Role of protein kinase B in insulin-regulated glucose uptake.

The activation of protein kinase B (or Akt) plays a central role in the stimulation of glucose uptake by insulin. Currently, however, numerous questions remain unanswered regarding the role of this kinase in bringing about this effect. For example, we do not know precisely where in the GLUT4 trafficking pathway this kinase acts. Nor do we know which protein substrates are responsible for mediating the effects of protein kinase B, although two recently identified proteins (AS160 and PIKfyve) may play a role. This paper addresses these important questions by reviewing recent progress in the field.

Dissociation between syntactic and semantic processing during idiom comprehension.

Syntactic and semantic processing of literal and idiomatic phrases were investigated with a priming procedure. In 3 experiments, participants named targets that were syntactically appropriate or inappropriate completions for semantically unrelated sentence contexts. Sentences ended with incomplete idioms (kick the...) and were biased for either a literal (ball) or an idiomatic (bucket) completion. Syntactically appropriate targets were named more quickly than inappropriate ones for both contextual biases, suggesting that syntactic analysis occurs for idioms. In a final experiment, targets were either concrete (expected) or abstract (unexpected) nouns. For literal sentences, the abstract targets were named more slowly than the concrete targets. In contrast, there was no concreteness effect for idiomatic sentences, suggesting that the literal meaning of the idiom is not processed. Overall, the results provide evidence for dissociation between syntactic and semantic processing.

CpG methylation regulates the Igf2/H19 insulator.

The differentially methylated 5'-flank of the mouse H19 gene unidirectionally regulates the communication between enhancer elements and gene promoters and presumably represses maternal Igf2 expression in vivo [1-6]. The specific activation of the paternally inherited Igf2 allele has been proposed to involve methylation-mediated inactivation of the H19 insulator function during male germline development [1-4, 6]. Here, we addressed the role of methylation by inserting a methylated fragment of the H19-imprinting control region (ICR) into a nonmethylated episomal H19 minigene construct, followed by the transfection of ligation mixture into Hep3B cells. Individual clones were expanded and analyzed for genotype, methylation status, chromatin conformation, and insulator function. The results show that the methylated status of the H19 ICR could be propagated for several passages without spreading into the episomal vector. Moreover, the nuclease hypersensitive sites, which are typical for the maternally inherited H19 ICR allele [1], were absent on the methylated ICR, underscoring the suggestion that the methylation mark dictates parent of origin-specific chromatin conformations [1] that involve CTCF [2]. Finally, the insulator function was strongly attenuated in stably maintained episomes. Collectively, these results provide the first experimental support that the H19 insulator function is regulated by CpG methylation.

In vitro methylation of specific regions in recombinant DNA constructs by excision and religation.

The first imprinted genes were identified in the early 1990s (e.g., refs. 1,2) and there are now over 40 mammalian genes known to be regulated by genomic imprinting (for an up-to-date list, see ref. 3). The details of the mechanism that discriminates between the active and silent alleles of these genes, based on their parent of origin, may differ from one imprinted gene to the next, but must include some form of epigenetic mark that distinguishes alleles that have passed through the male or female germline (4-7). The addition of methyl groups to cytosine residues of CpG dinucleotides might provide such a mark, since regions of differential methylation have been identified in the vicinity of many of the known imprinted genes (8,9). Moreover, analysis of imprinted gene expression in a methyltransferase knockout (Dnmt1(-/-)) mouse has shown that the imprint is lost in a number of cases, resulting in either two silent alleles (Igf2, Igf2r and Kvlqt) or two expressed alleles (H19, p57(kip2), Snrpn, and Xist) (4,10-12). Although there may be exceptions (for instance, imprinted expression of Mash2 is maintained in Dmnt1(-/-) embryos; ref. 13), differential methylation is likely to be an important aspect of the imprinting mechanism that is relevant to most of the imprinted genes in mammals. There is accumulating evidence that methylation is also important for the imprinting of plant genes (reviewed in ref. 14).

AHA environmental assessment.

