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1.
Nat Commun ; 15(1): 2871, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605019

RESUMO

The development of van der Waals heterostructures has introduced unconventional phenomena that emerge at atomically precise interfaces. For example, interlayer excitons in two-dimensional transition metal dichalcogenides show intriguing optical properties at low temperatures. Here we report on room-temperature observation of interface excitons in mixed-dimensional heterostructures consisting of two-dimensional tungsten diselenide and one-dimensional carbon nanotubes. Bright emission peaks originating from the interface are identified, spanning a broad energy range within the telecommunication wavelengths. The effect of band alignment is investigated by systematically varying the nanotube bandgap, and we assign the new peaks to interface excitons as they only appear in type-II heterostructures. Room-temperature localization of low-energy interface excitons is indicated by extended lifetimes as well as small excitation saturation powers, and photon correlation measurements confirm antibunching. With mixed-dimensional van der Waals heterostructures where band alignment can be engineered, new opportunities for quantum photonics are envisioned.

2.
Nat Commun ; 14(1): 8152, 2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38071345

RESUMO

Nanomaterials exhibit unique optical phenomena, in particular excitonic quantum processes occurring at room temperature. The low dimensionality, however, imposes strict requirements for conventional optical excitation, and an approach for bypassing such restrictions is desirable. Here we report on exciton transfer in carbon-nanotube/tungsten-diselenide heterostructures, where band alignment can be systematically varied. The mixed-dimensional heterostructures display a pronounced exciton reservoir effect where the longer-lifetime excitons within the two-dimensional semiconductor are funneled into carbon nanotubes through diffusion. This new excitation pathway presents several advantages, including larger absorption areas, broadband spectral response, and polarization-independent efficiency. When band alignment is resonant, we observe substantially more efficient excitation via tungsten diselenide compared to direct excitation of the nanotube. We further demonstrate simultaneous bright emission from an array of carbon nanotubes with varied chiralities and orientations. Our findings show the potential of mixed-dimensional heterostructures and band alignment engineering for energy harvesting and quantum applications through exciton manipulation.

3.
Rev Sci Instrum ; 94(6)2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37862511

RESUMO

We report on an Er-doped fiber (EDF)-laser-based dual-comb system that allows us to perform triggerless asynchronous optical sampling pump-probe measurements of ultrafast demagnetization and spin precession in magnetic materials. Because the oscillation frequencies of the two frequency-comb light sources are highly stabilized, the pulse-to-pulse timing jitter is sufficiently suppressed, and data accumulation without any trigger signals is possible. To effectively induce spin precession in ferromagnetic thin films, the spectral bandwidth of the output of one of the EDF frequency comb sources is broadened by a highly nonlinear fiber and then amplified at a wavelength of about 1030 nm by a Yb-doped fiber amplifier. The output of the other frequency comb source is converted to about 775 nm by second harmonic generation. We used this system to observe ultrafast demagnetization and spin precession dynamics on the picosecond and nanosecond time scales in a permalloy thin film. This time-domain spectroscopy system is promising for the rapid characterization of spin-wave generation and propagation dynamics in magnetic materials.

4.
Angew Chem Int Ed Engl ; 61(49): e202210600, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36097796

RESUMO

Understanding the mechanisms that connect heat and electron transport with crystal structures and defect chemistry is fundamental to develop materials with thermoelectric properties. In this work, we synthesized a series of self-doped compounds Cu2+x Mn1-x GeS4 through Cu for Mn substitution. Using a combination of powder X-ray diffraction, high resolution transmission electron microscopy and precession-assisted electron diffraction tomography, we evidence that the materials are composed of interconnected enargite- and stannite-type structures, via the formation of nanodomains with a high density of coherent interfaces. By combining experiments with ab initio electron and phonon calculations, we discuss the structure-thermoelectric properties relationships and clarify the interesting crystal chemistry in this system. We demonstrate that excess Cu+ substituted for Mn2+ dopes holes into the top of the valence band, leading to a remarkable enhancement of the power factor and figure of merit ZT.

