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1.
J Phys Chem Lett ; 13(1): 75-82, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-34958580

RESUMO

Octahedral symmetry is one of the parameters to tune the functional properties of complex oxides. VO2, a complex oxide with a 3d1 electronic system, exhibits an insulator-metal transition (IMT) near room temperature (∼68 °C), accompanying a change in the octahedral structure from asymmetrical to symmetrical. However, the role of octahedral symmetry in VO2 on the IMT characteristics is unclear. Crystal and electronic structure analyses combined with density-functional-theory calculations showed the bandwidth-controlled IMT characteristics of monoclinic VO2 with high octahedral symmetry. The expanded apical V-O length for a high octahedral symmetry of a VO2 film increased the bandwidth of the conduction band by depressing V 3d-O 2p hybridization. As a result, the interdimer hopping energy increased and thereby decreased the IMT temperature, although the short V-V chain enhanced electron correlation. These findings suggest that octahedral symmetry can control the IMT characteristics of VO2 by changing the orbital occupancy.

2.
J Invest Dermatol ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34756880

RESUMO

Vulvar squamous cell carcinoma pathogenesis is traditionally defined by the presence or absence of human papillomavirus (HPV), but the definition of these groups and their molecular characteristics remain ambiguous across studies. In this study, we present a retrospective cohort analysis of 36 patients with invasive vulvar squamous cell carcinoma where HPV status was determined using RNA in situ hybridization and PCR. Clinical annotation, p16 immunohistochemistry, PD-L1 immunohistochemistry, HPV16 circular E7 RNA detection, and RNA sequencing of the cases were performed. A combination of in situ hybridization and PCR identified 20 cases (55.6%) as HPV positive. HPV status did not impact overall survival (hazard ratio: 1.36, 95% confidence interval = 0.307-6.037, P = 0.6857) or progression-free survival (hazard ratio: 1.12, 95% confidence interval = 0.388-3.22, P = 0.8367), and no significant clinical differences were found between the groups. PD-L1 expression did not correlate with HPV status, but increased expression of PD-L1 correlated with worse overall survival. Transcriptomic analyses (n = 23) revealed distinct groups, defined by HPV status, with multiple differentially expressed genes previously implicated in HPV-induced cancers. HPV-positive tumors showed higher global expression of endogenous circular RNAs, including several circular RNAs that have previously been implicated in the pathogenesis of other cancers.

3.
ACS Appl Mater Interfaces ; 13(45): 54466-54475, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34739229

RESUMO

Understanding metal-to-insulator phase transitions in solids has been a keystone not only for discovering novel physical phenomena in condensed matter physics but also for achieving scientific breakthroughs in materials science. In this work, we demonstrate that the transport properties (i.e., resistivity and transition temperature) in the metal-to-insulator transitions of perovskite nickelates are tunable via the epitaxial heterojunctions of LaNiO3 and NdNiO3 thin films. A mismatch in the oxygen coordination environment and interfacial octahedral coupling at the oxide heterointerface allows us to realize an exotic phase that is unattainable in the parent compound. With oxygen vacancy formation for strain accommodation, the topmost LaNiO3 layer in LaNiO3/NdNiO3 bilayer thin films is structurally engineered and it electrically undergoes a metal-to-insulator transition that does not appear in metallic LaNiO3. Modification of the NdNiO3 template layer thickness provides an additional knob for tailoring the tilting angles of corner-connected NiO6 octahedra and the linked transport characteristics further. Our approaches can be harnessed to tune physical properties in complex oxides and to realize exotic physical phenomena through oxide thin-film heterostructuring.

