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1.
Molecules ; 29(12)2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38930994

RESUMO

The tetradentate ligand, merging a carbazole unit with high triplet energy and dimethoxy bipyridine, renowned for its exceptional quantum efficiency in coordination with metals like Pt, is expected to demonstrate remarkable luminescent properties. However, instances of tetradentate ligands such as bipyridine-based pyridylcarbazole derivatives remain exceptionally scarce in the current literature. In this study, we developed a tetradentate ligand based on carbazole and 2,3'-bipyridine and successfully complexed it with Pt(II) ions. This novel compound (1) serves as a sky-blue phosphorescent material for use in light-emitting diodes. Based on single-crystal X-ray analysis, compound 1 has a distorted square-planar geometry with a 5/6/6 backbone around the Pt(II) core. Bright sky-blue emissions were observed at 488 and 516 nm with photoluminescent quantum yields of 34% and a luminescent lifetime of 2.6 µs. TD-DFT calculations for 1 revealed that the electronic transition was mostly attributed to the ligand-centered (LC) charge transfer transition with a small contribution from the metal-to-ligand charge transfer transition (MLCT, ~14%). A phosphorescent organic light-emitting device was successfully fabricated using this material as a dopant, along with 3'-di(9H-carbazol-9-yl)-1,1'-biphenyl (mCBP) and 9-(3'-carbazol-9-yl-5-cyano-biphenyl-3-yl)-9H-carbazole-3-carbonitrile (CNmCBPCN) as mixed hosts. A maximum quantum efficiency of 5.2% and a current efficiency of 15.5 cd/A were obtained at a doping level of 5%.

2.
Transl Lung Cancer Res ; 13(3): 475-490, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38601456

RESUMO

Background: Immunotherapies using anti-programmed cell death ligand-1 (PD-L1) agents have recently shown remarkable outcomes in patients with non-small cell lung cancer (NSCLC). However, there was a poor correlation between PD-L1 expression and treatment response. Many researchers have focused on the clinicopathological factors associated with prognosis, but the results are conflicting. In the present study, we investigated the clinicopathological significance of PD-L1 overexpression in NSCLC cells. Methods: In total, 344 NSCLC cases with PD-L1 assays were retrospectively analyzed. PD-L1 expression was evaluated via immunohistochemical staining using antibodies against SP263 and SP142. The correlation between clinicopathological factors and PD-L1 expression was analyzed for various clinicopathological features. Results: PD-L1 expression significantly correlated with several poor clinicopathological factors, including the solid component of adenocarcinoma, lymphatic invasion, and recurrence. Squamous cell carcinoma, older age, and male sex were also associated with PD-L1 expression. However, we could not observe correlation between PD-L1 expression and disease-free survival (DFS). A novel finding was that lower metastasis was associated with high PD-L1 expression of SP142 in tumor-infiltrating immune cells (ICs). Conclusions: PD-L1 expression in NSCLC is associated with adverse clinicopathological features and recurrence; therefore, it could be utilized to predict poor prognosis. Furthermore, the high PD-L1 expression of SP142 in tumor-infiltrating ICs could be a potential marker for low metastasis.

3.
bioRxiv ; 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38645248

RESUMO

Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed PV immunostaining and whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. We found that the number of dentate PV+ cells was reduced in IHK treated mice. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) Spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) The amplitude of evoked IPSCs in DGCs by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous epileptiform activity in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished the epileptiform activity. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy. Highlights: Reduced number of dentate PV+ interneurons in TLE micePersistently reduced action potential firing rates of dentate PV+ interneurons in TLE miceEnhanced amplitude but decreased frequency of spontaneous IPSCs in the dentate gyrus in TLE miceIncreased amplitude of evoked IPSCs mediated by dentate PV+ interneurons in TLE miceChemogenetic activation of PV+ interneurons prevents epileptiform activity in TLE mice.

