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T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n = 12). Treatment was well tolerated, with a low incidence of both cytokine release syndrome (any grade, n = 6) and neurotoxicity (any grade, n = 3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow (BM). High disease burden (≥40% morphologic blasts) before CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. After infusion, CD8+ CAR T cells had a proliferative advantage over CD4+ CAR T cells and at peak expansion, had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation (AlloHCT) had sustained, durable responses. In summary, the initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03573700.

Supplementary Data from Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages

Current chimeric antigen receptor-modified (CAR) T-cell products are evaluated in bulk, without assessing functional heterogeneity. We therefore generated a comprehensive single-cell gene expression and T-cell receptor (TCR) sequencing data set using pre- and postinfusion CD19-CAR T cells from blood and bone marrow samples of pediatric patients with B-cell acute lymphoblastic leukemia. We identified cytotoxic postinfusion cells with identical TCRs to a subset of preinfusion CAR T cells. These effector precursor cells exhibited a unique transcriptional profile compared with other preinfusion cells, corresponding to an unexpected surface phenotype (TIGIT+, CD62Llo, CD27−). Upon stimulation, these cells showed functional superiority and decreased expression of the exhaustion-associated transcription factor TOX. Collectively, these results demonstrate diverse effector potentials within preinfusion CAR T-cell products, which can be exploited for therapeutic applications. Furthermore, we provide an integrative experimental and analytic framework for elucidating the mechanisms underlying effector development in CAR T-cell products. Significance: Utilizing clonal trajectories to define transcriptional potential, we find a unique signature of CAR T-cell effector precursors present in preinfusion cell products. Functional assessment of cells with this signature indicated early effector potential and resistance to exhaustion, consistent with postinfusion cellular patterns observed in patients. This article is highlighted in the In This Issue feature, p. 2007

Embankment dams have been constructed in Canada and the United States for over one hundred years. Embankment dams are owned by government bodies, mining and resource companies, hydroelectric producers, and other entities. Dams that have been in service for many years may have a high hazard rating due to the consequences of potential failure, as development tends to expand towards these structures over time. Older embankment dams precede the development of modern filter design criteria, which were first developed in the 1920s and have undergone considerable progress and refinement since. The lack of appropriate filter design in aging dams may increase risk of internal erosion and eventual failure. Risk assessment procedures and monitoring programs are the primary tools used by dam owners and operators to evaluate the risk of and detect potential failure events. A brief summary of modern filter design has been presented. Traditional particle-sized based criteria were reviewed and recent developments in constriction-based criteria were discussed. Considerations for challenging base soils, such as dispersive and broadly graded soils, were provided. The effects of aging on dam filter properties and performance were discussed. Evidence of filter degradation over time exists in the literature and has been attributed to several causes. These factors include filter clogging, changes in water quality, mechanical degradation, and the development of internal instability and each has been examined. A discussion of risk assessment and monitoring for aging dams has been provided. Three of the most widely-used methods were summarized. Most risk assessment methods use a potential failure mode analysis framework. The numerous uncertainties associated with an aging structure presents challenges when attempting to apply potential failure mode analysis. The results of a risk assessment investigation are typically used to identify areas that may require additional investigation, potential remediation actions, or increased monitoring. They are also used as a basis for emergency planning. Monitoring techniques provide information about the location and rate of seepage in and through the embankment. Monitoring is typically the first indication of an internal erosion event that may lead to failure. Improvements in monitoring techniques have decreased detection time and increase likelihood of successful interventions that prevent failure.

Autologous chimeric antigen receptor (CAR) T cells targeting the CD19 antigen have demonstrated a high complete response rate in relapsed/refractory B-cell malignancies. However, autologous CAR T cell therapy is not an option for all patients. Here we optimized conditions for clinical-grade manufacturing of allogeneic CD19-CAR T cells using CD45RA-depleted donor memory T cells (Tm) for a planned clinical trial. Tm were activated using the MACS GMP T Cell TransAct reagent and transduced in the presence of LentiBOOST with a clinical-grade lentiviral vector that encodes a 2nd generation CD19-CAR with a 41BB.zeta endodomain. Transduced T cells were transferred to a G-Rex cell culture device for expansion and harvested on day 7 or 8 for cryopreservation. The resulting CD19-CAR(Mem) T cells expanded on average 34.2-fold, and mean CAR expression was 45.5%. The majority of T cells were CD4