4.
Nature ; 597(7877): 503-510, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34552257

RESUMO

Large, distributed collections of miniaturized, wireless electronic devices1,2 may form the basis of future systems for environmental monitoring3, population surveillance4, disease management5 and other applications that demand coverage over expansive spatial scales. Aerial schemes to distribute the components for such networks are required, and-inspired by wind-dispersed seeds6-we examined passive structures designed for controlled, unpowered flight across natural environments or city settings. Techniques in mechanically guided assembly of three-dimensional (3D) mesostructures7-9 provide access to miniature, 3D fliers optimized for such purposes, in processes that align with the most sophisticated production techniques for electronic, optoelectronic, microfluidic and microelectromechanical technologies. Here we demonstrate a range of 3D macro-, meso- and microscale fliers produced in this manner, including those that incorporate active electronic and colorimetric payloads. Analytical, computational and experimental studies of the aerodynamics of high-performance structures of this type establish a set of fundamental considerations in bio-inspired design, with a focus on 3D fliers that exhibit controlled rotational kinematics and low terminal velocities. An approach that represents these complex 3D structures as discrete numbers of blades captures the essential physics in simple, analytical scaling forms, validated by computational and experimental results. Battery-free, wireless devices and colorimetric sensors for environmental measurements provide simple examples of a wide spectrum of applications of these unusual concepts.

5.
Sci Rep ; 11(1): 11333, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078937

RESUMO

This study aimed to assess the prognostic value of MRI-measured tumor thickness (MRI-TT) in patients with tongue squamous cell carcinoma (SCC). This single-center retrospective cohort study included 133 pathologically confirmed tongue SCC patients between January 2009 and October 2019. MRI measurements of tongue SCC were based on axial and coronal T2-weighted (T2WI) and contrast-enhanced T1-weighted (CE-T1WI) images. Two radiologists independently measured MRI-TT. Intraclass correlation coefficients (ICC) were calculated for inter-rater agreements. Spearman's rank correlation between MRI-TT and pathologic depth of invasion (pDOI) was assessed. Cox proportional hazards analyses on recurrence-free (RFS) and overall survival (OS) were performed for MRI-TT and pDOI. Kaplan-Meier survival curves were plotted with log-rank tests. The intra- and inter-rater agreements of MRI-TT were excellent (ICC: 0.829-0.897, all P < 0.001). The correlation between MRI-TT and pDOI was good (Spearman's correlation coefficients: 0.72-0.76, P < 0.001). MRI-TT were significantly greater than pDOI in all axial and coronal T2WI and CE-T1WI (P < 0.001). In multivariate Cox proportional hazards analysis, MRI-TT measured on axial CE-T1WI yielded a significant prognostic value for OS (hazards ratio 2.77; P = 0.034). MRI-TT demonstrated excellent intra- and inter-rater agreements as well as high correlation with pDOI. MRI-TT may serve as a prognostic predictor in patients with tongue SCC.


Assuntos
Imageamento por Ressonância Magnética/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias da Língua/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias da Língua/patologia
6.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34088848

RESUMO

Homeothermic vertebrates produce heat in cold environments through thermogenesis, in which brown adipose tissue (BAT) increases mitochondrial oxidation along with uncoupling of the electron transport chain and activation of uncoupling protein 1 (UCP1). Although the transcription factors regulating the expression of UCP1 and nutrient oxidation genes have been extensively studied, only a few other proteins essential for BAT function have been identified. We describe the discovery of FAM195A, a BAT-enriched RNA binding protein, which is required for cold-dependent thermogenesis in mice. FAM195A knockout (KO) mice display whitening of BAT and an inability to thermoregulate. In BAT of FAM195A KO mice, enzymes involved in branched-chain amino acid (BCAA) metabolism are down-regulated, impairing their response to cold. Knockdown of FAM195A in brown adipocytes in vitro also impairs expression of leucine oxidation enzymes, revealing FAM195A to be a regulator of BCAA metabolism and a potential target for metabolic disorders.


