Haploinsufficiency of microglial MyD88 ameliorates Alzheimer's pathology and vascular disorders in APP/PS1-transgenic mice

Growing evidence indicates that innate immune molecules regulate microglial activation in Alzheimer's disease (AD); however, their effects on amyloid pathology and neurodegeneration remain inconclusive. Here, we conditionally deleted one allele of myd88 gene specifically in microglia in APP/PS1-transgenic mice by 6 months and analyzed AD-associated pathologies by 9 months. We observed that heterozygous deletion of myd88 gene in microglia decreased cerebral amyloid β (Aβ) load and improved cognitive function of AD mice, which was correlated with reduced number of microglia in the brain and inhibited transcription of inflammatory genes, for example, tnf-α and il-1β, in both brain tissues and individual microglia. To investigate mechanisms underlying the pathological improvement, we observed that haploinsufficiency of MyD88 increased microglial recruitment toward Aβ deposits, which might facilitate Aβ clearance. Microglia with haploinsufficient expression of MyD88 also increased vasculature in the brain of APP/PS1-transgenic mice, which was associated with up-regulated transcription of osteopontin and insulin-like growth factor genes in microglia. Moreover, MyD88-haploinsufficient microglia elevated protein levels of LRP1 in cerebral capillaries of APP/PS1-transgenic mice. Cell culture experiments further showed that treatments with interleukin-1β decreased LRP1 expression in pericytes. In summary, haploinsufficiency of MyD88 in microglia at a late disease stage attenuates pro-inflammatory activation and amyloid pathology, prevents the impairment of microvasculature and perhaps also protects LRP1-mediated Aβ clearance in the brain of APP/PS1-transgenic mice, all of which improves neuronal function of AD mice

Connexin 43 phosphorylation by casein kinase 1 is essential for the cardioprotection by ischemic preconditioning

Myocardial connexin 43 (Cx43) forms gap junctions and hemichannels, and is also present within subsarcolemmal mitochondria. The protein is phosphorylated by several kinases including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and casein kinase 1 (CK1). A reduction in Cx43 content abrogates myocardial infarct size reduction by ischemic preconditioning (IPC). The present study characterizes the contribution of Cx43 phosphorylation towards mitochondrial function, hemichannel activity, and the cardioprotection by IPC in wild-type (WT) mice and in mice in which Cx43-phosphorylation sites targeted by above kinases are mutated to non-phosphorylatable residues (Cx43(MAPKmut), Cx43(PKCmut), and Cx43(CK1mut) mice). The amount of Cx43 in the left ventricle and in mitochondria was reduced in all mutant strains compared to WT mice and Cx43 phosphorylation was altered at residues not directly targeted by the mutations. Whereas complex 1 respiration was reduced in all strains, complex 2 respiration was decreased in Cx43(CK1mut) mice only. In Cx43 epitope-mutated mice, formation of reactive oxygen species and opening of the mitochondrial permeability transition pore were not affected. The hemichannel open probability was reduced in Cx43(PKCmut) and Cx43(CK1mut) but not in Cx43(MAPKmut) cardiomyocytes. Infarct size in isolated saline-perfused hearts after ischemia/reperfusion (45 min/120 min) was comparable between genotypes and was significantly reduced by IPC (3 x 3 min ischemia/5 min reperfusion) in WT, Cx43(MAPKmut), and Cx43(PKCmut), but not in Cx43(CK1mut) mice, an effect independent from the amount of Cx43 and the probability of hemichannel opening. Taken together, our study shows that alterations of Cx43 phosphorylation affect specific cellular functions and highlights the importance of Cx43 phosphorylation by CK1 for IPC's cardioprotection

Bethe-Ansatz density-functional theory of ultracold repulsive fermions in one-dimensional optical lattices

