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PubMedDate not supplied

The decline of the clinical incidence of cancers during human senescence.

Neoplastic growth occurs from the very beginning to the end of the human life span, with a predominant age span for the clinical incidence of each cancer. Most cancers are diagnosed during the second half of human life span, but their natural histories start much earlier than their clinical manifestations. The clinical incidence declines after ages 75-80 years. The histology, the evolution, and the distribution of the frequency of the different cancers during the human life span suggest that neoplastic growth is a dynamic process where new variables are continuously created, the result of the interaction of individual genetics, environmental aggressions, and the developmental stages of the human life span. Data suggest that in many instances tumor growth can be looked upon as a deviation from normal development. Mechanisms are described that can explain the decline of the incidence and the progression during senescence in terms of the changes occurring in the human organism during the last developmental stages.

Age Factors↗
PubMed1990

T-cell responsiveness towards various synthetic peptides of the P28 antigen in rat and mouse models during Schistosoma mansoni infection.

It has recently been demonstrated that the Schistosoma mansoni P28 antigen can induce a strong protective immunity after direct immunization in various experimental models. T lymphocytes from Fischer rats immunized with the recombinant P28 antigen were cultured in vitro in the presence of seven synthetic peptides derived from the amino acid sequence of the P28. The most significant and reproducible proliferation was obtained with the 24-43 and 115-131 synthetic peptides. In order to analyze whether these located determinants were also exposed to the host's immune system during the natural S. mansoni infection or after immunization with crude antigenic extracts of various development stages of the parasite, the T-cell responsiveness of infected or immunized Fischer rats and BALB/c mice was tested towards these synthetic peptides. The results showed that, in both permissive (mouse) and non-permissive (rat) hosts, 24-43 and 115-131 synthetic peptides are recognized during the course of infection and that there is a dynamic variation of this recognition. These peptides are also recognized by T cells educated against crude antigenic extracts of different developmental stages of the parasite which contained the native form of the P28 molecule. Taken together, the results indicated that these synthetic peptides derived from the recombinant P28 antigen can activate T lymphocytes educated against the native P28 molecule during the development and maturation of the parasite in their hosts. Therefore, they might be useful for the construction of synthetic vaccines against schistosomiasis.

Amino Acid Sequence↗
PubMed1987

Assessing the credibility of young children's allegations of sexual abuse: clinical issues.

In assessing the credibility of young children's (ages 2-7) allegations of sexual abuse clinicians need to know how dynamics of sexual abuse affect disclosure, what situations are most commonly associated with fictitious allegations and how the child's developmental stage affects disclosures. Understanding these issues allows for clear decision making. A clear decision making process flows naturally from an understanding of these issues.

Child↗
PubMed1989

Morphogen hunting in Dictyostelium.

A highly regulative pattern of prestalk and prespore tissue is formed during Dictyostelium development, starting from separate amoebae. Potential morphogens controlling this process have been hunted biochemically, using bioassays to monitor activity. All those discovered to date are low MW diffusible compounds: cAMP, adenosine, NH3 and DIFs 1-3. The DIFs are assayed by their ability to induce isolated amoebae to differentiate into stalk cells and have been identified as a family of chlorinated phenyl alkanones. The diversification of amoebae into prestalk and prespore cells seems to be brought about by cAMP and DIF-1. cAMP is necessary for both pathways of differentiation but DIF-1 specifically induces the differentiation of prestalk cells while suppressing that of prespores. When DIF-1 is added to intact slugs, it causes a substantial enlargement of the prestalk tissue at physiological concentrations in the time previously shown to be required for pattern regulation. DIF-1 is a dynamic molecule and we have found that it is metabolized along a pathway involving at least 8 compounds. Metabolism is developmentally regulated and may be important in producing DIF gradients or other effector molecules from DIF. Although we almost certainly have some of the central actors, it is difficult to formulate a satisfactory theory of pattern formation in Dictyostelium at the moment. We suspect that at least one important actor is missing.

Cell Differentiation↗
PubMed2005

Evolution of genetic potential.