4.
Materials (Basel) ; 16(11)2023 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-37297296

RESUMO

Organic light-emitting diodes (OLEDs) are energy-efficient; however, the coordinating ligand can affect their stability. Sky-blue phosphorescent Pt(II) compounds with a C^N chelate, fluorinated-dbi (dbi = [1-(2,4-diisopropyldibenzo [b,d]furan-3-yl)-2-phenyl-1H-imidazole]), and acetylactonate (acac) (1)/picolinate (pic) (2) ancillary ligands were synthesized. The molecular structures were characterized using various spectroscopic methods. The Pt(II) Compound Two exhibited a distorted square planar geometry, with several intra- and inter-molecular interactions involving Cπ⋯H/Cπ⋯Cπ stacking. Complex One emitted bright sky-blue light (λmax = 485 nm) with a moderate photoluminescent quantum efficiency (PLQY) of 0.37 and short decay time (6.1 µs) compared to those of 2. Theoretical calculations suggested that the electronic transition of 1 arose from ligand(C^N)-centered π-π* transitions combined with metal-to-ligand charge-transfer (MLCT), whereas that of 2 arose from MLCT and ligand(C^N)-to-ligand(pic) charge-transfer (LLCT), with minimal contribution from C^N chelate to the lowest unoccupied molecular orbital (LUMO). Multi-layered phosphorescent OLEDs using One as a dopant and a mixed host, mCBP/CNmCBPCN, were successfully fabricated. At a 10% doping concentration of 1, a current efficiency of 13.6 cdA-1 and external quantum efficiency of 8.4% at 100 cdm-2 were achieved. These results show that the ancillary ligand in phosphorescent Pt(II) complexes must be considered.

5.
Cell Stem Cell ; 30(5): 677-688.e5, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37019105

RESUMO

Human brain organoids provide unique platforms for modeling several aspects of human brain development and pathology. However, current brain organoid systems mostly lack the resolution to recapitulate the development of finer brain structures with subregional identity, including functionally distinct nuclei in the thalamus. Here, we report a method for converting human embryonic stem cells (hESCs) into ventral thalamic organoids (vThOs) with transcriptionally diverse nuclei identities. Notably, single-cell RNA sequencing revealed previously unachieved thalamic patterning with a thalamic reticular nucleus (TRN) signature, a GABAergic nucleus located in the ventral thalamus. Using vThOs, we explored the functions of TRN-specific, disease-associated genes patched domain containing 1 (PTCHD1) and receptor tyrosine-protein kinase (ERBB4) during human thalamic development. Perturbations in PTCHD1 or ERBB4 impaired neuronal functions in vThOs, albeit not affecting the overall thalamic lineage development. Together, vThOs present an experimental model for understanding nuclei-specific development and pathology in the thalamus of the human brain.


Assuntos
Núcleos Talâmicos , Tálamo , Humanos , Núcleos Talâmicos/patologia , Núcleos Talâmicos/fisiologia , Neurônios/fisiologia , Organoides
6.
Omega (Westport) ; 88(1): 66-94, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34452593

RESUMO

Extant grief studies examine the way humans mourn the loss of a nonhuman, be it an animal, object, or abstract concept. Yet little is known about grief when it comes to robots. As humans are increasingly brought into contact with more human-like machines, it is relevant to consider the nature of our relationship to these technologies. Centered on a qualitative analysis of 35 films, this study seeks to determine whether humans experience grief when a robot is destroyed, and if so, under what conditions. Our observations of the relevant film scenes suggest that eight variables play a role in determining whether and to what extent a human experiences grief in response to a robot's destruction. As a result, we have devised a psychological mechanism by which different types of grief can be classified as a function of these eight variables.


Assuntos
Robótica , Humanos , Filmes Cinematográficos , Pesar
7.
J Neurosci ; 42(37): 7077-7093, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36002261

