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"Li, P"
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Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory
Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer’s disease through the antagonism of adenosine A
2A
receptors (A
2A
Rs). To test if A
2A
R activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A
2A
R, we have developed a chimeric rhodopsin-A
2A
R protein (
optoA
2A
R
), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A
2A
R to confer specific A
2A
R signaling. The specificity of the
optoA
2A
R
signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A
2A
R. Supporting its physiological relevance,
optoA
2A
R
activation and the A
2A
R agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably,
optoA
2A
R
activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while
optoA
2A
R
activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A
2A
R signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A
2A
R signaling and functions depend on intracellular A
2A
R loops prompts the possibility of targeting the intracellular A
2A
R-interacting partners to selectively control different neuropsychiatric behaviors.
Journal Article
Towards optimal single-photon sources from polarized microcavities
An optimal single-photon source should deterministically deliver one, and only one, photon at a time, with no trade-off between the source’s efficiency and the photon indistinguishability. However, all reported solid-state sources of indistinguishable single photons had to rely on polarization filtering, which reduced the efficiency by 50%, fundamentally limiting the scaling of photonic quantum technologies. Here, we overcome this long-standing challenge by coherently driving quantum dots deterministically coupled to polarization-selective Purcell microcavities. We present two examples: narrowband, elliptical micropillars and broadband, elliptical Bragg gratings. A polarization-orthogonal excitation–collection scheme is designed to minimize the polarization filtering loss under resonant excitation. We demonstrate a polarized single-photon efficiency of 0.60 ± 0.02 (0.56 ± 0.02), a single-photon purity of 0.975 ± 0.005 (0.991 ± 0.003) and an indistinguishability of 0.975 ± 0.006 (0.951 ± 0.005) for the micropillar (Bragg grating) device. Our work provides promising solutions for truly optimal single-photon sources combining near-unity indistinguishability and near-unity system efficiency simultaneously.
Journal Article
Task-based language teaching : theory and practice
\"Task-based language teaching is an approach which differs from traditional approaches by emphasizing the importance of engaging learners' natural abilities for acquiring language incidentally through the performance of tasks that draw learners' attention to form. Drawing on the multiple perspectives and expertise of five leading authorities in the field, this books provides a comprehensive and balanced account of task-based language teaching (TBLT). Split into five sections, the book provides an historical account of the development of TBLT and introduces the key issues facing the area. A number of different theoretical perspectives that have informed TBLT are presented, followed by a discussion on key pedagogic aspects - syllabus design, methodology of a task-based lesson, and task-based assessment. The final sections consider the research that has investigated the effectiveness of TBLT, addresses critiques and suggest directions for future research. Task-based language teaching is now mandated by many educational authorities throughout the world and this book serves as a core source of information for researchers, teachers and students\"-- Provided by publisher.
Book
MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo
MicroRNAs (miRNAs) are believed to have fundamental roles in tumorigenesis and have great potential for the diagnosis and treatment of cancer. However, the roles of miRNAs in hepatocellular carcinogenesis are still not fully elucidated. We investigated the aberrantly expressed miRNAs involved in hepatoma by comparison of miRNA expression profiles in cancerous hepatocytes with normal primary human hepatocytes, and 37 dysregulated miRNAs were screened out by twofold change with a significant difference (
P
<0.05). Clustering analysis based on 13 miRNAs with changes over 15-folds showed that the miRNA expression patterns between the cancerous and normal hepatocytes were clearly different. Among the 13 miRNAs, we found that miR-375 was significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. Overexpression of miR-375 in liver cancer cells decreased cell proliferation, clonogenicity, migration/invasion and also induced G1 arrest and apoptosis. To unveil the molecular mechanism of miR-375-mediated phenotype in hepatoma cells described above, we examined the putative targets using bioinformatics tools and found that astrocyte elevated gene-1 (AEG-1) was a potential target of miR-375. Then we demonstrated that miR-375 bound directly to the 3′-untranslated region of AEG-1 and inhibited the expression of AEG-1. TaqMan quantitative reverse transcriptase–PCR and western blot analysis showed that miR-375 expression was inversely correlated with AEG-1 expression in HCC tissues. Knockdown of AEG-1 by RNAi in HCC cells, similar to miR-375 overexpression, suppressed tumor properties. Ectopic expression of AEG-1, conversely, could partially reverse the antitumor effects of miR-375. In a mouse model, therapeutic administration of cholesterol-conjugated 2′-
O
-methyl-modified miR-375 mimics (Chol-miR-375) could significantly suppress the growth of hepatoma xenografts in nude mice. In conclusion, our findings indicate that miR-375 targets AEG-1 in HCC and suppresses liver cancer cell growth
in vitro
and
in vivo
, and highlight the therapeutic potential of miR-375 in HCC treatment.