Organisms employ a multitude of strategies to cope with the dynamical environments in which they live. Homeostasis and physiological plasticity buffer changes within the lifetime of an organism, while stochastic developmental programs and hypermutability track changes on longer time-scales. An alternative long-term mechanism is "genetic potential"--a heightened sensitivity to the effects of mutation that facilitates rapid evolution to novel states. Using a transparent mathematical model, we illustrate the concept of genetic potential and show that as environmental variability decreases, the evolving population reaches three distinct steady state conditions: (1) organismal flexibility, (2) genetic potential, and (3) genetic robustness. As a specific example of this concept we examine fluctuating selection for hydrophobicity in a single amino acid. We see the same three stages, suggesting that environmental fluctuations can produce allele distributions that are distinct not only from those found under constant conditions, but also from the transient allele distributions that arise under isolated selective sweeps.

Journal Article↗
PubMed2000

The effect of age, size of target, and cognitive factors on accommodative responses of children with Down syndrome.

PURPOSE: To investigate possible factors that may be implicated in the poor accommodative responses of individuals with Down syndrome. This article evaluates the effect of age, angular size of target, and cognitive factors on accommodation. METHODS: Seventy-seven children with Down syndrome who are participating in an ongoing study of visual development were assessed. One hundred thirty-one developmentally normal children took part in a previous study and provided control data. Accommodation was measured using a modified Nott dynamic retinoscopy technique. RESULTS: Children with Down syndrome showed considerably poorer accommodative responses than normally developing children. No target used in the present study produced an improved response in children with Down syndrome. Age, angular subtense of target, and cognitive factors could not fully account for the poor accommodation in children with Down syndrome. CONCLUSIONS: Poor accommodation is a common feature of Down syndrome, regardless of the target used. The etiology of the deficit has yet to be established. It is imperative that educators and clinicians are aware that near vision is out of focus for these children.

Accommodation, Ocular↗
PubMed1990

The clinical challenge of children and adolescents with severe personality disorders.

Clinical experience has shown that short-term hospital treatment is inadequate for some severely disturbed children and adolescents and, in fact, may exacerbate their dysfunction. The author analyzes the dynamics of the treatment process and presents case examples to suggest that treatment of these children should be based on developmental needs rather than on short-sighted economic expediency. A developmentally based treatment approach requires the maintenance of institutions that can provide comprehensive, integrated, and extended treatment, as well as an environment for research on severe psychiatric disturbances.

Adolescent↗
PubMed2026

Feeding the epigenome: EZH2 as a metabolic integrator of cell fate in development and cancer.

Epigenetic regulation is intimately linked to cellular metabolism, enabling environmental and nutritional cues to shape gene expression programs through dynamic modifications of chromatin structure. This metabolism-epigenetics interface is mediated, in part, by the dependence of chromatin-modifying enzymes on key metabolites, including S-adenosylmethionine (SAM), acetyl-CoA, UDP-GlcNAc, and α-ketoglutarate, which serve as substrates or cofactors for DNA and histone modifications. Among these regulators, EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), has emerged as a key mediator linking metabolic state to epigenetic regulation by translating metabolic inputs into changes in chromatin architecture and gene expression. EZH2 governs developmental cell fate through H3K27me3-mediated gene repression and is frequently dysregulated in cancer, where it promotes dedifferentiation, tumor progression, and metabolic reprogramming. Importantly, EZH2 activity is itself modulated by cellular metabolic status through posttranslational modifications, including phosphorylation, acetylation, methylation, ubiquitination, and O-GlcNAcylation, which influence its stability, catalytic activity, and chromatin-binding capacity. These modifications are responsive to nutrient availability and signaling pathways involving glucose, SAM, NAD+, and other metabolic intermediates. Consequently, disruption of this finely tuned regulatory network can contribute to developmental abnormalities, metabolic dysfunction, and oncogenesis. In this review, we examine the molecular mechanisms governing EZH2 regulation and discuss how metabolic control of EZH2 shapes chromatin dynamics, cell fate decisions, and disease pathogenesis. Elucidating how metabolic signals modulate EZH2 activity will advance our understanding of development and disease while uncovering potential therapeutic opportunities to target metabolism-driven epigenetic dysregulation.

Humans↗
PubMed1998

The dynamics of globin gene expression and gene therapy vectors.

The most important level of the regulation of the beta-globin genes is by activation of all of the genes by the locus control region (LCR). Part of the developmental regulation of the locus is achieved by competition of the genes for the interaction with the LCR. Although this level of gene regulation is quantitatively of less importance than the direct repression mechanism for the early genes, it has important implications and has provided an excellent assay to probe the regulation of transcription at the single cell level. The results of these studies indicate that the LCR interacts with individual globin genes and that LCR/gene interactions are dynamic with complexes forming and dissociating continually. We conclude that transcription only appears to take place while the LCR and gene interact and that the level of transcription is determined by the frequency and duration of such interaction rather than by changes in the rate of transcription of the promoters. This mechanism has clear implications for the design of vectors for the purpose of gene therapy.

