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With the rapid development of 3D reconstruction, especially the emergence of algorithms such as NeRF and 3DGS, 3D reconstruction has become a popular research topic in recent years. 3D reconstruction technology provides crucial support for training extensive computer vision models and advancing the development of general artificial intelligence. With the development of deep learning and GPU technology, the demand for high-precision and high-efficiency 3D reconstruction information is increasing, especially in the fields of unmanned systems, human-computer interaction, virtual reality, and medicine. The rapid development of 3D reconstruction is becoming inevitable. This survey categorizes the various methods and technologies used in 3D reconstruction. It explores and classifies them based on three aspects: traditional static, dynamic, and machine learning. Furthermore, it compares and discusses these methods. At the end of the survey, which includes a detailed analysis of the trends and challenges in 3D reconstruction development, we aim to provide a comprehensive introduction for individuals who are currently engaged in or planning to conduct research on 3D reconstruction. Our goal is to help them gain a comprehensive understanding of the relevant knowledge related to 3D reconstruction.
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Anti-retroviral therapy (ART) generally suppresses HIV replication to undetectable levels in peripheral blood, but immune activation associated with increased morbidity and mortality is sustained during ART, and infection rebounds when treatment is interrupted. To identify drivers of immune activation and potential sources of viral rebound, we modified RNAscope in situ hybridization to visualize HIV-producing cells as a standard against which to compare the following assays of potential sources of immune activation and virus rebound following treatment interruption: (i) envelope detection by induced transcription-based sequencing (EDITS) assay; (ii) HIV-Flow; (iii) Flow-FISH assays that can scan tissues and cell suspensions to detect rare cells expressing env mRNA, gag mRNA/Gag protein and p24; and (iv) an ultrasensitive immunoassay that detects p24 in cell/tissue lysates at subfemtomolar levels. We show that the sensitivities of these assays are sufficient to detect one rare HIV-producing/env mRNA+/p24+ cell in one million uninfected cells. These high-throughput technologies provide contemporary tools to detect and characterize rare cells producing virus and viral antigens as potential sources of immune activation and viral rebound. IMPORTANCE Anti-retroviral therapy (ART) has greatly improved the quality and length of life for people living with HIV, but immune activation does not normalize during ART, and persistent immune activation has been linked to increased morbidity and mortality. We report a comparison of assays of two potential sources of immune activation during ART: rare cells producing HIV and the virus' major viral protein, p24, benchmarked on a cell model of active and latent infections and a method to visualize HIV-producing cells. We show that assays of HIV envelope mRNA (EDITS assay), gag mRNA, and p24 (Flow-FISH, HIV-Flow. and ultrasensitive p24 immunoassay) detect HIV-producing cells and p24 at sensitivities of one infected cell in a million uninfected cells, thereby providing validated tools to explore sources of immune activation during ART in the lymphoid and other tissue reservoirs.
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Infecciones por VIH , VIH-1 , ARN Viral , Tropismo Viral , Activación Viral , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Antígenos Virales/análisis , Antígenos Virales/genética , Antígenos Virales/metabolismo , Linfocitos T CD4-Positivos , Proteína p24 del Núcleo del VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , VIH-1/crecimiento & desarrollo , VIH-1/inmunología , Humanos , Inmunoensayo , Hibridación Fluorescente in Situ , ARN Mensajero/análisis , ARN Viral/análisis , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.
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Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , VIH-1 , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Linfocitos T CD4-Positivos , ADN/uso terapéutico , Receptor alfa de Estrógeno/metabolismo , Femenino , VIH-1/genética , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histonas/metabolismo , Histonas/uso terapéutico , Humanos , ARN/metabolismo , ARN/uso terapéutico , Tamoxifeno/efectos adversos , Tamoxifeno/metabolismo , Viremia/tratamiento farmacológico , Latencia del Virus , Vorinostat/metabolismo , Vorinostat/farmacología , Vorinostat/uso terapéuticoRESUMEN
We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.
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Proteína p24 del Núcleo del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo , Biomarcadores/sangre , Biopsia , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Femenino , Proteína p24 del Núcleo del VIH/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Humanos , Activación de LinfocitosRESUMEN
Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.
