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1.
PLoS Pathog ; 17(4): e1009417, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33861800

RESUMEN

Macrophages are important drivers of pathogenesis and progression to AIDS in HIV infection. The virus in the later phases of the infection is often predominantly macrophage-tropic and this tropism contributes to a chronic inflammatory and immune activation state that is observed in HIV patients. Pattern recognition receptors of the innate immune system are the key molecules that recognise HIV and mount the inflammatory responses in macrophages. The innate immune response against HIV-1 is potent and elicits caspase-1-dependent pro-inflammatory cytokine production of IL-1ß and IL-18. Although, NLRP3 has been reported as an inflammasome sensor dictating this response little is known about the pattern recognition receptors that trigger the "priming" signal for inflammasome activation, the NLRs involved or the HIV components that trigger the response. Using a combination of siRNA knockdowns in monocyte derived macrophages (MDMs) of different TLRs and NLRs as well as chemical inhibition, it was demonstrated that HIV Vpu could trigger inflammasome activation via TLR4/NLRP3 leading to IL-1ß/IL-18 secretion. The priming signal is triggered via TLR4, whereas the activation signal is triggered by direct effects on Kv1.3 channels, causing K+ efflux. In contrast, HIV gp41 could trigger IL-18 production via NAIP/NLRC4, independently of priming, as a one-step inflammasome activation. NAIP binds directly to the cytoplasmic tail of HIV envelope protein gp41 and represents the first non-bacterial ligand for the NAIP/NLRC4 inflammasome. These divergent pathways represent novel targets to resolve specific inflammatory pathologies associated with HIV-1 infection in macrophages.


Asunto(s)
Infecciones por VIH/virología , Inflamasomas/inmunología , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/virología , Fragmentos de Péptidos/metabolismo , Comunicación Celular/genética , Comunicación Celular/inmunología , Expresión Génica/genética , Expresión Génica/inmunología , Infecciones por VIH/metabolismo , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Inflamasomas/metabolismo , Macrófagos/inmunología , Proteína Inhibidora de la Apoptosis Neuronal/genética , Transducción de Señal/inmunología
2.
Chemistry ; 29(31): e202204007, 2023 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-36888902

RESUMEN

The peracid oxidation of hydrocarbons in chlorinated solvents is a low yielding and poorly selective process. Through a combination of DFT calculations, spectroscopic studies, and kinetic measurement it is shown that the origin of this is electronic in nature and can be influenced through the addition of hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA). Performing the reaction of a cycloalkane with mCPBA in a fluorinated alcohol solvent such as nonafluoro-tert-butanol (NFTB) or hexafluoroisopropanol (HFIP), which act as strong HBD and poor HBA, leads to significantly higher yields and selectivities being observed for the alcohol product. Application of the optimised reaction conditions allows for the selective oxidation of both cyclic and linear alkane substrates delivering the corresponding alcohol in up to 86 % yield. The transformation shows selectivity for tertiary centres over secondary centres and the oxidation of secondary centres is strongly influenced by stereoelectronic effects. Primary centres are not oxidised by this method. A simple computational model developed to understand this transformation provides a powerful tool to reliably predict the influence of substitution and functionality on reaction outcome.

3.
Am J Hum Genet ; 105(6): 1262-1273, 2019 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-31785788

RESUMEN

It has long been appreciated that genetic analysis of fetal or trophoblast cells in maternal blood could revolutionize prenatal diagnosis. We implemented a protocol for single circulating trophoblast (SCT) testing using positive selection by magnetic-activated cell sorting and single-cell low-coverage whole-genome sequencing to detect fetal aneuploidies and copy-number variants (CNVs) at ∼1 Mb resolution. In 95 validation cases, we identified on average 0.20 putative trophoblasts/mL, of which 55% were of high quality and scorable for both aneuploidy and CNVs. We emphasize the importance of analyzing individual cells because some cells are apoptotic, in S-phase, or otherwise of poor quality. When two or more high-quality trophoblast cells were available for singleton pregnancies, there was complete concordance between all trophoblasts unless there was evidence of confined placental mosaicism. SCT results were highly concordant with available clinical data from chorionic villus sampling (CVS) or amniocentesis procedures. Although determining the exact sensitivity and specificity will require more data, this study further supports the potential for SCT testing to become a diagnostic prenatal test.


