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1.
Opt Express ; 32(10): 18087-18098, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38858973

RESUMEN

In this paper, a highly sensitive sensor consisting of a silicon nanorod and symmetric rings (SNSR) is presented. Theoretically, three Fano resonances with high Q-factors are excited in the near-infrared range by breaking the symmetry structure based on quasi-bound states in the continuum (Q-BICs). The electromagnetic near-field analysis confirms that the resonances are mainly controlled by toroidal dipole (TD) resonance. The structure is optimized by adjusting different geometrical parameters, and the maximum Q-factor of the Fano resonances can reach 7427. To evaluate the sensing performance of the structure, the sensitivity and the figure of merit (FOM) are calculated by adjusting the environmental refractive index: the maximum sensitivity of 474 nm/RIU and the maximum FOM of 3306 RIU-1. The SNSR can be fabricated by semiconductor-compatible processes, which is experimentally evaluated for changes in transmission spectra at different solution concentrations. The results show that the sensitivity and the Q-factor of the designed metasurface can reach 295 nm/RIU and 850, while the FOM can reach 235 RIU-1. Therefore, the metasurface of SNSR is characterized by high sensitivity and multi-wavelength sensing, which are current research hotspots in the field of optics and can be applied to biomedical sensing and multi-target detection.

2.
J Dairy Sci ; 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38762104

RESUMEN

Milk fan cheese, a type of stretched -cheese, presents challenges in its stretch-forming. This study investigated the impacts of complex phosphates (sodium tripolyphosphate and sodium dihydrogen phosphate, STPP-DSP) on the gelling properties of acid-induced milk fan gel and the mechanisms contributing to its stretch-forming. The treatment of milk fan gel with STPP-DSP resulted in improved functional and textural properties compared with the control group. In particular, drawing length increased significantly from 69.67 nm to 80.33 nm, and adhesiveness increased from 1737.89 g/mm to 1969.79 g/mm. The addition of STPP-DSP also led to increased viscosity, elastic modulus (G'), and viscous modulus (G"). Microstructural analysis revealed the formation of a fibrous structure within the gel after STPP-DSP treatment, facilitating uniform embedding of fat globules and emulsification. Structural analysis showed that the addition of STPP-DSP increased ß-fold and decreased random coiling of the gel, facilitating the unfolding of protein structures. Additionally, UV absorption spectroscopy and excitation-emission matrix spectroscopy results indicated the formation of a chelate between STPP-DSP and milk fan gel, increasing protein-protein molecular interactions. Evidence from differential scanning calorimetry and x-ray diffraction demonstrated the formation of sodium caseinate chelate. Fourier transform infrared spectroscopy and zeta potential analysis revealed that the sodium caseinate chelate formed through hydrophobicity, hydrogen bonding, and electrostatic forces. These findings provided theoretical insights into how phosphates can improve the stretch-forming of milk fan gel, facilitating the application of phosphate additives in stretched -cheese processing.

3.
Sensors (Basel) ; 24(12)2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38931726

RESUMEN

This article shows an all-dielectric metasurface consisting of "H"-shaped silicon disks with tilted splitting gaps, which can detect the temperature and refractive index (RI). By introducing asymmetry parameters that excite the quasi-BIC, there are three distinct Fano resonances with nearly 100% modulation depth, and the maximal quality factor (Q-factor) is over 104. The predominant roles of different electromagnetic excitations in three distinct modes are demonstrated through near-field analysis and multipole decomposition. A numerical analysis of resonance response based on different refractive indices reveals a RI sensitivity of 262 nm/RIU and figure of merit (FOM) of 2183 RIU-1. This sensor can detect temperature fluctuations with a temperature sensitivity of 59.5 pm/k. The proposed metasurface provides a novel method to induce powerful TD resonances and offers possibilities for the design of high-performance sensors.

4.
Opt Express ; 31(6): 10805-10819, 2023 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-37157619

RESUMEN

In this paper, an all-dielectric metasurface consisting of a unit cell containing a nanocube array and organized periodically on a silicon dioxide substrate is designed and analyzed. By introducing asymmetric parameters that can excite the quasi-bound states in the continuum, three Fano resonances with high Q-factor and high modulation depth may be produced in the near-infrared range. Three Fano resonance peaks are excited by magnetic dipole and toroidal dipole, respectively, in conjunction with the distributive features of electromagnetism. The simulation results indicate that the discussed structure can be utilized as a refractive index sensor with a sensitivity of around 434 nm/RIU, a maximum Q factor of 3327, and a modulation depth equal to 100%. The proposed structure has been designed and experimentally investigated, and its maximum sensitivity is 227 nm/RIU. At the same time, the modulation depth of the resonance peak at λ = 1185.81 nm is nearly 100% when the polarization angle of the incident light is 0 °. Therefore, the suggested metasurface has applications in optical switches, nonlinear optics, and biological sensors.