Multiple-choice (MC) anatomy "spot-tests" (identification-based assessments on tagged cadaveric specimens) offer a practical alternative to traditional free-response (FR) spot-tests. Conversion of the two spot-tests in an upper limb musculoskeletal anatomy unit of study from FR to a novel MC format, where one of five tagged structures on a specimen was the answer to each question, provided a unique opportunity to assess the comparative validity and reliability of FR- and MC-formatted spot-tests and the impact on student performance following the change of test format to MC. Three successive year cohorts of health science students (n = 1,442) were each assessed by spot-tests formatted as FR (first cohort) or MC (following two cohorts). Comparative question difficulty was assessed independently by three examiners. There were more higher-order cognitive skill questions and more of the course objectives tested in the MC-formatted tests. Spot-test reliability was maintained with Cronbach's alpha reliability coefficients ≥ 0.80 and 80% of the MC items of high quality (having point-biserial correlation coefficients > 0.25). These results also demonstrated guessing was not an issue. The mean final score for the MC-formatted cohorts increased by 4.9%, but did not change for the final theory examination that was common to all three cohorts. Subgroup analysis revealed that the greatest change in spot-test marks was for the lower-performing students. In conclusion, our results indicate spot-tests formatted as MC are suitable alternatives to FR tests. The increase in mean scores for the MC-formatted spot-tests was attributed to the lower demand of the MC format.

With many ongoing clinical trials utilizing adeno-associated virus (AAV) gene therapy, it is necessary to find scalable and serotype-independent primary capture and recovery methods to allow for efficient and robust manufacturing processes. Here, we demonstrate the ability of a hydrophobic interaction chromatography membrane to capture and recover AAV1, AAV5, AAV8, and AAV “Mutant C” (a novel serotype incorporating elements of AAV3B and AAV8) particles from cell culture media and cell lysate with recoveries of 76%–100% of loaded material, depending on serotype. A simple, novel technique that integrates release and recovery of cell-associated AAV capsids is demonstrated. We show that by the addition of lyotropic salts to AAV-containing cell suspensions, AAV is released at an equivalent efficiency to mechanical lysis. The addition of the lyotropic salt also promotes a phase separation, which allows physical removal of large amounts of DNA and insoluble cellular debris from the AAV-containing aqueous fraction. The AAV is then captured and eluted from a hydrophobic interaction chromatography membrane. This integrated lysis and primary capture and recovery technique facilitates substantial removal of host-cell DNA and host-cell protein impurities., Graphical Abstract, We have developed a simple, integrated method for cellular lysis and primary capture and recovery of AAV via hydrophobic interaction chromatography. This method results in high recoveries, substantial impurity removal, is easily scalable, and is compatible with multiple industrially relevant serotypes of AAV.

Gender differences in the relationships between working memory (short-term storage and combined storage and processing) in both the visuo-spatial and verbal domains and children's alphabet transcription and text writing abilities were investigated. Data from 81 children (43 males) aged between 5;2 to 8;5 revealed no significant group differences between boys and girls in working memory or writing performance. However, individual difference analyses demonstrated variation associated with age and gender in the memory skills underpinning writing. Regression analyses revealed that verbal short-term memory abilities predicted the alphabet transcription skills of boys but not girls. Although visuo-spatial short-term memory predicted writing quality in both genders, predictors of writing fluency differed with verbal working memory skills predicting boys' writing fluency and visuo-spatial short-term memory predicting writing fluency in girls. The need to consider gender differences more critically from the perspective of individual differences in cognitive skills underpinning writing development and the strategic application of these skills during writing is discussed. Exploring relationships between working memory and writing: Individual differences associated with gender. Available from: https://www.researchgate.net/publication/276151649_Exploring_relationships_between_working_memory_and_writing_Individual_differences_associated_with_gender [accessed May 26, 2015].

Training and technical assistance organizations called intermediaries have sprung up in cities to help build the capacities of grassroots organizations, but they are lacking in rural communities an...

Background. The spontaneous recoding of visual stimuli into a phonological code to aid short-term retention has been associated with progress in learning to read (Palmer, 2000b). Aim. This study examined whether there was a comparable association with the development of writing skills. Sample. One hundred eight children (64 males) in the second year of the UK educational system (mean age 5:8 years, SD = 4 months) were recruited to the study. Methods. The children participated in tasks to assess their general cognitive abilities, reading skills, and their predominant short-term memory (STM) strategy for retaining visually presented stimuli. On the basis of their memory profile, children were classified as either engaging in verbal recoding of the stimuli (N = 31) or not (N = 77). Writing performance was indexed as alphabet transcription, spelling, and early text production skills. Results. Children classified as verbal recoders demonstrated better spelling performance and produced more individual letters, words, and T-units in their texts than did children who persisted with a visual memory strategy. In contrast, the alphabet transcription abilities of the groups did not differ. Hierarchical regression analyses revealed that variance in text production skills was associated with STM capacity and that moreover, significant independent variance in the number of words and T-units in the children's texts was predicted by individual differences in verbal recoding abilities. Conclusion. The results suggest that the development of verbal recoding skills in STM may play a role in children's early progress in writing, particularly their text generation skills.