Asunto(s)
Trastornos de los Cromosomas/diagnóstico , Marcadores Genéticos , Pruebas Prenatales no Invasivas/métodos , Placenta/metabolismo , Trofoblastos/citología , Trofoblastos/metabolismo , Adulto , Trastornos de los Cromosomas/genética , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Placenta/citología , Embarazo , Análisis de la Célula Individual , Adulto Joven
4.
Genet Med ; 24(2): 364-373, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34906496

RESUMEN

PURPOSE: BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity. METHODS: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes. RESULTS: We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1. CONCLUSION: We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.


Asunto(s)
Anomalías Múltiples , Deformidades Congénitas de la Mano , Micrognatismo , Anomalías Múltiples/genética , Actinas/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Exoma/genética , Deformidades Congénitas de la Mano/genética , Humanos , Micrognatismo/genética , Estudios Retrospectivos
5.
Am J Hum Genet ; 103(1): 154-162, 2018 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-29961569

RESUMEN

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.


Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Mutación Missense/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Adulto , Aminoácidos/genética , Niño , Preescolar , Exoma/genética , Femenino , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Sistema de Señalización de MAP Quinasas/genética , Masculino , Anomalías Musculoesqueléticas/genética , Fenotipo
6.
Chemistry ; 27(71): 17880-17888, 2021 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-34328642

RESUMEN

We present a one-step Ugi reaction protocol for the expedient synthesis of photoaffinity probes for live-cell MS-based proteomics. The reaction couples an amine affinity function with commonly used photoreactive groups, and a variety of handle functionalities. Using this technology, a series of pan-BET (BET: bromodomain and extra-terminal domain) selective bromodomain photoaffinity probes were obtained by parallel synthesis. Studies on the effects of photoreactive group, linker length and irradiation wavelength on photocrosslinking efficiency provide valuable insights into photoaffinity probe design. Optimal probes were progressed to MS-based proteomics to capture the BET family of proteins from live cells and reveal their potential on- and off-target profiles.


Asunto(s)
Proteómica
7.
Angew Chem Int Ed Engl ; 59(47): 21096-21105, 2020 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-32745361

RESUMEN

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space. Presented here is a fragment-screening platform, termed PhABits (PhotoAffinity Bits), which utilizes a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and the site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. The PhABit platform is envisioned to be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.


Asunto(s)
Antineoplásicos/análisis , Compuestos Bicíclicos Heterocíclicos con Puentes/análisis , Reactivos de Enlaces Cruzados/química , Etiquetas de Fotoafinidad/química , Pirazoles/análisis , Quinoxalinas/análisis , Sulfonamidas/análisis , Vemurafenib/análisis , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Humanos , Ligandos , Estructura Molecular , Proteínas/antagonistas & inhibidores , Proteínas/química , Pirazoles/farmacología , Quinoxalinas/farmacología , Sulfonamidas/farmacología , Vemurafenib/farmacología
8.
Genet Med ; 21(3): 663-675, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30158690

RESUMEN

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective. METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.


Asunto(s)
Variación Biológica Poblacional/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Adolescente , Alelos , Antígenos Nucleares/genética , Proteínas Portadoras/genética , Niño , Preescolar , Estudios de Cohortes , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/genética , Exoma/genética , Femenino , Frecuencia de los Genes/genética , Heterogeneidad Genética , Humanos , Mutación INDEL/genética , Masculino , Mutación , Proteínas Nucleares/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas/genética , Estudios Retrospectivos , Secuenciación del Exoma/métodos , Cohesinas
9.
J Transl Med ; 15(1): 258, 2017 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-29258604