5.
J Dent Res ; 101(12): 1537-1543, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35786034

RESUMO

The periodontal ligament (PDL) contains mesenchymal stem cells (MSCs) that can differentiate into osteoblasts, cementoblasts, and fibroblasts. Nevertheless, the distribution and characteristics of these cells remain uncertain. Gli1, an essential hedgehog signaling transcription factor, functions in undifferentiated cells during embryogenesis. Therefore, in the present study, the differentiation ability of Gli1+ cells was examined using Gli1-CreERT2/ROSA26-loxP-stop-loxP-tdTomato (iGli1/Tomato) mice. In 4-wk-old iGli1/Tomato mice, Gli1/Tomato+ cells were only slightly detected in the PDL, around endomucin-expressing blood vessels. These cells had proliferated over time, localizing in the PDL as well as on the bone and cementum surfaces at day 28. However, in 8-wk-old iGli1/Tomato mice, Gli1/Tomato+ cells were quiescent, as most cells were not immunoreactive for Ki-67. These cells in 8-wk-old mice exhibited high colony-forming unit fibroblast activity and were capable of osteogenic, chondrogenic, and adipogenic differentiation in vitro. In addition, after transplantation of teeth of iGli1/Tomato mice into the hypodermis of wild-type mice, Tomato fluorescence indicating the progeny of Gli1+ cells was detected in the osteoblasts and osteocytes of the regenerated bone. These results demonstrate that Gli1+ cells in the PDL were MSCs and could contribute to the alveolar bone regeneration.


Assuntos
Proteínas Hedgehog , Ligamento Periodontal , Camundongos , Animais , Proteína GLI1 em Dedos de Zinco , Antígeno Ki-67 , Diferenciação Celular , Homeostase , Sialomucinas
6.
New Microbes New Infect ; 44: 100933, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34631109

RESUMO

Bacteroides pyogenes is a member of the oral flora of cats and dogs. We report a case of B. pyogenes isolated from an appendiceal abscess in a patient without a history of animal contact. This species was identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and sequencing of 16S rRNA, rpoB, gyrB and hsp60 genes.

7.
ACS Appl Mater Interfaces ; 11(30): 27178-27182, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31276618

RESUMO

The atomic switches have attracted wide attention owing to their applications in nonvolatile electric devices. The atomic switch is operated by the formation and dissipation of a metallic filament inside a metal sulfide film, which is controlled by a solid electrochemical reaction. Although the metallic filament is considered to consist of metal atoms, the chemical species of the metallic filament are difficult to be identified due to challenges in observing the metallic filament inside the solid. In this study, we report the investigation on the metallic filament in the atomic switch with metal sulfide based on point-contact spectroscopy (PCS). By cooling the atomic switch, the switch voltage increased to 1 V, which allowed for the PCS measurement. The PCS revealed that the metallic filament was composed of Ag atoms in the case of the Pt/Ag2S/Ag atomic switch. We applied this technique to the Pt/Cu2S/Ag and Pt/Ag2S/Cu atomic switches to uncover the formation process of the metallic filament. In both atomic switches, the chemical species of the metallic filament were Ag. The metal atoms were supplied from both the metal electrode and the sulfide layer.

8.
Phys Chem Chem Phys ; 21(31): 16910-16913, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31123746

RESUMO

We have studied the stretch dependence of the electronic structure and vibrational energy for the 4,4'-bipyridine (BPY) single molecule junction, which was fabricated by the mechanically controllable break junction (MCBJ) using the highly stable nano MCBJ electrodes. The electronic structure and vibrational energy of the single molecule junction were studied by the current-voltage (I-V) curve and surface enhanced Raman scattering (SERS), respectively. The simultaneous SERS and I-V curve measurements revealed the lowest unoccupied molecular orbital (LUMO) and vibrational energy of the C-C stretching mode decreased with an increase in the metal-molecule distance. The molecular orbital energy shift and vibrational energy shift can be explained by the change in the degree of the hybridization of molecular and metal orbitals.

9.
Nanotechnology ; 30(12): 125202, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30620940

RESUMO

We have studied the formation process of the metal atomic filament for metal sulfide atomic switches by electrical measurement. The switching between ON and OFF states of the atomic switch is controlled by the application of the bias voltage for the atomic switches. The SET (OFF â†’ ON) and RESET (ON â†’ OFF) voltages were investigated for the atomic switch where the Ag2S or Cu2S layer were sandwiched between the Pt and Ag or Cu electrodes. The SET and RESET voltages of the Ag/Cu2S/Pt and Cu/Ag2S/Pt were close to those of the Ag/Ag2S/Pt atomic switch, and different from those of the Cu/Cu2S/Pt atomic switch. These results indicated that the dominant chemical species of the making and breaking part of the metal filament was Ag, and that the source of the metal filament was both the sulfide layer and the metal electrode.