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Infecciones por VIH , VIH-1 , Linfocitos T CD4-Positivos , ADN Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Provirus/genética , Latencia del VirusRESUMEN
BACKGROUND: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. METHODS: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ARTâ+âVâ+âV; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. FINDINGS: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ARTâ+âVâ+âV (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ARTâ+âVâ+âV group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. INTERPRETATION: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required. FUNDING: Medical Research Council (MR/L00528X/1).
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Vacunas contra el SIDA/administración & dosificación , Antirretrovirales/uso terapéutico , Reservorios de Enfermedades , Infecciones por VIH , Inhibidores de Histona Desacetilasas/administración & dosificación , Vorinostat/administración & dosificación , Adulto , ADN Viral/análisis , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Transcripción Genética/efectos de los fármacos , Resultado del TratamientoRESUMEN
Histone deacetylase inhibitors (HDACi) are the most widely studied HIV latency-reversing agents (LRAs). The HDACi suberoylanilide hydroxamic acid (vorinostat [VOR]) has been employed in several clinical HIV latency reversal studies, as well as in vitro models of HIV latency, and has been shown to effectively induce HIV RNA and protein expression. Despite these findings, response to HDACi can vary, particularly with intermittent dosing, and information is lacking on the relationship between the host transcriptional response and HIV latency reversal. Here, we report on global gene expression responses to VOR and examine the longevity of the transcriptional response in various cellular models. We found that many genes are modulated at 6 h post-VOR treatment in HCT116, Jurkat, and primary resting CD4 T cells, yet return to baseline levels after an 18-h VOR-free period. With repeat exposure to VOR in resting CD4 T cells, we found similar and consistent transcriptional changes at 6 h following each serial treatment. In addition, serial exposure in HIV-infected suppressed donor CD4 T cells showed consistent transcriptional changes after each exposure to VOR. We identified five host genes that were strongly and consistently modulated following histone deacetylase (HDAC) inhibition; three (H1F0, IRGM, and WIPI49) were upregulated, and two (PHF15 and PRDM10) were downregulated. These genes demonstrated consistent modulation in peripheral blood mononuclear cell (PBMC) samples from HIV-positive (HIV+) participants who received either single or multiple doses of 400 mg of VOR. Interestingly, the host transcriptional response did not predict induction of cell-associated HIV RNA, suggesting that other cellular factors play key roles in HIV latency reversal in vivo despite robust HDACi pharmacological activity.IMPORTANCE Histone deacetylase inhibitors are widely studied HIV latency-reversing agents (LRAs). VOR, an HDACi, induces histone acetylation and chromatin remodeling and modulates host and HIV gene expression. However, the relationship between these events is poorly defined, and clinical studies suggest diminished HIV reactivation in resting CD4 T cells with daily exposure to VOR. Our study provides evidence that VOR induces a consistent level of host cell gene transcription following intermittent exposure. In addition, in response to VOR exposure a gene signature that was conserved across single and serial exposures both in vitro and in vivo was identified, indicating that VOR can consistently and reproducibly modulate transcriptional host responses. However, as the HIV response to HDACi declines over time, other factors modulate viral reactivation in vivo despite robust HDAC activity. The identified host gene VOR biomarkers can be used for monitoring the pharmacodynamic activity of HDAC inhibitors.
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Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/tratamiento farmacológico , Vorinostat/farmacología , Acetilación , Linfocitos T CD4-Positivos/efectos de los fármacos , VIH-1/metabolismo , VIH-1/patogenicidad , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Células Jurkat , Leucocitos Mononucleares/efectos de los fármacos , Cultivo Primario de Células , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Vorinostat/metabolismoRESUMEN
A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC50s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.
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Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , VIH/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Relación Dosis-Respuesta a Droga , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Synteny and collinearity analysis is a standard investigative strategy done in many comparative genomic studies to understand genomic conservation and evolution. Currently, most visualization toolkits of synteny and collinearity do not emphasize the graphical representation of the results, especially the lack of extensible format on vector graphics outputs. This limitation becomes more apparent as 3rd generation sequencing brings high-throughput data, requiring relatively higher resolution for the resulting images. We developed VGSC2, the 2nd version of the web-based vector graph toolkit for genome synteny and collinearity analysis. The updated version enables four types of plots for synteny and collinearity, and three types of plots for gene family evolutionary research. Using web-based technologies, VGSC2 provides an easy-to-use user interface to display the homologous genomic result into vector graphs such as SVG, EPS, and PDF, as well as an online editor. VGSC2 is open source and freely available for use online through the web server available at http://bio.njfu.edu.cn/vgsc2.
