Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer's disease pathology

Studies suggest that activation of phosphoinositide 3-kinase-Akt may protect against neuronal cell death in Alzheimer's disease (AD). Here, however, we provide evidence of increased Akt activation, and hyperphosphorylation of critical Akt substrates in AD brain, which link to AD pathogenesis, suggesting that treatments aiming to activate the pathway in AD need to be considered carefully. A different distribution of Akt and phospho-Akt was detected in AD temporal cortex neurons compared with control neurons, with increased levels of active phosphorylated-Akt in particulate fractions, and significant decreases in Akt levels in AD cytosolic fractions, causing increased activation of Akt (phosphorylated-Akt/total Akt ratio) in AD. In concordance, significant increases in the levels of phosphorylation of total Akt substrates, including: GSK3ßSer9, tauSer214, mTORSer2448, and decreased levels of the Akt target, p27kip1, were found in AD temporal cortex compared with controls. A significant loss and altered distribution of the major negative regulator of Akt, PTEN (phosphatase and tensin homologue deleted on chromosome 10), was also detected in AD neurons. Loss of phosphorylated-Akt and PTEN-containing neurons were found in hippocampal CA1 at end stages of AD. Taken together, these results support a potential role for aberrant control of Akt and PTEN signalling in AD.

The 'Belfast' timber roof truss - is it sustainable and relevant today?

In the early 19th century the requirement for clear span industrial buildings brought about the development of a variety of timber truss types. The Belfast truss was introduced circa 1860 to meet the demand for efficient wide span industrial buildings. It has essentially a bow-string configuration with a curved top chord, straight horizontal bottom chord and close-spaced lattice web. Several thousand still exist in Ireland, many in buildings of historic significance. This paper sets out to demonstrate the efficiency of the Belfast truss and to show that, by modern structural design criteria, the concept, member sizes and joint details were well chosen. Trusses in historic buildings can be replicated almost exactly as originally fabricated. Results of a theoretical study are compared with the experimental behaviour of two full-scale trusses: one a replacement truss, tested in the laboratory; the other an 80-year-old truss tested on site. In addition, experimental results from a manufacturers archive material of full-scale truss tests carried out about 100 years ago are compared with theoretical models. As well as considering their significance in building conservation the paper proposes that Belfast trusses are an attractive sustainable alternative to other roof structures. The analysis, design, fabrication and testing of trusses have resulted in a better understanding of their behaviour which is not only of historic interest and fundamental to the repair/restoration of existing trusses, but also relevant to the design of modern timber trusses and the promotion of a sustainable form of roof construction.

Natural three-qubit interactions in one-way quantum computing

We address the effects of natural three-qubit interactions on the computational power of one-way quantum computation. A benefit of using more sophisticated entanglement structures is the ability to construct compact and economic simulations of quantum algorithms with limited resources. We show that the features of our study are embodied by suitably prepared optical lattices, where effective three-spin interactions have been theoretically demonstrated. We use this to provide a compact construction for the Toffoli gate. Information flow and two-qubit interactions are also outlined, together with a brief analysis of relevant sources of imperfection.

Specific and unspecific interactions in polar fluids in view of wideband dielectric far-infrared spectra

A simple molecular analytical theory of dielectric relaxation in strongly polar fluids is considered in terms of a semi- phenomenological approach. Theoretical spectra epsilon(v), a(v) of complex permittivity and absorption coefficient are fully determined by a form of intermolecular potential well, in which a dipole reorients. In a recent publication by VI. Gaiduk, O.F. Nielsen, and T.S. Perova [J. Molliq 95 (1002) 1-25] the wideband spectra of liquid H2O and D2O were described in terms of a composite model comprising the rectangular and the cosine squared potential wells. Much better results are achieved in this work, where the rectangular well is replaced by a well with a rounded bottom termed the hat-curved well. The spectrum of the auto-correlation function (ACF) is calculated for such a potential. The proposed theory of a composite model, comprising hat-curved and parabolic wells, is applied for liquid water. This model is capable for describing the Debye relaxation region, the second relaxation region in the submillimeter wavelength range, and the far infra-red (FIR) e(v), a(v) spectra, where an intense librational band and an additional weak band are placed, respectively, near 700 cm(-1) and 200 cm(-1). The latter band reflects the features of so-called specific (viz. directly related to H-bonds) interactions and the former band reflects the features of unspecific interactions. The physical mechanisms connected with these types of interactions are discussed in terms of two relevant types of water structure (types of molecular rotation). The proposed theory is also applied to a non-associated liquid in terms of one hat-curved potential well. (C) 2004 Elsevier B.V. All rights reserved.

