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1.
Nature ; 619(7968): 112-121, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37316654

RESUMEN

Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here we present data from the first phase of the Chinese Pangenome Consortium, including a collection of 116 high-quality and haplotype-phased de novo assemblies based on 58 core samples representing 36 minority Chinese ethnic groups. With an average 30.65× high-fidelity long-read sequence coverage, an average contiguity N50 of more than 35.63 megabases and an average total size of 3.01 gigabases, the CPC core assemblies add 189 million base pairs of euchromatic polymorphic sequences and 1,367 protein-coding gene duplications to GRCh38. We identified 15.9 million small variants and 78,072 structural variants, of which 5.9 million small variants and 34,223 structural variants were not reported in a recently released pangenome reference1. The Chinese Pangenome Consortium data demonstrate a remarkable increase in the discovery of novel and missing sequences when individuals are included from underrepresented minority ethnic groups. The missing reference sequences were enriched with archaic-derived alleles and genes that confer essential functions related to keratinization, response to ultraviolet radiation, DNA repair, immunological responses and lifespan, implying great potential for shedding new light on human evolution and recovering missing heritability in complex disease mapping.


Asunto(s)
Pueblos del Este de Asia , Etnicidad , Variación Genética , Genoma Humano , Genética Humana , Grupos Minoritarios , Humanos , Pueblos del Este de Asia/clasificación , Pueblos del Este de Asia/genética , Etnicidad/genética , Genoma Humano/genética , Análisis de Secuencia de ADN , Rayos Ultravioleta , Genética Humana/normas , Minorías Étnicas y Raciales , Estándares de Referencia , Haplotipos/genética , Eucromatina/genética , Alelos , Reparación del ADN/genética , Queratinas/genética , Queratinas/metabolismo , Longevidad/genética , Inmunidad/genética
2.
Nature ; 598(7879): 174-181, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34616072

RESUMEN

Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits.


Asunto(s)
Encéfalo/citología , Forma de la Célula , Neuronas/clasificación , Neuronas/metabolismo , Análisis de la Célula Individual , Atlas como Asunto , Biomarcadores/metabolismo , Encéfalo/anatomía & histología , Encéfalo/embriología , Encéfalo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Neocórtex/anatomía & histología , Neocórtex/citología , Neocórtex/embriología , Neocórtex/metabolismo , Neurogénesis , Neuroglía/citología , Neuronas/citología , RNA-Seq , Reproducibilidad de los Resultados
3.
Nucleic Acids Res ; 52(8): 4257-4275, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38366571

RESUMEN

Complex biological processes are regulated by both genetic and epigenetic programs. One class of epigenetic modifications is methylation. Evolutionarily conserved methyl-CpG-binding domain (MBD)-containing proteins are known as readers of DNA methylation. MBD5 is linked to multiple human diseases but its mechanism of action remains unclear. Here we report that the zebrafish Mbd5 does not bind to methylated DNA; but rather, it directly binds to 5-methylcytosine (m5C)-modified mRNAs and regulates embryonic development, erythrocyte differentiation, iron metabolism, and behavior. We further show that Mbd5 facilitates removal of the monoubiquitin mark at histone H2A-K119 through an interaction with the Polycomb repressive deubiquitinase (PR-DUB) complex in vivo. The direct target genes of Mbd5 are enriched with both RNA m5C and H2A-K119 ubiquitylation signals. Together, we propose that zebrafish MBD5 is an RNA m5C reader that potentially links RNA methylation to histone modification and in turn transcription regulation in vivo.


Asunto(s)
5-Metilcitosina , Histonas , Ubiquitinación , Proteínas de Pez Cebra , Pez Cebra , Animales , Histonas/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , 5-Metilcitosina/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Metilación de ADN , Desarrollo Embrionario/genética , Epigénesis Genética
4.
Nat Methods ; 19(1): 111-118, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34887551

RESUMEN

Recent whole-brain mapping projects are collecting large-scale three-dimensional images using modalities such as serial two-photon tomography, fluorescence micro-optical sectioning tomography, light-sheet fluorescence microscopy, volumetric imaging with synchronous on-the-fly scan and readout or magnetic resonance imaging. Registration of these multi-dimensional whole-brain images onto a standard atlas is essential for characterizing neuron types and constructing brain wiring diagrams. However, cross-modal image registration is challenging due to intrinsic variations of brain anatomy and artifacts resulting from different sample preparation methods and imaging modalities. We introduce a cross-modal registration method, mBrainAligner, which uses coherent landmark mapping and deep neural networks to align whole mouse brain images to the standard Allen Common Coordinate Framework atlas. We build a brain atlas for the fluorescence micro-optical sectioning tomography modality to facilitate single-cell mapping, and used our method to generate a whole-brain map of three-dimensional single-neuron morphology and neuron cell types.


