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PubMed2004

Autism as a disorder of neural information processing: directions for research and targets for therapy.

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.

Animals↗
PubMed2026

From activation to desensitization: How ABA balances plant growth and abiotic stress response?

Abscisic acid (ABA) signaling is a central regulator of plant adaptation to abiotic stress, dynamically coordinating stress responses with growth and development. Rapid activation of ABA signaling promotes plant survival during the early stages of stress, whereas prolonged stress requires timely attenuation of the pathway to restore growth and prevent excessive stress responses. Recent studies have uncovered diverse mechanisms underlying ABA desensitization, including regulation of SnRK2 kinases, phytohormone crosstalk, nutrient signaling, protein trafficking, post-translational modifications, and feedback regulatory networks. Together, these interconnected mechanisms enable plants to fine-tune ABA signaling in response to developmental and environmental cues. In this review, we summarize recent advances in understanding the molecular mechanisms that attenuate ABA signaling and restore the balance between growth and stress adaptation during prolonged stress. We also highlight outstanding questions and discuss strategies for engineering ABA signaling dynamics to improve crop resilience, productivity, and adaptation to increasingly variable environments.

Abscisic Acid↗
PubMed2006

Population dynamics of thrips prey and their mite predators in a refuge.

Prey refuges are expected to affect population dynamics, but direct experimental tests of this hypothesis are scarce. Larvae of western flower thrips Frankliniella occidentalis use the web produced by spider mites as a refuge from predation by the predatory mite Neoseiulus cucumeris. Thrips incur a cost of using the refuge through reduced food quality within the web due to spider mite herbivory, resulting in a reduction of thrips developmental rate. These individual costs and benefits of refuge use were incorporated in a stage-structured predator-prey model developed for this system. The model predicted higher thrips numbers in presence than in absence of the refuge during the initial phase. A greenhouse experiment was carried out to test this prediction: the dynamics of thrips and their predators was followed on plants damaged by spider mites, either with or without web. Thrips densities in presence of predators were higher on plants with web than on unwebbed plants after 3 weeks. Experimental data fitted model predictions, indicating that individual-level measurements of refuge costs and benefits can be extrapolated to the level of interacting populations. Model-derived calculations of thrips population growth rate enable the estimation of the minimum predator density at which thrips benefit from using the web as a refuge. The model also predicted a minor effect of the refuge on the prey density at equilibrium, indicating that the effect of refuges on population dynamics hinges on the temporal scale considered.

Animals↗
PubMed2005

Neuronal expression of Nogo-A mRNA and protein during neurite outgrowth in the developing rat olfactory system.

The major impediments to axonal regeneration in the central nervous system are growth-inhibitory proteins present in the myelin sheath, and Nogo-A is one of the most potent inhibitors synthesized by oligodendrocytes. However, neuronal expression of Nogo-A during development suggests that it may have an additional role. The spatio-temporal regulation of both Nogo-A mRNA and protein expression was examined by in situ hybridization and immunohistochemistry in the developing rat olfactory system. During embryonic and postnatal development (from E13 to P6), Nogo-A mRNA and protein were strongly expressed by differentiating neurons in the olfactory epithelium and in the olfactory bulb. From the second postnatal week, a progressive down-regulation of both Nogo-A mRNA and protein occurred, such that only a weak expression persisted in the adult olfactory system. Using double-immunostainings in the adult olfactory epithelium, we determined that Nogo-A was preferentially expressed by immature olfactory receptor neurons extending axonal processes toward the olfactory bulb. At all developmental stages, Nogo-A protein was preferentially targeted in olfactory axons emerging from the olfactory epithelium. Using an in vitro model of olfactory axon growth, we demonstrated that, in addition to its presence along the entire axon length, Nogo-A accumulated in axonal growth cone and at axonal branching points, with a distribution similar to that of microtubule-associated proteins. Moreover, Nogo-A was transiently expressed in dendritic processes in the postnatal olfactory bulb. Together, our data suggest that, in non-pathological conditions, Nogo-A may be involved in the processes of axonal growth and dendritic modeling through the regulation of microtubule dynamics.