Multiple proton translocation in biomolecular systems: concerted to stepwise transition in a simple model

In this paper we study a simple model potential energy surface (PES) useful for describing multiple proton translocation mechanisms. The approach presented is relevant to the study of more complex biomolecular systems like enzymes. In this model, at low temperatures, proton tunnelling favours a concerted proton transport mechanism, while at higher temperatures there is a crossover from concerted to stepwise mechanisms; the crossover temperature depends on the energetic features of the PES. We illustrate these ideas by calculating the crossover temperature using energies taken from ab initio calculations on specific systems. Interestingly, typical crossover temperatures lie around room temperature; thus both concerted and stepwise reaction mechanisms should play an important role in biological systems, and one can be easily turned into another by external means such as modifying the temperature or the pH, thus establishing a general mechanism for modulation of the biomolecular function by external effectors.

Clinical Features of Dominant and Recessive Interferon γ Receptor 1 Deficiencies

Background Interferon ? receptor 1 (IFN? R1) deficiency is a primary immunodeficiency with allelic dominant and recessive mutations characterised clinically by severe infections with mycobacteria. We aimed to compare the clinical features of recessive and dominant IFN?R1 deficiencies. Methods We obtained data from a large cohort of patients worldwide. We assessed these people by medical histories, records, and genetic and immunological studies. Data were abstracted onto a standard form. Findings We identified 22 patients with recessive complete IFN?R1 deficiency and 38 with dominant partial deficiency. BCG and environmental mycobacteria were the most frequent pathogens. In recessive patients, 17 (77%) had environmental mycobacterial disease and all nine BCG-vaccinated patients had BCG disease. In dominant patients, 30 (79%) had environmental mycobacterial disease and 11 (73%) of 15 BCG-vaccinated patients had BCG disease. Compared with dominant patients, those with recessive deficiency were younger at onset of first environmental mycobacterial disease (mean 3·1 years [SD 2·5] vs 13·4 years [14·3], p=0·001), had more mycobacterial disease episodes (19 vs 8 per 100 person-years of observation, p=0·0001), had more severe mycobacterial disease (mean number of organs infected by Mycobacterium avium complex 4·1 [SD 0·8] vs 2·0 [1·1], p=0·004), had shorter mean disease-free intervals (1·6 years [SD 1·4] vs 7·2 years [7·6], p

Translational control of SEPT9 isoforms is perturbed in disease

A common feature of the mammalian septin gene family is complex genomic architecture with multiple alternate splice variants. Septin 9 has 18 distinct transcripts encoding 15 polypeptides, with two transcripts (SEPT9_v4 and v4*) encoding the same polypeptide. We have previously reported that the ratio of these distinct transcripts is altered in neoplasia, with the v4 transcript being the usual form in normal cells but v4* becoming predominant in tumours. This led us to ask what the functional differences between these two transcripts might be. The 5'-UTRs of v4 and v4* have distinct 5' ends encoded by exons 1 beta (v4) and 1 zeta and 2 (v4*) and a common 3' region and initiating ATG encoded within exon 3. Here we show that the two mRNAs are translated with different efficiencies and that cellular stress can alter this. A putative internal ribosome entry site can be identified in the common region of the v4 and v4* 5'-UTRs and translation is modulated by an upstream open-reading frame in the unique region of the v4 5'-UTR. Germline mutations in hereditary neuralgic amyotrophy (HNA) map to the region which is common to the two UTRs. These mutations dramatically enhance the translational efficiency of the v4 5'-UTR, leading to elevated SEPT9_v4 protein under hypoxic conditions. Our data provide a mechanistic insight into how the HNA mutations can alter the fine control of SEPT9_v4 protein and its regulation under physiologically relevant conditions and are consistent with the episodic and stress-induced nature of the clinical features of HNA.

An FPGA Based Coprocessor for GLCM and Haralick Texture Features and Their Application in Prostate Cancer Classification

Grey Level Co-occurrence Matrix (GLCM), one of the best known tool for texture analysis, estimates image properties related to second-order statistics. These image properties commonly known as Haralick texture features can be used for image classification, image segmentation, and remote sensing applications. However, their computations are highly intensive especially for very large images such as medical ones. Therefore, methods to accelerate their computations are highly desired. This paper proposes the use of programmable hardware to accelerate the calculation of GLCM and Haralick texture features. Further, as an example of the speedup offered by programmable logic, a multispectral computer vision system for automatic diagnosis of prostatic cancer has been implemented. The performance is then compared against a microprocessor based solution.