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Programas Informáticos , Sintenía , Genoma , Genómica/métodos , Familia de MultigenesRESUMEN
Clearance of HIV-infected germinal center (GC) CD4+ follicular helper T cells (Tfh) after combination antiretroviral therapy (ART) is essential to an HIV cure. Blocking B cell lymphoma 6 (BCL6; the master transcription factor for Tfh cells) represses HIV infection of tonsillar CD4+ Tfh ex vivo, reduces GC formation, and limits immune activation in vivo We assessed the anti-HIV activity of a novel BCL6 inhibitor, FX1, in Tfh/non-Tfh CD4+ T cells and its impact on T cell activation and SAMHD1 phosphorylation (Thr592). FX1 repressed HIV-1 infection of peripheral CD4+ T cells and tonsillar Tfh/non-Tfh CD4+ T cells (P < 0.05) and total elongated and multispliced HIV-1 RNA production during the first round of viral life cycle (P < 0.01). Using purified circulating CD4+ T cells from uninfected donors, we demonstrate that FX1 treatment resulted in downregulation pSAMHD1 expression (P < 0.05) and T cell activation (HLA-DR, CD25, and Ki67; P < 0.01) ex vivo corresponding with inhibition of HIV-1 and HIV-2 replication. Ex vivo HIV-1 reactivation using purified peripheral CD4+ T cells from HIV-infected ART-suppressed donors was also blocked by FX1 treatment (P < 0.01). Our results indicate that BCL6 function contributes to Tfh/non-Tfh CD4+ T cell activation and cellular susceptibility to HIV infection. BCL6 inhibition represents a novel therapeutic strategy to potentiate HIV suppression in Tfh/non-Tfh CD4+ T cells without reactivation of latent virus.IMPORTANCE The expansion and accumulation of HIV-infected BCL6+ Tfh CD4+ T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4+ T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling HIV replication in lymphoid tissues, and (ii) cytotoxic CD8+ T cells within lymphoid tissues express low levels of chemokine receptor (CXCR5), thus limiting their ability to enter the GCs to control/eliminate HIV-infected Tfh cells. Our results indicate that the BCL6 inhibitor FX1 can not only repress HIV infection of tonsillar Tfh ex vivo but also suppress HIV infection and reactivation in primary, non-Tfh CD4+ T cells. Our study provides a rationale for targeting BCL6 protein to extend ART-mediated reduction of persistent HIV and/or support strategies toward HIV remission beyond ART cessation.
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Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/metabolismo , Indoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteína 1 que Contiene Dominios SAM y HD/metabolismo , Tiazolidinedionas/farmacología , Adulto , Regulación hacia Abajo , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , VIH-1/fisiología , VIH-2/efectos de los fármacos , VIH-2/fisiología , Humanos , Activación de Linfocitos/efectos de los fármacos , Persona de Mediana Edad , Fosforilación , Replicación Viral/efectos de los fármacos , Adulto JovenRESUMEN
A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.
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Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Cetonas/farmacología , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Línea Celular Tumoral , Perros , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Cetonas/síntesis química , Cetonas/farmacocinética , Pruebas de Sensibilidad Microbiana , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacologíaRESUMEN
The synthesis and SAR development of a trisubstituted imidazole HDAC inhibitor is described. The compounds were synthesized with high diastereocontrol by leveraging Ellman sulfinyl imine chemistry. Structural elucidation provided insight into binding mode and supported design rational. Pharmacokinetic properties of lead compounds were determined.