Animals↗
PubMed1989

Membrane dynamics in insect malpighian tubules.

Urine formation in insects occurs in the Malpighian tubules by means of active ion transport and osmotically coupled water flow. The rates of urine formation can vary with time and can be modulated by diuretic hormones, developmental events, and intracellular parasitism. This paper reviews a number of recent studies in which it has been demonstrated that variations in transport rate are associated with substantial changes in tubule ultrastructure in the form of membrane insertion into and deletion from the apical microvilli. The principal driving force for fluid movement in Malpighian tubules is thought to be a common cation pump located in the apical membranes. It is proposed that modulation of the apical microvillar membrane may reflect regulation by the cells of the number of common cation pump units involved in fluid secretion.

Aedes↗
PubMed2003

A very-short-term intermittency of fetal heart rates and developmental milestone.

We noticed that fetal heart rates (FHR) of immature fetuses intermittently showed unstable sudden and brief falls below baseline FHR that occur over a few or several heartbeats. The frightening falls do not occur in mature fetuses. In nonlinear dynamics, the degree of such abrupt falls in time series is quantified as intermittency. We aimed to investigate the nature and maturational changes of intermittency of the FHR in normal fetuses and to present the intermittency values of normal fetuses according to gestational weeks. FHR data of 450 normal fetuses between 23 and 40 wk of gestation were studied. We performed multifractal analysis and highlighted a very-short-term intermittency (C1alpha, 4 </= scale < 16 heartbeats). The C1alpha values exhibited a strong negative linear correlation (r = -0.732, p = 0.0001) with the gestational weeks. At 27-28, 29-30, 33-34, and 37-38 gestational weeks, the C1alpha values were significantly lower than those of the previous 2 or 4 gestational weeks. The maturation of normal fetuses is related to decreasing the severity of the unstable sudden and brief falls in FHR that is measured by C1alpha, the very-short-term intermittency. The C1alpha values according to the gestational weeks that we presented can be used as credible normal milestone values when estimating the degree of maturity of certain FHR. Because the C1alpha captures the degree of the unstable fall in FHR, the C1alpha may also be used in identifying sick fetuses that are associated with hemodynamic instability and sudden bradycardia.

Female↗
PubMed1999

Dynamic and tissue-specific expression of eIF4E during zebrafish embryogenesis.

The regulation of protein synthesis is critical to diverse cellular processes and plays a pivotal role in regulating gene expression during embryogenesis. The cap-binding protein eIF4E is a translational factor whose activity appears to be both ubiquitous and central to the regulation of protein synthesis in all cell-types. As a cell-cycle regulator, mesoderm inducer and proto-oncogene, the amount and activity of the translational factor eIF4E must be under strict control, but the range of its expression and its concentration as a function of position and time in the developing embryo are unknown. Consequently, we have initiated studies to elucidate the expression of the eIF4E gene and its role in the regulating embryonic development. We have cloned a zebrafish gene encoding eIF4E, zeIF4E, and measured its developmental expression. Unexpectedly, we found that the zeIF4E gene produces two alternatively spliced transcripts that potentially encode different forms of the initiation factor. Molecular analyses and in situ hybridization reveal a potential role for eIF4E in regulating protein synthesis during vertebrate oogenesis, gastrulation, and erythropoiesis. The dynamic and asymmetric expression of eIF4E during zebrafish embryogenesis reveals that this ostensibly general translation factor may act as a tissue-specific translational enhancer.

Alternative Splicing↗
PubMed2026

Longitudinal development of infant oral ecosystem: salivary metabolomic, bacteriome, and virome dynamics in early infancy.