Animals↗
PubMed1997

Dynamics of GABA(A) receptor binding in the ventromedial hypothalamus during postnatal development in the rat.

In vitro quantitative autoradiography of [3H]muscimol binding was used to examine the developmental pattern of GABA(A) receptor expression in the ventromedial hypothalamus (VMN) of Long-Evans rats. Peak levels of [3H]muscimol binding were observed in the VMN on postnatal day 14 (PN14), binding levels were significantly lower in the VMN at earlier (PN0 and PN7) and later (PN70) ages. The developmental pattern of [3H]muscimol binding observed in the VMN differed from that seen in the hippocampus where binding was found to increase progressively from PN0 to PN14 and was maintained at high levels in adulthood. Although the profile of GABA(A) receptor expression in the developing VMN undergoes considerable modification during the critical period for sexual differentiation, no significant differences in [3H]muscimol binding were observed between male and female animals at any developmental age.

Aging↗
PubMed2000

A developmental perspective on the regulation of arousal states.

Arousal regulation is an organizing construct for describing the relations between stimulation, stress, and cortical activity and performance. It describes a dynamic process of cortical activation and behavior in response to varying levels of stimulation. Contemporary neurobiological perspectives provide evidence that the concept of arousal regulation involves complex interactions among different neurochemical systems in the pontine and midbrain reticular formation. These interactive arousal systems serve as multilevel gates that both protect cortex from excessive stimulation and facilitate coordination between attentional, executive, and sensory cortical systems. The coordination between these systems emerges over the course of development with increasing balance of inhibitory and excitatory processes. The threshold for switching between more executive and more automatic modes of functioning also changes with development and may be particularly sensitive to early stressful and/or traumatic experiences.

Aging↗
PubMed2000

Time-limited psychotherapy with adolescents.

Short-term dynamic therapies, characterized by abbreviated lengths (10-40 sessions) and, in many cases, preset termination dates, have become more widespread in the past three decades. Short-term therapies are based on rapid psychodynamic diagnosis, a therapeutic focus, a rapidly formed therapeutic alliance, awareness of termination and separation processes, and the directive stance of the therapist. The emotional storm of adolescence, stemming from both developmental and psychopathological sources, leaves many adolescents in need of psychotherapy. Many adolescents in need of therapy resist long-term attachment and involvement in an ambiguous relationship, which they experience as a threat to their emerging sense of independence and separateness. Short-term dynamic therapy can be the treatment of choice for many adolescents because it minimizes these threats and is more responsive to their developmental needs. The article presents treatment and follow-up of a 17-year-old youth, using James Mann's time-limited psychotherapy method.

Adolescent↗
PubMed1997

Dynamic mental representation in infancy.

Recent research indicates that 4- to 8-month-old infants can track and anticipate the final orientation of an object following different invisible spatial transformations (Rochat, P., Hespos, S.J. (1996). Cognitive Development, 11, 3-17). Six experiments were designed to specify further the nature and development of early expectation for a set of dynamic events. A violation of expectation method was used to assess infants' reactions to probable and improbable outcomes of an objects' orientation following an invisible transformation. The availability of orientation cues, the path of motion, and the amount of invisible spatial transformation was systematically varied. The studies indicate that infants as young as 4 months of age detect orientation-specific cues for objects undergoing invisible spatial transformations. Developmental differences in this ability between 4 and 6 months of age lend insight to the nature and limitations of this early representational ability. These findings provide evidence for dynamic mental representation in infancy.

Attention↗
PubMed2025

A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.

PURPOSE: Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB. METHODS: Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. RESULTS: Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. CONCLUSION: We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.

Humans↗
PubMed2003

Making headway: the roles of Hox genes and neural crest cells in craniofacial development.