Assuntos
Adipócitos Marrons , Tecido Adiposo Marrom , Temperatura Baixa , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Termogênese , Aminoácidos de Cadeia Ramificada/genética , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Linhagem Celular Transformada , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout
7.
PLoS Pathog ; 17(5): e1009582, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33999949

RESUMO

Circular RNAs (circRNAs) are a conserved class of RNAs with diverse functions, including serving as messenger RNAs that are translated into peptides. Here we describe circular RNAs generated by human polyomaviruses (HPyVs), some of which encode variants of the previously described alternative large T antigen open reading frame (ALTO) protein. Circular ALTO RNAs (circALTOs) can be detected in virus positive Merkel cell carcinoma (VP-MCC) cell lines and tumor samples. CircALTOs are stable, predominantly located in the cytoplasm, and N6-methyladenosine (m6A) modified. The translation of MCPyV circALTOs into ALTO protein is negatively regulated by MCPyV-generated miRNAs in cultured cells. MCPyV ALTO expression increases transcription from some recombinant promoters in vitro and upregulates the expression of multiple genes previously implicated in MCPyV pathogenesis. MCPyV circALTOs are enriched in exosomes derived from VP-MCC lines and circALTO-transfected 293T cells, and purified exosomes can mediate ALTO expression and transcriptional activation in MCPyV-negative cells. The related trichodysplasia spinulosa polyomavirus (TSPyV) also expresses a circALTO that can be detected in infected tissues and produces ALTO protein in cultured cells. Thus, human polyomavirus circRNAs are expressed in human tumors and infected tissues and express proteins that have the potential to modulate the infectious and tumorigenic properties of these viruses.


Assuntos
Antígenos Virais de Tumores/genética , Carcinoma de Célula de Merkel/virologia , Poliomavírus das Células de Merkel/genética , Infecções por Polyomavirus/virologia , RNA Circular/genética , Infecções Tumorais por Vírus/virologia , Exossomos , Regulação Viral da Expressão Gênica , Células HEK293 , Humanos , MicroRNAs/genética , RNA Mensageiro/genética , RNA Viral/genética
8.
Hum Brain Mapp ; 42(10): 3295-3304, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33939212

RESUMO

This study investigated the empathic response of postpartum women to babies in pain and the underlying neural mechanism. Postpartum women responded with more empathy and speed to babies over other stimuli compared to controls. Brain scans taken 3 months after birth showed more elevated activation in the Middle cingulate cortex/middle frontal gyrus (MCC/MFG) than the controls regardless of the task condition. When compared to the adult and neutral conditions, the posterior cingulate cortex (PCC) region was consistently more activated when postpartum women saw babies than controls. In addition, higher activation levels in the PCC region for the baby condition significantly correlated with faster and more empathic responses to babies. Considering that PCC is a core region for the theory of mind or mentalizing which requires cognitive reasoning to understand others, these results suggest that PCC might be a pivotal neural locus facilitating cognitive efforts to empathize with babies during the postpartum period. In a follow-up experiment at 12 months after birth, we were still able to observe higher activity in the MCC/MFG of postpartum women. However, previously observed PCC activation patterns disappeared 12 months after birth, despite the women's response patterns to babies still being maintained. These results suggest that the mentalizing process activated to empathize with babies in the early postpartum period becomes less cognitively demanding over time.

9.
G3 (Bethesda) ; 11(4)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33713107

RESUMO

In microbiome research, metagenomic sequencing generates enormous amounts of data. These data are typically classified into taxa for taxonomy analysis, or into genes for functional analysis. However, a joint analysis where the reads are classified into taxa-specific genes is often overlooked. To enable the analysis of this biologically meaningful feature, we developed a novel bioinformatic toolkit, MetaPrism, which can analyze sequence reads for a set of joint taxa/gene analyses to: 1) classify sequence reads and estimate the abundances for taxa-specific genes; 2) tabularize and visualize taxa-specific gene abundances; 3) compare the abundances between groups; and 4) build prediction models for clinical outcome. We illustrated these functions using a published microbiome metagenomics dataset from patients treated with immune checkpoint inhibitor therapy and showed the joint features can serve as potential biomarkers to predict therapeutic responses. MetaPrism is a toolkit for joint taxa and gene analysis. It offers biological insights on the taxa-specific genes on top of the taxa-alone or gene-alone analysis. MetaPrism is open-source software and freely available at https://github.com/jiwoongbio/MetaPrism. The example script to reproduce the manuscript is also provided in the above code repository.