The first step in planning is to assess your environment. Ask the long-range questions: What does your current market look like? What are the demographic trends that will influence your community? How will the workforce issue and the regulatory environment affect your hospital? Hospitals & Health Networks presents the American Hospital Association's environmental assessment, which may help you to conduct your own.

Human papillomaviruses and their role in cervical cancer.

Human papillomaviruses (HPVs) have been linked to a variety of human diseases, most notably cancer of the cervix, a disease responsible for at least 200,000 deaths per year worldwide. Over 100 different types of HPV have been identified and these can be divided into two groups. Low-risk HPV types are the causative agent of benign warts. High-risk HPV types are associated with cancer. This review focuses on the role of high-risk HPV types in cervical tumorigenesis. Recent work has uncovered new cellular partners for many of the HPV early proteins and thrown light on many of the pathways and processes in which these viral proteins intervene. At the same time, structural and biochemical studies are revealing the molecular details of viral protein function. Several of these new avenues of research have the potential to lead to new approaches to the treatment and prevention of cervical cancer.

The role of computational models in neuropsychological investigations of language: reply to Ruml and Caramazza (2000).

W. Ruml and A. Caramazza's (2000) analysis of the model of normal and aphasic lexical access proposed by G. S. Dell, M. F. Schwartz, N. Martin, E. M. Saffran, and D. A. Gagnon (1997) is completely at odds with current practice concerning the use of models in psychology. An evaluation of Dell et al.'s original claims using Ruml and Caramazza's model parameters sustains these claims in all respects.

Effect of ambiguity and lexical availability on syntactic and lexical production.

Speakers only sometimes include the that in sentence complement structures like The coach knew (that) you missed practice. Six experiments tested the predictions concerning optional word mention of two general approaches to language production. One approach claims that language production processes choose syntactic structures that ease the task of creating sentences, so that words are spoken opportunistically, as they are selected for production. The second approach claims that a syntactic structure is chosen that is easiest to comprehend, so that optional words like that are used to avoid temporarily ambiguous, difficult-to-comprehend sentences. In all experiments, speakers did not consistently include optional words to circumvent a temporary ambiguity, but they did omit optional words (the complementizer that) when subsequent material was either repeated (within a sentence) or prompted with a recall cue. The results suggest that speakers choose syntactic structures to permit early mention of available material and not to circumvent disruptive temporary ambiguities.

Structural priming as implicit learning: a comparison of models of sentence production.

Structural priming reflects a tendency to generalize recently spoken or heard syntactic structures to different utterances. We propose that it is a form of implicit learning. To explore this hypothesis, we developed and tested a connectionist model of language production that incorporated mechanisms previously used to simulate implicit learning. In the model, the mechanism that learned to produce structured sequences of phrases from messages also exhibited structural priming. The ability of the model to account for structural priming depended on representational assumptions about the nature of messages and the relationship between comprehension and production. Modeling experiments showed that comprehension-based representations were important for the model's generalizations in production and that nonatomic message representations allowed a better fit to existing data on structural priming than traditional thematic-role representations.

The Prince Edward Island Conceptual Model for Nursing: a nursing perspective of primary health care.

The philosophy of primary health care (PHC) recognizes that health is a product of individual, social, economic, and political factors and that people have a right and a duty, individually and collectively, to participate in the course of their own health. The majority of nursing models cast the client in a dependent role and do not conceptualize health in a social, economic, and political context. The Prince Edward Island Conceptual Model for Nursing is congruent with the international move towards PHC. It guides the nurse in practising in the social and political environment in which nursing and health care take place. This model features a nurse/client partnership, the goal being to encourage clients to act on their own behalf. The conceptualization of the environment as the collective influence of the determinants of health gives both nurse and client a prominent position in the sociopolitical arena of health and health care.

Speech errors, phonotactic constraints, and implicit learning: a study of the role of experience in language production.

