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Exaggerated femoral anteversion and acetabular development: experimental study in growing dogs.

Femoral excessive anteversion caused by femoral osteotomy in growing dogs is an accurate dynamic model of experimental acetabular dysplasia. Radiographic and CT scan examinations were performed throughout the growing period. Evolution showed an incomplete femoral detorsion. It induced acetabular developmental modification leading to an anterior and superior acetabular dysplasia. At the end of the growing period, hips were not dislocated, but signs of femoral and acetabular osteoarthritis were obvious, which shows the importance of mechanical force modification in the creation of experimental osteoarthritis. The links between hip osteoarthritis and exaggerated femoral anteversion are discussed. Might acetabular dysplasia be secondary to femoral anteversion, which could justify a corrective osteotomy during childhood? Our experiment leads to a better comprehension of this phenomenon.

Acetabulum↗

Reduced accommodation in children with Down syndrome.

PURPOSE: To examine the accommodative accuracy and amplitude in children with Down syndrome. Accommodation is usually assumed to be good in children and is rarely measured. METHODS: A dynamic retinoscopy technique was developed that allows rapid and reliable measures of accuracy and amplitude of accommodation in infants and children. RESULTS: Use of the dynamic technique with a small sample of schoolchildren with Down syndrome shows that 80% have reduced amplitude of accommodation, in comparison to a control group of developmentally normal children. CONCLUSIONS: Optometric management of children with Down syndrome should include consideration of accommodation.

Accommodation, Ocular↗

Restricted expression of a truncated adenylyl cyclase in the cephalic furrow of Drosophila melanogaster.

We have identified a novel isoform of adenylyl cyclase, DAC78C, in Drosophila melanogaster that encodes two structurally distinct proteins in a developmentally restricted manner. The protein corresponding to one transcript is potently activated by G protein and protein kinase C and is expressed ubiquitously. The protein corresponding to the second transcript is expressed in a dynamic pattern in gastrulation stage embryos; it is restricted to the cephalic furrow and dorsal transverse folds, active regions of cell movement of unknown function in the Drosophila embryo. We propose that DAC78C and the cAMP pathway play an important role in directing these morphogenetic movements, and that this gene may provide clues to the functional significance of these structures in gastrulation.

Adenylyl Cyclases↗

Essential role of RGS-PX1/sorting nexin 13 in mouse development and regulation of endocytosis dynamics.

RGS-PX1 (also known as sorting nexin 13) is a member of both the regulator of G protein signaling (RGS) and sorting nexin (SNX) protein families. Biochemical and cell culture studies have shown that RGS-PX1/SNX13 attenuates Galphas-mediated signaling through its RGS domain and regulates endocytic trafficking and degradation of the epidermal growth factor receptor. To understand the functions of RGS-PX1/SNX13 in vivo, we generated mice carrying targeted mutations of Snx13 and found that systemic Snx13-null mice were embryonic lethal around midgestation. Snx13-null embryos had significant overall growth retardation and defects in neural tube closure, blood vessel formation, and the formation of the placental labyrinthine layer. Moreover, the Snx13-null visceral yolk sac endoderm cells showed dramatic changes in the organization of endocytic compartments, abundant autophagic vacuoles, and abnormal localization of several endocytic markers, including megalin, a receptor for nutrients and proteins; ARH, a coat protein that binds megalin; LAMP2; and LC3. These changes suggest that Snx13-null embryos are defective in nutrient uptake and transport, which may contribute to the other developmental abnormalities observed. Taken together, our findings demonstrate an essential role for RGS-PX1/SNX13 in mouse development and provide previously undescribed insights into its cellular function in the regulation of endocytosis dynamics.

Animals↗

Amphiphysin I antisense oligonucleotides inhibit neurite outgrowth in cultured hippocampal neurons.

