The pro-apoptotic factor BAX has recently been shown to contribute to Purkinje cell (PC) apoptosis induced by the neurotoxic prion-like protein Doppel (Dpl) in the prion-protein-deficient Ngsk ...Prnp(0/0) (NP(0/0)) mouse. In view of cellular prion protein (PrP(c)) ability to counteract Dpl neurotoxicity and favor neuronal survival like BCL-2, we investigated the effects of the anti-apoptotic factor BCL-2 on Dpl neurotoxicity by studying the progression of PC death in aging NP(0/0)-Hu-bcl-2 double mutant mice overexpressing human BCL-2 (Hu-bcl-2). Quantitative analysis showed that significantly more PCs survived in NP(0/0)-Hu-bcl-2 double mutants compared with the NP(0/0) mutants. However, number of PCs remained inferior to wild-type levels and to the increased number of PCs observed in Hu-bcl-2 mutants. In the NP(0/0) mutants, Dpl-induced PC death occurred preferentially in the aldolase C-negative parasagittal compartments of the cerebellar cortex. Activation of glial cells exclusively in these compartments, which was abolished by the expression of Hu-bcl-2 in the double mutants, suggested that chronic inflammation is an indirect consequence of Dpl-induced PC death. This partial rescue of NP(0/0) PCs by Hu-bcl-2 expression was similar to that observed in NP(0/0):Bax(-/-) double mutants with bax deletion. Taken together, these data strongly support the involvement of BCL-2 family-dependent apoptotic pathways in Dpl neurotoxicity. The capacity of BCL-2 to compensate PrP(c) deficiency by rescuing PCs from Dpl-induced death suggests that the BCL-2-like property of PrP(c) may impair Dpl-like neurotoxic pathways in wild-type neurons.
Chitinases are important enzymes that contribute to the generation of carbon and nitrogen from chitin, a long chain polymer of N-acetylglucosamine that is abundant in insects, fungi, invertebrates ...and fish. Although mammals do not produce chitin, chitinases have been identified in bacteria that are key virulence factors in severe respiratory, gastrointestinal and urinary diseases. However, it is unclear how these enzymes are able to carry out this dual function. Legionella pneumophila is the causative agent of Legionnaires' disease, an often-fatal pneumonia and its chitinase ChiA is essential for the survival of L. pneumophila in the lung. Here we report the first atomic resolution insight into the pathogenic mechanism of a bacterial chitinase. We derive an experimental model of intact ChiA and show how its N-terminal region targets ChiA to the bacterial surface after its secretion. We provide the first evidence that L. pneumophila can bind mucins on its surface, but this is not dependent on ChiA. This demonstrates that additional peripheral mucin binding proteins are also expressed in L. pneumophila. We also show that the ChiA C-terminal chitinase domain has novel Zn2+-dependent peptidase activity against mammalian mucin-like proteins, namely MUC5AC and the C1-esterase inhibitor, and that ChiA promotes bacterial penetration of mucin gels. Our findings suggest that ChiA can facilitate passage of L. pneumophila through the alveolar mucosa, can modulate the host complement system and that ChiA may be a promising target for vaccine development.
The Lurcher mutant has been extensively studied as a model for cell-autonomous and target-related cell death, yet there are still many unknowns concerning the mechanisms of neuronal degeneration in ...this mutant. As a key regulator of apoptosis, a bcl-2 transgene has been overexpressed in the heterozygous Lurcher mutant to investigate the effects of BCL-2 on two types of in vivo neuronal cell loss in Lurcher: cell-autonomous Purkinje cell degeneration and target-related olivary neuron death. Six adult +/Lc mutants expressing a human bcl-2 transgene (Hu-bcl-2) were generated by crossing +/Lc mutants with NSE71 Hu-bcl-2 transgenic mice. Analysis of these brains showed that bcl-2 overexpression did not prevent +/Lc Purkinje cell degeneration, but it did rescue most olivary neurons from target-related cell death. Although the number of olivary neurons was equivalent to wild-type numbers, the inferior olive nucleus was significantly shorter in its rostrocaudal extent, suggesting that olivary neurons are atrophied. We propose that Lurcher gene action causes Purkinje cell degeneration independently of a BCL-2-mediated pathway. Furthermore, although bcl-2 overexpression rescues olivary neurons from target-related cell death, it does not prevent the atrophy associated with the loss of target-related trophic support.
Does congruity between an ad and its context improve ad memory? This research examines task orientation and perceived ad clutter as moderating and mediating influences on the relationship between ...ad-context congruity and ad memory in an e-magazine context. The results show ad-context congruity increases ad recognition for information seekers, whereas it does not have any effect for surfers of an e-magazine. Perceived clutter plays a crucial role in this relationship, partially mediating the impact of ad-context congruity on recall and completely mediating the effect of ad-context congruity on recognition. The managerial implications for the burgeoning e-magazine format include indications that when recall is paramount, adjacent incongruent ads and content can be used, but when recognition is important, congruent ads and content should be used and targeted toward people who consume the medium to gather specific information.