This prospective cohort study investigated the longitudinal development of the salivary bacteriome, virome, and metabolome during early infancy. We assessed the associations between oral bacteria, viruses, and metabolites from 10 mother-infant dyads, with oral samples collected at 1 and 2 years of age. Forty saliva and plaque samples underwent untargeted metabolomic analysis, and infant saliva samples underwent metagenomic sequencing. Maternal salivary and plaque metabolomic profiles remained largely stable, whereas infant profiles were clearly separated from maternal profiles and changed with age. Notably, infant dental plaque metabolism underwent more substantial changes from year 1 to year 2 than saliva, with age-dependent metabolite shifts mainly involving energy, amino acid, nucleotide, and lipid metabolic pathways. Our findings also revealed significant developmental shifts in salivary bacteriome, virome, and functional pathway profiles during early childhood. The most abundant oral bacteria in early life, comprising over 75% of total abundance, included Veillonella, Streptococcus, Rothia, Prevotella, Neisseria, and Actinomyces species. While human viruses like Roseolovirus were detected, bacteriophages constituted the majority of the virome. Comparing infants at year 1 and year 2, we identified differentially abundant bacteria, viruses, metabolic functional pathways, and specific metabolites. We observed associations between bacteria and viruses, noting that these cross-kingdom relationships attenuated as infants grew. The study results underscore the complex and dynamic development of the oral microbiome, virome, and metabolome during early childhood.IMPORTANCEThe human oral cavity undergoes substantial microbial and metabolic development during early childhood, yet the temporal changes in the infant oral ecosystem remain incompletely understood. In this study, we longitudinally profiled the salivary metabolome, bacteriome, and virome of infants at 1 and 2 years of age. We demonstrated that the infant oral metabolome undergoes substantial developmental shifts, particularly in pathways related to energy, amino acid, and lipid metabolism; whereas maternal metabolic profiles remained stable over the same period. Furthermore, our results revealed the dynamic assembly of infant salivary virome and bacteriome and their associations with the functional pathways and metabolites. These findings provide new insights into the complex and dynamic development of the oral microbiome, virome, and metabolome in early infancy.

bacteriome↗
PubMed2002

A direct role of SRY and SOX proteins in pre-mRNA splicing.

The mammalian testis determining factor SRY and its related Sox factors are critical developmental regulators. They share significant similarity in their high mobility group (HMG) domain and display discrete patterns of tissue-specific expression. Here we show that SRY and the Sox protein SOX6 colocalize with splicing factors in the nucleus and are dynamically redistributed following the blockage of splicing in living cells. Anti-SOX6 antibodies supershift the spliceosomal complex from assembled splicing reactions and inhibit splicing in vitro of multiple pre-mRNA substrates. Most importantly, SOX6-depleted nuclear extracts have impaired splicing activity, which is efficiently restored by addition of the recombinant SOX6 HMG domain and also by recombinant SRY and the SOX9 HMG domain. These results reveal an unexpected biological function of the SRY, SOX6, and SOX9 gene products and provide a functional link to the biochemical mechanisms operating in mammalian sex determination and in other developmental processes regulated by Sox genes.

Animals↗
PubMed2000

Phospho-dependent association of neurofilament proteins with kinesin in situ.