Craniofacial development is an extraordinarily complex process requiring the orchestrated integration of multiple specialized tissues such as the surface ectoderm, neural crest, mesoderm, and pharyngeal endoderm in order to generate the central and peripheral nervous systems, axial skeleton, musculature, and connective tissues of the head and face. How do the characteristic facial structures develop in the appropriate locations with their correct shapes and sizes, given the widely divergent patterns of cell movements that occur during head development? The patterning information could depend upon localized interactions between the epithelial and mesenchymal tissues or alternatively, the developmental program for the characteristic facial structures could be intrinsic to each individual tissue precursor. Understanding the mechanisms that control vertebrate head development is an important issue since craniofacial anomalies constitute nearly one third of all human congenital defects. This review discusses recent advances in our understanding of neural crest cell patterning and the dynamic nature of the tissue interactions that are required for normal craniofacial development.

Animals↗
PubMed2000

Expression of FGFR1, FGFR2 and FGFR3 during early neural development in the chick embryo.

Studies involving chick embryos have implicated FGFs in neural induction and patterning as well as in other developmental events. Detailed analyses of FGF receptor expression at early stages of neural development have not been reported for the chick embryo and are incomplete for other vertebrate classes. Here we show the expression patterns of three FGF receptors, (FGFR1, FGFR2 and FGFR3) in embryonic stages between gastrulation and limb bud formation, focussing particularly on neural tissues. Between neural induction and neurulation, all three receptors are expressed in the neural plate albeit with distinct and overlapping distributions. During early neuromere formation FGFR1 transcripts are present throughout the neural tube, while transcripts for FGFR2 and FGFR3 become restricted to regions of the diencephalon and spinal cord. A little later, FGFR2 and FGFR3 are additionally expressed in the anterior midbrain and within the hindbrain. During later neuromere development, FGFR1 transcripts become localised to the telencephalon, anterior dorsal diencephalon and throughout the midbrain and hindbrain, whereas FGFR2 mRNA is restricted to dorsal telencephalon, dorsoanterior midbrain and hindbrain. FGFR3 is also expressed in anterior midbrain and hindbrain during this developmental period, and is additionally expressed in the posterior telencephalon, in the pretectum, and at the zona limitans intrathalamica. The observed expression patterns of all three receptors within the hindbrain, including rhombomere boundaries, are complex and dynamic. Expression patterns within the somites, eye, head mesenchyme, branchial arches, limb buds, nephric kidney and pharynx are also described.

Animals↗
PubMed2004

Cdc42 Effector Protein 2 (XCEP2) is required for normal gastrulation and contributes to cellular adhesion in Xenopus laevis.

BACKGROUND: Rho GTPases and their downstream effector proteins regulate a diverse array of cellular processes during embryonic development, including reorganization of cytoskeletal architecture, cell adhesion, and transcription. Changes in the activation state of Rho GTPases are converted into changes in cellular behavior by a diversity of effector proteins, which are activated in response to changes in the GTP binding state of Rho GTPases. In this study we characterize the expression and function of one such effector, XCEP2, that is present during gastrulation stages in Xenopus laevis. RESULTS: In a search for genes whose expression is regulated during early stages of embryonic development in Xenopus laevis, a gene encoding a Rho GTPase effector protein (Xenopus Cdc42 effector protein 2, or XCEP2) was isolated, and found to be highly homologous, but not identical, to a Xenopus sequence previously submitted to the Genbank database. These two gene sequences are likely pseudoalleles. XCEP2 mRNA is expressed at constant levels until mid- to late- gastrula stages, and then strongly down-regulated at late gastrula/early neurula stages. Injection of antisense morpholino oligonucleotides directed at one or both pseudoalleles resulted in a significant delay in blastopore closure and interfered with normal embryonic elongation, suggesting a role for XCEP2 in regulating gastrulation movements. The morpholino antisense effect could be rescued by co-injection with a morpholino-insensitive version of the XCEP2 mRNA. Antisense morpholino oligonucleotides were found to have no effect on mesodermal induction, suggesting that the observed effects were due to changes in the behavior of involuting cells, rather than alterations in their identity. XCEP2 antisense morpholino oligonucleotides were also observed to cause complete disaggregation of cells composing animal cap explants, suggesting a specific role of XCEP2 in maintenance or regulation of cell-cell adhesion in early embryos. This loss of cell adhesion could be rescued by co-injection with a morpholino-insensitive version of the XCEP2 mRNA. CONCLUSIONS: XCEP2 appears to be an essential component in the early developmental program in Xenopus laevis. XCEP2 is involved in maintenance of cell-cell adhesion, and as such may constitute a regulatory component that could help to balance the need for tissue integrity and plasticity during the dynamic cellular rearrangements of gastrulation.

Alleles↗