Speech errors follow the phonotactics of the language being spoken. For example, in English, if [n] is mispronounced as [n], the [n] will always appear in a syllable coda. The authors created an analogue to this phenomenon by having participants recite lists of consonant-vowel-consonant syllables in 4 sessions on different days. In the first 2 experiments, some consonants were always onsets, some were always codas, and some could be both. In a third experiment, the set of possible onsets and codas depended on vowel identity. In all 3 studies, the production errors that occurred respected the "phonotactics" of the experiment. The results illustrate the implicit learning of the sequential constraints present in the stimuli and show that the language production system adapts to recent experience.

Lexical access in aphasic and nonaphasic speakers.

An interactive 2-step theory of lexical retrieval was applied to the picture-naming error patterns of aphasic and nonaphasic speakers. The theory uses spreading activation in a lexical network to accomplish the mapping between the conceptual representation of an object and the phonological form of the word naming the object. A model developed from the theory was parameterized to fit normal error patterns. It was then "lesioned" by globally altering its connection weight, decay rates, or both to provide fits to the error patterns of 21 fluent aphasic patients. These fits were then used to derive predictions about the influence of syntactic categories on patient errors, the effect of phonology on semantic errors, error patterns after recovery, and patient performance on a single-word repetition task. The predictions were confirmed. It is argued that simple quantitative alterations to a normal processing model can explain much of the variety among patient patterns in naming.

The origins of formal paraphasias in aphasics' picture naming.

Accounts of spoken word production differ on whether aphasics' formal paraphasias derive solely from segmental distortion or whether some derive instead from whole word substitution. Form-related paraphasias produced by nine aphasics during picture naming were examined for evidence of lexical effects (word, frequency, and grammatical class biases) and for the manner in which target phonemes and word shape were preserved. Preservation patterns were consistent with previous descriptions of aphasic and nonaphasic form-related speech errors. Evidence for word and frequency biases was found, as well as a grammatical class bias sensitive to the degree of target-response segmental overlap. In conjunction, the results indicate that formal paraphasias arise, at least in part, via word substitution. The findings are supportive of interactive models with phonological-to-lemma feedback and/or modular models with a grammatically organized lexeme level.

Language production and serial order: a functional analysis and a model.

In speech production, previously spoken and upcoming words can impinge on the word currently being said, resulting in perseverations (e.g., "beef needle soup") and anticipations (e.g., "cuff of coffee"). These errors reveal the extent to which the language-production system is focused on the past, the present, and the future and therefore are informative about how the system deals with serial order. This article offers a functional analysis of serial order in language and develops a general formal model. The centerpiece of the model is a prediction that the fraction of serial-order errors that are anticipatory, as opposed to perseveratory, can be closely predicted by overall error rate. The lower the error rate, the more anticipatory the errors are, regardless of the factors influencing error rate. The model is successfully applied to experimental and natural error data dealing with the effects of practice, speech rate, individual differences, age, and brain damage.

Regulation of a promoter from the mouse insulin like growth factor II gene by glucocorticoids.

We have microinjected constructs containing the murine IG II P3 promoter linked to different flanking sequences and a luciferase reporter gene into mouse pronuclei to establish transgenic lines of mice. The offspring was used as a source of embryonic fibroblast cultures and the effect of exogenous addition of glucocorticoids on transgene expression was analysed. It was found that both dexamethasone and hydrocortisone gave rise to a functional stimulation of the IGF II P3 promoter when the construct also contained other elements. This study demonstrates for the first time that there is an effect of glucocorticoids on the activation of an embryonic IGF II promoter, thus providing a molecular rationale for previous findings that glucocorticoids can under certain circumstances give rise to an increased transcriptional activity of the IGF II gene.

Multiple signal transduction systems regulate angiotensin II type 1 (AT1) receptor mRNA expression in bovine adrenocortical cells.

