5,304 research outputs found
Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease
No full textBackground: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Clinically, AD is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-beta (A beta) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with A beta and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the protoconcogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice. Results: We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than their vehicle treated counterparts as well as non-transgenic mice. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble A beta(40) and A beta(42) levels, as well as a 45.2 % reduction in A beta(42) plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38 %. Mechanistically, these changes were linked to a significant increase in proteasome activity. Conclusion: These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce A beta and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors
Finite element approximation of Maxwell’s equations with Debye memory
No full textCopyright © 2010 Simon Shaw. All rights reserved.This article has been made available through the Brunel Open Access Publishing Fund.Maxwell’s equations in a bounded Debye medium are formulated in terms of the standard partial differential equations of electromagnetism with a Volterra-type history dependence of the polarization on the electric field intensity. This leads to Maxwell’s equations with memory. We make a correspondence between this type of constitutive law and the hereditary integral constitutive laws from linear viscoelasticity, and are then able to apply known results from viscoelasticity theory to this Maxwell system. In particular we can show long-time stability by shunning Gronwall’s lemma and estimating the history kernels more carefully by appeal to the underlying physical fading memory. We also give a fully discrete scheme for the electric field wave equation and derive stability bounds which are exactly analagous to those for the continuous problem, thus providing a foundation for long-time numerical integration. We finish by also providing error bounds for which the constant grows, at worst, linearly in time (excluding the time dependence in the norms of the exact solution). Although the first (mixed) finite element error analysis for the Debye problem was given by Jichun Li (in Comp. Meth. Appl. Mech. Eng., 196, (2007), pp. 3081–3094) this seems to be the the first time sharp constants have been given for this problem.This article is available through the Brunel Open Access Publishing Fund
Reduced protein turnover mediates functional deficits in transgenic mice expressing the 25 kDa C-terminal fragment of TDP-43
No full textAmyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) are two neurodegenerative disorders characterized by the accumulation of TDP-43. TDP-43 is proteolitically cleaved to generate two major C-terminal fragments of 35 and 25 kDa. The latter, known as TDP-25, is a consistent feature of FTLD-TDP and ALS; however, little is known about its role in disease pathogenesis. We have previously developed transgenic mice overexpressing low levels of TDP-25 (TgTDP-25(+/0)), which at 6 months of age show mild cognitive impairments and no motor deficits. To better understand the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP, we generated TDP-25 homozygous mice (TgTDP-25(+/+)), thereby further increasing TDP-25 expression. We found a gene-dosage effect on cognitive and motor function at 15 months of age, as the TgTDP-25(+/+) showed more severe spatial and working memory deficits as well as worse motor performance than TgTDP-25(+/0) mice. These behavioral deficits were associated with increased soluble levels of TDP-25 in the nucleus and cytosol. Notably, high TDP-25 levelswere also linked to reduced autophagy induction and proteasome function, two events that have been associated with both ALS and FTLD-TDP. In summary, we present strong in vivo evidence that high levels of TDP-25 are sufficient to cause behavioral deficits and reduce function of two of the major protein turnover systems: autophagy and proteasome. These mice represent a new tool to study the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP
Hyponatremia and long-term outcomes in chronic heart failure--an observational study from the Duke Databank for Cardiovascular Diseases.