10.
RSC Adv ; 9(16): 9001-9005, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35517651

RESUMO

We studied the effect of dielectric heating on the enhancement of freeze-drying by electromagnetic waves (EMWs) under different frequencies: 2.45 GHz microwaves (MWs), and 27 and 200 MHz radio frequencies (RFs). The irradiation with RFs, particularly at 27 MHz, reduced the duration of freeze-drying by 67%. We further analysed the water structure by in situ Raman spectroscopy during freeze-drying under EMWs. The phase transition from ice to water occurred soon after starting irradiation by MWs at 2.45 GHz, while the ice phase was almost maintained at an RF of 27 MHz.

11.
BJS Open ; 2(4): 195-202, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30079388

RESUMO

BACKGROUND: The optimal level for inferior mesenteric artery ligation during anterior resection for rectal cancer is controversial. The aim of this randomized trial was to clarify whether the inferior mesenteric artery should be tied at the origin (high tie) or distal to the left colic artery (low tie). METHODS: Patients were allocated randomly to undergo either high- or low-tie ligation and were stratified by surgical approach (open or laparoscopic). The primary outcome was the incidence of anastomotic leakage. Secondary outcomes were duration of surgery, blood loss and 5-year overall survival. RESULTS: Some 331 patients entered the trial between June 2006 and September 2012. The trial was stopped prematurely as recruitment was slow. Seven patients were excluded after randomization but before operation because of procedural changes. High tie and low tie were performed in 164 and 160 patients respectively. The incidence of anastomotic leakage was not significantly different (17·7 versus 16·3 per cent respectively; P = 0·731). The incidence of severe complications requiring intervention was 2·4 versus 5·0 per cent for high and low tie respectively (P = 0·222). In multivariable analysis, risk factors for anastomotic leakage included male sex (odds ratio 4·36, 95 per cent c.i. 1·56 to 12·18) and distance of the tumour from the anal verge (odds ratio 0·99, 0·98 to 1·00). At 5 years there were no significant differences in overall (87·2 versus 89·4 per cent respectively; P = 0·386) and disease-free (76·3 versus 77·6 per cent; P = 0·765) survival. CONCLUSION: The level of ligation of the inferior mesenteric artery does not significantly influence the rate of anastomotic leakage. Registration number: NCT01861678 ( https://clinicaltrials.gov).

12.
Phys Chem Chem Phys ; 20(12): 7947-7952, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29505056

RESUMO

We have investigated the electric conductance and atomic structure of single molecular junctions of pyrazine (Py), 4,4'-bipyridine (BiPy), fullerene (C60), and 1,4-diaminobutane (DAB). The single molecular junctions were fabricated by breaking Au contacts between an Au tip and the Au electrode surface in the presence of the target molecules (breaking process) or approaching the Au tip to the Au electrode surface covered by the molecules (making process). In the making process, no major conductance state was observed in the conductance histogram for DAB, while single conductance states were observed for the π-conjugated molecules of Py (10 mG0, G0∼ 77.45 µΩ-1), BiPy (3 mG0), and C60 (5 mG0). In contrast to the making process, two major conductance states were observed for Py (1 mG0 and 0.3 mG0), BiPy (0.6 mG0 and 0.2 mG0), and C60 (30 mG0 and 3 mG0) in the breaking process. The observed conductance behavior could be explained by the characters of the anchoring unit of molecules. In the making process, anchoring of molecules cannot be established by the point contact between the Au electrode and the localized lone pair of the N atom of DAB, Py, and BiPY, while molecules anchor on the Au electrode by using the plane-like contact between the Au electrode and the delocalized π electrons in the aromatic ring of Py, BiPY, and C60, which explains the difference in the observed conductance behavior between DAB and the π conjugated molecules of Py, BiPY, and C60 in the making process. In the breaking process, the delocalized π-electrons of Py, BiPY, and C60 can make a contact with the Au electrode surface and the lone pair on the N atom of DAB as well as Py and BiPY can bind to Au atoms, and therefore, single molecular junctions were formed for all systems. The present results indicate that the π-plane is important for making metal-molecule contacts and for the formation of the single molecular junction in the making process.