RESUMO

Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs) after TBI may contribute to the synaptic reorganization that occurs in PTE, but how neurogenesis at different times relative to the injury contributes to feedback inhibition and recurrent excitation in the dentate gyrus is unknown. Thus, we examined whether DGCs born at different postnatal ages differentially participate in feedback inhibition and recurrent excitation in the dentate gyrus using the controlled cortical impact (CCI) model of TBI. Both sexes of transgenic mice expressing channelrhodopsin2 (ChR2) in postnatally born DGCs were used for optogenetic activation of three DGC cohorts: postnatally early born DGCs, or those born just before or after CCI. We performed whole-cell patch-clamp recordings from ChR2-negative, mature DGCs and parvalbumin-expressing basket cells (PVBCs) in hippocampal slices to determine whether optogenetic activation of postnatally born DGCs increases feedback inhibition and/or recurrent excitation in mice 8-10 weeks after CCI and whether PVBCs are targets of ChR2-positive DGCs. In the dentate gyrus ipsilateral to CCI, activation of ChR2-expressing DGCs born before CCI produced increased feedback inhibition in ChR2-negative DGCs and increased excitation in PVBCs compared with those from sham controls. This upregulated feedback inhibition was less prominent in DGCs born early in life or after CCI. Surprisingly, ChR2-positive DGC activation rarely evoked recurrent excitation in mature DGCs from any cohort. These results support that DGC birth date-related increased feedback inhibition in of DGCs may contribute to altered excitability after TBI.SIGNIFICANCE STATEMENT Dentate granule cells (DGCs) control excitability of the dentate gyrus through synaptic interactions with inhibitory GABAergic interneurons. Persistent changes in DGC synaptic connectivity develop after traumatic brain injury, contributing to hyperexcitability in post-traumatic epilepsy (PTE). However, the impact of DGC neurogenesis on synaptic reorganization, especially on inhibitory circuits, after brain injury is not adequately described. Here, upregulation of feedback inhibition in mature DGCs from male and female mice was associated with increased excitation of parvalbumin-expressing basket cells by postnatally born DGCs, providing novel insights into underlying mechanisms of altered excitability after brain injury. A better understanding of these inhibitory circuit changes can help formulate hypotheses for development of novel, evidence-based treatments for post-traumatic epilepsy by targeting birth date-specific subsets of DGCs.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Epilepsia Pós-Traumática , Animais , Giro Denteado/fisiologia , Modelos Animais de Doenças , Retroalimentação , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Parvalbuminas , Regulação para Cima
8.
Adv Sci (Weinh) ; 9(13): e2103275, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35240004

RESUMO

To provide a unique opportunity for on-chip scaled bioelectronics, a symmetrically gated metal-oxide electric double layer transistor (EDLT) with ion-gel (IG) gate dielectric and simple in-plane Corbino electrode architecture is proposed. Using amorphous indium-gallium-zinc oxide (a-IGZO) semiconductor and IG dielectric layers, low-voltage driven EDLTs with high ionotronic effects can be realized. More importantly, in contrast to the conventional asymmetric rectangular EDLTs which can cause non-uniform potential variation in the active channel layer and eventually degrade the sensing performance, the new symmetrical in-plane type EDLTs achieve high and spatially uniform ion responsive behaviors. The symmetrically gated a-IGZO EDLTs exhibited a responsivity of 129.4% to 5 ppm mercury (Hg2+ ) ions which are approximately three times higher than that with conventional electrode structure (responsivity of 38.5%). To confirm the viability of the new device architectures and the findings, the detailed mechanism of the symmetric gating effects in the in-plane EDLTs with a variety of electrical characterization and 3D fine element analysis simulations is also discussed.


Assuntos
Transistores Eletrônicos , Óxido de Zinco , Íons/química , Óxidos/química , Semicondutores , Zinco/química , Óxido de Zinco/química
9.
Sensors (Basel) ; 22(6)2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35336363

RESUMO

In the fault classification process, filter methods that sequentially remove unnecessary features have long been studied. However, the existing filter methods do not have guidelines on which, and how many, features are needed. This study developed a multi-filter clustering fusion (MFCF) technique, to effectively and efficiently select features. In the MFCF process, a multi-filter method combining existing filter methods is first applied for feature clustering; then, key features are automatically selected. The union of key features is utilized to find all potentially important features, and an exhaustive search is used to obtain the best combination of selected features to maximize the accuracy of the classification model. In the rotating machinery examples, fault classification models using MFCF were generated to classify normal and abnormal conditions of rotational machinery. The obtained results demonstrated that classification models using MFCF provide good accuracy, efficiency, and robustness in the fault classification of rotational machinery.

10.
Small Methods ; 5(12): e2101293, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34928010

RESUMO

Multicomponent oxide systems are one of the essential building blocks in a broad range of electronic devices. However, due to the complex physical correlation between the cation components and their relations with the system, finding an optimal combination for desired physical and/or chemical properties requires an exhaustive experimental procedure. Here, a machine learning (ML)-based synthetic approach is proposed to explore the optimal combination conditions in a ternary cationic compound indium-zinc-tin oxide (IZTO) semiconductor exhibiting high carrier mobility. In particular, by using support vector regression algorithm with radial basis function kernel, highly accurate mobility prediction can be achieved for multicomponent IZTO semiconductor with a sufficiently small number of train datasets (15-20 data points). With a synergetic combination of solution-based synthetic route for IZTO fabrication enabling a facile control of the composition ratio and tailored ML process for multicomponent system, the prediction of high-performance IZTO thin-film transistors is possible with expected field-effect mobility as high as 13.06 cm2 V-1 s-1 at the In:Zn:Sn ratio of 63:27:10. The ML prediction is successfully translated into the empirical analysis with high accuracy, validating the protocol is reliable and a promising approach to accelerate the optimization process for multicomponent oxide systems.