In order to communicate understanding, students are often required to produce texts which present an explicit, coherent argument. This study examined the extent to which individual differences in undergraduates' topic knowledge and working memory skills were related to their ability to revise texts to better fulfil these goals. Forty-seven students revised texts containing three types of error: language, structure and argument. Topic knowledge was indexed by multiple choice test performance. Verbal short-term and working memory were measured using forward and backward digit recall and reading span. Rates of identification, diagnosis and correction of errors were generally poor. Contrary to expectations neither topic knowledge nor verbal working memory was associated with text revision although significant associations were identified with verbal short-term memory. When revising texts students may focus on the surface features of the text rather than addressing issues of structure and argument. Possible accounts of this tendency are considered.

A common precursor, tetronic acid, was used in the synthesis of several vulpinic acids and pulvinic acids, which are pigments found in several lichens and mushrooms. The key features of this method are a two-step alkylidenation of benzyl tetronate and a Suzuki–Miyaura cross-coupling. The synthesis of several natural products, vulpinic acid, pinastric acid, xerocomic acid is described.

A short, convergent synthesis of the mushroom pigment norbadione A is described. The construction of an appropriately substituted naphtholactone intermediate involved a regioselective Diels-Alder reaction between a bis(triisopropylsilyloxy)diene and 2,6-dichlorobenzo-1,4-quinone. A double Suzuki-Miyaura cross-coupling between a diboronate and two identical enol triflates was another key feature of the synthesis.

Several vulpinic acids were synthesized in a few steps from a single precursor, the tetronic acid. This commercial compound was converted in a few steps to an iodide. Suzuki–Miyaura cross-couplings involving this common intermediate and various arylboronates allowed to gain access to several vulpinic acids (or methyl pulvinates). Among them, two natural products, vulpinic acid and pinastric acid, were prepared.

This study investigates whether working memory skills of children are related to teacher ratings of their progress towards learning goals at the time of school entry, at 4 or 5 years of age. A sample of 194 children was tested on measures of working memory, phonological awareness, and non-verbal ability, in addition to the school-based baseline assessments in the areas of reading, writing, mathematics, speaking and listening, and personal and social development. Various aspects of cognitive functioning formed unique associations with baseline assessments; for example complex memory span with rated writing skills, phonological short-term memory with both reading and speaking and listening skills, and sentence repetition scores with both mathematics and personal and social skills. Rated reading skills were also uniquely associated with phonological awareness scores. The findings indicate that the capacity to store and process material over short periods of time, referred to as working memory, and also the awareness of phonological structure, may play a crucial role in key learning areas for children at the beginning of formal education.

Isolated (non-syndromic) congenital cataract may be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive trait. Considerable progress has been made in identifying genes and loci for dominantly inherited cataract, but the molecular basis for autosomal recessive disease is less well defined. Hence we undertook genetic linkage studies in four consanguineous Pakistani families with non-syndromic autosomal recessive congenital cataracts. In two families linkage to a 38 cM region 9q13-q22 was detected. Although a locus for recessive congenital cataracts had not been mapped previously to this region, the target interval encompasses the candidate region autosomal recessive adult-onset pulverulent cataracts (CAAR). The CAAR was mapped previously to 9q13-q22, and may therefore be allelic to non-syndromic autosomal recessive congenital cataracts. The other two families did not demonstrate linkage to 9q, but both had a region of homozygosity at 16q22 containing the heat shock transcription factor 4 (HSF4) gene. The HSF4 mutations have been reported in four families with autosomal dominant cataracts and, recently, in a single kindred with autosomal recessive congenital cataract. Mutation analysis of HSF4 revealed homozygous mutations (p.Arg175Pro and c.595_599delGGGCC, respectively) in the two families. These findings confirm that mutations in HSF4 may result in both autosomal dominant and autosomal recessive congenital cataract, and highlight the locus heterogeneity in autosomal recessive congenital cataract.