We present an extensive numerical study of ground-state properties of confined repulsively interacting fermions on one-dimensional optical lattices. Detailed predictions for the atom-density profiles are obtained from parallel Kohn-Sham density-functional calculations and quantum Monte Carlo simulations. The density-functional calculations employ a Bethe-Ansatz-based local-density approximation for the correlation energy, which accounts for Luttinger-liquid and Mott-insulator physics. Semi-analytical and fully numerical formulations of this approximation are compared with each other and with a cruder Thomas-Fermi-like local-density approximation for the total energy. Precise quantum Monte Carlo simulations are used to assess the reliability of the various local-density approximations, and in conjunction with these allow to obtain a detailed microscopic picture of the consequences of the interplay between particle-particle interactions and confinement in one-dimensional systems of strongly correlated fermions.Comment: 14 pages, 11 figures, 1 table, submitte

Spin and interaction effects on charge distribution and currents in one-dimensional conductors and rings within the Hartree-Fock approximation

Using the self--consistent Hartree-Fock approximation for electrons with spin at zero temperature, we study the effect of the electronic interactions on the charge distribution in a one-dimensional continuous ring containing a single $\delta$ scatterer. We reestablish that the interaction suppresses the decay of the Friedel oscillations. Based on this result, we show that in an infinite one dimensional conductor containing a weak scatterer, the current is totally suppressed because of a gap opened at the Fermi energy. In a canonical ensemble of continuous rings containing many scatterers, the interactions enhance the average and the typical persistent current.Comment: 5 pages, 4 figure

Информационная система заказа, обслуживания и мониторинга доставки продукции в пределах городской черты

В работе рассматриваются программные компоненты информационной системы доставки: заказ продукции широкого потребительского профиля в магазинах города с возможностью определения магазина по требуемой клиентом продукции, обслуживание доставки продавцом и курьером, а также мониторинг процесса доставки заказа клиентом. Система состоит из серверной (программный интерфейс приложения, база данных, сервис кэширования) и клиентской части (мобильное и веб-приложение).The study considers the software components of the delivery information system: ordering products of a wide consumer profile in city stores with the ability to determine the store for the products required by the client, delivery service by the seller and courier, as well as monitoring the process of order delivery by the client. The system consists of a server (application programming interface, database, caching service) and a client (mobile and web application)

Vacuum-assisted breast biopsy: A comparison of 11-gauge and 8-gauge needles in benign breast disease

© 2008 Hahn et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Determination of the Michel Parameters rho, xi, and delta in tau-Lepton Decays with tau --> rho nu Tags

Using the ARGUS detector at the $e^+ e^-$ storage ring DORIS II, we have measured the Michel parameters $\rho$, $\xi$, and $\xi\delta$ for $\tau^{\pm}\to l^{\pm} \nu\bar\nu$ decays in $\tau$-pair events produced at center of mass energies in the region of the $\Upsilon$ resonances. Using $\tau^\mp \to \rho^\mp \nu$ as spin analyzing tags, we find $\rho_{e}=0.68\pm 0.04 \pm 0.08$, $\xi_{e}= 1.12 \pm 0.20 \pm 0.09$, $\xi\delta_{e}= 0.57 \pm 0.14 \pm 0.07$, $\rho_{\mu}= 0.69 \pm 0.06 \pm 0.08$, $\xi_{\mu}= 1.25 \pm 0.27 \pm 0.14$ and $\xi\delta_{\mu}= 0.72 \pm 0.18 \pm 0.10$. In addition, we report the combined ARGUS results on $\rho$, $\xi$, and $\xi\delta$ using this work und previous measurements.Comment: 10 pages, well formatted postscript can be found at http://pktw06.phy.tu-dresden.de/iktp/pub/desy97-194.p

Raster-scanned carbon ion therapy for malignant salivary gland tumors: acute toxicity and initial treatment response