11.
Acta Crystallogr E Crystallogr Commun ; 77(Pt 12): 1224-1228, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34925886

RESUMO

In the title compound, [Ag(CF3SO3)(C10H6F2N2)2], the AgI centre adopts a highly distorted trigonal-planar coordination environment resulting from its coordination by one O atom of the tri-fluoro-methane-sulfonate anion and the pyridine N atoms of two crystallographically independent 2',6'-di-fluoro-2,3'-bi-pyridine ligands, which display very similar conformations to one another. Pairwise Ag⋯O-SO2CF3 - [Ag⋯O = 2.8314 (14) Å] inter-actions and inter-molecular C-H⋯O inter-actions between inversion-related units lead to the formation of an eight-membered cyclic dimer in which the silver atoms are separated by 6.2152 (3) Å. In the crystal, the dimers are linked through C-H⋯O hydrogen bonds, halogen⋯π and weak π-π stacking inter-actions, resulting in the formation of a three-dimensional supra-molecular network. The title compound exhibits a strong and broad emission band from 400 nm to 550 nm in solution and its photoluminescence quantum efficiency is estimated to be ca 0.2, indicating that the title compound could have applications as an emitting material in organic light-emitting diodes (OLEDs).

12.
J Soc Work End Life Palliat Care ; 17(4): 317-348, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34039235

RESUMO

Extant research on the topic of death and dying in modern society frequently includes the observation that death is now rendered invisible, and dying individuals are stigmatized and socially avoided. The current research speculated that lack of contact with a dying individual may promote negative perceptions of the dying, and this may in turn lead to further avoidance of them. Three studies were conducted: The first study examined how frequently the current U.S. participants had social contact with a dying individual; the second study investigated what perceptions they have of the dying, and the third study tested for potential causal links between negative perceptions of the dying and social avoidance of them. The results indicated: Only a small number of the U.S. participants ever had frequent social contact with a dying individual outside their family; they, nevertheless, shared several common negative perceptions of the dying; and those negative perceptions exerted different effects on one's avoidant attitude toward a dying individual-only making males more avoidant, especially in a physically close social relationship. Two concepts, medicalization and masculinism, were suggested as possible explanations for why dying individuals are stigmatized and avoided in modern society.


Assuntos
Atitude Frente a Morte , Humanos , Masculino
13.
Exp Neurol ; 342: 113724, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915166

RESUMO

Temporal lobe epilepsy (TLE) is characterized by recurrent spontaneous seizures and behavioral comorbidities. Reduced hippocampal theta oscillations and hyperexcitability that contribute to cognitive deficits and spontaneous seizures are present beyond the sclerotic hippocampus in TLE. However, the mechanisms underlying compromised network oscillations and hyperexcitability observed in circuits remote from the sclerotic hippocampus are largely unknown. Cholecystokinin (CCK)-expressing basket cells (CCKBCs) critically participate in hippocampal theta rhythmogenesis, and regulate neuronal excitability. Thus, we examined whether CCKBCs were vulnerable in nonsclerotic regions of the ventral hippocampus remote from dorsal sclerotic hippocampus using the intrahippocampal kainate (IHK) mouse model of TLE, targeting unilateral dorsal hippocampus. We found a decrease in the number of CCK+ interneurons in ipsilateral ventral CA1 regions from epileptic mice compared to those from sham controls. We also found that the number of boutons from CCK+ interneurons was reduced in the stratum pyramidale, but not in other CA1 layers, of ipsilateral hippocampus in epileptic mice, suggesting that CCKBCs are vulnerable. Electrical recordings showed that synaptic connectivity and strength from surviving CCKBCs to CA1 pyramidal cells (PCs) were similar between epileptic mice and sham controls. In agreement with reduced CCKBC number in TLE, electrical recordings revealed a significant reduction in amplitude and frequency of IPSCs in CA1 PCs evoked by carbachol (commonly used to excite CCK+ interneurons) in ventral CA1 regions from epileptic mice versus sham controls. These findings suggest that loss of CCKBCs beyond the hippocampal lesion may contribute to hyperexcitability and compromised network oscillations in TLE.