Amphiphysin I is an SH3 domain-containing neuronal protein, enriched in axon terminals, which was reported to act as a physiological binding partner for dynamin I in synaptic vesicle endocytosis. Rvs167 and Rvs161, the yeast homologs of amphiphysin I, have been implicated in endocytosis, actin function, and cell polarity. Now we have explored the possibility that amphiphysin I also may have a role in actin dynamics and cell polarity by testing the effect of amphiphysin I suppression on neurite outgrowth. Freshly plated hippocampal neurons were exposed to antisense oligonucleotides via a new delivery system based on a polycationic amphipathic polymer, PS980. Western blot analysis revealed that amphiphysin I levels steadily increased with neuronal differentiation, whereas in antisense-treated cultures amphiphysin I levels were reduced to approximately 10% of control levels at 48 hr. Concomitantly, a collapse of growth cones and a severe inhibition of neurite outgrowth and axon formation were observed. A similar effect was observed previously after dynamin I suppression in the same culture system (). We also have found that amphiphysin I and dynamin I colocalize in developing neurons at all developmental stages and that a pool of both proteins is colocalized with actin patches at the leading edge of growth cones. Our findings suggest a conserved role of the amphiphysin protein family in the dynamics of the cortical cell cytoskeleton and provide new evidence for a close functional link between amphiphysin I and dynamin I.

Actins↗

Nourishing the body through use of process prescriptions in group therapy.

OBJECTIVE: This clinical report describes a creative process for developing between-session prescriptions which sustain and strengthen the momentum of change occurring in group treatment sessions. METHOD: Therapists in this model use words and phrases depicting the group as a body in order to guide the treatment process and develop between-session prescriptions. Maintaining a perspective of the treatment group as a body facilitates development of member commitment to the well-being of a physical and psychological body, and between-session assignments employ the developmental phases of the therapy for illuminating the disorder and effecting its resolution. This approach was developed in an ongoing, open-ended treatment group provided at a community mental health center for 14 years. RESULTS: Examples are presented of process prescriptions which simultaneously address several dynamic levels: (a) the theme of interactions between the individuals in each session; (b) the particular stage of the group's development, and the ways this level of maturation determines how interactions arise and themes are selected; and (c) the underlying functions of the eating disorder. DISCUSSION: Using the metaphor of the body to guide the language of between-session prescriptions links developmental group treatment process with members' day-to-day engagement with the eating disorder. By participating directly in the development of the treatment experience, the group members become committed to a developmental process that engages them in accountability and caring for a body, and, by extension, their own bodies.

Adult↗

Adolescent PTSD and developmental consequences of crack dealing.

The effect of crack dealing on emotionally disturbed adolescents in two African-American inner-city communities is examined and illustrated by case examples. Crack dealing was most often found to have dynamics and consequences separate from those of crack use. These include post-traumatic stress disorder and other significant emotional disturbances arising from the violence associated with crack dealing, and the shaping of adolescent identity by the associated culture of violence and guns. Implications for school drug abuse education are explored.

Adolescent↗

The nurse internship experience: a dynamic learning environment for the novice.

This article highlights the history of nurse internship programs and reviews the application process, the content, and the design of a nurse internship program. The program described has proven to be a developmental process for the nurse intern, the preceptor, and the staff development specialist. Recommendations are presented for implementation of a successful nurse internship program.

Education, Nursing, Continuing↗

Human brain plasticity: evidence from sensory deprivation and altered language experience.