<p>Abstract</p> <p>Background and purpose</p> <p>To investigate toxicity and efficacy in high-risk malignant salivary gland tumors (MSGT) of the head and neck. Local control in R2-resected adenoid cystic carcinoma was already improved with a combination of IMRT and carbon ion boost at only mild side-effects, hence this treatment was also offered to patients with MSGT and microscopic residual disease (R1) or perineural spread (Pn+).</p> <p>Methods</p> <p>From November 2009, all patients with MSGT treated with carbon ion therapy were evaluated. Acute side effects were scored according to CTCAE v.4.03. Tumor response was assessed according to RECIST where applicable.</p> <p>Results</p> <p>103 patients were treated from 11/2009 to 03/2011, median follow-up is 6 months. 60 pts received treatment following R2 resections or as definitive radiation, 43 patients received adjuvant radiation for R1 and/or Pn+. 16 patients received carbon ion treatment for re-irradiation. Median total dose was 73.2 GyE (23.9 GyE carbon ions + 49,9 Gy IMRT) for primary treatment and 44.9 GyE carbon ions for re-irradiation. All treatments were completed as planned and generally well tolerated with no > CTC°III toxicity. Rates of CTC°III toxicity (mucositis and dysphagia) were 8.7% with side-effects almost completely resolved at first follow-up.</p> <p>47 patients showed good treatment responses (CR/PR) according to RECIST.</p> <p>Conclusion</p> <p>Acute toxicity remains low in IMRT with carbon ion boost also in R1-resected patients and patients undergoing re-irradiation. R2-resected patients showed high rates of treatment response, though follow-up is too short to assess long-term disease control.</p

How Preussag became TUI : kissing too many toads can make you a toad

In the period 1997-2004, Preussag, a diversified German conglomerate of old economy businesses, changed itself into TUI, a company focused almost entirely on tourism and logistics. This paper analyzes how this strategy was executed and how it contributed to Preussag’s underperformance of the stock market. We collect 417 announcements of acquisitions, financial disclosures and other news and disentangle the impact of different parts of the company’s strategy. We find that only the divestitures created value, that the strategy to invest in tourism destroyed value, and that the acquisition premiums Preussag paid were mostly unjustified. Bad luck like the events of September 11, 2001 cannot account for the poor performance of the stock. Poor management resulted from poor governance, combining a state-owned bank as the largest shareholder, board interlocks, and insufficient managerial incentives. The case shows how divestiture programs increase the liquid resources available to management beyond free operating cash flows and casts doubt on the positive governance role of institutional blockholders

Impacts of variations in Caspian Sea surface area on catchment-scale and large-scale climate

The Caspian Sea (CS) is the largest inland lake in the world. Large variations in sea level and surface area occurred in the past and are projected for the future. The potential impacts on regional and large-scale hydroclimate are not well understood. Here, we examine the impact of CS area on climate within its catchment and across the northern hemisphere, for the first time with a fully coupled climate model. The Community Earth System Model (CESM1.2.2) is used to simulate the climate of four scenarios: (1) larger than present CS area, (2) current area, (3) smaller than present area, and (4) no-CS scenario. The results reveal large changes in the regional atmospheric water budget. Evaporation (E) over the sea increases with increasing area, while precipitation (P) increases over the south-west CS with increasing area. P-E over the CS catchment decreases as CS surface area increases, indicating a dominant negative lake-evaporation feedback. A larger CS reduces summer surface air temperatures and increases winter temperatures. The impacts extend eastwards, where summer precipitation is enhanced over central Asia and the north-western Pacific experiences warming with reduced winter sea ice. Our results also indicate weakening of the 500-hPa troughs over the northern Pacific with larger CS area. We find a thermal response triggers a southward shift of the upper troposphere jet stream during summer. Our findings establish that changing CS area results in climate impacts of such scope that CS area variations should be incorporated into climate model simulations, including palaeo and future scenarios. Plain Language Summary The Caspian Sea is the largest land-locked water body in the world. It is filled by rivers draining a vast region from northern Russia to Iran. The size of the Caspian Sea has varied considerably over recent centuries and millennia due to various factors, including changes in climate. Conversely, as the area of the sea changes it also has impacts on the climate, but there are significant questions about how and where those impacts would be felt. In this study we used a state-of-the-art climate model in which we specified different sizes of Caspian Sea in order to examine how the climate changes as its area increases. We observed that the local seasonal cycle of temperatures gets smaller, and evaporation increases, while there are more spatially complex changes in local rainfall. Furthermore, the impacts on atmospheric circulation occur as far as the north Pacific, with resulting increases in temperature and decreases in sea-ice coverage in winter as the Caspian area increases. The climate impacts are so significant and geographically extensive that climate models used to simulate climate change (both in future and past scenarios) should incorporate changes to the Caspian Sea area if they are to robustly model regional climate