No full textNetelia (Paropheltes) inedita
No full textNetelia (Paropheltes) inedita (Kokujev, 1899) Material examined: MALTA, Buskett, Verdala Palace, 1.xii.2016 –30. i.2017, 2 ♀♀, in Malaise trap, DM, NMS [determined by Mark Shaw]. Notes: New record for the Maltese Islands. This species was only collected via malaise traps but we are including it in this work since it represents a new record for Malta and the genus is known to comprise only koinobiont ectoparasitoids of Lepidoptera.Published as part of Mifsud, David, Farrugia, Lucia & Shaw, Mark R., 2019, Braconid and ichneumonid (Hymenoptera) parasitoid wasps of Lepidoptera from the Maltese Islands, pp. 47-60 in Zootaxa 4567 (1) on page 53, DOI: 10.11646/zootaxa.4567.1.3, http://zenodo.org/record/259303
Homolobus (Phylacter) meridionalis van Achterberg 1979
No full textHomolobus (Phylacter) meridionalis van Achterberg, 1979 Material examined: MALTA, Buskett, Verdala Palace, 1.xii.2016 –30. i.2017, 1 ♀, in Malaise trap, DM, DMC [parasitoid determined by Mark Shaw]. Notes: Even though this koinobiont endoparasitoid was not reared from a lepidopteran host, it is being included for two reasons: (i) it represents a new record for the Maltese Islands and (ii) because its only known host is a lepidopteran. This species was recorded as a parasitoid of the noctuid, Dryobota labecula (Esper, 1788) feeding in spring on Quercus in southern France, but it is probably a bivoltine species and likely to parasitize low-feeding noctuids in its overwintering generation (Shaw, 2015).Published as part of Mifsud, David, Farrugia, Lucia & Shaw, Mark R., 2019, Braconid and ichneumonid (Hymenoptera) parasitoid wasps of Lepidoptera from the Maltese Islands, pp. 47-60 in Zootaxa 4567 (1) on page 54, DOI: 10.11646/zootaxa.4567.1.3, http://zenodo.org/record/259303
Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease
No full textAging is the most important risk factor associated with Alzheimer's disease (AD); however, the molecular mechanisms linking aging to AD remain unclear. Suppression of the ribosomal protein S6 kinase 1 (S6K1) increases healthspan and lifespan in several organisms, from nematodes to mammals. Here we show that S6K1 expression is upregulated in the brains of AD patients. Using a mouse model of AD, we found that genetic reduction of S6K1 improved synaptic plasticity and spatial memory deficits, and reduced the accumulation of amyloid-beta and tau, the two neuropathological hallmarks of AD. Mechanistically, these changes were linked to reduced translation of tau and the beta-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the generation of amyloid-beta. Our results implicate S6K1 dysregulation as a previously unidentified molecular mechanism underlying synaptic and memory deficits in AD. These findings further suggest that therapeutic manipulation of S6K1 could be a valid approach to mitigate AD pathology
Dynamics of small bubble interface perturbations in vertical hele‐shaw cell with magnetic liquid under the action of normal magnetic field
No full textA linearized problem of dynamics for small perturbations of the gas bubble rising in the Hele‐Shaw cell filled with magnetic liquid is considered. It is reduced to searching of eigenvalues and eigenfunctions for a linear operator with periodic boundary conditions. The obtained operator is presented as a sum of two linear operators: the second order differential operator with varying coefficients and the integro ‐ differential operator with the singularity of the Cauchy type. The spectral problem is solved by the Degenerate Matrices (DM) method using Chebyshev polynomials of the first and second kind.
Burbulo paviršiaus mažų žadinimų dinamika vertikalioje Hele-Shaw ląstelėje, užpildytoje magnetiniu skysčių veikiamo normaliniu magnetiniu lauku
Santrauka
Dujų burbulo, judančio vertikalią Hele‐Shaw ląstelę užpildančiu magnetiniu skysčiu, paviršiaus dinamikos matematinis modelis yra suformuluotas kaip spektrinis uždavinys tam tikram tiesiniam operatoriui su periodinėmis kraštinėmis sąlygomis. Pastarasis uždavinys yra išspręstas skaitmeniškai išsigimstančių matricų metodu.
First Published Online: 14 Oct 201
Entanglement and quantity in quantum space - About quantum measurement (II)
No full textAs a continuation and extension of "quantity in phase space" "quantity in quantum space" is introduced. With that, the disappearing of quantum interference discussed in a previous paper [S. Durr, et al., Nature 395 (1998) 33] is explained in the same spirit as our recent papers [Ren De-Ming, Commun. Theor. Phys. (Beijing, China) 41 (2004) 685, 833].Physics, MultidisciplinarySCI(E)中国科学引文数据库(CSCD)1ARTICLE133-364
Cutting Edge: HLA-DO Impairs the Incorporation of HLA-DM into Exosomes
No full textAbstract
In multivesicular bodies, HLA-DM (DM) assists the loading of antigenic peptides on classical MHC class II molecules such as HLA-DR. In cells expressing HLA-DO (DO), DM is redistributed from the internal vesicles to the limiting membrane of these organelles. This suggests that DO might reduce DM incorporation into exosomes, which are shed upon fusion of multivesicular bodies with the plasma membrane. To test this hypothesis, we used the 721.45 B lymphoblastoid cell line and different HeLa cell transfectants. We demonstrate that the poor recovery of DM in exosomes as compared with HLA-DR is not the mere reflection of differences in protein expression. Indeed, we found that DO contributes to the inefficient transfer of DM to exosomes. This negative regulation requires an intact di-leucine endosomal sorting motif in the cytoplasmic tail of HLA-DOβ. These results demonstrate that canonical sorting signals and protein–protein interactions modulate the selection of MHC protein cargos.</jats:p
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