The results from the language studies taken as a whole point to different developmental time courses and developmental vulnerabilities of aspects of grammatical and semantic/lexical processing. They thus provide support for conceptions of language that distinguish these subprocesses within language. Similarly, following auditory deprivation, processes associated with the dorsal visual pathway were more altered than were functions associated with the ventral pathway, providing support for conceptions of visual system organization that distinguish functions along these lines. Could the effects observed in blind and deaf adults be accounted for, at least in part, by the redundant connectivity of the immature human brain? One way we tested this hypothesis was to study the differentiation of visual and auditory sensory responses in normal development (Neville, 1995). In normal adults, auditory stimuli elicit ERP responses that are large over temporal brain regions but small or absent over occipital regions. By contrast, in 6-month-old children we observed that auditory ERPs are equally large over temporal and visual brain regions, consistent with the idea that there is less specificity and more redundancy of connections between the auditory and visual cortex at this time. Between 6 and 36 months, however, we observed a gradual decrease in the amplitude of the auditory ERP over visual areas, while the amplitude over the temporal areas was unchanged. These results suggest that early in human development, there exists a redundancy of connections between auditory and visual areas and that this overlap gradually decreases after birth. This loss of redundancy may be a boundary condition that determines when sensory deprivation can result in alterations in the organization of remaining sensory systems. The considerable variability in timing of sensitive periods may also be in part due to temporal differences in the occurrence of redundancy within different systems. Ongoing studies of infants and children employing different types of stimuli will test for the specificity of these effects (Mitchell et al., 1999). Differences in the degree of plasticity may also be due to differences in the overall level of redundant connectivity within different systems. For example, it may be that aspects of sensory systems that are specialized for high spatial acuity (e.g., central vision and central audition) exhibit fewer developmental redundancies, decreased modifiability and more specificity than those displaying less acuity and precision (e.g., peripheral representations within vision and audition). There is some evidence for this hypothesis within the visual system (Chalupa and Dreher, 1991). In addition, there may be molecular differences between systems displaying different levels and patterns of experience-dependent plasticity. It is of interest that all levels of the dorsal pathway of the visual system, which in the studies reviewed here shows a high level of modifiability, displays strong immunoreactivity for the monoclonal antibody CAT 301 in macaque monkeys (DeYoe et al., 1990). By contrast there is very little labeling within the ventral visual pathway. Moreover, the expression of CAT 301 immunoreactivity shows marked experience-dependent plasticity, suggesting it may play a role in the guidance and/or stabilization of synaptic structure (Sur et al., 1988). Further research along these lines within the auditory system and in animal models of sensory deprivation and other developmental disorders may elucidate the role of specific molecular factors in the developmental plasticity of different neural systems. A related, more general hypothesis that may account for the different patterns of plasticity within both vision and language is that systems employing fundamentally different learning mechanisms (perhaps mediated by different anatomical and molecular substrates) display different patterns of developmental plasticity. It may be that systems that display experience-dependent change throughout life, including the topography of sensory maps (Merzenich et al., 1988; Gilbert, 1995; Kaas, 1995), lexical acquisition (i.e. object-word associations), and the establishment of form, face, and object representations (i.e., ventral pathway functions) rely upon very general, associative learning mechanisms that permit learning and adaptation throughout life. By contrast, systems that are important for computing dynamically shifting relations among locations, objects and events (including the dorsal visual pathway and the systems of the brain that mediate grammar) appear dependent on and modifiable by experience primarily during more limited periods in development. This could account for both the greater developmental deficits and enhancements of dorsal pathway function following various developmental anomalies and for the greater effects of altered language experience on grammatical functions. Further research is necessary to characterize systems that become constrained in this way and those that can be modified throughout life. This type of developmental evidence can contribute to fundamental descriptions of the architecture of different cognitive systems and can guide future studies of the cellular and molecular mechanisms important in neuroplasticity. Additionally, in the long run, they may contribute to the design of educational and habilitative programs for both normally and abnormally developing children.

Adaptation, Physiological↗

Respiratory plasticity following intermittent hypoxia: developmental interactions.

Intermittent hypoxia (IH) is the most frequent form of hypoxia occurring in the developing mammal. On one hand, the maturational process of neural, mechanical, pulmonary, and sleep state-dependent factors will favor the occurrence of IH during early postnatal life. On the other hand, it has also become clear that hypoxia, even when short lasting, can modify subsequent respiratory responses to hypoxia and induce a variety of genes whose consequences will persist for much longer periods than the duration of the hypoxic stimulus itself, i.e., functional and adaptive plasticities. The dynamic interactions between the overall duration and recurring frequency of IH, the severity of IH, and the level of neural maturity at the time of IH will modify the ventilatory, metabolic, and cardiovascular responses to hypoxia. We propose that the earlier IH will occur in the developmental course the more likely that the physiological responses to an ulterior hypoxic challenge will be altered even into adulthood. At this point in time, a critical examination of the field would suggest that the short-term alterations of the hypoxic ventilatory response (HVR) of the developing mammal to IH are qualitatively similar to those of the adult and display a biphasic pattern, namely, initial enhancement of the HVR followed by a reduction in HVR. However, the short- and long-term effects of IH on the modulation of neurotransmitter release, receptor binding and expression, intracellular signaling cascades, transcriptional regulation, and gene expression as a function of animal maturity are almost completely unknown. Further delineation of such complex responses to IH may permit the formulation of interventional strategies aiming at reducing the overall vulnerability of the young infant and child to apnea and sudden death.

Animals↗

Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark.