RESUMEN

BACKGROUND: Metabolic syndrome (MetS) is a highly prevalent condition that identifies individuals at risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Prevention of these diseases relies on early detection and intervention in order to preserve pancreatic ß-cells and arterial wall integrity. Yet, the clinical criteria for MetS are insensitive to the early-stage insulin resistance, inflammation, cholesterol and clotting factor abnormalities that characterize the progression toward type 2 diabetes and atherosclerosis. Here we report the discovery and initial characterization of an atypical new biomarker that detects these early conditions with just one measurement. METHODS: Water T2, measured in a few minutes using benchtop nuclear magnetic resonance relaxometry, is exquisitely sensitive to metabolic shifts in the blood proteome. In an observational cross-sectional study of 72 non-diabetic human subjects, the association of plasma and serum water T2 values with over 130 blood biomarkers was analyzed using bivariate, multivariate and logistic regression. RESULTS: Plasma and serum water T2 exhibited strong bivariate correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with fasting hyperinsulinemia, dyslipidemia and subclinical inflammation. Plasma water T2 exhibited 100% sensitivity and 87% specificity for detecting early insulin resistance in normoglycemic subjects, as defined by the McAuley Index. Sixteen normoglycemic subjects with early metabolic abnormalities (22% of the study population) were identified by low water T2 values. Thirteen of the 16 did not meet the harmonized clinical criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Low water T2 values were associated with increases in the mean concentrations of 6 of the 16 most abundant acute phase proteins and lipoproteins in plasma. CONCLUSIONS: Water T2 detects a constellation of early abnormalities associated with metabolic syndrome, providing a global view of an individual's metabolic health. It circumvents the pitfalls associated with fasting glucose and hemoglobin A1c and the limitations of the current clinical criteria for metabolic syndrome. Water T2 shows promise as an early, global and practical screening tool for the identification of individuals at risk for diabetes and atherosclerosis.


Asunto(s)
Biomarcadores/sangre , Espectroscopía de Resonancia Magnética , Síndrome Metabólico/sangre , Agua/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Sanguíneas/metabolismo , Análisis por Conglomerados , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Curva ROC , Sensibilidad y Especificidad , Adulto Joven
10.
Biochim Biophys Acta Proteins Proteom ; 1865(10): 1274-1286, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28698152

RESUMEN

BACKGROUND: Three NPXY motifs and one FERM domain in CCM1 makes it a versatile scaffold protein for tethering the signaling components together within the CCM signaling complex (CSC). The cellular role of CCM1 protein remains inadequately expounded. Both phosphotyrosine binding (PTB) and pleckstrin homology (PH) domains were recognized as structurally related but functionally distinct domains. METHODS: By utilizing molecular cloning, protein binding assays and RT-qPCR to identify novel cellular partners of CCM1 and its cellular expression patterns; by screening candidate PTB/PH proteins and subsequently structurally simulation in combining with current X-ray crystallography and NMR data to defined the essential structure of PTB/PH domain for NPXY-binding and the relationship among PTB, PH and FERM domain(s). RESULTS: We identified a group of 28 novel cellular partners of CCM1, all of which contain either PTB or PH domain(s), and developed a novel classification system for these PTB/PH proteins based on their relationship with different NPXY motifs of CCM1. Our results demonstrated that CCM1 has a wide spectrum of binding to different PTB/PH proteins and perpetuates their specificity to interact with certain PTB/PH domains through selective combination of three NPXY motifs. We also demonstrated that CCM1 can be assembled into oligomers through intermolecular interaction between its F3 lobe in FERM domain and one of the three NPXY motifs. Despite being embedded in FERM domain as F3 lobe, F3 module acts as a fully functional PH domain to interact with NPXY motif. The most salient feature of the study was that both PTB and PH domains are structurally and functionally comparable, suggesting that PTB domain is likely evolved from PH domain with polymorphic structural additions at its N-terminus. CONCLUSIONS: A new ß1A-strand of the PTB domain was discovered and new minimum structural requirement of PTB/PH domain for NPXY motif-binding was determined. Based on our data, a novel theory of structure, function and relationship of PTB, PH and FERM domains has been proposed, which extends the importance of the NPXY-PTB/PH interaction on the CSC signaling and/or other cell receptors with great potential pointing to new therapeutic strategies. GENERAL SIGNIFICANCE: The study provides new insight into the structural characteristics of PTB/PH domains, essential structural elements of PTB/PH domain required for NPXY motif-binding, and function and relationship among PTB, PH and FERM domains.