Assuntos
Metagenômica , Microbiota , Algoritmos , Biologia Computacional , Humanos , Metagenoma , Microbiota/genética , Análise de Sequência de DNA , Software
10.
Adv Mater ; 33(10): e2007550, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33538016

RESUMO

Despite the importance of carrier mobility, recent research efforts have been mainly focused on the improvement of volumetric capacitance in order to maximize the figure-of-merit, µC* (product of carrier mobility and volumetric capacitance), for high-performance organic electrochemical transistors. Herein, high-performance microfiber-based organic electrochemical transistors with unprecedentedly large µC* using highly ordered crystalline poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) microfibers with very high carrier mobilities are reported. The strain engineering via uniaxial tension is employed in combination with solvent-mediated crystallization in the course of drying coagulated fibers, resulting in the permanent preferential alignment of crystalline PEDOT:PSS domains along the fiber direction, which is verified by atomic force microscopy and transmission wide-angle X-ray scattering. The resultant strain-engineered microfibers exhibit very high carrier mobility (12.9 cm2 V-1 s-1 ) without the trade-off in volumetric capacitance (122 F cm-3 ) and hole density (5.8 × 1020  cm-3 ). Such advantageous electrical and electrochemical characteristics offer the benchmark parameter of µC* over ≈1500 F cm-1  V-1  s-1 , which is the highest metric ever reported in the literature and can be beneficial for realizing a new class of substrate-free fibrillar and/or textile bioelectronics in the configuration of electrochemical transistors and/or electrochemical ion pumps.


Assuntos
Equipamentos e Provisões Elétricas , Microtecnologia/instrumentação , Compostos Orgânicos , Anisotropia
11.
Nanoscale ; 13(8): 4475-4484, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33595003

RESUMO

Fabrication of plasmonic nanostructures in a precise and reliable manner is a topic of huge interest because their structural details significantly affect their plasmonic properties. Herein, we present nanotip indentation lithography (NTIL) based on atomic force microscopy (AFM) indentation for the patterning of plasmonic nanostructures with precisely controlled size and shape. The size of the nanostructures is controlled by varying the indentation force of AFM tips into the mask polymer; while their shapes are determined to be nanodisks (NDs) or nanotriangles (NTs) depending on the shapes of the AFM tip apex. The localized surface plasmon resonance of the NDs is tailored to cover most of the visible-wavelength regime by controlling their size. The NTs show distinct polarization-dependent plasmon modes consistent with full-wave optical simulations. For the demonstration of the light-matter interaction control capability of NTIL nanostructures, we show that photoluminescence enhancement from MoS2 layers can be deliberately controlled by tuning the size of the nanostructures. Our results pave the way for the AFM-indentation-based fabrication of plasmonic nanostructures with a highly precise size and shape controllability and reproducibility.

12.
Nat Commun ; 12(1): 690, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514739

RESUMO

Lamins and transmembrane proteins within the nuclear envelope regulate nuclear structure and chromatin organization. Nuclear envelope transmembrane protein 39 (Net39) is a muscle nuclear envelope protein whose functions in vivo have not been explored. We show that mice lacking Net39 succumb to severe myopathy and juvenile lethality, with concomitant disruption in nuclear integrity, chromatin accessibility, gene expression, and metabolism. These abnormalities resemble those of Emery-Dreifuss muscular dystrophy (EDMD), caused by mutations in A-type lamins (LMNA) and other genes, like Emerin (EMD). We observe that Net39 is downregulated in EDMD patients, implicating Net39 in the pathogenesis of this disorder. Our findings highlight the role of Net39 at the nuclear envelope in maintaining muscle chromatin organization, gene expression and function, and its potential contribution to the molecular etiology of EDMD.