Regulation of AT1 receptor mRNA expression is an important determinant of angiotensin II-induced steroidogenesis. We have PCR-amplified the bovine adrenal AT1 receptor coding region using primers designed from the published bovine AT1 receptor sequence. This has been used as a probe on Northern blots to detect changes in the levels of AT1 receptor mRNA in primary cultures of bovine zona fasciculata cells in response to activation of several different signal transduction mechanisms in addition to two major adrenal steroid products, cortisol and aldosterone. AT1 receptor mRNA decreased in response to 6hr AII (10 nM) treatment, but returned to basal levels following 48h AII treatment. This effect was mimicked by the phorbol ester PMA (1 microM) and the calcium ionophore A23187 (1 microM), both singly and in combination. Activation of the cAMP pathway by ACTH (1 nM) and 8-bromo-cAMP (0.1 microM) also decreased AT1 receptor mRNA levels. In contrast, both IGF-1 (10 ng/ml) and potassium ions (12 mM) increased the levels of AT1 receptor mRNA. Finally, cortisol (10 microM) but not aldosterone (100 nM) decreased AT1 receptor mRNA. We conclude that the regulation of AT1 receptor mRNA in bovine zona fasciculata cells could involve several different signal transduction systems in addition to adrenocortical steroids themselves.

Recovery in deep dysphasia: evidence for a relation between auditory - verbal STM capacity and lexical errors in repetition.

This study investigates the changes in auditory-verbal short-term memory (AVSTM) and error patterns in repetition observed in a Wernicke's aphasic, NC, over a period of about 2 years following the onset of a left middle cerebral artery aneurysm. When first tested, NC demonstrated deep dysphasia, a disorder characterized by the production of semantic errors in repetition and a severe disability in repeating nonwords. At this stage, his AVSTM span, assessed in a pointing task, was less than one item. As NC recovered somewhat, his performance on AVSTM tasks improved (span increased to two items), and his pattern of error in word repetition changed (fewer semantic errors, more formal paraphasias and neologisms). Other features of his span performance after some recovery resembled patterns associated with STM-based repetition impairments (reduced recency effects and reduced word length effects). In a series of computer simulation and empirical studies, we show that NC's repetition performance can be accounted for by varying two parameters of an interactive activation model of repetition adapted from Dell and O'Seaghdha's (1991) model of production: decay rate and temporal interval. These results provide support for the view that AVSTM performance depends on storage capacities intrinsic to the language processing system. Such a model allows deep dysphasia and STM-based repetition disorders to be seen as quantitative variants of the same underlying disturbance.

The sequential curing effect in speech production.

How are the sounds of words represented in plans for speech production? In Experiment 1, subjects produced sequences of four CVCs as many times as possible in 8s. We varied the number of repetitions of the initial consonant, vowel, final consonant, CV, rhyme, and whole CVC each sequence required, and measured subjects' speaking rate. Subjects produced more CVCs when the final consonant or whole word was repeated, but were slowed when only initial sounds or CVs were repeated. Two other experiments replicate the location-based effects and extended them to bisyllabic words. We attribute the locational effects to competition between words that are formally similar, and specifically, to competition between discrepant phonemes in the two words to occupy a particular wordframe position. The fact that only discrepant initial, but not final sounds slow production suggests that phonemes are activated sequentially, from left to right.

Origins of paraphasias in deep dysphasia: testing the consequences of a decay impairment to an interactive spreading activation model of lexical retrieval.

This study investigates an account of atypical error patterns within the framework of an interactive spreading activation model. Martin and Saffran (1992) described a patient, NC, whose error pattern was unusual for the occurrence of higher rates of form-related than meaning-related word substitutions in naming and the production of semantic errors in repetition. They proposed that NC's error pattern could be accounted for by a pathologically rapid decay of primed nodes in the semantic-lexical-phonological network that shifts the probabilities of error outcome in lexical retrieval. In the present study, Martin and Saffran's account was tested and supported in a series of simulations that reproduce essential features of NC's lexical error pattern in naming and repetition. Also described here are the results of a longitudinal study of NC's naming and repetition, which revealed a shift in relative lexical error rates toward a qualitatively normal pattern. This change in error pattern was simulated by assuming that recovery reflects resolution of the rapid decay rate toward normal levels. The patient data and computational studies are discussed in terms of their significance for the understanding of aphasic impairments and their implications for models of lexical retrieval.