Dysfunction of microtubule-associated proteins of MAP2/tau family in Prion disease

The aggregation of PrP^Sc is thought to be crucial for the neuropathology of prion diseases. A growing body of evidence demonstrates that the perturbation of the microtubule network contributes to PrP^Sc-mediated neurodegeneration. Microtubules are a component of the cytoskeleton and play a central role in organelle transport, axonal elongation and cellular architecture in neurons. The polymerization, stabilization, arrangement of microtubules can be modulated by interactions with a series of microtubule-associated proteins (MAPs). Recent studies have proposed the abnormal alterations of two major microtubule-associated proteins, tau and MAP2, in the brain tissues of naturally occurred and experimental human and animal prion diseases. Increased total tau protein and hyperphosphorylation of tau at multiple residues are observed at the terminal stage of prion disease. The abnormal aggregation of tau protein disturbs its binding ability to microtubules and affects the microtubule dynamic. Significantly downregulated MAP2 is detected in the brain tissues of scrapie-infected hamsters and PrP106–126 treated cells, which corresponds well with the remarkably low levels of tubulin. In conclusion, dysfunction of MAP2/tau family leads to disruption of microtubule structure and impairment of axonal transport, and eventually triggers apoptosis in neurons, which becomes an essential pathway for prion to induce the neuropathology.     

Global Alzheimer Research Summit: Basic and clinical research Present and future Alzheimer research

We report here on the proceedings of the Global Alzheimer Summit that took place September 22–23, 2011 in Madrid, Spain. As Alzheimer disease (AD) is the leading cause of neurodegeneration in elderly individuals and, as yet, has no effective therapeutic option, it continues to stimulate global research interests. At the conference, leaders in the field of AD research provided insights into current developments in various areas of research, namely molecular mechanisms, genetics, novel aspects of AD research and translational research. Emphasis was also placed on the importance of biomarkers in the diagnosis of AD and development of current therapeutic strategies.     

Investigating sensitivity coefficients characterizing the response of a model of tau protein transport in an axon to model parameters

Evaluating the sensitivity of biological models to various model parameters is a critical step towards advancing our understanding of biological systems. In this paper, we investigated sensitivity coefficients for a model simulating transport of tau protein along the axon. This is an important problem due to the relevance of tau transport and agglomeration to Alzheimer’s disease and other tauopathies, such as some forms of parkinsonism. The sensitivity coefficients that we obtained characterize how strongly three observables (the tau concentration, average tau velocity, and the percentage of tau bound to microtubules) depend on model parameters. The fact that the observables strongly depend on a parameter characterizing tau transition from the retrograde to the anterograde kinetic states suggests the importance of motor-driven transport of tau. The observables are sensitive to kinetic constants characterizing tau concentration in the free (cytosolic) state only at small distances from the soma. Cytosolic tau can only be transported by diffusion, suggesting that diffusion-driven transport of tau only plays a role in the proximal axon. Our analysis also shows the location in the axon in which an observable has the greatest sensitivity to a certain parameter. For most parameters, this location is in the proximal axon. This could be useful for designing an experiment aimed at determining the value of this parameter. We also analyzed sensitivity of the average tau velocity, the total tau concentration, and the percentage of microtubule-bound tau to cytosolic diffusivity of tau and diffusivity of bound tau along the MT lattice. The model predicts that at small distances from the soma the effect of these two diffusion processes is comparable.     

Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme

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食料对南亚果实蝇解毒酶活力的影响

昆虫解毒酶是一类异质酶系, 对分解大量的内源或外源有毒物质、维持正常生理代谢起着重要作用。本文采用生物化学的方法测定了5种寄主果实对南亚果实蝇Bactrocera tau Walker 3个虫态体内总蛋白含量和5种解毒酶的活力。双因子方差分析显示, 南亚果实蝇种群取食黄瓜Cucumis sativus L.、南瓜Cucurbita moschala L.、丝瓜Luffa cylindrical L.、冬瓜Benincasa hispida (Thunb.) Coqn.和苦瓜Momordica charantia L.后, 体内蛋白含量和解毒酶活性均存在显著差异。以丝瓜为食料时, 南亚果实蝇体内蛋白含量较高; 而以黄瓜和冬瓜为食料时蛋白含量则相对较低。在以上5种寄主果实间, 南亚果实蝇的羧酸酯酶（CarE）活性在黄瓜和南瓜上较高, 细胞色素P450 O-脱甲基和谷胱甘肽S-转移酶（GST）活性在苦瓜上较高, 酸性磷酸酯酶（ACP）和碱性磷酸酯酶（ALP）活性却分别在黄瓜和南瓜上较低。在幼虫、蛹和成虫3个虫态间, 解毒酶活性亦存在显著差异, 成虫具有较高的CarE活性;幼虫具有较高的细胞色素P450 O-脱甲基, GST和ALP活性,但具有较低的ACP活性;除ACP外,蛹期解毒酶活性均较低。据以上结果可以推测,南亚果实蝇解毒酶活力受寄主果实种类以及该种群本身发育阶段的影响。     

Rapid acquisition of preference in concurrent schedules: effects of reinforcement amount

Four pigeons were trained on concurrent variable-interval 30-s schedules. Relative reinforcer amounts arranged across the two alternatives were varied across sessions according to a pseudorandom binary sequence [cf., Hunter, I., Davison, M., 1985. Determination of a behavioral transfer function: white-noise analysis of session-to-session response-ratio dynamics on concurrent VI schedules. J. Exp. Anal. Behav. 43, 43-59]; the ratios (left/right) were either 1/7 or 7/1. Reinforcer amount was manipulated by varying the number of 1.2s hopper presentations. Sessions ended after 30 reinforcers (15 for each alternative). After approximately 30 sessions, response ratios for all pigeons began to track the changes in amount ratio (i.e., subjects' responding showed a moderate increase in sensitivity of responding to reinforcer amount). Characteristics of responding were similar to procedures in which reinforcer rate and immediacy have been manipulated, although sensitivity estimates for amount were lower than those previously obtained with rate and immediacy. This procedure may serve as a useful method for studying the effects of certain environmental manipulations (e.g., drug administration) on sensitivity to reinforcer amount.     

Blocking the apolipoprotein E/Amyloid β interaction in triple transgenic mice ameliorates Alzheimer's disease related amyloid β and tau pathology

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late‐onset Alzheimer's disease (AD). Studies have shown that the binding between apoE and amyloid‐β (Aβ) peptides occurs at residues 244–272 of apoE and residues 12–28 of Aβ. ApoE4 has been implicated in promoting Aβ deposition and impairing clearance of Aβ. We hypothesized that blocking the apoE/Aβ interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Aβ12‐28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy. In the present study, we investigated whether the Aβ12‐28P elicits a therapeutic effect on tau‐related pathology in addition to amyloid pathology using old triple transgenic AD mice (3xTg, with PS1_M146V, APP_Swe and tau_P30IL transgenes) with established pathology from the ages of 21 to 26 months. We show that treatment with Aβ12‐28P substantially reduces tau pathology both immunohistochemically and biochemically, as well as reducing the amyloid burden and suppressing the activation of astrocytes and microglia. These affects correlate with a behavioral amelioration in the treated Tg mice.

     

At-sea abundance and spatial distribution of South American sea lion (Otaria byronia) in Chilean Northern Patagonia: How many are there?

The South American sea lion (Otaria byronia) (SSL) is a widespread opportunistic predator that inhabits waters ranging from Southern Ecuador to Southern Chile in the Pacific Ocean and from Southern Brazil to Southern Argentina in the Atlantic. SSL abundance estimates, as for many pinniped species, have relied on shore censuses, with the uncertainty that an indeterminate number of individuals at sea might remain uncounted. The proportion of the population that remains at sea during censuses and their distribution patterns are not clear and has been scarcely assessed. We used line transect sampling to gather information about at-sea abundance, density and spatial distribution of SSL in coastal waters off the Chilean Northern Patagonia. A total of 123 groups were sighted while on-effort, with an estimated density of 0.393 ind./km² (95%CI = 0.262–0.591) and a total abundance, for the surveyed area, of 13,721 individuals (95%CI = 9127–20,627). Even when our survey was rather restricted in spatial range, generalized additive model results showed that depth, distance to SSL rockeries, coastline complexity and geographical coordinates had a significant influence on SSL spatial distribution. The results on abundance and spatial distribution of SSL at sea are discussed in terms of current population estimates. Our substantial at-sea abundance estimate suggests that shore censuses might have been historically biased. Several aspects should be taken into account in further research on SSL abundance, such as including pelagic waters and undertaking simultaneously on-rockery and marine SSL abundance estimates. The results presented here provide valuable insights for revisiting and possibly improve population estimates of SSL and other pinnipeds species worldwide. This is particularly relevant when management and conservation actions need to be taken on those species that have strong interactions with fisheries and aquaculture.     