Recent studies demonstrate co-localization of kinesin with neurofilament (NF) subunits in culture and suggest that kinesin participates in NF subunit distribution. We sought to determine whether kinesin was also associated with NF subunits in situ. Axonal transport of NF subunits in mouse optic nerve was perturbed by the microtubule (MT)-depolymerizing drug vinblastine, indicating that NF transport was dependent upon MT dynamics. Kinesin co-precipitated during immunoprecipitation of NF subunits from optic nerve. The association of NFs and kinesin was regulated by NF phosphorylation, since (1) NF subunits bearing developmentally delayed phospho-epitopes did not co-purify in a microtubule motor preparation from CNS while less phosphorylated forms did; (2) subunits bearing these phospho-epitopes were selectively not co-precipitated with kinesin; and (3) phosphorylation under cell-free conditions diminished the association of NF subunits with kinesin. The nature and extent of this association was further examined by intravitreal injection of (35)S-methionine and monitoring NF subunit transport along optic axons. As previously described by several laboratories, the wave of NF subunits underwent a progressive broadening during continued transport. The front, but not the trail, of this broadening wave of NF subunits was co-precipitated with kinesin, indicating that (1) the fastest-moving NFs were associated with kinesin, and (2) that dissociation from kinesin may foster trailing of NF subunits during continued transport. These data suggest that kinesin participates in NF axonal transport either by directly translocating NFs and/or by linking NFs to transporting MTs. Both Triton-soluble as well as cytoskeleton-associated NF subunits were co-precipitated with kinesin; these data are considered in terms of the form(s) in which NF subunits undergo axonal transport.

Animals↗
PubMed2000

Nitric oxide modulates retinal ganglion cell axon arbor remodeling in vivo.

Nitric oxide (NO) has been postulated to act as an activity-dependent retrograde signal that can mediate multiple aspects of synaptic plasticity during development. In the visual system, a role for NO in activity-dependent structural modification of presynaptic arbors has been proposed based on NO's ability to prune inappropriate projections and segregate axon terminals. However, evidence demonstrating that altered NO signaling does not perturb ocular dominance map formation leaves unsettled the role of NO during the in vivo refinement of visual connections. To determine whether NO modulates the structural remodeling of individual presynaptic terminal arbors in vivo we have: 1. Used NADPH-diaphorase histochemistry to determine the onset of NO synthase (NOS) expression in the Xenopus visual system. 2. Used in vivo time-lapse imaging to examine the role of NO during retinal ganglion cell (RGC) axon arborization. We show that NOS expression in the target optic tectum is developmentally regulated and localized to neurons that reside in close proximity to arborizing RGC axons. Moreover, we demonstrate that perturbations in tectal NO levels rapidly and significantly alter the dynamic branching of RGC arbors in vivo. Tectal injection of NO donors increased the addition of new branches, but not their stabilization in the long term. Tectal injection of NOS inhibitors increased the dynamic remodeling of axonal arbors by increasing branch addition and elimination and by lengthening pre-existing branches. Thus, these results indicate that altering NO signaling significantly modifies axon branch dynamics in a manner similar to altering neuronal activity levels (Cohen-Cory, 1999). Consequently, our results support a role for NO during the dynamic remodeling of axon arbors in vivo, and suggest that NO functions as an activity-dependent retrograde signal during the refinement of visual connections.

Animals↗
PubMed1983

Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation.

Two to nine months after the median nerve was transected and ligated in adult owl and squirrel monkeys, the cortical sectors representing it within skin surface representations in Areas 3b and 1 were completely occupied by 'new' and expanded representations of surrounding skin fields. Some occupying representations were 'new' in the sense that (1) there was no evidence that these skin surfaces were represented in this region prior to median nerve transection; and (2) these skin surfaces retained their normal representation elsewhere within these two cortical representations of hand surfaces. Large 'new' representations of the dorsal surfaces of digits 1 and 2 (innervated by the radial nerve) and large 'new' representations of the hypothenar eminence (innervated by the ulnar nerve) were consistently recorded. Some surrounding skin surface representations expanded into the former median nerve zone, so that bordering skin surfaces (the ulnar insular palmar pad, the third digital palmar pad, glabrous ulnar digit 3, radial hand dorsum) were represented over far larger than normal cortical areas. These expanded representations of always-innervated skin sometimes appeared to move in entirety into the former median nerve representational zone (e.g. in the zone of representation of glabrous digit 4) were also consistently recorded. Reorganizational changes following median nerve sections were much more variable in Area 1 than in Area 3b. The topographic order of the reorganized cortical zone was comparable to normal. In at least most cortical sectors, there was a consistent, maintained relationship between receptive field size and magnification, i.e. as representations enlarged, receptive fields were correspondingly reduced in size. These studies indicate that topographic representations of the skin surface in adult monkeys are maintained dynamically. They clearly reveal that this projection system retains a self-organizing capacity in adult monkeys. They suggest that processes perhaps identical to a part of the original developmental organizing processes (by which details of field topographics are established) are operational throughout life in this projection system in primates. Some of the implications of these studies for the neural origins of tactile perception are discussed.