Asunto(s)
Encéfalo/citología , Encéfalo/diagnóstico por imagen , Imagenología Tridimensional/métodos , Algoritmos , Animales , Aprendizaje Profundo , Imagen por Resonancia Magnética , Masculino , Ratones Endogámicos C57BL , Flujo de Trabajo
5.
Nucleic Acids Res ; 51(D1): D1109-D1116, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36243989

RESUMEN

Structural variations (SVs) play important roles in human evolution and diseases, but there is a lack of data resources concerning representative samples, especially for East Asians. Taking advantage of both next-generation sequencing and third-generation sequencing data at the whole-genome level, we developed the database PGG.SV to provide a practical platform for both regionally and globally representative structural variants. In its current version, PGG.SV archives 584 277 SVs obtained from whole-genome sequencing data of 6048 samples, including 1030 long-read sequencing genomes representing 177 global populations. PGG.SV provides (i) high-quality SVs with fine-scale and precise genomic locations in both GRCh37 and GRCh38, covering underrepresented SVs in existing sequencing and microarray data; (ii) hierarchical estimation of SV prevalence in geographical populations; (iii) informative annotations of SV-related genes, potential functions and clinical effects; (iv) an analysis platform to facilitate SV-based case-control association studies and (v) various visualization tools for understanding the SV structures in the human genome. Taken together, PGG.SV provides a user-friendly online interface, easy-to-use analysis tools and a detailed presentation of results. PGG.SV is freely accessible via https://www.biosino.org/pggsv.


Asunto(s)
Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Genómica/métodos , Secuenciación Completa del Genoma , Genoma Humano , Bases de Datos Genéticas , Variación Estructural del Genoma , Análisis de Secuencia de ADN/métodos
6.
J Infect Dis ; 229(1): 223-231, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-37506257

RESUMEN

BACKGROUND: The impact of metagenomic next-generation sequencing (mNGS) on antimicrobial stewardship in patients with lower respiratory tract infections (LRTIs) is still unknown. METHODS: This retrospective cohort study included patients who had LRTIs diagnosed and underwent bronchoalveolar lavage between September 2019 and December 2020. Patients who underwent both mNGS and conventional microbiologic tests were classified as the mNGS group, while those with conventional tests only were included as a control group. A 1:1 propensity score match for baseline variables was conducted, after which changes in antimicrobial stewardship between the 2 groups were assessed. RESULTS: A total of 681 patients who had an initial diagnosis of LRTIs and underwent bronchoalveolar lavage were evaluated; 306 patients were finally included, with 153 in each group. mNGS was associated with lower rates of antibiotic escalation than in the control group (adjusted odds ratio, 0.466 [95% confidence interval, .237-.919]; P = .02), but there was no association with antibiotic de-escalation. Compared with the control group, more patients discontinued the use of antivirals in the mNGS group. CONCLUSIONS: The use of mNGS was associated with lower rates of antibiotic escalation and may facilitate the cessation of antivirals, but not contribute to antibiotic de-escalation in patients with LRTIs.


Asunto(s)
Programas de Optimización del Uso de los Antimicrobianos , Infecciones del Sistema Respiratorio , Humanos , Líquido del Lavado Bronquioalveolar , Estudios Retrospectivos , Secuenciación de Nucleótidos de Alto Rendimiento , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Antibacterianos/uso terapéutico , Dimercaprol , Metagenómica , Antivirales , Sensibilidad y Especificidad
7.
Bioinformatics ; 39(1)2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36610985