13.
Lett Appl Microbiol ; 66(6): 542-548, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29574855

RESUMO

This study investigated the occurrence of Escherichia coli pathotypes in sanitary wastewater and drinking water in a Bangladeshi urban slum and the potential associations between these sources. We examined 621 E. coli isolates from sanitary wastewater and stored drinking water by multiplex PCR and dual-index sequencing, classifying them into eight pathotypes based on 14 virulence genes and additionally evaluating the possession of the human-specific E. coli genetic biomarker H8. The proportions of pathogenic E. coli were significantly different (P < 0·001) between wastewater (18·6%) and drinking water (1·7%). StIb-positive enterotoxigenic E. coli (ETEC) were predominant in wastewater, indicating that people in the site carried ETEC. In contrast, no ETEC was present in drinking water and the proportion of H8-positive isolates was significantly smaller (7·8%) than that in wastewater (16·3%) (P = 0·001). Our findings indicate that sanitary wastewater from the slum was heavily contaminated with pathogenic E. coli, posing a great health risk. Furthermore, E. coli contamination of drinking water could be derived from not only human but also other sources. SIGNIFICANCE AND IMPACT OF THE STUDY: Sanitary wastewater from an urban slum was heavily contaminated with pathogenic Escherichia coli. It is worth noting a great health risk of accidental exposure to pathogenically contaminated wastewater improperly discharged in and around urban slums. The distinct difference in pathotypes between wastewater and drinking water and the significantly smaller positive proportion of the human-specific E. coli genetic biomarker (H8) in drinking water indicate that drinking water contamination could be derived from not only human but also other sources. This highlights that pathotyping in association with the H8 marker provides an indication of pathogen contamination sources of environmental transmission media.


Assuntos
Água Potável/microbiologia , Escherichia coli Enterotoxigênica/isolamento & purificação , Escherichia coli Enterotoxigênica/patogenicidade , Áreas de Pobreza , Águas Residuárias/microbiologia , Bangladesh , Escherichia coli Enterotoxigênica/classificação , Infecções por Escherichia coli/microbiologia , Humanos , Tipagem Molecular , Reação em Cadeia da Polimerase Multiplex , Toxina Shiga/biossíntese , Virulência , Microbiologia da Água , Poluição da Água
14.
AJNR Am J Neuroradiol ; 39(3): 524-531, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29371253

RESUMO

BACKGROUND AND PURPOSE: Dual-energy CT can distinguish iodine-enhanced tumors from nonossified cartilage and has been investigated for evaluating cartilage invasion in patients with laryngeal and hypopharyngeal squamous cell carcinomas. In this study, we compared the diagnostic accuracy of MR imaging and of a combination of weighted-average and iodine overlay dual-energy CT images in detecting cartilage invasion by laryngeal and hypopharyngeal squamous cell carcinomas, in particular thyroid cartilage invasion. MATERIALS AND METHODS: Fifty-five consecutive patients who underwent 3T MR imaging and 128-slice dual-energy CT for preoperative initial staging of laryngeal or hypopharyngeal squamous cell carcinomas were included. Two blinded observers evaluated laryngeal cartilage invasion on MR imaging and dual-energy CT using a combination of weighted-average and iodine-overlay images. Pathologic findings of surgically resected specimens were used as the reference standard for evaluating sensitivity, specificity, and the areas under the receiver operating characteristic curve of both modalities for cartilage invasion by each type of cartilage and for all cartilages together. Sensitivity and specificity were compared using the McNemar test and generalized linear mixed models. RESULTS: Dual-energy CT showed higher specificity than MR imaging for diagnosing all cartilage together (84% for MR imaging versus 98% for dual-energy CT, P < .004) and for thyroid cartilage (64% versus 100%, P < .001), with a similar average area under the curve (0.94 versus 0.95, P = .70). The sensitivity did not differ significantly for all cartilages together (97% versus 81%, P = .16) and for thyroid cartilage (100% versus 89%, P = .50), though there was a trend toward increased sensitivity with MR imaging. CONCLUSIONS: Dual-energy CT showed higher specificity and acceptable sensitivity in diagnosing laryngeal cartilage invasion compared with MR imaging.


Assuntos
Neoplasias Hipofaríngeas/diagnóstico por imagem , Neoplasias Laríngeas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Metástase Neoplásica/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Hipofaríngeas/patologia , Cartilagens Laríngeas/diagnóstico por imagem , Cartilagens Laríngeas/patologia , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Curva ROC , Sensibilidade e Especificidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Cartilagem Tireóidea/diagnóstico por imagem , Cartilagem Tireóidea/patologia
15.
Nitric Oxide ; 72: 46-51, 2018 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-29183803