An enantioselective synthesis of the piperidine alkaloids (+)-sedamine and (-)-prosophylline is reported. The synthesis of (+)-sedamine has been achieved in 12 steps with an overall yield of 20% from benzaldehyde, and (-)-prosophylline was obtained in 15 steps with an overall yield of 9.2%, starting from D-glyceraldehyde acetonide 14. The key steps are enantioselective allyltitanation reactions and ring-closing or cross-metathesis reactions.

Retinitis pigmentosa (RP), the commonest form of inherited retinal dystrophies is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of peripheral visual field. RP is inherited either in an autosomal dominant, autosomal recessive or X-linked mode. A locus (RP18) for autosomal dominant RP was previously mapped by linkage analysis in two large pedigrees to chromosome 1p13-q21. The human HPRP3 gene, the orthologue of the yeast pre-mRNA splicing factor (PRP3), localizes within the RP18 disease interval. The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families. So far, two different missense mutations in two English, a Danish family and in three RP individuals have been identified. Both mutations are clustered within a two-codon stretch in the 11th exon of the HPRP3 gene. Interestingly, one of the mutations (T494M) is seen repeatedly in apparently unlinked families raising the possibility of a mutation hot spot. This has been confirmed by haplotype analysis using SNPs spanning the HPRP3 gene region supporting multiple origins of the mutation. The altered HPRP3 amino acids, which are highly conserved in all known HPRP3 orthologues, indicate a major function of that domain in the splicing process. The identification of mutations in a third pre-mRNA splicing factor gene further highlights a novel mechanism of photoreceptor degeneration due to defects in the splicing process.

An enantioselective synthesis of the indolizidine alkaloid (-)-slaframine from aldehyde 1 is reported. The stereogenic centers at C-1 and C-8a are introduced by an enantioselective allyltitanation and a Mitsunobu reaction. Reductive double cyclization of the acyclic compound (-)-10 affords the bicyclic skeleton of (-)-slaframine.

This study has two theoretical dimensions: (a) to explore which components of Baddeley's (1986) working memory model are associated with children's spoken language comprehension, and (b) to compare the extent to which measures of the components of this fractionated model and an index of a unitary model (listening span) are able to predict individual differences in spoken language comprehension. Correlational analyses revealed that within a group of 66 4- and 5-year-old children both listening span and phonological memory, but not visuospatial memory, were associated with vocabulary knowledge and spoken language comprehension. However, of the proposed measures of central executive function - dual task coordination, sustained attention, verbal fluency - only the latter was related to children's ability to understand spoken language. Hierarchical regression analyses indicated that variance in vocabulary knowledge was best explained by phonological memory skills, whereas individual differences in spoken langu...

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye1. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.

An enantioselective synthesis of the piperidine alkaloids (+)-sedamine and (-)-prosophylline is reported. The synthesis of (+)-sedamine has been achieved in 12 steps with an overall yield of 20% from benzaldehyde, and (-)-prosophylline was obtained in 15 steps with an overall yield of 9.2%, starting from D-glyceraldehyde acetonide 14. The key steps are enantioselective allyltitanation reactions and ring-closing or cross-metathesis reactions.

An enantioselective synthesis of the indolizidine alkaloid (-)-slaframine from aldehyde 1 is reported. The stereogenic centers at C-1 and C-8a are introduced by an enantioselective allyltitanation and a Mitsunobu reaction. Reductive double cyclization of the acyclic compound (-)-10 affords the bicyclic skeleton of (-)-slaframine.

The nature of the developmental association between phonological memory and vocabulary knowledge was explored in a longitudinal study. At each of 4 waves (at ages 4, 5, 6, and 8 yrs), measures of vocabulary, phonological memory, nonverbal intelligence, and reading were taken from 80 children. Comparisons of cross-lagged partial correlations revealed a significant shift in the causal underpinnings of the relationship between phonological memory and vocabulary development before and after 5 yrs of age. Between 4 and 5 yrs, phonological memory skills appeared to exert a direct causal influence on vocabulary acquisition. Subsequently, though, vocabulary knowledge became the major pacemaker in the developmental relationship, with the earlier influence of phonological memory on vocabulary development subsiding to a nonsignificant level. (PsycINFO Database Record (c) 2008 APA, all rights reserved)

A comprehensive working memory battery and tests of mathematical skills were administered to 90 children—41 in Year 1 (5–6 years of age) and 49 in Year 3 (7–8 years of age). Working memory could explain statistically significant variance in number writing, magnitude judgment, and single-digit arithmetic, but the different components of working memory had different relationships with the different skills. Visual–spatial sketchpad (VSSP) functioning predicted unique variance in magnitude judgments and number writing. Central executive functioning explained unique variance in the addition accuracy of Year 1 children. The unique variance explained in Year 3 multiplication explained by phonological loop functioning just missed conventional levels of significance (p = .06). The results are consistent with the VSSP having a role in the development of number writing and magnitude judgments but a lesser role in early arithmetic.