Afferent Pathways↗
PubMedDate not supplied

Manipulation of the oocyte: possible damage to the spindle apparatus.

Oocytes are structured, polarized cells. For high developmental potential, it is essential that the distribution of organelles and molecules, and the function of meiotic spindles remain intact during handling of oocytes in assisted reproduction. Spindles are dynamic cell organelles. Spindle formation depends on activity of motor proteins, energy supply and temperature. Disturbances in spindle function may predispose oocytes to aneuploidy or maturation arrest. Thus, perturbation of the cytoskeletal integrity of oocytes may critically influence the fate of the embryo. Recently, enhanced polarizing microscopy has been developed for non-invasive analysis of spindle morphology in living mammalian oocytes. Chemically induced dynamic alterations have been characterized in the spindle in individual mouse oocytes and it has been shown that spindle aberrations are predictive of risks for non-disjunction. Spindle imaging identified adverse, irreversible effects of handling in living human oocytes (for instance, the extreme susceptibility of human oocytes to cooling). Also, oocyte immaturity may be detected. Selection of metaphase II oocytes and an injection site for intracytoplasmic sperm injection (ICSI) that avoids spindle damage may increase the yield of euploid embryos. The detection of genetic, environmentally induced, or treatment-related defects in oocyte maturation by non-invasive spindle imaging can improve quality control and assist in the selection of morphologically normal oocytes for assisted reproduction.

Aneuploidy↗
PubMed2000

Stigma and mental disorder: conceptions of illness, public attitudes, personal disclosure, and social policy.

The end of the last millennium witnessed an unprecedented degree of public awareness regarding mental disorder as well as motivation for policy change. Like Sartorius, we contend that the continued stigmatization of mental illness may well be the central issue facing the field, as nearly all attendant issues (e.g., standards of care, funding for basic and applied research efforts) emanate from professional, societal, and personal attitudes towards persons with aberrant behavior. We discuss empirical and narrative evidence for stigmatization as well as historical trends regarding conceptualizations of mental illness, including the field's increasing focus on genetic and neurobiological causes and determinants of mental disorder. We next define stigma explicitly, noting both the multiple levels (community, societal, familial, individual) through which stigma operates to dehumanize and delegitimize individuals with mental disorders and the impact of stigma across development. Key developmental psychopathology principles are salient in this regard. We express concern over the recent oversimplification of mental illness as "brain disorder," supporting instead transactional models which account for the dynamic interplay of genes, neurobiology, environment, and self across development and which are consistent with both compassion and societal responsibility. Finally, we consider educational and policy-related initiatives regarding the destigmatization of mental disorder. We conclude that attitudes and policy regarding mental disorder reflect, in microcosmic form, two crucial issues for the next century and millennium: (a) tolerance for diversity (vs. pressure for conformity) and (b) intentional direction of our species' evolution, given fast-breaking genetic advances.

Attitude to Health↗
PubMed1992

The dependent personality: developmental, social, and clinical perspectives.

Developmental, social, and clinical studies of dependency have produced remarkably consistent results. A review and integration of these findings allow strong conclusions to be drawn regarding the etiology and dynamics of dependency. The etiology of dependency appears to lie in overprotective, authoritarian parenting. In social settings, dependency is associated with suggestibility, conformity, compliance, interpersonal yielding, affiliative behavior, and sensitivity to interpersonal cues. Dependency predicts the onset of certain psychological disorders and follows the onset of others. It seems that the fundamental motivation of the dependent person, from which the behaviors that are exhibited in different situations are derived, is a strong desire to obtain and maintain nurturant, supportive relationships. Implications of these findings for different theoretical models of dependency are discussed.