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Inhibidores de Histona Desacetilasas/metabolismo , Histona Desacetilasas/metabolismo , Animales , Linfocitos T CD4-Positivos/virología , Cristalografía por Rayos X , VIH-1/efectos de los fármacos , VIH-1/fisiología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Humanos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacología , Concentración 50 Inhibidora , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
BACKGROUND: The latent reservoir in resting CD4(+) T cells presents a major barrier to HIV cure. Latency-reversing agents are therefore being developed with the ultimate goal of disrupting the latent state, resulting in induction of HIV expression and clearance of infected cells. Histone deacetylase inhibitors (HDACi) have received a significant amount of attention for their potential as latency-reversing agents. RESULTS: Here, we have investigated the in vitro and systemic in vivo effect of panobinostat, a clinically relevant HDACi, on HIV latency. We showed that panobinostat induces histone acetylation in human PBMCs. Further, we showed that panobinostat induced HIV RNA expression and allowed the outgrowth of replication-competent virus ex vivo from resting CD4(+) T cells of HIV-infected patients on suppressive antiretroviral therapy (ART). Next, we demonstrated that panobinostat induced systemic histone acetylation in vivo in the tissues of BLT humanized mice. Finally, in HIV-infected, ART-suppressed BLT mice, we evaluated the effect of panobinostat on systemic cell-associated HIV RNA and DNA levels and the total frequency of latently infected resting CD4(+) T cells. Our data indicate that panobinostat treatment resulted in systemic increases in cellular levels of histone acetylation, a key biomarker for in vivo activity. However, panobinostat did not affect the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells. CONCLUSION: We have demonstrated robust levels of systemic histone acetylation after panobinostat treatment of BLT humanized mice; and we did not observe a detectable change in the levels of cell-associated HIV RNA, HIV DNA, or latently infected resting CD4(+) T cells in HIV-infected, ART-suppressed BLT mice. These results are consistent with the modest effects noted in vitro and suggest that combination therapies may be necessary to reverse latency and enable clearance. Animal models will contribute to the progress towards an HIV cure.
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Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/virología , ADN Viral/metabolismo , VIH-1/efectos de los fármacos , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , ARN Viral/metabolismo , Latencia del Virus/efectos de los fármacos , Acetilación , Animales , Fármacos Anti-VIH/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , VIH-1/fisiología , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Transgénicos , Panobinostat , ARN Viral/sangre , Activación Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
A hallmark of Alzheimer's disease (AD) brain is the amyloid ß (Aß) plaque, which is comprised of Aß peptides. Multiple lines of evidence suggest that Aß oligomers are more toxic than other peptide forms. We sought to develop a robust assay to quantify oligomers from CSF. Antibody 19.3 was compared in one-site and competitive ELISAs for oligomer binding specificity. A two-site ELISA for oligomers was developed using 19.3 coupled to a sensitive, bead-based fluorescent platform able to detect single photons of emitted light. The two-site ELISA was >2500× selective for Aß oligomers over Aß monomers with a limit of detection â¼ 0.09 pg/ml in human CSF. The lower limit of reliable quantification of the assay was 0.18 pg/ml and the antibody pairs recognized Aß multimers comprised of either synthetic standards, or endogenous oligomers isolated from confirmed human AD and healthy control brain. Using the assay, a significant 3- to 5-fold increase in Aß oligomers in human AD CSF compared with comparably aged controls was demonstrated. The increase was seen in three separate human cohorts, totaling 63 AD and 54 controls. CSF oligomers ranged between 0.1 and 10 pg/ml. Aß oligomer levels did not strongly associate with age or gender, but had an inverse correlation with MMSE score. The C statistic for the Aß oligomer ROC curve was 0.86, with 80% sensitivity and 88% specificity to detect AD, suggesting reasonable discriminatory power for the AD state and the potential for utility as a diagnostic marker.
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Envejecimiento/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/inmunología , Anticuerpos/inmunología , Especificidad de Anticuerpos , Biomarcadores/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Reacciones Falso Positivas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Curva ROC , Reproducibilidad de los Resultados , Dispersión de RadiaciónRESUMEN
BACE, a ß-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the ß-secretase pathway and a lowering of CNS amyloid-ß (Aß) levels. The interaction of the ß-secretase and α-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated Aß and soluble APPß (sAPPß), with increased newly generated sAPPα. A stable isotope labeling kinetics experiment in NHPs was performed with a (13)C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPPα, sAPPß, and Aß in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPß, and Aß were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPPß and sAPPα kinetics were similar, but both significantly slower than Aß. BACE inhibition resulted in decreased labeled sAPPß and Aß in CSF, without observable changes in labeled CSF sAPPα. ELISA concentrations of sAPPß and Aß both decreased and sAPPα increased. sAPPα increased by ELISA, with no difference by labeled sAPPα kinetics indicating increases in product may be due to APP shunting from the ß-secretase to the α-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.