5.
Sensors (Basel) ; 23(21)2023 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-37960433

RESUMEN

With the wide application of flow sensors, their reliability under extreme conditions has become a concern in recent years. The reliability of a Micro Electro Mechanical Systems (MEMS) flow sensor under temperature (Ts) is researched in this paper. This flow sensor consists of two parts, a sensor chip and a signal-processing system (SPS). Firstly, the step-stress accelerated degradation test (SSADT) is implemented. The sensor chip and the flow sensor system are tested. The results show that the biggest drift is 3.15% for sensor chips under 150 °C testing conditions, while 32.91% is recorded for the flowmeters. So, the attenuation of the SPS is significant to the degeneration of this flowmeter. The minimum drift of the SPS accounts for 82.01% of this flowmeter. Secondly, using the Coffin-Manson model, the relationship between the cycle index and Ts is established. The lifetime with a different Ts is estimated using the Arrhenius model. In addition, Weibull distribution (WD) is applied to evaluate the lifetime distribution. Finally, the reliability function of the WD is demonstrated, and the survival rate within one year is 87.69% under 85 °C conditions. With the application of accelerated degradation testing (ADT), the acquired results are innovative and original. This research illustrates the reliability research, which provides a relational database for the application of this flow sensor.

6.
Opt Express ; 27(5): 6037-6046, 2019 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-30876197

RESUMEN

We present a high-resolution and miniature multi-wavelength Fiber Bragg Grating (FBG) interrogator based on a thermally tunable microring resonator (MRR) array. A phase detection method using dithering signals is exploited to generate an antisymmetric error signal curve, which is utilized for the feedback locking of the MRR with the FBG sensor. Dynamic strain sensing of both single FBG and multiple FBGs are experimentally demonstrated, with a dynamic strain resolution of 30 nε/√Hz over 100 Hz to 1 kHz. The proposed interrogator shows the great improvements in both resolution and wavelength accuracy compared with the reported MRR-based interrogators and is promising for scalable multiplexed sensing applications.

7.
Appl Opt ; 58(17): 4708-4713, 2019 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-31251291

RESUMEN

Taking advantage of the near-infrared (IR) absorption characteristics of gases, a sensor with an ultrasmall sample volume composed of a sealed slot waveguide and based on evanescent field absorption is proposed in this paper. Compared with a traditional open-slot waveguide, it features small volume antiparticles depositing pollution over the long-term and is insensitive to surroundings. Working at 1645 nm, a large evanescent field ratio of 0.27 is obtained by simulation and optimization; meanwhile, the propagation loss is around 1.6 dB/cm. The needed sample volume of the designed sensor under the structure parameters of w_air=40 nm, h_air=400 nm, and waveguide length=3 cm is approximately 480 µm3, which helps the sensor demonstrate excellent performance for gas analysis with an ultrasmall sample volume.

8.
Angew Chem Int Ed Engl ; 58(40): 14089-14094, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31270915

RESUMEN

Gas sensing technologies for smart cities require miniaturization, cost-effectiveness, low power consumption, and outstanding sensitivity and selectivity. On-chip, tailorable capacitive sensors integrated with metal-organic framework (MOF) films are presented, in which abundant coordinatively unsaturated metal sites are available for gas detection. The in situ growth of homogeneous Mg-MOF-74 films is realized with an appropriate metal-to-ligand ratio. The resultant sensors exhibit selective detection for benzene vapor and carbon dioxide (CO2 ) at room temperature. Postsynthetic modification of Mg-MOF-74 films with ethylenediamine decreases sensitivity toward benzene but increases selectivity to CO2 . The reduced porosity and blocked open metal sites caused by amine coordination account for a deterioration in the sensing performance for benzene (by ca. 60 %). The enhanced sensitivity for CO2 (by ca. 25 %) stems from a tailored amine-CO2 interaction. This study demonstrates the feasibility of tuning gas sensing properties by adjusting MOF-analyte interactions, thereby offering new perspectives for the development of MOF-based sensors.

