Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia that is characterized by the retention of polymers of neuroserpin as inclusions within the endoplasmic reticulum (ER) of neurons. We have developed monoclonal antibodies that detect polymerized neuroserpin and have used COS-7 cells, stably transfected PC12 cell lines and transgenic Drosophila melanogaster to characterize the cellular handling of all four mutant forms of neuroserpin that cause FENIB. We show a direct correlation between the severity of the disease-causing mutation and the accumulation of neuroserpin polymers in cell and fly models of the disease. Moreover, mutant neuroserpin causes locomotor deficits in the fly allowing us to demonstrate a direct link between polymer accumulation and neuronal toxicity.

The autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies is characterized by the accumulation of ordered polymers of mutant neuroserpin within the endoplasmic reticulum of neurones. We show here that intracellular neuroserpin polymers activate NF-B by a pathway that is independent of the IRE1, ATF6, and PERK limbs of the canonical unfolded protein response but is dependent on intracellular calcium. This pathway provides a mechanism for cells to sense and react to the accumulation of folded structures of mutant serpins within the endoplasmic reticulum. Our results provide strong support for the endoplasmic reticulum overload response being independent of the unfolded protein response.

It has been claimed that Williams syndrome (WS), a rare neurodevelopmental disorder, is characterized by serious cognitive deficits alongside intact language. The syndrome is often used as a prime example of the modularity of an innate faculty for morphosyntactic rules. We challenge this claim and hypothesize that morphosyntax, although surprisingly good given WS level of mental retardation, is by no means intact. We make an initial test of this hypothesis through an analysis of the receptive language of a group of English-speaking WS individuals on a standardized morphosyntactic test. We then present an experimental study of expressive language that examines grammatical gender assignment in French-speaking WS patients. Despite a Verbal Mental Age selected to be higher than the chronological age of the young control group, these people with WS continue even in adulthood to show clear-cut deficits in their production of an aspect of morphosyntax that normal children acquire effortlessly very early. The results of the 2 studies, one focusing on receptive language and the other on expressive language, challenge the notion that comprehension and use of morphosyntactic rules in WS individuals are intact. The Within-domain dissociations regarding the use of grammatical gender assignment across several sentence clements and their difficulties in understanding embedded sentences-two quintessentially linguistic skills-suggest that we must rethink the notion of spared, modular, language capacities in Williams syndrome. We conclude that WS language follows a different path to normal acquisition and may turn out to be more like second language learning.

We present the results from a recent study of the structure and energies of the low-index surfaces of spinel IMgA1,04) using atomistic simulation techniques. These illustrate the complexity of modelling the surfaces of ternary oxides, particularly since cation ordering, resulting in the formation of inverse spinel, plays a crucial role in determining the relative surface stability. The simulations show some agreement with the very limited experimental data available for the spinel class of compounds. However, agreement with the most common experimental morphologies requires the consideration of kinetic factors.

This paper reports the results of cognitive, linguistic, and academic assessments in a representative sample of 62 adults with Williams syndrome. The average age of the group was 26 years and their mean full scale IQ was 61. Differences between Verbal and Performance IQ, and between receptive and expressive language skills, were smaller than generally found in studies of children with this condition. However, an examination of subtest scores revealed an almost identical cognitive profile to that found in children. Skills in other areas, such as reading, spelling, arithmetic, and social adaptation remained at a low level, with functioning generally being around a 6-8-year age equivalent. The consistency of reports on intellectual abilities in both child and adult studies of individuals with Williams syndrome lends increased support to the notion of a syndrome specific pattern of cognitive, linguistic, and adaptive functioning.

It has been claimed that Williams syndrome (WS), a rare neurodevelopmental disorder, is characterized by serious cognitive deficits alongside intact language. The syndrome is often used as a prime example of the modularity of an innate faculty for morphosyntactic rules. We challenge this claim and hypothesize that morphosyntax, although surprisingly good given WS level of mental retardation, is by no means intact. We make an initial test of this hypothesis through an analysis of the receptive language of a group of English-speaking WS individuals on a standardized morphosyntactic test. We then present an experimental study of expressive language that examines grammatical gender assignment in French-speaking WS patients. Despite a Verbal Mental Age selected to be higher than the chronological age of the young control group, these people with WS continue even in adulthood to show clear-cut deficits in their production of an aspect of morphosyntax that normal children acquire effortlessly very early. The results of the 2 studies, one focusing on receptive language and the other on expressive language, challenge the notion that comprehension and use of morphosyntactic rules in WS individuals are intact. The Within-domain dissociations regarding the use of grammatical gender assignment across several sentence clements and their difficulties in understanding embedded sentences-two quintessentially linguistic skills-suggest that we must rethink the notion of spared, modular, language capacities in Williams syndrome. We conclude that WS language follows a different path to normal acquisition and may turn out to be more like second language learning.

Williams syndrome (WS), a rare neurodevelopmental disorder of genetic origin, is characterised by a relative advantage of language over more serious deficits in other cognitive domains. In this study the relationship of phonological short-term memory to WS language, in particular vocabulary, was explored. Using Gathercole and Baddeley's Children's Test of Nonword Repetition (CNRep) (Gathercole & Baddeley, 1996), we examined the pattern of performance by WS participants on that task and compared it to performance on measures of receptive language, visuospatial ability, and digit span. In addition, a comparison was made of WS nonword repetition score with those of two groups of individually matched normally developing 5-year-olds, one on the basis of nonverbal test age and the other on the basis of verbal test age. As expected WS repetition scores showed an effect of nonword length but not of phonological complexity. Nonwords that were relatively wordlike were better repeated than nonwords that were less wordlike. CNRep scores were correlated with test ages on TROG, Ravens, and digit span but not with chronological age. Test age on the CNRep was at a similar level to that on TROG, Ravens, and digit span but significantly lower than on BPVS. The results lend support to the view that phonology in WS is a relative strength. In contrast, despite relatively good productive and receptive vocabulary, certain aspects of the processes of word learning in WS do not seem to develop beyond that of normal 4year-olds. The good vocabulary scores of older children and adults with WS may be simply due to their relatively good phonological short-term memory.

Insulin-like growth factor binding protein-4 (IGFBP-4) is an important member of the insulin-like growth factor (IGF) system. The IGFBP-4 has three domains of which the N-terminal sequence is important for the binding of IGF. It acts as a transport protein for IGF-I and IGF-II and modulates their biological effects. There is increasing evidence that IGFBP-4 inhibits IGF-induced cellular growth both in vitro and in vivo. IGFBP-4 can also mediate its actions through a mechanism independent of IGFs. IGFBP-4 level and expression in various tissues are influenced by IGFBP protease, nutrition, several growth factors and hormones. Overexpression of IGFBP-4 in transgenic animal models causes reduced growth of organs containing smooth muscle. Most cancers express IGFBP-4 at levels which correlate with their state of differentiation. However, the effects of IGFBP-4 on tumor growth are uncertain. In vitro studies have shown that overexpression of IGFBP-4 inhibit the growth of some colon cancer cells. Overexpression of IGFBP-4 in vivo has been reported to decrease the growth of prostate cancer. The effect of altered expression of IGFBP-4 in vivo in colon and other cancers needs to be explored as locally available IGFs appear to stimulate mitogenesis. Contents 1. Introduction 2. Structure and binding characteristics of IGFBP-4 3. Biological actions of IGFBP-4 4. Factors controlling IGFBP-4 expression 5.