Journal Article
Polymer-stabilized Cas9 nanoparticles and modified repair templates increase genome editing efficiency
Versatile and precise genome modifications are needed to create a wider range of adoptive cellular therapies
1
–
5
. Here we report two improvements that increase the efficiency of CRISPR–Cas9-based genome editing in clinically relevant primary cell types. Truncated Cas9 target sequences (tCTSs) added at the ends of the homology-directed repair (HDR) template interact with Cas9 ribonucleoproteins (RNPs) to shuttle the template to the nucleus, enhancing HDR efficiency approximately two- to fourfold. Furthermore, stabilizing Cas9 RNPs into nanoparticles with polyglutamic acid further improves editing efficiency by approximately twofold, reduces toxicity, and enables lyophilized storage without loss of activity. Combining the two improvements increases gene targeting efficiency even at reduced HDR template doses, yielding approximately two to six times as many viable edited cells across multiple genomic loci in diverse cell types, such as bulk (CD3
+
) T cells, CD8
+
T cells, CD4
+
T cells, regulatory T cells (Tregs), γδ T cells, B cells, natural killer cells, and primary and induced pluripotent stem cell-derived
6
hematopoietic stem progenitor cells (HSPCs).
Precise genome editing is made more efficient by stabilizing Cas9 and enhancing shuttling to the nucleus.
Journal Article
Quercetin alleviates cerebral ischemia and reperfusion injury in hyperglycemic animals by reducing endoplasmic reticulum stress through activating SIRT1
Hyperglycemia aggravates cerebral ischemic reperfusion injury (CIRI). Neuroprotective drugs that are effective in reducing CIRI in animals with normoglycemic condition are ineffective in ameliorating CIRI under hyperglycemic condition. This study investigated whether quercetin alleviates hyperglycemic CIRI by inhibiting endoplasmic reticulum stress (ERS) through modulating the SIRT1 signaling pathway. A middle cerebral artery occlusion/reperfusion (MCAO/R) model was induced in STZ-injected hyperglycemic rats. High glucose and oxygen glucose deprivation/reoxygenation (OGD/R) models were established in HT22 cells. The results demonstrated that hyperglycemia exacerbated CIRI, and quercetin pretreatment decreased the neurological deficit score and cerebral infarct volume, and alleviated neuron damage in the cortex of the penumbra in hyperglycemic MCAO/R rats, indicating that quercetin could be a candidate for treating hyperglycemic CIRI. Moreover, quercetin pretreatment reduced apoptosis, inhibited the expression of the ERS marker proteins GRP78 and ATF6, and mitigated the expression of the ERS-mediated proapoptotic protein CHOP in hyperglycemic MCAO/R rats, suggesting that quercetin alleviated hyperglycemic CIRI by inhibiting ERS and ERS-mediated apoptosis. Furthermore, quercetin upregulated Sirt1 expression in HG+OGD/R treated HT22 cells and inhibited PERK, p-eIF2α, ATF4, and CHOP expression. In contrast, the SIRT1 selective inhibitor EX-527 blocked the effect of quercetin on protein expression in the SIRT1/PERK pathway and aggravated HT22 cell injury. These findings indicate that quercetin inhibits ERS-mediated apoptosis through modulating the SIRT1 and PERK pathway. In conclusion, quercetin alleviates hyperglycemic CIRI by inhibiting ERS-mediated apoptosis through activating SIRT1 that consequently suppressed ERS signaling.
Journal Article
Launching of hyperbolic phonon-polaritons in h-BN slabs by resonant metal plasmonic antennas
Launching and manipulation of polaritons in van der Waals materials offers novel opportunities for field-enhanced molecular spectroscopy and photodetection, among other applications. Particularly, the highly confined hyperbolic phonon polaritons (HPhPs) in h-BN slabs attract growing interest for their capability of guiding light at the nanoscale. An efficient coupling between free space photons and HPhPs is, however, hampered by their large momentum mismatch. Here, we show —by far-field infrared spectroscopy, infrared nanoimaging and numerical simulations— that resonant metallic antennas can efficiently launch HPhPs in thin h-BN slabs. Despite the strong hybridization of HPhPs in the h-BN slab and Fabry-Pérot plasmonic resonances in the metal antenna, the efficiency of launching propagating HPhPs in h-BN by resonant antennas exceeds significantly that of the non-resonant ones. Our results provide fundamental insights into the launching of HPhPs in thin polar slabs by resonant plasmonic antennas, which will be crucial for phonon-polariton based nanophotonic devices.
Momentum mismatch prevents efficient coupling between free space photons and hyperbolic phonon polaritons. The authors show, using far-field infrared spectroscopy, infrared nanoimaging and numerical simulations, that resonant metallic antennas can efficiently launch hyperbolic phonon polaritons in thin h-BN slabs.
Journal Article