9.
J Neurosci ; 36(47): 11946-11958, 2016 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-27881780

RESUMEN

Rett syndrome (RTT) is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here, we report a test of the hypothesis of shared pathophysiology of RTT and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein-synthesis-dependent synaptic plasticity were similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated "translatome." We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that were functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5-negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In Mecp2 KO mice, we found that mGluR5 NAM treatment significantly reduced the level of overexpressed ribosome-associated transcripts, particularly those that were also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and lifespan. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through coregulation of a subset of genes relevant to synaptic functions. SIGNIFICANCE STATEMENT: Altered regulation of synaptic protein synthesis has been hypothesized to contribute to the pathophysiology that underlies multiple forms of intellectual disability and autism spectrum disorder. Here, we show in a mouse model of Rett syndrome (Mecp2 KO) that metabotropic glutamate receptor 5 (mGluR5)- and protein-synthesis-dependent synaptic plasticity are abnormal in the hippocampus. We found that a subset of ribosome-bound mRNAs was aberrantly upregulated in hippocampal CA1 neurons of Mecp2 KO mice, that these significantly overlapped with FMRP direct targets and/or SFARI human autism genes, and that chronic treatment of Mecp2 KO mice with an mGluR5-negative allosteric modulator tunes down upregulated ribosome-bound mRNAs and partially improves mutant mice phenotypes.


Asunto(s)
Hipocampo/fisiopatología , Imidazoles/administración & dosificación , Complejos Multienzimáticos/metabolismo , Piridinas/administración & dosificación , Receptor del Glutamato Metabotropico 5/metabolismo , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/fisiopatología , Regulación Alostérica/efectos de los fármacos , Animales , Regulación hacia Abajo/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Síndrome de Rett/patología
10.
Opt Express ; 22(20): 24104-10, 2014 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-25321985

RESUMEN

Here, we demonstrate a chip-scale integrated optical wavelength tracker with fast response and compact format. By exploiting the electro-optic(EO) effect on a thermally controlled silicon micro-ring resonator filter, the proposed tracker can operate over a wide wavelength range according to the thermo-optic (TO) effect; meanwhile, the tracker's response speed is greatly improved through the EO effect (i.e. tracking within 1 ns), as compared to the traditional TO controlled methods (typical ~10 µs). With the integration of a photodiode onto the photonics chip, the compact chip is with a footprint of 0.5 mm × 1.5 mm. This tracker has potential applications for wavelength tacking in advanced DWDM network systems, tunable laser sources, and high performance optical sensors.

11.
Opt Express ; 22(20): 24235-40, 2014 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-25321998

RESUMEN

We report a novel lateral packaging approach using laser welding technique with angle polished fiber coupling to grating coupler embedded silicon photonic circuit. Measurements show the relax alignment tolerance for fiber packaging process. The packaging excess loss of 1.2 dB is achieved. The use of angle polished fiber for lateral fiber coupling enables an alternative way for cost-effective deployment of silicon photonics packaging in telecommunication systems.

12.
Micromachines (Basel) ; 15(4)2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38675285

RESUMEN

Ozone (O3) is a critical gas in various industrial applications, particularly in semiconductor manufacturing, where it is used for wafer cleaning and oxidation processes. Accurate and reliable detection of ozone concentration is essential for process control, ensuring product quality, and safeguarding workplace safety. By studying the UV absorption characteristics of O3 and combining the specific operational needs of semiconductor process gas analysis, a pressure-insensitive ozone gas sensor has been developed. In its optical structure, a straight-through design without corners was adopted, achieving a coupling efficiency of 52% in the gas chamber. This device can operate reliably in a temperature range from 0 °C to 50 °C, with only ±0.3% full-scale error across the entire temperature range. The sensor consists of a deep ultraviolet light-emitting diode in a narrow spectrum centered at 254 nm, a photodetector, and a gas chamber, with dimensions of 85 mm × 25 mm × 35 mm. The performance of the sensor has been meticulously evaluated through simulation and experimental analysis. The sensor's gas detection accuracy is 750 ppb, with a rapid response time (t90) of 7 s, and a limit of detection of 2.26 ppm. It has the potential to be applied in various fields for ozone monitoring, including the semiconductor industry, water treatment facilities, and environmental research.