Assuntos
Proteínas de Membrana/deficiência , Músculo Esquelético/patologia , Distrofia Muscular de Emery-Dreifuss/genética , Membrana Nuclear/patologia , Proteínas Nucleares/metabolismo , Fosfatidato Fosfatase/metabolismo , Animais , Linhagem Celular , Cromatina/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Lamina Tipo A/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Músculo Esquelético/citologia , Distrofia Muscular de Emery-Dreifuss/patologia , Proteínas Nucleares/genética , Fosfatidato Fosfatase/genética , RNA-Seq , Estudos Retrospectivos
13.
J Antimicrob Chemother ; 76(2): 385-395, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33164081

RESUMO

BACKGROUND: Approximately half of clinical carbapenem-resistant Enterobacterales (CRE) isolates lack carbapenem-hydrolysing enzymes and develop carbapenem resistance through alternative mechanisms. OBJECTIVES: To elucidate development of carbapenem resistance mechanisms from clonal, recurrent ESBL-positive Enterobacterales (ESBL-E) bacteraemia isolates in a vulnerable patient population. METHODS: This study investigated a cohort of ESBL-E bacteraemia cases in Houston, TX, USA. Oxford Nanopore Technologies long-read and Illumina short-read sequencing data were used for comparative genomic analysis. Serial passaging experiments were performed on a set of clinical ST131 Escherichia coli isolates to recapitulate in vivo observations. Quantitative PCR (qPCR) and qRT-PCR were used to determine copy number and transcript levels of ß-lactamase genes, respectively. RESULTS: Non-carbapenemase-producing CRE (non-CP-CRE) clinical isolates emerged from an ESBL-E background through a concurrence of primarily IS26-mediated amplifications of blaOXA-1 and blaCTX-M-1 group genes coupled with porin inactivation. The discrete, modular translocatable units (TUs) that carried and amplified ß-lactamase genes mobilized intracellularly from a chromosomal, IS26-bound transposon and inserted within porin genes, thereby increasing ß-lactamase gene copy number and inactivating porins concurrently. The carbapenem resistance phenotype and TU-mediated ß-lactamase gene amplification were recapitulated by passaging a clinical ESBL-E isolate in the presence of ertapenem. Clinical non-CP-CRE isolates had stable carbapenem resistance phenotypes in the absence of ertapenem exposure. CONCLUSIONS: These data demonstrate IS26-mediated mechanisms underlying ß-lactamase gene amplification with concurrent outer membrane porin disruption driving emergence of clinical non-CP-CRE. Furthermore, these amplifications were stable in the absence of antimicrobial pressure. Long-read sequencing can be utilized to identify unique mobile genetic element mechanisms that drive antimicrobial resistance.


Assuntos
Bacteriemia , Porinas , Antibacterianos/farmacologia , Bacteriemia/tratamento farmacológico , Proteínas de Bactérias/genética , Carbapenêmicos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Porinas/genética , beta-Lactamases/genética , beta-Lactamases/metabolismo
14.
Biostatistics ; 22(3): 522-540, 2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31844880

RESUMO

Microbiome omics approaches can reveal intriguing relationships between the human microbiome and certain disease states. Along with identification of specific bacteria taxa associated with diseases, recent scientific advancements provide mounting evidence that metabolism, genetics, and environmental factors can all modulate these microbial effects. However, the current methods for integrating microbiome data and other covariates are severely lacking. Hence, we present an integrative Bayesian zero-inflated negative binomial regression model that can both distinguish differentially abundant taxa with distinct phenotypes and quantify covariate-taxa effects. Our model demonstrates good performance using simulated data. Furthermore, we successfully integrated microbiome taxonomies and metabolomics in two real microbiome datasets to provide biologically interpretable findings. In all, we proposed a novel integrative Bayesian regression model that features bacterial differential abundance analysis and microbiome-covariate effects quantifications, which makes it suitable for general microbiome studies.