Asunto(s)
Proteínas Sanguíneas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Fosfotirosina/metabolismo , Dominios Homólogos a Pleckstrina/fisiología , Dominios Proteicos/fisiología , Secuencias de Aminoácidos , Sitios de Unión , Unión Proteica
11.
Adv Exp Med Biol ; 924: 165-169, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27753038

RESUMEN

Circulating cell-free DNA (ccfDNA) is a promising diagnostic tool and its size fractionation is of interest. However, kits for isolation of ccfDNA available on the market are designed for small volumes hence processing large sample volumes is laborious. We have tested a new method that enables enrichment of ccfDNA from large volumes of plasma and subsequently allows size-fractionation of isolated ccfDNA into two fractions with individually established cut-off levels of ccfDNA length. This method allows isolation of low-abundant DNA as well as separation of long and short DNA molecules. This procedure may be important e.g., in prenatal diagnostics and cancer research that have been already confirmed by our primary experiments. Here, we report the results of selective separation of 200- and 500-bp long synthetic DNA fragments spiked in plasma samples. Furthermore, we size-fractionated ccfDNA from the plasma of pregnant women and verified the prevalence of fetal ccfDNA in all fractions.


Asunto(s)
ADN/sangre , ADN/aislamiento & purificación , Biología Molecular/métodos , Diagnóstico Prenatal/métodos , Sistema Libre de Células , ADN/genética , Femenino , Humanos , Reacción en Cadena de la Polimerasa/métodos , Embarazo , Reproducibilidad de los Resultados
12.
J Magn Reson Imaging ; 42(6): 1560-71, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25920095

RESUMEN

PURPOSE: To quantify the change in cerebral spinal fluid (CSF) production rate and maximum systolic velocity in astronauts before and after exposure to microgravity and identify any physiologic trend and/or risk factor related to intracranial hypertension. MATERIALS AND METHODS: Following Institutional Review Board (IRB) approval, with waiver of informed consent, a retrospective review of 27 astronauts imaged at 3T was done. Qualitative analysis was performed on T2 -weighted axial images through the orbits for degree of flattening of the posterior globe according to the following grades: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. One grade level change postflight was considered significant for exposure to intracranial hypertension. CSF production rate and maximum systolic velocity was calculated from cine phase-contrast magnetic resonance imaging and compared to seven healthy controls. RESULTS: Fourteen astronauts were studied. The preflight CSF production rate in astronauts was similar to controls (P = 0.83). Six astronauts with significant posterior globe flattening demonstrated a 70% increase in CSF production rate postflight compared to baseline (P = 0.01). There was a significant increase in CSF maximum systolic velocity in the subgroup without posterior globe flattening (P = 0.01). CONCLUSION: The increased postflight CSF production rate in astronauts with positive flattening is compatible with the hypothesis of microgravity-induced intracranial hypertension inferring downregulation in CSF production in microgravity that is upregulated upon return to normal gravity. Increased postflight CSF maximum systolic velocity in astronauts with negative flattening suggests increased craniospinal compliance and a potential negative risk factor to microgravity-induced intracranial hypertension.


Asunto(s)
Astronautas , Líquido Cefalorraquídeo/fisiología , Hipertensión Intracraneal/etiología , Hipertensión Intracraneal/patología , Imagen por Resonancia Magnética/métodos , Ingravidez/efectos adversos , Biomarcadores/líquido cefalorraquídeo , Líquido Cefalorraquídeo/citología , Método Doble Ciego , Humanos , Hidrodinámica , Hipertensión Intracraneal/líquido cefalorraquídeo , Presión Intracraneal , Masculino , Persona de Mediana Edad
13.
Org Biomol Chem ; 13(40): 10131-5, 2015 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-26411833

RESUMEN

Efficient conversion of ketones into kinetic enol phosphates under mild and accessible conditions has been realised using the developed methods with di-tert-butylmagnesium and bismesitylmagnesium. Optimisation of the quench protocol resulted in high yields of enol phosphates from a range of cyclohexanones and aryl methyl ketones, with tolerance of a range of additional functional units.