Assuntos
Região CA1 Hipocampal/metabolismo , Colecistocinina/biossíntese , Epilepsia do Lobo Temporal/metabolismo , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Ácido Caínico/toxicidade , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Colecistocinina/genética , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/genética , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Expressão Gênica , Interneurônios/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Acta Crystallogr E Crystallogr Commun ; 77(Pt 2): 107-110, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33614135

RESUMO

The title compound, [Pt(C21H12F2N3O)Cl], crystallizes with two crystallographically independent mol-ecules (A and B) in the asymmetric unit, which adopt similar conformations. The PtII atoms in both mol-ecules adopt distorted square-planar geometries, coordinated by one C and two N atoms from the tridentate 2',6'-di-fluoro-6-[3-(pyridin-2-yl-oxy)phen-yl]-2,3'-bi-pyridine ligand and a chloride anion: the C and Cl atoms are trans. In the crystal, C-H⋯Cl/F hydrogen bonds, F⋯π and weak π-π stacking inter-actions between adjacent A and B mol-ecules and between pairs of inversion-related B mol-ecules lead to the formation of a two-dimensional supra-molecular network lying parallel to the ab plane. The sheets are stacked along the c-axis direction and linked by F⋯π and weak π-π stacking inter-actions between pairs of inversion-related A mol-ecules, forming a three-dimensional supra-molecular network. The photoluminescence quantum efficiency of the title compound in the blue-green region of the visible region (λmax = 517 and 544 nm) is estimated to be ∼0.2-0.3, indicating that the title compound could be a suitable candidate as the emitting material in organic light-emitting diode (OLED) applications.

15.
Omega (Westport) ; 83(3): 487-507, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31213150

RESUMO

Kastenbaum and Aisenberg identified a phenomenon, wherein American subjects personified death in four distinctive figures: Macabre, Gentle Comforter, Gay Deceiver, and Automaton. Until recently, though, researchers did not attempt to answer the question, "What specific aspects of the death experience can be attributed to each of those four personifications?" To answer this question, the current qualitative research asked individuals to envision the causes, places, and contexts of death after imagining each personification of death. The results have revealed that people associated each personification of death with distinct causes, places, and contexts of death: Macabre-murder taking place outside the home, Gentle Comforter-peaceful death by old age at home, Gay Deceiver-death from heart attack, and Automaton-death from cancer in a modern hospital. This article also discusses unanswered questions, limitations, and directions to take its research in the future.


Assuntos
Atitude Frente a Morte , Humanos
16.
Sensors (Basel) ; 20(16)2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796568

RESUMO

The human foot is easily deformed owing to the innate form of the foot or an incorrect walking posture. Foot deformations not only pose a threat to foot health but also cause fatigue and pain when walking; therefore, accurate diagnoses of foot deformations are required. However, the measurement of foot deformities requires specialized personnel, and the objectivity of the diagnosis may be insufficient for professional medical personnel to assess foot deformations. Thus, it is necessary to develop an objective foot deformation classification model. In this study, a model for classifying foot types is developed using image and numerical foot pressure data. Such heterogeneous data are used to generate a fine-tuned visual geometry group-16 (VGG16) and K-nearest neighbor (k-NN) models, respectively, and a stacking ensemble model is finally generated to improve accuracy and robustness by combining the two models. Through k-fold cross-validation, the accuracy and robustness of the proposed method have been verified by the mean and standard deviation of the f1 scores (0.9255 and 0.0042), which has superior performance compared to single models generated using only numerical or image data. Thus, the proposed model provides the objectivity of diagnosis for foot deformation, and can be used for analysis and design of foot healthcare products.


Assuntos
Aprendizado Profundo , , Humanos , Postura , Caminhada
17.
Mol Cell ; 79(1): 84-98.e9, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32526163

RESUMO

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.


Assuntos
Azepinas/farmacologia , Encéfalo/patologia , Proteínas de Ciclo Celular/metabolismo , Interneurônios/patologia , Proteína 2 de Ligação a Metil-CpG/fisiologia , Síndrome de Rett/patologia , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Triazóis/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ciclo Celular/genética , Feminino , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Fenótipo , Síndrome de Rett/tratamento farmacológico , Síndrome de Rett/genética , Síndrome de Rett/metabolismo , Fatores de Transcrição/genética
18.
Acta Crystallogr C Struct Chem ; 76(Pt 5): 381-388, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32367817