RESUMEN

SUMMARY: Vaa3D is a software package that has been widely used to visualize and analyze multidimensional microscopic images in a number of cutting edge bioimage informatics applications. However, due to many recent updates of both software development environments and operating systems, it was highly requested to maintain Vaa3D and disseminate it on latest operating systems. In addition, there has never been a showcase about how to use Vaa3D's cross-platform visualization and immersive exploration functions for multidimensional and teravoxel-scale images. Here, we introduce a newly developed version of the software, called Vaa3D-x, to address all the above issues. AVAILABILITY AND IMPLEMENTATION: Vaa3D-x is released in both binary and Open-Source available at vaa3d.org and GitHub (https://github.com/Vaa3D). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Biología Computacional , Procesamiento de Imagen Asistido por Computador , Programas Informáticos , Microscopía
8.
Opt Lett ; 49(13): 3810-3813, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38950273

RESUMEN

Exceptional points (EPs) of non-Hermitian systems are sensitive to perturbations and facilitate the development of highly sensitive gyroscopes. We propose a compact multi-mode optical gyroscope protocol that incorporates two coupled rings and exhibits a fourth-order EP, achieving higher sensitivity compared to gyroscopes based on second-order EPs. We show that the gyroscope sensitivity can be further improved by deviating from the fourth-order EP due to the gain dependence on the cavity intensity. Furthermore, our protocol exhibits resilience against backscattering from counter-propagating modes, which leads to a reduced angular random walk (ARW) factor and increased sensitivity. These features make our protocol highly promising for advancing high-performance optical gyroscopes and enhancing angular velocity sensing technologies.

9.
FASEB J ; 37(10): e23198, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37742307

RESUMEN

DOCK (dedicator of cytokinesis) is an 11-member family of typical guanine nucleotide exchange factors (GEFs) expressed in the brain, spinal cord, and skeletal muscle. Several DOCK proteins have been implicated in maintaining several myogenic processes such as fusion. We previously identified DOCK3 as being strongly upregulated in Duchenne muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patients and dystrophic mice. Dock3 ubiquitous KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. We generated Dock3 conditional skeletal muscle knockout mice (Dock3 mKO) to characterize the role of DOCK3 protein exclusively in the adult muscle lineage. Dock3 mKO mice presented with significant hyperglycemia and increased fat mass, indicating a metabolic role in the maintenance of skeletal muscle health. Dock3 mKO mice had impaired muscle architecture, reduced locomotor activity, impaired myofiber regeneration, and metabolic dysfunction. We identified a novel DOCK3 interaction with SORBS1 through the C-terminal domain of DOCK3 that may account for its metabolic dysregulation. Together, these findings demonstrate an essential role for DOCK3 in skeletal muscle independent of DOCK3 function in neuronal lineages.


Asunto(s)
Metabolismo de los Hidratos de Carbono , Distrofia Muscular de Duchenne , Humanos , Adulto , Animales , Ratones , Músculo Esquelético , Encéfalo , Ratones Noqueados , Glucosa , Proteínas del Tejido Nervioso , Factores de Intercambio de Guanina Nucleótido/genética
10.
Muscle Nerve ; 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38922958

RESUMEN

INTRODUCTION/AIMS: The precise relationship between molecular mimicry and tissue-specific autoimmunity is unknown. Major histocompatibility complex (MHC) class II antigen presenting cell-CD4+ T-cell receptor complex interactions are necessary for adaptive immunity. This study aimed to determine the role of endoneurial endothelial cell MHC class II in autoimmune polyneuropathy. METHODS: Cryopreserved Guillain-Barré syndrome (GBS) patient sural nerve biopsies and sciatic nerves from the severe murine experimental autoimmune neuritis (sm-EAN) GBS model were studied. Cultured conditional ready MHC Class II antigen A-alpha chain (H2-Aa) embryonic stem cells were used to generate H2-Aaflox/+ C57BL/6 mice. Mice were backcrossed and intercrossed to the SJL background to generate H2-Aaflox/flox SJL mice, bred with hemizygous Tamoxifen-inducible von Willebrand factor Cre recombinase (vWF-iCre/+) SJL mice to generate H2-Aaflox/flox; vWF-iCre/+ mice to study microvascular endothelial cell adaptive immune responses. Sm-EAN was induced in Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+, H2-Aaflox/flox; +/+, H2-Aa+/+; vWF-iCre/+ and untreated H2-Aaflox/flox; vWF-iCre/+ adult female SJL mice. Neurobehavioral, electrophysiological and histopathological assessments were performed at predefined time points. RESULTS: Endoneurial endothelial cell MHC class II expression was observed in normal and inflamed human and mouse peripheral nerves. Tamoxifen-treated H2-Aaflox/flox; vWF-iCre/+ mice were resistant to sm-EAN despite extensive MHC class II expression in lymphoid and non-lymphoid tissues. DISCUSSION: A conditional MHC class II knockout mouse to study cell- and time-dependent adaptive immune responses in vivo was developed. Initial studies show microvascular endothelial cell MHC class II expression is necessary for peripheral nerve specific autoimmunity, as advocated by human in vitro adaptive immunity and ex vivo transplant rejection studies.