Asunto(s)
Carbono/química , Magnesio/química , Fosfatos/síntesis química , Cetonas/química , Cinética , Estructura Molecular , Fosfatos/química
14.
J Magn Reson Imaging ; 39(6): 1374-83, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24243801

RESUMEN

PURPOSE: To implement high resolution diffusion tensor imaging (DTI) for visualization and quantification of peripheral nerves in human forearm. MATERIALS AND METHODS: This HIPAA-compliant study was approved by our Institutional Review Board and written informed consent was obtained from all the study participants. Images were acquired with T1 -and T2 -weighted turbo spin echo with/without fat saturation, short tau inversion recovery (STIR). In addition, high spatial resolution (1.0 × 1.0 × 3.0 mm(3) ) DTI sequence was optimized for clearly visualizing ulnar, superficial radial and median nerves in the forearm. Maps of the DTI derived indices, fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity (λ// ) and radial diffusivity (λ⊥ ) were generated. RESULTS: For the first time, the three peripheral nerves, ulnar, superficial radial, and median, were visualized unequivocally on high resolution DTI-derived maps. DTI delineated the forearm nerves more clearly than other sequences. Significant differences in the DTI-derived measures, FA, MD, λ// and λ⊥ , were observed among the three nerves. A strong correlation between the nerve size derived from FA map and T2 -weighted images was observed. CONCLUSION: High spatial resolution DTI is superior in identifying and quantifying the median, ulnar, and superficial radial nerves in human forearm. Consistent visualization of small nerves and nerve branches is possible with high spatial resolution DTI. These normative data could potentially help in identifying pathology in diseased nerves. J. Magn. Reson. Imaging 2014;39:1374-1383. © 2013 Wiley Periodicals, Inc.


Asunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Imagen de Difusión Tensora/métodos , Antebrazo/inervación , Nervio Mediano/anatomía & histología , Nervio Radial/anatomía & histología , Nervio Cubital/anatomía & histología , Adulto , Anisotropía , Femenino , Antebrazo/anatomía & histología , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Nervios Periféricos/anatomía & histología , Valores de Referencia , Adulto Joven
15.
Sci Rep ; 14(1): 13776, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38877091

RESUMEN

This study examines the effect of coarse recycled aggregates (CRAs) and processed coarse recycled aggregates (PCRAs) on the behaviour of alkali-activated concrete (AAC) before and after exposure to marine seawater and acidic environments (5% HCl and 5% H2SO4 solutions). Measurements of compressive strength and the microstructure changes were conducted over periods of 56 and 90 days to assess these effects. The experimental design included varying the replacement levels of NAs with CRAs and PCRAs from (0-100%) and using ground-granulated blast furnace slag and fly ash as constant components. In addition to durability tests, sorptivity assessments were conducted to gauge the material's porosity and water absorption capabilities. Advanced microstructure techniques, such as scanning electron microscopy (SEM) and X-ray diffraction (XRD), were employed to detail the pre and post-exposure mineralogical and microstructural transformations within the AAC blends. The AAC mixtures incorporating PCRAs emerged as durable, showcasing better strength and a denser, more compact matrix facilitated by the synergistic formation of NASH and CASH gels after exposure to aggressive agents compared to untreated CRAs. In addition, the results show that the samples exposed to marine seawater exhibited improved mechanical performance compared to those exposed to acidic environments. The novelty of this study lies in its exploration of the effects of recycling plant-based CRAs and PCRAs on AAC for marine and acid exposure.

16.
J Med Chem ; 67(12): 10464-10489, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38866424

RESUMEN

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.


Asunto(s)
Administración Intravenosa , Animales , Administración Oral , Ratones , Relación Estructura-Actividad , Humanos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Estructura Molecular
17.
Chemistry ; 19(29): 9655-62, 2013 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-23765429

RESUMEN

The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of (hydroxymethyl)oxazoles and (hydroxymethyl)thiazoles. The reactions use a sustainable solvent and only require short reaction times. These are highly competitive methods for the construction of two classes of valuable heteroarenes, which bear a useful locus for further elaboration. Electronic structure calculations have shown that the order of events involves chalcogen atom attack at sp(3) carbon and alkyl-oxygen cleavage. The critical role of acid catalysis was shown clearly, and the importance of acid strength was demonstrated. The calculated barriers were also fully consistent with the observed order of thioamide and amide reactivity. Spontaneous ring opening involves a modest degree of C-O cleavage, moderating the extent of strain relief. On the acid-catalysed pathway, C-O cleavage is less extensive still, but proton transfer to the nucleofuge is well advanced with the carboxylic acid catalysts, and essentially complete with methanesulfonic acid.


