research directions based on the current status of bioluminescent systems for further expansion of their potential.
Assuntos
Técnicas Biossensoriais , Medições Luminescentes , Fotoquimioterapia , Nanomedicina Teranóstica , Humanos , Medições Luminescentes/métodos , Nanomedicina Teranóstica/métodos , Animais , Técnicas Biossensoriais/métodos , Fotoquimioterapia/métodos , Optogenética/métodos , Engenharia de Proteínas/métodosRESUMO
Current clinical tools for breast cancer (BC) diagnosis are insufficient but liquid biopsy of different bodily fluids has recently emerged as a minimally invasive strategy that provides a real-time snapshot of tumour biomarkers for early diagnosis, active surveillance of progression, and post-treatment recurrence. Extracellular vesicles (EVs) are nano-sized membranous structures 50-1000 nm in diameter that are released by cells into biological fluids. EVs contain proteins, nucleic acids, and lipids which play pivotal roles in tumourigenesis and metastasis through cell-to-cell communication. Proteins and miRNAs from small EVs (sEV), which range in size from 50-150 nm, are being investigated as a potential source for novel BC biomarkers using mass spectrometry-based proteomics and next-generation sequencing. This review covers recent developments in sEV isolation and single sEV analysis technologies and summarises the sEV protein and miRNA biomarkers identified for BC diagnosis, prognosis, and chemoresistance. The limitations of current sEV biomarker research are discussed along with future perspective applications.
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Neoplasias da Mama , Vesículas Extracelulares , MicroRNAs , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Biomarcadores/metabolismo , Prognóstico , Vesículas Extracelulares/metabolismo , Biomarcadores Tumorais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Microsatellite instability (MSI) status is an important prognostic marker for various cancers. Furthermore, because immune checkpoint inhibitors are much more effective in tumors with high level of MSI (MSI-H), MSI status is routinely tested in multiple cancer types. Therefore, many studies have tested the feasibility of deep learning (DL)-based prediction of MSI status from hematoxylin and eosin (H&E)-stained tissue slides. In the present study, we attempted a fully automated classification of MSI status in gastric cancer (GC) tissue slides. For frozen and formalin-fixed paraffin-embedded (FFPE) GC tissues from The Cancer Genome Atlas (TCGA), the areas under the curves (AUCs) for the receiver operating characteristic (ROC) curves were 0.893 and 0.902, respectively. The classifier trained with the TCGA FFPE tissues performed well on an external validation Asian FFPE cohort, with an AUC of 0.874. However, the DL-based classifier seems incompatible with cancers from different organs because morphologic features of MSI-H tissues are different. Analysis of histomorphologic features of MSI-H GC tissues suggested that MSI-H GC could largely be divided into two groups: intestinal type tumors with moderate to poor differentiation and diffuse type mucinous tumors. However, the recognizable morphologic features cannot completely explain the good performance of the DL-based classifier. These results indicate that DL could automatically learn the optimal features for discrimination of MSI status in GC tissue slides. This study demonstrated the potential of a DL-based MSI classifier as a screening tool for definitive cases.
Assuntos
Aprendizado Profundo , Neoplasias Gástricas , Humanos , Instabilidade de Microssatélites , Neoplasias Gástricas/genética , Inibidores de Checkpoint Imunológico , Área Sob a CurvaRESUMO
N6-Methyladenosine (m6A), the most prevalent internal modification associated with eukaryotic mRNAs, influences many steps of mRNA metabolism, including splicing, export, and translation, as well as stability. Recent studies have revealed that m6A-containing mRNAs undergo one of two distinct pathways of rapid degradation: deadenylation via the YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2; an m6A reader protein)-CCR4/NOT (deadenylase) complex or endoribonucleolytic cleavage by the YTHDF2-HRSP12-ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some m6A-containing circular RNAs (circRNAs) are also subject to endoribonucleolytic cleavage by YTHDF2-HRSP12-RNase P/MRP. Here, we highlight recent progress on the molecular mechanisms underlying rapid mRNA degradation via m6A and describe our current understanding of the dynamic regulation of m6A-mediated mRNA decay through the crosstalk between m6A (or YTHDF2) and other cellular factors.