Assuntos
Microbiota , Bactérias , Teorema de Bayes , Humanos , Modelos Estatísticos
15.
Genes (Basel) ; 12(1)2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33374967

RESUMO

Autism spectrum disorder (ASD) is a highly heritable condition caused by a combination of environmental and genetic factors such as de novo and inherited variants, as well as rare or common variants among hundreds of related genes. Previous genome-wide association studies have identified susceptibility genes; however, most ASD-associated genes remain undiscovered. This study aimed to examine rare de novo variants to identify genetic risk factors of ASD using whole exome sequencing (WES), functional characterization, and genetic network analyses of identified variants using Korean familial dataset. We recruited children with ASD and their biological parents. The clinical best estimate diagnosis of ASD was made according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5TM), using comprehensive diagnostic instruments. The final analyses included a total of 151 individuals from 51 families. Variants were identified and filtered using the GATK Best Practices for bioinformatics analysis, followed by genome alignments and annotation to the reference genome assembly GRCh37 (liftover to GRCh38), and further annotated using dbSNP 154 build databases. To evaluate allele frequencies of de novo variants, we used the dbSNP, gnomAD exome v2.1.1, and genome v3.0. We used Ingenuity Pathway Analysis (IPA, Qiagen) software to construct networks using all identified de novo variants with known autism-related genes to find probable relationships. We identified 36 de novo variants with potential relations to ASD; 27 missense, two silent, one nonsense, one splice region, one splice site, one 5' UTR, and one intronic SNV and two frameshift deletions. We identified six networks with functional relationships. Among the interactions between de novo variants, the IPA assay found that the NF-κB signaling pathway and its interacting genes were commonly observed at two networks. The relatively small cohort size may affect the results of novel ASD genes with de novo variants described in our findings. We did not conduct functional experiments in this study. Because of the diversity and heterogeneity of ASD, the primary purpose of this study was to investigate probable causative relationships between novel de novo variants and known autism genes. Additionally, we based functional relationships with known genes on network analysis rather than on statistical analysis. We identified new variants that may underlie genetic factors contributing to ASD in Korean families using WES and genetic network analyses. We observed novel de novo variants that might be functionally linked to ASD, of which the variants interact with six genetic networks.


Assuntos
Transtorno do Espectro Autista/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , /genética , Criança , Pré-Escolar , Biologia Computacional , Exoma , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Mutação , República da Coreia , Fatores de Risco , Sequenciamento Completo do Exoma
16.
Children (Basel) ; 7(12)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255281

RESUMO

This study compared the demineralization resistance of teeth treated with silver diamine fluoride (SDF) to that treated with fluoride varnish. A total of 105 healthy bovine incisors were divided into control, fluoride varnish, and SDF groups. The enamel surface density change was then measured by micro-computed tomography (micro-CT) at three depths. The demineralized zone volume was measured on 3D micro-CT images to evaluate the total demineralization rate. The enamel surface morphology was assessed by scanning electron microscope. The enamel density had continuously decreased while demineralization increased in the control and fluoride varnish groups. The enamel density had increased in the SDF group till the 7th day of demineralization treatment and decreased thereafter. However, the decrease in the SDF group was less severe than that in the other groups (p < 0.05). The demineralized enamel volume had increased through treatment and was the highest in the control group, followed by the fluoride varnish and SDF group. The enamel surface morphology was the roughest and most irregular in the control group, followed by the fluoride varnish group and SDF groups.

17.
Microorganisms ; 9(1)2020 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-33375757

RESUMO

Deinoxanthin, a xanthophyll derived from Deinococcus species, is a unique organic compound that provides greater antioxidant effects compared to other carotenoids due to its superior scavenging activity against singlet oxygen and hydrogen peroxide. Therefore, it has attracted significant attention as a next-generation organic compound that has great potential as a natural ingredient in a food supplements. Although the microbial identification of deinoxanthin has been identified, mass production has not yet been achieved. Here, we report, for the first time, the development of an engineered extremophilic microorganism, Deinococcus radiodurans strain R1, that is capable of producing deinoxanthin through rational metabolic engineering and process optimization. The genes crtB and dxs were first introduced into the genome to reinforce the metabolic flux towards deinoxanthin. The optimal temperature was then identified through a comparative analysis of the mRNA expression of the two genes, while the carbon source was further optimized to increase deinoxanthin production. The final engineered D. radiodurans strain R1 was able to produce 394 ± 17.6 mg/L (102 ± 11.1 mg/g DCW) of deinoxanthin with a yield of 40.4 ± 1.2 mg/g sucrose and a productivity of 8.4 ± 0.2 mg/L/h from 10 g/L of sucrose. The final engineered strain and the strategies developed in the present study can act as the foundation for the industrial application of extremophilic microorganisms.