RESUMO

Osteoclasts are multinucleated giant cells differentiated from monocyte-macrophage-lineage cells under stimulation of receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) produced by osteoblasts and osteocytes. Although it has been reported that nitric oxide (NO) and reactive oxygen species (ROS) are involved in this process, the mechanism by which these labile molecules promote osteoclast differentiation are not fully understood. In this study, we investigated the formation and function of 8-nitro-cGMP, a downstream molecule of NO and ROS, in the process of osteoclast differentiation in vitro. 8-Nitro-cGMP was detected in mouse bone marrow macrophages and osteoclasts differentiated from macrophages in the presence of RANKL. Inhibition of NO synthase suppressed the formation of 8-nitro-cGMP as well as RANKL-induced osteoclast differentiation from macrophages. On the other hand, RANKL-induced osteoclast differentiation was promoted by addition of 8-nitro-cGMP to the cultures. In addition, 8-nitro-cGMP enhanced the mRNA expression of RANK, the receptor for RANKL. However, 8-bromo-cGMP, a membrane-permeable derivative of cGMP, did not have an effect on either RANKL-induced osteoclast differentiation or expression of the RANK gene. These results suggest that 8-nitro-cGMP is a novel positive regulator of osteoclast differentiation, which might help to explain the roles of NO and ROS in osteoclast differentiation.


Assuntos
Diferenciação Celular , GMP Cíclico/análogos & derivados , Osteoclastos/fisiologia , Ligante RANK/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Macrófagos/citologia , Masculino , Camundongos Endogâmicos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Ligante RANK/farmacologia , Receptor Ativador de Fator Nuclear kappa-B/genética
16.
Soft Matter ; 13(41): 7562-7570, 2017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-28972614

RESUMO

Micrometer-sized monodisperse polystyrene (PS) particles carrying a pH-responsive poly[2-(diethylamino)ethyl methacrylate] (PDEA) colloidal stabilizer were synthesized via free radical dispersion polymerization. X-ray photoelectron spectroscopy and electrophoretic measurements verified that PDEA covered the PS particle surface. At pH 3.0 and 6.3, where the PDEA is protonated and cationically charged, the PDEA-PS particles were well dispersed in aqueous media thanks to the water soluble PDEA stabilizer and slowly sedimented due to gravity and enriched at the bottom of the glass vials. At pH 10.0, where the PDEA is non-protonated and neutral, the PDEA-PS particles weakly aggregated due to non-hydrated and collapsed PDEA. These PDEA-PS particles and aggregates sedimented to the bottom. The sediment height observed at pH 10.0 was higher than those observed at pH 3.0 and 6.3 in both wet and dry systems, which indicated that a larger porosity was formed at pH 10.0. Mechanical testing experiments confirmed that the fracture toughness of the dried materials decreased with an increase of pH. The fracture toughness was found to be correlated with the degree of particle ordering in the dried particulate materials: more ordered, dense packings lead to a higher fracture toughness compared to amorphous, less dense packings. Thus, we could tune fracture toughness and degree of particle ordering by controlling the pH.

17.
Neuroimage ; 163: 177-182, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28916178

RESUMO

From expert percussionists to individuals who cannot dance, there are widespread differences in people's abilities to perceive and synchronize with a musical beat. The aim of our study was to identify candidate brain regions that might be associated with these abilities. For this purpose, we used Voxel-Based-Morphometry to correlate inter-individual differences in performance on the Harvard Beat Assessment Tests (H-BAT) with local inter-individual variations in gray matter volumes across the entire brain space in 60 individuals. Analysis revealed significant co-variations between performances on two perceptual tasks of the Harvard Beat Assessment Tests associated with beat interval change discrimination (faster, slower) and gray matter volume variations in the cerebellum. Participant discrimination thresholds for the Beat Finding Interval Test (quarter note beat) were positively associated with gray matter volume variation in cerebellum lobule IX in the left hemisphere and crus I bilaterally. Discrimination thresholds for the Beat Interval Test (simple series of tones) revealed the tendency for a positive association with gray matter volume variations in crus I/II of the left cerebellum. Our results demonstrate the importance of the cerebellum in beat interval discrimination skills, as measured by two perceptual tasks of the Harvard Beat Assessment Tests. Current findings, in combination with evidence from patients with cerebellar degeneration and expert dancers, suggest that cerebellar gray matter and overall cerebellar integrity are important for temporal discrimination abilities.