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Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Sistema Nervioso Central/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Isótopos de Carbono/metabolismo , Línea Celular Tumoral , Sistema Nervioso Central/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Humanos , Inmunoprecipitación , Leucina/metabolismo , Macaca mulatta , Espectrometría de Masas , Neuroblastoma , Fragmentos de Péptidos , TransfecciónRESUMEN
The ß-amyloid peptides (Aß) are thought to play a critical role in the pathophysiology of Alzheimer's disease. One therapeutic strategy aimed to reduce or eliminate the production of Aß peptides is inhibition of the γ-secretase enzyme, which cleaves amyloid precursor protein to form Aß peptides. We studied the in vivo effects of the potent, orally bioavailable and brain penetrant γ-secretase inhibitor (GSI), MRK-560, on both Aßx-40 and Aßx-42 in multiple compartments (plasma, the brain and cerebrospinal fluid) of rat. Although there were differences in the time course and magnitude of the changes, the results showed that MRK-560 caused marked inhibition of both Aßx-40 and Aßx-42 in all three compartments. We identified good correlations between plasma Aßx-40 versus brain Aßx-40 (r = 0.84), and plasma Aßx-40 versus CSF Aßx-40 (r = 0.85), indicating that these pools of Aß are related dynamically. These results suggest that central Aß changes that occur following acute dosing with MRK-560 can be predicted based on plasma Aß changes and could thus serve as a useful biomarker to help accelerate decision-making during early clinical development.
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Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Sulfonamidas/farmacología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Masculino , Ratas , Ratas Sprague-Dawley , Estadística como Asunto , Factores de TiempoRESUMEN
BACKGROUND: N-terminally truncated, pyroglutamate-modified amyloid-ß (Aß) peptides are major constituents of amyloid deposits in Alzheimer's disease (AD). METHODS: Using a newly developed ELISA for Aß modified at glutamate 3 with a pyroglutamate (pE3Aß), brain pE3Aß was characterized in human AD in an AD mouse model harboring double knock-in amyloid precursor protein (APP)-KM670/671NL and presenilin 1 (PS1)-P264L (APP/PS1-dKI) mutations, and in a second mouse model with transgenic overexpression of human APP695 with APP-KM670/671NL (Tg2576). RESULTS: pE3Aß increased in the AD brain versus age-matched controls, with pE3Aß/total Aß at 45 and 10%, respectively. Compared to controls, the AD brain demonstrated 8.5-fold increased pE3Aß compared to non-pE3Aß species, which increased 2.7-fold. In the APP/PS1-dKI brain, pE3Aß/total Aß increased from 7% at 3 months to 16 and 19% at 15 and 19 months, respectively. In Tg2576, pE3Aß/total Aß was only 1.5% at 19 months, suggesting that APP/PS1-dKI, despite less total Aß compared to Tg2576 at comparable ages, more closely mimics AD brain pathology. CONCLUSION: This report supports a significant role for pE3Aß in AD pathogenesis by confirming that pE3Aß represents a large fraction of Aß within the AD brain. Compared to the age-matched control brain, pE3Aß increased to a greater extent compared to Aß species without this N-terminal modification. Further, the APP/PS1-dKI model more closely resembles the AD brain in this regard, compared to the Tg2576 model.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/inmunología , Precursor de Proteína beta-Amiloide/genética , Animales , Anticuerpos , Ensayo de Inmunoadsorción Enzimática , Técnicas de Sustitución del Gen , Humanos , Ratones , Ratones Transgénicos , Presenilina-1/genética , Ácido Pirrolidona Carboxílico/químicaRESUMEN
Muscle growth stands as a pivotal economic trait within pig production, governed by a complex interplay of multiple genes, each playing a role in its quantitative manifestation. Understanding the intricate regulatory mechanisms of porcine muscle development is crucial for enhancing both pork yield and quality. This study used the GSE99749 dataset downloaded from the GEO database, conducting a detailed analysis of the RNA-seq results from the longissimus dorsi muscle (LD) of Tibetan pigs (TP), Wujin pigs (WJ) and large white pigs (LW) at 60 days of gestation, representing diverse body sizes and growth rates. Comparative analyses between TPvsWJ and TPvsLW, along with differential gene expression (DEG) analysis, functional enrichment analysis, and protein-protein interaction (PPI) network analysis, revealed 1048 and 1157 significantly differentially expressed genes (p < 0.001) in TPvsWJ and TPvsLW, respectively. With stricter screening criteria, 37 DEGs were found to overlap between the 2 groups. PPI analysis identified MYL5, MYL4, and ACTC1 as the three core genes. This article focuses on exploring the MYL4 gene. Molecular-level experimental validation, through overexpression and interference of the MYL4 gene combined with EDU staining experiments, demonstrated that overexpression of MYL4 significantly promoted the proliferation of porcine skeletal muscle satellite cells (PSMSC), while interference with MYL4 inhibited their proliferation. Furthermore, by examining the effects of overexpressing and interfering with the MYL4 gene on the muscle hypertrophy marker Fst gene and the muscle degradation marker FOXO3 gene, the pivotal role of the MYL4 gene in promoting muscle growth and preventing muscle degradation was further confirmed. These findings offer a new perspective on the molecular mechanisms behind porcine muscle growth and development, furnishing valuable data and insights for muscle biology research.