It has recently been suggested that the developmental association between nonword repetition performance and vocabulary knowledge reflects the contribution of phonological memory processes to vocabulary acquisition (e.g., Gathercole & Baddeley, 1989). An alternative account of the association is that the child uses existing vocabulary knowledge to support memory for nonwords. The present article tests between these two alternative accounts by evaluating the role of phonological memory and linguistic factors in nonword repetition. In a longitudinal database, repetition accuracy in 4-, 5-, and 6-year-olds was found to be sensitive to two independent factors: a phonological memory factor, nonword length, and a linguistic factor, wordlikeness. To explain these combined influences, it is suggested that repeating nonwords involves temporary phonological memory storage which may be supported by either a specific lexical analogy or by an appropriate abstract phonological frame generated from structurally similar vocabulary items.

A study of 4-and 5-year-old children investigated whether measures of phonological memory and rhyme awareness reflect a common phonological processing skill or differentiable phonological abilities. Tests of phonological memory, rhyme oddity detection, reading, vocabulary and non-verbal intelligence were given to the children in each age group. Factor analyses performed on the measures showed that phonological memory and rhyme awareness measures did indeed share a common phonological processing component, but other analyses established that the two types of phonological processing task were nonetheless differentially linked with reading and vocabulary development. The two phonological memory measures taken in the study–non-word repetition and digit span–were significantly related to vocabulary knowledge in both the ages 4 and 5 groups, and to reading achievement at age 5, but not age 4. These findings replicate and extend our earlier findings. In contrast, rhyme awareness scores were not significantly associated with vocabulary knowledge at either age, but were strongly related to scores on one of the reading tests, a multiple-choice measure, at both ages 4 and 5. The pattern of findings indicates that, although there appears to be a common phonological processing component underpinning phonological memory and phonological awareness tasks, the tasks also reflect separate cognitive skills which make differential contributions to reading and vocabulary development.

Several vulpinic acids were synthesized in a few steps from a single precursor, the tetronic acid. This commercial compound was converted in a few steps to an iodide. Suzuki–Miyaura cross-couplings involving this common intermediate and various arylboronates allowed to gain access to several vulpinic acids (or methyl pulvinates). Among them, two natural products, vulpinic acid and pinastric acid, were prepared.

This study investigated associations between working memory (measured by complex memory tasks) and both reading and mathematics abilities, as well as the possible mediating factors of fluid intelligence, verbal abilities, short-term memory (STM), and phonological awareness, in a sample of 46 6- to 11-year-olds with reading disabilities. As a whole, the sample was characterized by deficits in complex memory and visuospatial STM and by low IQ scores; language, phonological STM, and phonological awareness abilities fell in the low average range. Severity of reading difficulties within the sample was significantly associated with complex memory, language, and phonological awareness abilities, whereas poor mathematics abilities were linked with complex memory, phonological STM, and phonological awareness scores. These findings suggest that working memory skills indexed by complex memory tasks represent an important constraint on the acquisition of skill and knowledge in reading and mathematics. Possible mechanisms for the contribution of working memory to learning, and the implications for educational practice, are considered.

This study investigates the distinctive working memory profiles of children with learning difficulties. A sample of 64 children aged 7 to 11 years with recognised special educational needs at varying stages participated in this study. They were tested on measures of the central executive, phonological loop and visuospatial skills. The children in all three special needs subgroups performed below the expected attainment levels for their age in central executive and visuo-spatial tasks, but not in measures of the phonological loop. Very low levels of working memory performance were many times more common in the special needs sample than in a large sample of children without special educational needs. Deficits in working memory performance were more marked in children with statements of special needs than those at earlier stages of recognition of the need for educational support, particularly in measures of the central executive. These children struggle to meet the demands of complex tasks that require them to process, maintain, and store information simultaneously. It is suggested that this difficulty may underpin their failures to make normal educational progress.