RESUMO

The title compounds, C21H13F2N3O (1) and C23H19N3O3 (2), have been synthesized by typical cross-coupling reactions. Both compounds have been characterized by single-crystal X-ray diffraction. Bipyridine 1 exhibits a fully extended structure in which the terminal pyridine rings are oriented away from each other, while bipyridine 2 displays a bent structure in which terminal pyridine rings are oriented in the same direction. Several intermolecular interactions lead to the formation of two- and three-dimensional supramolecular networks in the crystal structures of 1 and 2, respectively. Compound 1 bears fluorine substituents and emits a strong fluorescence with λmax = 325 nm, while methoxy-substituted compound 2 displays red-shifted emissions with λmax = 366 nm. The emissions observed in both compounds originate from phenyl- and 2,3'-bipyridine-based π-π* transitions, according to theoretical calculations. Both compounds have high triplet energies (T1) ranging from 2.64 to 2.65 eV, which makes them potential host materials in organic light-emitting diodes (OLEDs).

19.
Neuropharmacology ; 162: 107787, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550457

RESUMO

Gamma network oscillations in the brain are fast rhythmic network oscillations in the gamma frequency range (~30-100 Hz), playing key roles in the hippocampus for learning, memory, and spatial processing. There is evidence indicating that GABAergic interneurons, including parvalbumin-expressing basket cells (PVBCs), contribute to cortical gamma oscillations through synaptic interactions with excitatory cells. However, the molecular, cellular, and circuit underpinnings underlying generation and maintenance of cortical gamma oscillations are largely elusive. Recent studies demonstrated that intrinsic and synaptic properties of GABAergic interneurons and excitatory cells are regulated by a slowly inactivating or non-inactivating sodium current (i.e., persistent sodium current, INaP), suggesting that INaP is involved in gamma oscillations. Here, we tested whether INaP plays a role in hippocampal gamma oscillations using pharmacological, optogenetic, and electrophysiological approaches. We found that INaP blockers, phenytoin (40 µM and 100 µM) and riluzole (10 µM), reduced gamma oscillations induced by optogenetic stimulation of CaMKII-expressing cells in CA1 networks. Whole-cell patch-clamp recordings further demonstrated that phenytoin (100 µM) reduced INaP and firing frequencies in both PVBCs and pyramidal cells without altering threshold and amplitude of action potentials, but increased rheobase in both cell types. These results suggest that INaP in pyramidal cells and PVBCs is required for hippocampal gamma oscillations, supporting a pyramidal-interneuron network gamma model. Phenytoin-mediated modulation of hippocampal gamma oscillations may be a mechanism underlying its anticonvulsant efficacy, as well as its contribution to cognitive impairments in epilepsy patients.


Assuntos
Região CA1 Hipocampal/fisiologia , Neurônios GABAérgicos/fisiologia , Ritmo Gama/fisiologia , Interneurônios/fisiologia , Células Piramidais/fisiologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Ritmo Gama/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Camundongos , Optogenética , Parvalbuminas/metabolismo , Técnicas de Patch-Clamp , Fenitoína/farmacologia , Células Piramidais/efeitos dos fármacos , Riluzol/farmacologia , Sódio/metabolismo
20.
Acta Crystallogr E Crystallogr Commun ; 75(Pt 11): 1646-1649, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31709084

RESUMO

In the title com-pound, C29H22N4O3, the carbazole system forms a dihedral angle of 68.45 (3)° with the mean plane of the bi-pyridine ring system. The bi-pyridine ring system, with two meth-oxy substituents, is approximately planar (r.m.s. deviation = 0.0670 Å), with a dihedral angle of 7.91 (13)° between the planes of the two pyridine rings. Intra-molecular C-H⋯O/N hydrogen bonds may promote the planarity of the bipyridyl ring system. In the pyridyl-substituted carbazole fragment, the pyridine ring is tilted by 56.65 (4)° with respect to the mean plane of the carbazole system (r.m.s. deviation = 0.0191 Å). In the crystal, adjacent mol-ecules are connected via C-H⋯O/N hydrogen bonds and C-H⋯π inter-actions, resulting in the formation of a three-dimensional (3D) supra-molecular network. In addition, the 3D structure contains inter-molecular π-π stacking inter-actions, with centroid-centroid distances of 3.5634 (12) Šbetween pyridine rings. The title com-pound exhibits a high energy gap (3.48 eV) and triplet energy (2.64 eV), indicating that it could be a suitable host material in organic light-emitting diode (OLED) applications.

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