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Personalized medical diagnostics and monitoring have become increasingly important due to inefficient and delayed medical services of traditional centralized healthcare systems. To enhance the comfort and portability, flexible health monitoring systems have been developed in recent years. In particular, smart fiber/textile-based sensing devices show superiority for continuously monitoring personal health and vital physiological parameters owing to their light weight, good flexibility and inherent miniaturization. This review focuses on the recent advances in smart fiber/textile-based sensing devices for wearable electronic applications. First, fabrication strategies of smart sensing fibers/textiles are introduced in detail. In addition, sensing performances, working principles and applications of smart sensing fibers/textiles such as pressure sensing fibers/textiles, stretchable strain sensing fibers/textiles, temperature sensing fibers/textiles, and biofluid, gas and humidity sensing fibers/textiles in health monitoring are also reviewed systematically. Finally, we propose current challenges and future prospects in the area of fiber/textile-based sensors for wearable healthcare monitoring and diagnosis systems. In general, this review aims to give an overall perspective of the promising field by reviewing various fiber/textile-based sensing devices and highlighting the importance for researchers to keep up with the sequential exploration of soft sensing fibers/textiles for applications in wearable smart systems.
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Textiles , Dispositivos Electrónicos Vestibles , Humanos , Monitoreo Fisiológico/instrumentación , Monitoreo Fisiológico/métodos , Medicina de Precisión/instrumentación , Medicina de Precisión/métodos , Diseño de Equipo , Técnicas Biosensibles/instrumentación , Técnicas Biosensibles/métodosRESUMEN
BACKGROUND: Insulin Resistance (IR) are associated with Hypertension (HTN). Triglyceride glucose-body mass index (TyG-BMI) is a readily available and clinically significant indicator of IR. This study aimed to investigate whether TyG-BMI is independently associated with HTN. METHODS: A total of 15,464 patients with normal blood glucose from 2004 to 2016 participated in this study. Participants were divided into four groups using the quartile method: TyG-BMI below 153.1, between 153.1 and 174.2, between 174.2 and 199.3, and over 199.3. The covariates included age, sex, BMI, WC, HDL-C, TC, TG, HbA1c, FPG, ALT, AST, GGT, SBP, DBP, smoking status, alcohol consumption, and exercise habits. RESULTS: The average age was 43.7 ± 8.9 years, and 45.4% were men. The prevalence of HTN was 6.2% (964/15464) of the population. TyG-BMI remained significantly associated with HTN after multivariate adjustment for TyG-BMI as a continuous variable (adjusted OR = 2.87, 95% CI: 1.90-4.34). Each 10-unit rise in TyG-BMI (continuous variable) was linked to a 31% increase in the prevalence of HTN (adjusted OR = 1.31, 95% CI: 1.25-1.37). In the subgroup analysis stratified by age, sex, waist circumference, and smoking status, the association between TyG-BMI and HTN were stable. CONCLUSION: In this study, TyG-BMI was highly correlated with HTN, but more experiments and different populations are needed to verify this.