The aim of this study was to investigate the functional organisation of working memory and related cognitive abilities in young children. A sample of 633 children aged between 4 and 6 years were tested on measures of verbal short-term memory, complex memory span, sentence repetition, phonological awareness, and nonverbal ability. The measurement model that provided the best fit of the data incorporates constructs that correspond to the central executive, phonological loop, and episodic buffer subcomponents of working memory, plus distinct but associated constructs associated with phonological awareness and nonverbal ability.

Two experiments investigated the contribution of phonological short-term memory to the processing of spoken sentences by 4- and 5-year-old children. In Experiment 1, sentences contained either short or longer words, and varied in syntactic structure. Overall, repetition but not comprehension of the sentences was significantly influenced by word length. In Experiment 2, children selected on the basis of their high phonological short-term memory ability were founded to be superior at repeating sentences to children of lower phonological short-term memory ability, although the two groups did not differ in their comprehension accuracy for the same sentences. In both experiments, comprehension and repetition performance were differently influenced by particular sentence structures. It is proposed that sentence repetition in children is constrained by phonological memory capacity, and is therefore directly influenced by memory-related factors that include the length and number of words in sentences, and individual differences in memory skills.

Usher syndrome (USH) is a combination of a progressive pigmentary retinopathy, indistinguishable from retinitis pigmentosa, and some degree of sensorineural hearing loss. USH can be subdivided in Usher type I (USHI), type II (USHII) and type III (USHIII), all of which are inherited as autosomal recessive traits. The three subtypes are genetically heterogeneous, with six loci so far identified for USHI, three for USHII and only one for USHIII. Mutations in a novel gene, USH2A, encoding the protein usherin, have recently been shown to be associated with USHII. The gene encodes a protein with partial sequence homology to both laminin epidermal growth factor and fibronectin motifs. We analysed 35 British and one Pakistani Usher type II families with at least one affected member, for sequence changes in the 20 translated exons of the USH2A gene, using heteroduplex analysis and sequencing. Probable disease-causing mutations in USH2A were identified in 15 of 36 (41.7%) Usher II families. The most frequently encountered mutation (11/15 families or 11/18 mutated alleles) was del2299G in exon 13, resulting in a frameshift and premature stop codon. Other mutations include insertions and point mutations, of which two are previously unreported. Five different polymorphisms were also detected. Our results indicate that mutations in this gene are responsible for disease in a large proportion of British Usher type II patients. Moreover, if screening for mutations in USH2A is considered, it is sensible to screen for the del2299G mutation first.

This article presents findings from the Children's Test of Nonword Repetition (CNRep). Normative data based on its administration to over 600 children aged between four and nine years are reported. Close developmental links are established between CNRep scores and vocabulary, reading, and comprehensive skills in children during the early school years. The links between nonword repetition and language skills are shown to be consistently higher and more specific than those obtained between language skills and another simple verbal task with a significant phonological memory component, auditory digit span. The psychological mechanisms underpinning these distinctive developmental relationships between nonword repetition and language development are considered.

Summary. We consider a spherically symmetric, non-rotating earth consisting of an isotropic, perfect elastic material where the density and the S-wave velocity may have one or two discontinuities in the upper mantle. We show that given the velocity throughout the mantle and the crust and given the density in the lower mantle, then the frequencies of the torsional oscillations of one angular order (one torsional spectrum), determine the density in the upper mantle and in the crust uniquely. If the velocity is known only in the lower mantle, then the frequencies of the torsional oscillations of two angular orders uniquely determine both the density and the velocity in the upper mantle and in the crust. In particular, the position and size of the discontinuities in the density and velocity are uniquely determined by two torsional spectra.

A moving boundary problem which arises during transport with precipitation-dissolution reactions is solved by three different numerical methods. Two of these methods (one explicit and one implicit) are based on an integral formulation of mass balance and lead to an approximation of a weak solution. These methods are compared to a front-tracking scheme. Although the two approaches are conceptually different, the numerical solutions showed good agreement. As the ratio of dispersion to convection decreases, the methods based on the integral formulation become computationally more efficient. Specific reactions were modeled to examine the dependence of the system on the physical and chemical parameters. Although the water flow rate does not explicitly appear in the equation for the velocity of the moving boundary, the speed of the boundary depends more on the flux rate than on the dispersion coefficient. The discontinuity in the gradient of the solute concentration profile at the boundary increases with convection and with the initial concentration of the mineral. Our implicit method is extended to allow participation of the solutes in complexation reactions as well as the precipitation-dissolution reaction. This extension is easily made and does not change the basic method.