18.
J Med Chem ; 63(22): 14054-14066, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33180487

RESUMO

A phenotypic high-throughput screen identified a benzamide small molecule with activity against small cell lung cancer cells. A "clickable" benzamide probe was designed that irreversibly bound a single 50 kDa cellular protein, identified by mass spectrometry as ß-tubulin. Moreover, the anti-cancer potency of a series of benzamide analogs strongly correlated with probe competition, indicating that ß-tubulin was the functional target. Additional evidence suggested that benzamides covalently modified Cys239 within the colchicine binding site. Consistent with this mechanism, benzamides impaired growth of microtubules formed with ß-tubulin harboring Cys239, but not ß3 tubulin encoding Ser239. We therefore designed an aldehyde-containing analog capable of trapping Ser239 in ß3 tubulin, presumably as a hemiacetal. Using a forward genetics strategy, we identified benzamide-resistant cell lines harboring a Thr238Ala mutation in ß-tubulin sufficient to induce compound resistance. The disclosed chemical probes are useful to identify other colchicine site binders, a frequent target of structurally diverse small molecules.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/química , Colchicina/metabolismo , Microtúbulos/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Antineoplásicos/química , Sítios de Ligação , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Microtúbulos/metabolismo , Conformação Proteica , Carcinoma de Pequenas Células do Pulmão/patologia , Relação Estrutura-Atividade , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química
19.
J Phys Chem Lett ; 11(22): 9680-9688, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33135900

RESUMO

Studies on the hydrogen incorporated M1 phase of VO2 film have been widely reported. However, there are few works on an M2 phase of VO2. Recently, the M2 phase in VO2 has received considerable attention due to the possibility of realizing a Mott transition field-effect transistor. By varying the postannealing environment, systematic variations of the M2 phase in (020)-oriented VO2 films grown on Al2O3(0001) were observed. The M2 phase converted to the metallic M1 phase at first and then to the metallic rutile phase after hydrogen annealing (i.e., for H2/N2 mixture and H2 environments). From the diffraction and spectroscopy measurements, the transition is attributed to suppressed electron interactions, not structural modification caused by hydrogen incorporation. Our results suggest the understanding of the phase transition process of the M2 phase by hydrogen incorporation and the possibility of realization of the M2 phased-based Mott transition field-effect transistor.

20.
Hum Brain Mapp ; 41(18): 5313-5324, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32897599

RESUMO

We investigated the narrow-sense heritability of MRI-visible dilated perivascular spaces (dPVS) in healthy young adult twins and nontwin siblings (138 monozygotic, 79 dizygotic twin pairs, and 133 nontwin sibling pairs; 28.7 ± 3.6 years) from the Human Connectome Project. dPVS volumes within basal ganglia (BGdPVS) and white matter (WMdPVS) were automatically calculated on three-dimensional T2-weighted MRI. In univariate analysis, heritability estimates of BGdPVS and WMdPVS after age and sex adjustment were 65.8% and 90.2%. In bivariate analysis, both BGdPVS and WMdPVS showed low to moderate genetic correlations (.30-.43) but high shared heritabilities (71.8-99.9%) with corresponding regional volumes, intracranial volumes, and other regional dPVS volumes. Older age was significantly associated with larger dPVS volume in both regions even after adjusting for clinical and volumetric variables, while blood pressure was not associated with dPVS volume although there was weak genetic correlation. dPVS volume, particularly WMdPVS, was highly heritable in healthy young adults, adding evidence of a substantial genetic contribution in dPVS development and differential effect by location. Age affects dPVS volume even in young adults, while blood pressure might have limited role in dPVS development in its normal range.

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