THE CELLULAR NUCLEIC ACID BINDING PROTEIN IN AGING AND DISEASE

The ZNF9 gene on chromosome 3 encodes the cellular nucleic acid binding protein (CNBP), a ubiquitously expressed, 177 amino acid (≈19.5kDa) protein that is highly conserved among vertebrates. The function of the protein is largely unknown, however an expansion in the first intron of the protein results in myotonic dystrophy type 2 (DM2), a multisystemic disease featuring cardiac arrhythmia, muscle wasting, cataracts, and a range of neuropathologies. Remarkably, we recently discovered that CNBP is involved in regulating the activity of β-secretase, the enzyme that produces the first cleavage event in the generation of the amyloid-β peptide (Aβ). The progressive fibrillization and deposition of Aβ is widely believed to be the primary causal factor in the development of Alzheimer’s disease (AD), and AD-like pathology in individuals with Down syndrome (DS). DS provides a unique model for evaluating how these factors change in the aged brain as compared to young brain, and how such changes affect the proportion of DS patients with AD. In the AD brain, both BACE1 and BACE2 increased from an early stage of disease; in DS brains, BACE1 significantly decreased (p\u3c0.04) with age, whereas BACE2 was unchanged, even though the gene for BACE2 is located within the DS obligate region of chromosome 21. BACE1 and BACE2 activity levels were highly correlated in this series (r2 = 0.95), indicating that there may be a higher degree of shared regulation than previously believed. This implicates regulators of BACE as potentially critical for the development of AD, and our data suggests that CNBP may be one such regulator. In AD, CNBP increases early in the disease process, a change that does not occur in the normal aging process or in DS. CNBP and BACE protein levels were correlated in these cases (p\u3c0.001), while there was no relationship between CNBP and age, or CNBP and Aβ, in either the human or mouse brain, indicating that CNBP does not increase as a consequence of normal aging. Thirty day overexpression of CNBP following adeno-associated viral delivery in murine gastrocnemius muscle resulted in an increase in BACE1 protein (p\u3c0.01) and a consequential increase in Aβ production (p\u3c0.01). Other experiments indicated that CNBP overexpression did not affect the half-life of BACE1 mRNA or protein, but resulted in an increase in BACE1 translation. These data indicate that CNBP is an important regulator of β-secretase, and may play an important role in the onset and progression of AD

Faint star counts in the near-infrared

We discuss near-infrared star counts at the Galactic pole with a view to guiding the NGST and ground-based NIR cameras. Star counts from deep K-band images from the CFHT are presented, and compared with results from the 2MASS survey and some Galaxy models. With appropriate corrections for detector artifacts and galaxies, the data agree with the models down to K~18, but indicate a larger population of fainter red stars. There is also a significant population of compact galaxies that extend to the observational faint limit of K=20.5. Recent Galaxy models agree well down to K$\sim$19, but diverge at fainter magnitudes.Comment: 14 pages and 4 diagrams; to appear in PAS

β-Secretases, Alzheimer's Disease, and Down Syndrome

Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer's disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of the β-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein by β-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβ peptide. Increased amounts of APP in the DS brain result in increased amounts of Aβ and extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS

β-Secretases, Alzheimer\u27s Disease, and Down Syndrome

Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer\u27s disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of the β-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein by β-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβ peptide. Increased amounts of APP in the DS brain result in increased amounts of Aβ and extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS

Experimentation and self learning in continuous database marketing

We present a method for continuous database marketing that identifies target customers for a number of marketing offers using predictive models. The algorithm then selects the appropriate offer for the customer. Experimental design principles are encapsulated to capture more information that will be used to monitor and refine the predictive models. The updated predictive models are then used for the next round of marketing offers.<br /

Easily Administered Recognition of Linguistically-Handicapped Youngsters

This study investigates the feasibility of involving parents as evaluators using an objective screening test for their children who are 36 to 42 months of age. A more available and nonthreatening assessor is needed as physicians, dentists and other allied health professionals who are typically used to screen children for speech, language and hearing have not been effective with this age group. This is partially due to the limited contacts they have with these children and the environmental limitations for eliciting an adequate speech and language sample (Behrens, 1978; Webb, 197B; Hirsch, 1981). An objective-type screening instrument has been designed specifically for parent administration. Commonly used screening items were selected and analyzed to determine which were the best discriminators for a pass/fail score, thus reducing scoring error and interpretation difficulties. Parents were found to be capable evaluators when giving the Easily Administered Recognition of Linguistically-Handicapped Youngsters (EARLY). The EARLY also had a high correlation with the Preschool Language Scale (PLS) (Zimmerman, Steiner, and Evatt, 1979). By using the EARLY, parents will be alerted to speech and language problems and will be able to seek professional intervention at an early age. With this early identification, the speech language pathologist will be able to take advantage of the critical language-learning time period which occurs between the ages of 24 and 48 months (Eisenson, 1972; Bzoch and League, 1971)

A systemic approach to the database marketing process

The role of database marketing (DBM) has become increasingly important for organisations that have large databases of information on customers with whom they deal directly. At the same time, DBM models used in practice have increased in sophistication. This paper examines a systemic view of DBM and the role of analytical techniques within DBM. It extends existing process models to develop a systemic model that encompasses the increased complexity of DBM in practice. The systemic model provides a framework to integrate data mining, experimental design and prioritisation decisions. This paper goes on to identify opportunities for research in DBM, including DBM process models used in practice, the use of evolutionary operations techniques in DBM, prioritisation decisions, and the factors that surround the uptake of DBM.<br /

‘When you're sitting in the room with two people one of whom… has bashed the hell out of the other’:Possibilities and challenges in the use of FGCs and restorative approaches following domestic violence

Domestic violence continues to be a primary reason for referrals to state child welfare services in advanced industrialised countries. There is growing concern in many state child welfare services to develop responses to it that are both more effective and more humane. The use of restorative approaches, in particular Family Group Conferences (FGCs), has been suggested as one such response. This article draws from data gathered from an evaluation of a UK Government funded “Innovation Project” part of which extended the use of FGCs in an urban local authority area which was already making extensive use of them. This paper presents and explores a typology of FGCs used in situations of domestic violence: pragmatic, resolution-focussed and restorative FGCs, developed from the evaluation data and augmented by relevant literature. The study data revealed pragmatic FGCs to be the most used, restorative the least. It is suggested that each type of FGC brings potential benefits but only restorative FGCs offer the possibility of full restoration in the traditionally understood sense. It is argued that the present mother-centric, risk-adverse, child protection systems which currently operate in many countries provide a powerful resistor to the greater implementation of this restorative way of working.</p