Adult↗
PubMed1997

The Ras target AF-6 interacts with ZO-1 and serves as a peripheral component of tight junctions in epithelial cells.

The dynamic rearrangement of cell-cell junctions such as tight junctions and adherens junctions is a critical step in various cellular processes, including establishment of epithelial cell polarity and developmental patterning. Tight junctions are mediated by molecules such as occludin and its associated ZO-1 and ZO-2, and adherens junctions are mediated by adhesion molecules such as cadherin and its associated catenins. The transformation of epithelial cells by activated Ras results in the perturbation of cell-cell contacts. We previously identified the ALL-1 fusion partner from chromosome 6 (AF-6) as a Ras target. AF-6 has the PDZ domain, which is thought to localize AF-6 at the specialized sites of plasma membranes such as cell-cell contact sites. We investigated roles of Ras and AF-6 in the regulation of cell-cell contacts and found that AF-6 accumulated at the cell-cell contact sites of polarized MDCKII epithelial cells and had a distribution similar to that of ZO-1 but somewhat different from those of catenins. Immunoelectron microscopy revealed a close association between AF-6 and ZO-1 at the tight junctions of MDCKII cells. Native and recombinant AF-6 interacted with ZO-1 in vitro. ZO-1 interacted with the Ras-binding domain of AF-6, and this interaction was inhibited by activated Ras. AF-6 accumulated with ZO-1 at the cell-cell contact sites in cells lacking tight junctions such as Rat1 fibroblasts and PC12 rat pheochromocytoma cells. The overexpression of activated Ras in Rat1 cells resulted in the perturbation of cell-cell contacts, followed by a decrease of the accumulation of AF-6 and ZO-1 at the cell surface. These results indicate that AF-6 serves as one of the peripheral components of tight junctions in epithelial cells and cell-cell adhesions in nonepithelial cells, and that AF-6 may participate in the regulation of cell-cell contacts, including tight junctions, via direct interaction with ZO-1 downstream of Ras.

Animals↗
PubMed2003

Doublecortin functions at the extremities of growing neuronal processes.

Type I lissencephaly is a cortical malformation disorder characterized by disorganized cortical layers and gyral abnormalities and associated with severe cognitive impairment and epilepsy. The exact pathophysiological mechanisms underlying the epilepsy and mental retardation in this and related disorders remain unknown. Two genes, LIS1 and doublecortin, have both been shown to be mutated in a large proportion of cases of type I lissencephaly and a milder allelic disorder, subcortical laminar heterotopia (SCLH). Studying the protein products of these genes and the biochemical pathways in which they belong is likely to yield important information concerning both normal and abnormal cortical development. The relationships between the LIS1 and Doublecortin proteins are not yet well defined, but both are believed to play a critical role in cortical neuronal migration. Lis1 is expressed from very early development in the mouse and in both proliferating cells and post-mitotic neurons of the cortex. This protein is likely to have multiple functions since it is a subunit of the enzyme platelet-activating factor acetylhydrolase, which degrades platelet activating factor, and has also been shown to be involved in microtubule dynamics, potentially influencing nuclear migration through its interaction with the dynein motor protein complex. Doublecortin on the other hand is exclusively expressed in post-mitotic neurons and is developmentally regulated. In young developing neurons Doublecortin has a specific subcellular localization at the ends of neuritic and leading processes. This localization, combined with our previous data showing that it is a microtubule-associated protein and that it interacts with adapter complexes involved in vesicle trafficking, suggests a role in the growth of neuronal processes, downstream of directional or guidance signals. The observations summarized here favor the suggestion that whereas LIS1 may play a role in nuclear migration, Doublecortin is instead restricted to functions at the leading edge of the cell.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