Asunto(s)
Carbono/química , Calcógenos/química , Éteres Cíclicos/química , Oxazoles/síntesis química , Oxígeno/química , Tiazoles/síntesis química , Tioamidas/síntesis química , Catálisis , Computadores Moleculares , Microondas , Oxazoles/química , Solventes , Tiazoles/química , Tioamidas/química
18.
Polymers (Basel) ; 15(9)2023 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-37177125

RESUMEN

Wood is a cellulosic material that is most abundantly available in nature. Wood has been extensively used as reinforcement in polymer composite materials. Wood polymer composite (WPC) is an environmentally friendly and sustainable material exploited in building and construction within the marine, packaging, housewares, aerospace, and automotive industries. However, the precision of testing equipment for finding the properties of WPCs becomes less feasible compared to experimental analysis due to a high degree of differences in the measurement of properties such as stress, strain and deformation. Thus, evaluating the mechanical properties of WPCs using finite element analysis (FEA) can aid in overcoming the inadequacies in measuring physical properties prior to experimental analyses. Furthermore, the prediction of mechanical properties using simulation tools has evolved to analyze novel material performance under various conditions. The current study aimed to examine the mechanical properties of saw dust-reinforced recycled polypropylene (rPP) through experimentation and FEA. A model was developed using SolidWorks, and simulation was performed in ANSYS to predict the mechanical properties of the WPCs. To validate the obtained results, the simulated static tension test results were confirmed with experimental tension tests, and both assessments were well in accordance with each other. Using FEA to predict material properties could be a cost-effective technique in studying new materials under varied load conditions.

19.
J Magn Reson Imaging ; 36(4): 920-7, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22689475

RESUMEN

PURPOSE: To implement a diffusion tensor imaging (DTI) protocol for visualization of peripheral nerves in human forearm. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPAA)-compliant study was approved by our Institutional Review Board and written informed consent was obtained from 10 healthy participants. T(1) - and T(2) -weighted turbo spin echo with fat saturation, short tau inversion recovery (STIR), and DTI sequences with 21 diffusion-encoding directions were implemented to acquire images of the forearm nerves with an 8 channel knee coil on a 3T MRI scanner. Identification of the nerves was based on T(1) -weighted, T(2) -weighted, STIR, and DTI-derived fractional anisotropy (FA) images. Maps of the DTI-derived indices, FA, mean diffusivity (MD), longitudinal diffusivity (λ(//) ), and radial diffusivity (λ(⟂) ) along the length of the nerves were generated. RESULTS: DTI-derived maps delineated the forearm nerves more clearly than images acquired with other sequences. Only ulnar and median nerves were clearly visualized on the DTI-derived FA maps. No significant differences were observed between the left and right forearms in any of the DTI-derived measures. Significant variation in the DTI measures was observed along the length of the nerve. Significant differences in the DTI measures were also observed between the median and ulnar nerves. CONCLUSION: DTI is superior in visualizing the median and ulnar nerves in the human forearm. The normative data could potentially help distinguish normal from diseased nerves.


Asunto(s)
Imagen de Difusión por Resonancia Magnética/métodos , Antebrazo/inervación , Nervio Mediano/anatomía & histología , Nervio Cubital/anatomía & histología , Adulto , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto Joven
20.
Polymers (Basel) ; 14(19)2022 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-36236115

RESUMEN

The use of biodegradable polymers in daily life is increasing to reduce environmental hazards. In line with this, the present study aimed to develop a fully biodegradable polymer composite that was environmentally friendly and exhibited promising mechanical and thermal properties. Bamboo powder (BP)-reinforced polycaprolactone (PCL) composites were prepared using the solvent casting method. The influence of BP content on the morphology, wettability, and mechanical and thermal properties of the neat matrix was evaluated. In addition, the degradation properties of the composites were analysed through soil burial and acidic degradation tests. It was revealed that BP contents had an evident influence on the properties of the composites. The increase in the BP content has significantly improved the tensile strength of the PCL matrix. A similar trend is observed for thermal stability. Scanning electron micrographs demonstrated uniform dispersion of the BP in the PCL matrix. The degradation tests revealed that the biocomposites with 40 wt·% of BP degraded by more than 20% within 4 weeks in the acidic degradation test and more than 5% in the soil burial degradation test. It was noticed that there was a considerable difference in the degradation between the PCL matrix and the biocomposites of PCL and BP. These results suggest that biodegradable composites could be a promising alternative material to the existing synthetic polymer composites.

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