Cells employ elaborate mechanisms to introduce structural and chemical variation into chromatin. Here, we focus on one such element of variation: methylation of lysine 4 in histone H3 (H3K4). We assess a growing body of literature, including treatment of how the mark is established, the patterns of methylation, and the functional consequences of this epigenetic signature. We discuss structural aspects of the H3K4 methyl recognition by the downstream effectors and propose a distinction between sequence-specific recruitment mechanisms and stabilization on chromatin through methyl-lysine recognition. Finally, we hypothesize how the unique properties of the polyvalent chromatin fiber and associated effectors may amplify small differences in methyl-lysine recognition, simultaneously allowing for a dynamic chromatin architecture.

Amino Acid Sequence↗

Turnover of binding sites for transcription factors involved in early Drosophila development.

Despite the importance of cis-regulatory regions in evolution, little is know about their evolutionary dynamics. In this report, we analyze the process of evolution of binding sites for transcription factors using as a model a well characterized system, the Drosophila early developmental enhancers. We compare the sequences of eight enhancer regions for early developmental genes between Drosophila melanogaster and other two species, Drosophila virilis and Drosophila pseudoobscura, searching for the presence/absence of 104 biochemically verified binding sites from D. melanogaster. We also modeled the binding specificity of each binding site by the use of well-defined positional weight matrices (PWMs). The comparisons showed that turnover of binding sites seems to fit a molecular clock, at an approximate rate of 0.94% of gain/loss of binding sites per million years. This intense turnover affects both high and low affinity binding sites at the same extent. Furthermore, the subset of overlapping binding sites is also subjected to this high turnover. Conserved binding sites seem to be constrained to maintain not only location but also the exact sequence at each particular position. Finally, we detected a significant decrease in mean PWM scores for the D. virilis binding sites in the case of Hunchback. Possible explanations for this fact are discussed.

Animals↗

Ferenczi's "A Little Chanticleer": a child's favorite song recall.

In response to the recent special issue of The American Journal of Psychoanalysis dedicated to Sándor Ferenczi's works, this article highlights his essay entitled, "A Little Chanticleer" as a first-of-its-kind legacy of a description of conscious and unconscious dynamics linked to a child's musical preferences in daily life. In addition to its historical value, Ferenczi's essay merits study from contemporary viewpoints on infant developmental research, including implications for treatment of adults. It is hoped that at least in the context of song recall Ferenczi's essay will gain its due recognition.

Child↗

Ubiquitination and degradation of the zebrafish paired-like homeobox protein VSX-1.

Vsx-1 is a paired-like : CVC homeobox protein dynamically expressed during zebrafish development. Previous results indicate that Vsx-1 influences bipolar cell differentiation and maintenance of these cells in the adult retina. To understand the developmental regulation of this transcription factor, we investigated ubiquitination as a possible posttranslational mechanism. In vitro, Vsx-1 was conjugated with multiple ubiquitin moieties. Proteasome inhibitors and added ubiquitin increased the accumulation of Vsx-1-ubiquitin(n) complexes and stabilized unmodified Vsx-1. Also, in transiently transfected COS-7 cells, Vsx-1 is ubiquitinated, and pulse-chase experiments show that Vsx-1 proteolysis occurs. Vsx-1 proteins with C-terminal deletions retained the capacity for initial modification by ubiquitin but lost the capacity for efficient chain elongation. These results show that Vsx-1 is a substrate of the ubiquitin/proteasome pathway and suggest that C-terminal sequences of Vsx-1 are critical for ubiquitin chain elongation. In addition, our findings suggest that ubiquitin-dependent proteolysis regulates Vsx-1 during zebrafish retinal development.

Adenosine Triphosphatases↗

Language and brain: what is up? What is coming up?

The classical aphasiological model of brain/language relationships is nowadays complemented by independent results from functional neuroimaging studies using techniques such as Positron Emission Tomography, functional Magnetic Resonance Imaging, or Event-Related Electro-Encephalography and Magneto-Encephalography mapping. Although brain mapping of language is still hampered by many methodological pitfalls, these methods now appear reliable and provide a renewed description of the temporal spatial dynamics of neural ensembles subserving language functions. Moreover, neuroimaging techniques should also shed a new light on remaining difficult issues such as neural and functional plasticity in developmental or post-lesional contexts.

Aphasia↗

B cell development in aging mice: lessons from mathematical modeling.