SUMMARY
Seismic and geodetic examinations of the Hikurangi subduction zone (HSZ) indicate a remarkably diverse and complex system. Here, we investigate the 3-D P-wave velocity structure of the HSZ by ...applying an iterative, nested regional-global tomographic algorithm. The new model reveals enhanced details of seismic variations along the HSZ. We also relocate over 57 000 earthquakes using this newly developed 3-D model and then further improve the relative locations for 75 per cent of the seismicity using waveform cross-correlation. Double seismic zone characteristics, including occurrence, depth distribution and thickness change along the strike of the HSZ. An aseismic but fast Vp zone separates the upper and lower planes of seismicity in the southern and northern North Island. The upper plane of seismicity correlates with low Vp zones below the slab interface, indicating fluid-rich channels formed on top and/or within a dehydrated crust. A broad low Vp zone is resolved in the lower part of the subducting slab that could indicate hydrous mineral breakdown in the slab mantle. In the northern North Island and southern North Island, the lower plane of seismicity mostly correlates with the top of these low Vp zones. The comparison between the thermal model and the lower plane of seismicity in the northern North Island supports dehydration in the lower part of the slab. The mantle wedge of the Taupo volcanic zone (TVZ) is characterized by a low velocity zone underlying the volcanic front (fluid-driven partial melting), a fast velocity anomaly in the forearc mantle (a stagnant cold nose) and an underlying low velocity zone within the slab (fluids from dehydration). These arc-related anomalies are the strongest beneath the central TVZ with known extensive volcanism. The shallow seismicity (<40 km depth) correlates with geological terranes in the overlying plate. The aseismic impermeable terranes, such as the Rakaia terrane, may affect the fluid transport at the plate interface and seismicity in the overlying plate, which is consistent with previous studies. The deep slow slip events (25–60 km depths) mapped in the Kaimanawa, Manawatu and Kapiti regions coincide with low Vp anomalies. These new insights on the structure along the HSZ highlight the change in the locus of seismicity and dehydration at depth that is governed by significant variations in spatial and probably temporal attributes of subduction zone processes.
Background: Scaphoid non:::union::: remains a challenging problem for hand surgeons. In this study, we assessed the functional outcome of scaphoid non:::union::: treatment and the influence of a ...number of variables on it.Methods: In this study we recruited 24 patients with scaphiod non:::union::: by consecutive sampling at Dr. Ali Shariati Teaching Hospital, in Tehran, Iran in 2008-2011. We examined the patients by antero-posterior (AP) and lateral view radiographies and wrist MRIs. Functional outcome of surgery was scaled according to Mayo wrist and Quick DASH scoring systems.Results: Among 10 cases with osteonecrosis, there were 7 (70%) cases of radiological :::union:::. In 13 (92%) out of 14 cases who had no signs of osteonecrosis, we radiologically confirmed scaphoid :::union::: after the treatment. The total :::union::: rate was estimated to be 83% at the end of 24 months follow up (P<0.05).Conclusion: The results showed that patients with scaphoid non:::union::: have improved function after surgical treatment.
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•Assessing various optimization methods for selected GSHP system;•Proposing a comprehensive model of the GSHP system with respect to the design parameters of the GHE;•Finding the ...optimum length of the GHE;•Obtaining the optimum value of the GHE design parameters;•Find the optimal refrigerant for the GSHP.
Ground Source Heat Pumps (GSHP) are commonly implemented to reduce energy consumption. This study seeks to delineate optimum operating conditions and borehole geometry configurations for GSHPs on the basis of multi-objective evolutionary algorithms. A thermodynamic heat transfer model is proposed to describe the GSHP behavior, and an economic model is proposed to assess the GSHP total cost for the amount of energy provided. An exergoeconmic optimization is employed to estimate the Pareto optimal solution for the GSHP, along with the optimum operating conditions and borehole configuration. Three prominent points of the Pareto frontier (equilibrium point, total cost rate objective and exergy efficiency objective) are used to isolate and illustrate each objective’s performance. Scatter density distribution plots of design parameters are also obtained to find their trends, which can give more insight into GSHPs design parameters. The solutions from five different Evolutionary Algorithms (EAs), NSGA-II, GDE3, IBEA, SMPSO, and SPEA2, are compared. Three different refrigerants (R134-a, R123 and isobutene) are also compared to find the most suitable working fluid for the decision space delineated. This study attempts to find the optimal configuration of ground heat exchangers (GHEs) based upon the most reliable multi-objective evolutionary algorithm.
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