13.
Micromachines (Basel) ; 15(3)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38542542

RESUMEN

Metal oxide gas sensors usually require a few tens of milliwatts of power consumption to operate at high temperature, which limits their application in mobile and portable devices. Here, we proposed a cantilever structure to build an ultra-low power gas sensor for hydrogen sulfide gas detection. By employing a nano-film size effect to reduce the thermal conductivity of the material, and self-heated corrugation configuration, the power consumption of the gas sensor is significantly reduced. Through numerical analysis and finite element simulation, two different gas sensors were designed and the power consumption and stress distribution were analyzed and optimized. Under the operating temperature of 200 °C, only 0.27 mW power is consumed, the stress value is less than 250 MPa and the displacement is a few hundred of nanometers. The results serve as a guide and reference for ultra-low power MEMS device designs.

14.
Biomed Opt Express ; 15(4): 2406-2418, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38633064

RESUMEN

A multi-function sensor based on an all-dielectric metastructure for temperature and refractive index sensing simultaneously is designed and analyzed in this paper. The structure is composed of a periodic array of silicon dimers placed on the silicon dioxide substrate. By breaking the symmetry of the structure, the ideal bound states in the continuum can be converted to the quasi-bound states in the continuum, and three Fano resonances are excited in the near-infrared wavelength. Combining with the electromagnetic field distributions, the resonant modes of three Fano resonances are analyzed as magnetic dipole, magnetic toroidal dipole, and electric toroidal dipole, respectively. The proposed sensor exhibits an impressive maximal Q-factor of 9352, with a modulation depth approaching 100%. Our investigation into temperature and refractive index sensing properties reveals a maximum temperature sensitivity of 60 pm/K. Regarding refractive index sensing, the sensitivity and figure of merit are determined to be 279.5 nm/RIU and 2055.1 RIU-1, respectively. These findings underscore the potential of the all-dielectric metastructure for simultaneous multi-parameter measurements. The sensor's versatility suggests promising applications in biological and chemical sensing.

15.
Proc Natl Acad Sci U S A ; 107(42): 18161-6, 2010 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-20921386

RESUMEN

MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function as posttranscriptional regulators of gene expression. Many miRNAs are expressed in the developing brain and regulate multiple aspects of neural development, including neurogenesis, dendritogenesis, and synapse formation. Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Although Mecp2 is known to act as a global transcriptional regulator, miRNAs that are directly regulated by Mecp2 in the brain are not known. Using massively parallel sequencing methods, we have identified miRNAs whose expression is altered in cerebella of Mecp2-null mice before and after the onset of severe neurological symptoms. In vivo genome-wide analyses indicate that promoter regions of a significant fraction of dysregulated miRNA transcripts, including a large polycistronic cluster of brain-specific miRNAs, are DNA-methylated and are bound directly by Mecp2. Functional analysis demonstrates that the 3' UTR of messenger RNA encoding Brain-derived neurotrophic factor (Bdnf) can be targeted by multiple miRNAs aberrantly up-regulated in the absence of Mecp2. Taken together, these results suggest that dysregulation of miRNAs may contribute to RTT pathoetiology and also may provide a valuable resource for further investigations of the role of miRNAs in RTT.


Asunto(s)
Modelos Animales de Enfermedad , Estudio de Asociación del Genoma Completo , Proteína 2 de Unión a Metil-CpG/fisiología , MicroARNs/genética , Síndrome de Rett/genética , Regiones no Traducidas 3' , Animales , Inmunoprecipitación de Cromatina , Ensayo de Inmunoadsorción Enzimática , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas , Síndrome de Rett/metabolismo
16.
Micromachines (Basel) ; 14(11)2023 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-38004867

RESUMEN

In this paper, we demonstrate a multi-functional metasurface for microwave beam-shaping application. The metasurface consists of an array of programmable unit cells, and each unit cell is integrated with one varactor diode. By turning the electrical bias on the diode on and off, the phase delay of the microwave reflected by the metasurface can be switched between 0 and π at a 6.2 GHz frequency, which makes the metasurface 1-bit-coded. By programming the 1-bit-coded metasurface, the generation of a single-focus beam, a double-focus beam and a focused vortex beam was experimentally demonstrated. Furthermore, the single-focus beam with tunable focal lengths of 54 mm, 103 mm and 152 mm was experimentally observed at 5.7 GHz. The proposed programmable metasurface manifests robust and flexible beam-shaping ability which allows its application to microwave imaging, information transmission and sensing applications.