Previous studies have not completely clarified the precise defect that characterizes B cell development in aged animals. The question of which developmental mechanism is actually deficient in aging remains controversial. The goal of this study was to elucidate the effects of aging on bone marrow B cell population dynamics. We used mathematical modeling to predict the outcome of the different possible effects, and then compared these predictions to experimental data, to find the most plausible effects. Our model shows that the three main differences between B cell development in young and old mice are a decrease in the maximum number of cells in the pre-B compartment and increases in the rate of transition from cycling pre-B cells to resting pre-B cells and in the fractions of static cells included in the immature B cell subset.

Aging↗

VEGF is crucial for the hepatic vascular development required for lipoprotein uptake.

Hepatic lipid catabolism begins with the transport of lipoprotein remnants from the sinusoidal vasculature into hepatocytes by endocytosis via microvilli. To test the hypothesis that fenestrated sinusoidal endothelial cells (SECs) are crucial for this process, we selectively disrupted SECs by downregulating vascular endothelial growth factor (VEGF) signaling, using hepatocyte-specific, tetracycline-regulatable expression of a VEGF receptor that can sequester VEGF but cannot relay its signal. Newborn mutant livers appeared grossly normal, but displayed a dark-red color that was distinguishable from normal physiological lipid-rich pink livers. Mutant sinusoidal networks were reduced and their SECs lacked fenestrae. Hepatocellular lipid levels were profoundly reduced, as determined by Oil Red O staining and transmission electron microscopy, and fewer hepatocytic microvilli were evident, indicating impaired lipoprotein endocytosis. Levels of apolipoprotein (APO) E bound to mutant sinusoidal networks were significantly reduced, and fluorescently-labeled murine remnant lipoproteins injected into the blood stream failed to accumulate in the space of Disse and diffuse into hepatocytes, providing evidence that reduced hepatocellular lipid levels in mutant livers are due to impaired lipoprotein uptake. Temporal downregulation of VEGF signaling revealed that it is crucial at all developmental stages of hepatic vascular morphogenesis, and repression of the dominant-negative effect can rescue the phenotype. These findings provide the first genetic evidence that VEGF dynamically regulates SEC fenestration during liver organogenesis, a process that is required for lipoprotein uptake by the liver.

Animals↗

Motor protein KIFC5A interacts with Nubp1 and Nubp2, and is implicated in the regulation of centrosome duplication.

Inhibition of motor protein activity has been linked with defects in the formation of poles in the spindle of dividing cells. However, the molecular mechanisms underlying the functional relationship between motor activity and centrosome dynamics have remained uncharacterised. Here, we characterise KIFC5A, a mouse kinesin-like protein that is highly expressed in dividing cells and tissues, and is subject to developmental and cell-type-specific regulation. KIFC5A is a minus-end-directed, microtubule-dependent motor that produces velocities of up to 1.26 microm minute(-1) in gliding assays and possesses microtubule bundling activity. It is nuclear in interphase, localises to the centre of the two microtubule asters at the beginning of mitosis, and to spindle microtubules in later mitotic phases. Overexpression of KIFC5A in mouse cells causes the formation of aberrant, non-separated microtubule asters and mitotic arrest in a prometaphase-like state. KIFC5A knockdown partly rescues the phenotype caused by inhibition of plus-end-directed motor Eg5 by monastrol on the mitotic spindle, indicating that it is involved in the balance of forces determining bipolar spindle assembly and integrity. Silencing of KIFC5A also results in centrosome amplification detectable throughout the cell cycle. Supernumerary centrosomes arise primarily as a result of reduplication and partly as a result of cytokinesis defects. They contain duplicated centrioles and have the ability to organise microtubule asters, resulting in the formation of multipolar spindles. We show that KIFC5A interacts with nucleotide-binding proteins 1 and 2 (Nubp1 and Nubp2), which have extensive sequence similarity to prokaryotic division-site-determining protein MinD. Nubp1 and Nubp2 also interact with each other. Knockdown of Nubp1 or double knockdown of Nubp1 and Nubp2 (Nubp1&Nubp2) both phenocopy the KIFC5A silencing effect. These results implicate KIFC5A and the Nubp proteins in a common regulatory pathway involved in the control of centrosome duplication in mammalian cells.

Adenosine Triphosphatases↗