11.
Eur Radiol ; 34(1): 622-631, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37566263

RESUMEN

OBJECTIVE: To compare contrast-enhanced ultrasound (CEUS) with microbubbles containing sulfur hexafluoride (SHF) and perfluorobutane (PFB) for the detection of colorectal liver metastasis (CRLM). METHODS: In this prospective study, conducted from September to November 2021, patients with colorectal cancer were consecutively recruited and underwent same-day ultrasound, SHF-CEUS, and PFB-CEUS. The reference standard was contrast-enhanced MRI and follow-up imaging. The size, depth, echogenicity, and calcification of each focal liver lesion were recorded. The number and conspicuity of CRLMs, based on washout appearance during the late phase (LP) (> 120 s)/Kupffer phase (KP), were evaluated offsite by two blinded readers. RESULTS: Overall, 230 lesions (CRLMs, n = 219; benign lesions, n = 11) in 78 patients were evaluated. Lesion conspicuity (p = 0.344) and accuracy in the detection of CRLM were comparable for SHF- and PFB-CEUS (0.877 for SHF vs. 0.770 for PFB, p = 0.087). More CRLMs ≥ 10 mm were identified by LP contrast washout in SHF-CEUS than in KP PFB-CEUS (p < 0.001). More CRLMs < 10 mm were identified by KP washout in PFB-CEUS than in LP SHF-CEUS (p < 0.001). Conspicuity was better on PFB-CEUS than on SHF-CEUS (p = 0.027). In hyperechoic lesions, lesions located deeper than 80 mm, and calcified lesions, CRLM conspicuity on PFB-CEUS was inferior to that on SHF-CEUS (p < 0.05). CONCLUSIONS: The overall accuracy of detection and conspicuity of washout in CRLMs were comparable between SHF and PFB-CEUS. PFB-CEUS has the advantage of identifying washout in small CRLMs. However, larger, hyperechogenic, deep-seated, or calcified lesions were better identified using SHF-CEUS. CLINICAL RELEVANCE STATEMENT: Accuracy of detection and conspicuity of washout in CRLMs were comparable between SHF- and PFB-CEUS. PFB-CEUS has the advantage in detecting small CRLMs, whereas SHF-CEUS is better for detecting larger, hyperechogenic, deep-seated, or calcified lesions. KEY POINTS: Contrast-enhanced ultrasound with sulfur hexafluoride in the late phase and perfluorobutane microbubbles in the Kupffer phase were comparable in terms of accuracy in the detection and conspicuity of colorectal liver metastases. Small colorectal liver metastases (< 10 mm) were more often identified in the Kupffer phase contrast-enhanced ultrasound imaging when using perfluorobutane microbubbles. Larger, hyperechogenic, deep-seated, or calcified lesions were better identified in the late phase contrast-enhanced ultrasound imaging (> 120 s) when using sulfur hexafluoride microbubbles.


Asunto(s)
Neoplasias Colorrectales , Fluorocarburos , Neoplasias Hepáticas , Humanos , Hexafluoruro de Azufre , Medios de Contraste , Estudios Prospectivos , Microburbujas , Neoplasias Hepáticas/patología , Ultrasonografía/métodos
12.
Retina ; 44(1): 166-174, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37695977

RESUMEN

PURPOSE: To investigate the possible correlation factors of choroidal thickness in ABCA4 -related retinopathy. METHODS: A total of 66 patients were included in the cohort. It is a retrospective, cross-sectional laboratory investigation. The patients were tested using whole-exon sequencing and ophthalmic examinations, including slit-lamp examinations, best-corrected visual acuity, spectral-domain optical coherence tomography, fundus photograph, and fundus autofluorescence. RESULTS: Besides demographic characteristics (age, onset age, duration), we selected genetic factors and ocular characteristics on spectral-domain optical coherence tomography as the candidates related to choroidal thickness. Mutation type (inframe mutation or premature termination codon), epiretinal membrane, retinal pigment epithelium- Bruch membrane integrity, and macular curvature changes were identified as related factors to choroidal thickness in ABCA4 -related retinopathy after the adjustment of Logistic LASSO regression. CONCLUSION: Mutation type, epiretinal membrane, retinal pigment epithelium-Bruch membrane integrity, and macular curvature changes are related factors to choroidal thinning. These findings could provide us a further understanding for the pathological process and clinical features of ABCA4 mutation.