Assuntos
Cerebelo/fisiologia , Dança/fisiologia , Música , Desempenho Psicomotor/fisiologia , Adulto , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Oncogene ; 36(42): 5885-5896, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-28628120

RESUMO

Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated ApcΔ716 Trp53LSL•R270H villin-CreER compound mice, in which mutant p53R270H was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids. Mutant Trp53R270H, but not Trp53-null mutation accelerated submucosal invasion with generation of desmoplastic microenvironment. The nuclear accumulation of p53 was evident in ApcΔ716 Trp53R270H/R270H homozygous tumors like human CRC. Although p53 was distributed to the cytoplasm in ApcΔ716 Trp53+/R270H heterozygous tumors, it accumulated in the nuclei at the invasion front, suggesting a regulation mechanism for p53 localization by the microenvironment. Importantly, mutant p53 induced drastic morphological changes in the tumor organoids to complex glandular structures, which was associated with the acquisition of invasiveness. Consistently, the branching scores of human CRC that carry TP53 mutations at codon 273 significantly increased in comparison with those of TP53 wild-type tumors. Moreover, allografted ApcΔ716 Trp53R270H/R270H organoid tumors showed a malignant histology with an increased number of myofibroblasts in the stroma. These results indicate that nuclear-accumulated mutant p53R270H induces malignant progression of intestinal tumors through complex tumor gland formation and acquisition of invasiveness. Furthermore, RNA sequencing analyses revealed global gene upregulation by mutant p53R270H, which was associated with the activation of inflammatory and innate immune pathways. Accordingly, it is possible that mutant p53R270H induces CRC progression, not only by a cell intrinsic mechanism, but also by the generation or activation of the microenvironment, which may synergistically contribute to the acceleration of submucosal invasion. Therefore, the present study indicates that nuclear-accumulated mutant p53R270H is a potential therapeutic target for the treatment of advanced CRCs.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Intestinais/patologia , Neoplasias Hepáticas/secundário , Mutação , Proteína Supressora de Tumor p53/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Neoplasias Intestinais/genética , Neoplasias Intestinais/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Invasividade Neoplásica , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Microambiente Tumoral , Proteína Supressora de Tumor p53/metabolismo
19.
Leukemia ; 31(11): 2303-2314, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28210006

RESUMO

Lysine-specific demethylase 1 (LSD1) regulates gene expression by affecting histone modifications and is a promising target for acute myeloid leukemia (AML) with specific genetic abnormalities. Novel LSD1 inhibitors, NCD25 and NCD38, inhibited growth of MLL-AF9 leukemia as well as erythroleukemia, megakaryoblastic leukemia and myelodysplastic syndromes (MDSs) overt leukemia cells in the concentration range that normal hematopoiesis was spared. NCD25 and NCD38 invoked the myeloid development programs, hindered the MDS and AML oncogenic programs, and commonly upregulated 62 genes in several leukemia cells. NCD38 elevated H3K27ac level on enhancers of these LSD1 signature genes and newly activated ~500 super-enhancers. Upregulated genes with super-enhancer activation in erythroleukemia cells were enriched in leukocyte differentiation. Eleven genes including GFI1 and ERG, but not CEBPA, were identified as the LSD1 signature with super-enhancer activation. Super-enhancers of these genes were activated prior to induction of the transcripts and myeloid differentiation. Depletion of GFI1 attenuated myeloid differentiation by NCD38. Finally, a single administration of NCD38 causes the in vivo eradication of primary MDS-related leukemia cells with a complex karyotype. Together, NCD38 derepresses super-enhancers of hematopoietic regulators that are silenced abnormally by LSD1, attenuates leukemogenic programs and consequently exerts anti-leukemic effect against MDS-related leukemia with adverse outcome.


Assuntos
Benzamidas/farmacologia , Elementos Facilitadores Genéticos , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Leucemia/patologia , Síndromes Mielodisplásicas/complicações , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Cariotipagem , Leucemia/etiologia , Leucemia/genética , Camundongos , Camundongos Endogâmicos NOD
20.
Phys Chem Chem Phys ; 19(7): 5145-5154, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-28140409

RESUMO

The electronic and magnetic properties of chemically modified graphene armchair edges are studied using a combination of tight-binding calculations, first-principles modelling, and low temperature scanning tunneling microscopy (STM) experiments. The atomically resolved STM images of the hydrogen etched graphitic edges suggest the presence of localized states at the Fermi level for certain armchair edges. We demonstrate theoretically that the topological zero-energy edge mode may emerge at armchair boundaries with asymmetrical chemical termination of the two outermost atoms in the unit cell. We particularly focus our attention on armchair edges terminated by various combinations of the hydrogen (H, H2) and methylene (CH2) groups. The inclusion of the spin component in our calculations reveals the appearance of π-electron-based magnetism at the armchair edges under consideration.

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