Exploring the effects of spatial autocorrelation when identifying key drivers of wildlife crop‐raiding

Few universal trends in spatial patterns of wildlife crop‐raiding have been found. Variations in wildlife ecology and movements, and human spatial use have been identified as causes of this apparent unpredictability. However, varying spatial patterns of spatial autocorrelation (SA) in human–wildlife conflict (HWC) data could also contribute. We explicitly explore the effects of SA on wildlife crop‐raiding data in order to facilitate the design of future HWC studies. We conducted a comparative survey of raided and nonraided fields to determine key drivers of crop‐raiding. Data were subsampled at different spatial scales to select independent raiding data points. The model derived from all data was fitted to subsample data sets. Model parameters from these models were compared to determine the effect of SA. Most methods used to account for SA in data attempt to correct for the change in P‐values; yet, by subsampling data at broader spatial scales, we identified changes in regression estimates. We consequently advocate reporting both model parameters across a range of spatial scales to help biological interpretation. Patterns of SA vary spatially in our crop‐raiding data. Spatial distribution of fields should therefore be considered when choosing the spatial scale for analyses of HWC studies. Robust key drivers of elephant crop‐raiding included raiding history of a field and distance of field to a main elephant pathway. Understanding spatial patterns and determining reliable socio‐ecological drivers of wildlife crop‐raiding is paramount for designing mitigation and land‐use planning strategies to reduce HWC. Spatial patterns of HWC are complex, determined by multiple factors acting at more than one scale; therefore, studies need to be designed with an understanding of the effects of SA. Our methods are accessible to a variety of practitioners to assess the effects of SA, thereby improving the reliability of conservation management actions.     

A Monte Carlo study of the influence of focal spot size,intensity distribution,breast thickness and magnification on spatial resolution of an a-Se digital mammography system using the generalized MTF

In this study the generalized Modulation Transfer Function (GMTF) and the geometric sharpness (S_geo) were used (i) to study the effects of various focal spot sizes (0.04 mm–0.3 mm), x-ray intensity distributions (Gaussian and double Gaussian), breast thicknesses (2–7 cm) and magnifications M (1.0–2.0) on the spatial resolution of an a-Se digital mammography system, (ii) to identify suitable focal spots for magnification mammography and (iii) derive optimum magnifications. For the calculation of GMTF the required components were: focal spot MTF, obtained from theory, detector MTF, scatter MTF and scatter fraction obtained from Monte Carlo simulations. The results showed that focal spots with sizes up to 0.18 mm are suitable for magnification mammography offering a GMTF which is >50% and >20% at the respective object frequencies of 6.5 mm⁻¹ and 9 mm⁻¹. Focal spots with sizes < 0.16 mm and Gaussian. intensity distribution, or sizes ≤ 0.1 mm and double Gaussian, offer a system resolution which improves or does not deteriorate with magnification for most object frequencies. For larger focal spots, i.e. 0.16–0.18 mm for a Gaussian and 0.12–0.18 mm for a double Gaussian. intensity distribution, optimum magnifications exist which depend on the object frequency and breast thickness. System resolution (in terms of S_geo) is maximized at M = 1.8–2.0 (all breast thicknesses) for Gaussian intensity distribution, and at M = 1.4–1.6 (breast thicknesses ≤ 4 cm) and M = 1.6–1.8 (thicker breasts) for double Gaussian.