Asunto(s)
Membrana Epirretinal , Enfermedades de la Retina , Humanos , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodos , Estudios Transversales , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Enfermedades de la Retina/patología , Transportadoras de Casetes de Unión a ATP/genética
13.
BMC Ophthalmol ; 24(1): 215, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760766

RESUMEN

BACKGROUND: To investigate the clinical effects of double-dose (4 mg) aflibercept treatment in neovascular age-related macular degeneration (nAMD), compared with the standard-dose (2 mg) treatment. METHODS: A total of 108 eyes from 97 patients with nAMD and received intravitreal aflibercept 2 mg and/or 4 mg treatment were retrospectively reviewed. The changes of central macular thickness (CMT)/ pigmental epithelium detachment height and the recurrence rate of exudation during the 12-month follow-up were compared between the 2 mg group and the 4 mg group. Self-control comparisons (2 mg switch to 4 mg) were also made between two regimens. RESULTS: Compared with the 2 mg group, tendencies of lower intraretinal fluid incidence and more CMT reduction were observed in the 4 mg group. The later one was also observed when eyes switching from 2 mg to 4 mg regimen. The median remission interval was 5 months in the 4 mg group, 2 months longer than the 3 months in the 2 mg group (P = 0.452). Injections needed in the 4 mg group were 3.644 ± 1.670, less than the 4.286 ± 2.334 injections in the 2 mg group within 12 months as well (P = 0.151). However, no associated vision benefits were gained from the double-douse regimen. No markedly increased-intraocular pressure events, or other adverse events were found in two groups. CONCLUSIONS: Compared to the aflibercept 2 mg treatment in nAMD, tendencies of anatomic gains and relieving treatment burden were brought by the aflibercept 4 mg treatment. This study may have additional importance, given the further application of high-dose aflibercept in real-world settings.


Asunto(s)
Inhibidores de la Angiogénesis , Inyecciones Intravítreas , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Tomografía de Coherencia Óptica , Agudeza Visual , Degeneración Macular Húmeda , Humanos , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéutico , Masculino , Femenino , Estudios Retrospectivos , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Agudeza Visual/fisiología , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/diagnóstico , Tomografía de Coherencia Óptica/métodos , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Estudios de Seguimiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Resultado del Tratamiento , Angiografía con Fluoresceína/métodos
14.
Int Ophthalmol ; 44(1): 295, 2024 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-38951350

RESUMEN

PURPOSE: This study sought to provide an overview of the current research and further analyze publication trends in the field of vascular endothelial growth factor (VEGF) and anti-VEGF treatment for neovascular age-related macular degeneration (NVAMD). METHODS: We downloaded all related publications from 2001 to 2020 from the Web of Science Core Collection and conducted a bibliometric analysis using the bibiometrix package in R programming software. RESULTS: A total of 3717 publications were included in the analysis. The USA contributed the largest number of publications (1443), and achieved the highest number of citations (74,946) and H-index value (28). Johns Hopkins University, USA, was the top institution with the most publications, and Peter A. Campochiaro was the most productive professor at The Wilmer Eye Institute, USA. 9.60% of the total publications were from the Journal of Retinal and Vitreous Diseases. Trend analysis demonstrated that anti-VEGF therapy was introduced in early 2000 after steroids, and the last 2 decades have witnessed the blossom of several anti-VEGF agents. "Treat-and-extend" and "resistance" were two popular trend topics in recent years. CONCLUSIONS: The USA occupies a dominant position in the research field of VEGF and anti-VEGF treatments in NVAMD. Steroid administration, photodynamic therapy, and anti-VEGF therapy have been pivotal advances in the treatment of NVAMD patients over the past 2 decades. Limited acting period and resistance are potential investigation directions in future studies.