17.
J Neurosci ; 31(22): 8306-19, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21632951

RESUMEN

The endoribonuclease, Dicer, is indispensable for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in the mammalian CNS. Although functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here, we report the effect of Cre-loxP-mediated conditional deletion of Dicer selectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology before postnatal week 5. Thereafter, mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements, and premature death by postnatal week 9-10. Integrated transcription profiling, histological, and functional analyses of cerebella showed that deletion of Dicer in cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state before the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell-autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders.


Asunto(s)
Astrocitos/metabolismo , Astrocitos/fisiología , Cerebelo/crecimiento & desarrollo , Cerebelo/patología , Degeneración Nerviosa/fisiopatología , Trastornos Psicomotores/genética , Trastornos Psicomotores/patología , Ribonucleasa III/fisiología , Animales , Cerebelo/metabolismo , Cerebelo/fisiopatología , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteína Ácida Fibrilar de la Glía , Ácido Glutámico/metabolismo , Técnicas In Vitro , Integrasas/genética , Masculino , Ratones , Ratones Mutantes Neurológicos , Ratones Transgénicos , Degeneración Nerviosa/metabolismo , Proteínas del Tejido Nervioso/genética , Técnicas de Placa-Clamp/métodos , Trastornos Psicomotores/metabolismo , Trastornos Psicomotores/fisiopatología , Células de Purkinje/patología , Ribonucleasa III/genética , Transducción de Señal/genética , Transducción de Señal/fisiología
18.
Nat Chem Biol ; 6(9): 645-51, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20657584

RESUMEN

Mechanistic studies of O-GlcNAc glycosylation have been limited by an inability to monitor the glycosylation stoichiometries of proteins obtained from cells. Here we describe a powerful method to visualize the O-GlcNAc-modified protein subpopulation using resolvable polyethylene glycol mass tags. This approach enables rapid quantification of in vivo glycosylation levels on endogenous proteins without the need for protein purification, advanced instrumentation or expensive radiolabels. In addition, it establishes the glycosylation state (for example, mono-, di-, tri-) of proteins, providing information regarding overall O-GlcNAc site occupancy that cannot be obtained using mass spectrometry. Finally, we apply this strategy to rapidly assess the complex interplay between glycosylation and phosphorylation and discover an unexpected reverse 'yin-yang' relationship on the transcriptional repressor MeCP2 that was undetectable by traditional methods. We anticipate that this mass-tagging strategy will advance our understanding of O-GlcNAc glycosylation, as well as other post-translational modifications and poorly understood glycosylation motifs.


Asunto(s)
Acetilglucosamina/análisis , Acetilglucosamina/metabolismo , Polietilenglicoles/química , Procesamiento Proteico-Postraduccional , Acetilglucosamina/química , Glicosilación , Cinética , Espectrometría de Masas , Proteína 2 de Unión a Metil-CpG/genética , Proteína 2 de Unión a Metil-CpG/metabolismo , Fosforilación , Polietilenglicoles/análisis , Procesamiento Proteico-Postraduccional/genética , Transcripción Genética
19.
Proc Natl Acad Sci U S A ; 106(12): 4882-7, 2009 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-19225110

RESUMEN

Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett syndrome. As a chromatin-associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. Although neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here, we report the identification of several MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors.


Asunto(s)
Cromatina/metabolismo , Proteína 2 de Unión a Metil-CpG/metabolismo , Neuronas/metabolismo , Fosfoserina/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Anticuerpos Fosfo-Específicos/metabolismo , Encéfalo/metabolismo , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Proteína 2 de Unión a Metil-CpG/química , Ratones , Datos de Secuencia Molecular , Actividad Motora , Mutación/genética , Fosforilación , Regiones Promotoras Genéticas/genética , Unión Proteica , Ratas
20.
J Neurosci ; 28(24): 6182-95, 2008 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-18550760

RESUMEN

To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.


Asunto(s)
Cromosomas Artificiales Bacterianos/fisiología , Enfermedad de Huntington/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Péptidos/genética , Factores de Edad , Análisis de Varianza , Animales , Conducta Animal , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica/fisiología , Histonas/metabolismo , Humanos , Proteína Huntingtina , Enfermedad de Huntington/fisiopatología , Potenciales de la Membrana/genética , Ratones , Ratones Transgénicos , Microscopía Electrónica de Transmisión/métodos , Proteínas del Tejido Nervioso/metabolismo , Neuronas/fisiología , Proteínas Nucleares/metabolismo , Técnicas de Placa-Clamp/métodos , Fracciones Subcelulares/metabolismo
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