Asunto(s)
Inhibidores de la Angiogénesis , Bibliometría , Factor A de Crecimiento Endotelial Vascular , Degeneración Macular Húmeda , Humanos , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Degeneración Macular Húmeda/tratamiento farmacológico , Degeneración Macular Húmeda/diagnóstico , Inyecciones Intravítreas
15.
EMBO J ; 38(9)2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-30858280

RESUMEN

The RNA-binding protein ALYREF plays key roles in nuclear export and also 3'-end processing of polyadenylated mRNAs, but whether such regulation also extends to non-polyadenylated RNAs is unknown. Replication-dependent (RD)-histone mRNAs are not polyadenylated, but instead end in a stem-loop (SL) structure. Here, we demonstrate that ALYREF prevalently binds a region next to the SL on RD-histone mRNAs. SL-binding protein (SLBP) directly interacts with ALYREF and promotes its recruitment. ALYREF promotes histone pre-mRNA 3'-end processing by facilitating U7-snRNP recruitment through physical interaction with the U7-snRNP-specific component Lsm11. Furthermore, ALYREF, together with other components of the TREX complex, enhances histone mRNA export. Moreover, we show that 3'-end processing promotes ALYREF recruitment and histone mRNA export. Together, our results point to an important role of ALYREF in coordinating 3'-end processing and nuclear export of non-polyadenylated mRNAs.


Asunto(s)
Histonas/metabolismo , Proteínas Nucleares/metabolismo , Procesamiento Postranscripcional del ARN , Transporte de ARN , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Ribonucleoproteína Nuclear Pequeña U7/metabolismo , Factores de Transcripción/metabolismo , Transporte Activo de Núcleo Celular , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/metabolismo , Histonas/genética , Humanos , Proteínas Nucleares/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Ribonucleoproteína Nuclear Pequeña U7/genética , Factores de Transcripción/genética
16.
Cell Immunol ; 385: 104676, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36780770

RESUMEN

Myeloid-derived suppressor cells (MDSCs) are a population of immature bone marrow cells that accumulate in large numbers in the spleen, peripheral blood, bone marrow, lymph nodes, and local and metastatic foci of tumors. C/EBP homologous protein (CHOP) and CCAAT/enhancer binding protein ß (C/EBPß) play key roles in regulating the immunosuppressive function and differentiation of MDSCs. Our study revealed that the long noncoding RNA Lnc-17Rik was able to promote immunosuppression in tumors by facilitating the activation and expression of key genes involved in MDSC differentiation. Lnc-17Rik was shown to directly interact with CHOP and C/EBPß LIP to facilitate their dissociation from the transcriptional repressor complex involving C/EBP LAP/LIP/CHOP. Moreover, Lnc-17Rik increased the association of WD repeat-containing protein 5 (WDR5) with C/EBP LAP, promoting H3K4me3 enrichment in the promoter regions of arginase 1 (Arg-1), cyclooxygenase 2 (COX2), nitric oxide synthase 2 (NOS2) and NADPH oxidase 2 (NOX2) to enhance the expression of these genes. Furthermore, using a CD45 chimeric model we confirmed that Lnc-17Rik promoted the differentiation of monocytic (M)-MDSCs in vivo with the introduction of Lnc-17Rik-overexpressing MDSCs shown to promote tumor growth as a result of enhancing their immunosuppressive function. Notably, human Lnc-17Rik is highly homologous to mouse Lnc-17Rik and fulfills similar functions in human MDSC-like cells. In addition, we also found a high level of Lnc-17Rik in peripheral blood MDSC of patients with esophageal cancer. These findings suggest that Lnc-17Rik plays an important role in controlling the immunosuppressive function of MDSCs in the tumor environment and may further serve as a potential therapeutic target for patients with esophageal cancer.


Asunto(s)
Neoplasias Esofágicas , Células Supresoras de Origen Mieloide , ARN Largo no Codificante , Animales , Humanos , Ratones , Diferenciación Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Monocitos , Células Mieloides , Células Supresoras de Origen Mieloide/metabolismo , ARN Largo no Codificante/genética
17.
Opt Express ; 31(6): 9275-9286, 2023 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-37157500

RESUMEN

Curvature measurement plays an important role in various applications. An optical curvature sensor based on polarization characteristics of optical fiber is proposed and verified by experiments. The direct bending of the fiber causes a change in birefringence, which results in a change of Stokes parameters of the transmitted light. The large curvature measurement range of tens to more than 100 m-1 has been realized in the experiment. For micro bending, a cantilever beam structure is used to achieve a sensitivity of up to 12.26/ m-1 and a linearity of 99.49% in the measurement range of 0 to 0.15 m-1, with a resolution of up to 10-6 m-1 order of magnitude, which reaches the level of the latest report. The method with the advantages of simple fabrication, low cost and good real-time performance gives a new development direction to the curvature sensor.

18.
Cancer Control ; 30: 10732748231202466, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37728233

RESUMEN

BACKGROUND: Tumor markers (TMs) are important for the prognosis of gastric cancer (GC). However, the prognostic importance of the tumor marker index (TMI) based on GC-specific TMs for advanced gastric cancer (AGC) still needs to be further explored. METHODS: We retrospectively examined patients who underwent radical gastric cancer surgery between February 2014 and June 2016 at the Department of Gastroenterological Surgery, Affiliated Cancer Hospital, Harbin Medical University. The patients were divided into training and validation groups. TMI was determined as the geometric mean of the standard cancer antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels. Patient overall survival was assessed using the Kaplan-Meier method. Independent prognosis-associated risk factors were identified using Cox hazard regression models. A nomogram model incorporating TMI and clinicopathological factors was developed, and its performance was evaluated using a decision curve analysis, concordance index, and calibration plots. RESULTS: In the TMI training cohort, the cutoff value was set at .439, categorizing patients into TMI-High and TMI-Low groups. The 5-year survival rate in the TMI-Low group significantly surpassed that in the TMI-High group (78.2% vs 58.1% and 49.7 vs 41.6, P < .001). TMI emerged as an independent prognostic factor. The nomogram accurately predicted patient prognosis by using TMI and clinicopathological characteristics. Validation of the TMI in the independent cohort yielded satisfactory results. CONCLUSION: The TMI constructed based on specific TMs associated with gastric cancer can offer a precise prognostic prediction for patients.


Asunto(s)
Biomarcadores de Tumor , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Pronóstico
19.
Inorg Chem ; 62(25): 9964-9970, 2023 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-37307399

RESUMEN

Developing highly efficient and persistent transition-metal-phosphide (TMP)-based electrocatalysts is critical for the hydrogen evolution reaction (HER) via water splitting in alkaline media. Herein, we constructed a unique heterostructured CoFeP/CoP grown on a nickle foam (NF) via hydrothermal and dipping methods followed by phosphorization at different temperatures for HER. The experimental results exhibit that the HER activity of CoFeP/CoP-400 is accelerated after the construction of heterostructures. The unique heterostructure provides plentiful active sites and a large surface area, which are beneficial for HER in 1.0 M KOH. CoFeP/CoP-400 displays a small overpotential of 78 mV at a current density of 10 mA cm-2 and a smaller Tafel slope of 55.5 mV dec-1. Moreover, CoFeP/CoP-400 shows excellent stability with a long-term operating time of 12 h. This work provides an effective method for the construction of TMPs with heterostructures for promoting energy conversion.

20.
Nanotechnology ; 34(36)2023 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-37307796

RESUMEN

Efficient conversion of glycerol to 1,3-dihydroxyacetone (DHA) is the affirmation and guarantee of the feasible development of biodiesel industry, but the biocompatibility of catalyst must be considered due to the wide application of DHA in food and medicine industries. In this work, an environmentally benign biosynthesis approach withSyringa oblata Lindl.(SoL) leaf extract was employed to fabricate Au/CuO catalysts for the oxidation of glycerol to DHA. The biosynthesizedSoL-Au/CuO catalysts were characterized and the effects of plant extracts concentration, gold loading, calcination temperature and reaction conditions on the catalytic performance were systematically analyzed. High catalytic performance with glycerol conversion rate of 95.7% and DHA selectivity of 77.9% can be attained under optimum conditions. This work provides the first example of preparing biocompatible catalyst for the thermal catalytic oxidation of glycerol to DHA, which can not only reach efficient conversion of glycerol and selectivity to DHA, but also is simple, green, environmentally friendly, and promising.


Asunto(s)
Dihidroxiacetona , Glicerol , Oxidación-Reducción , Extractos Vegetales
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