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PubMed2006

Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo.

While memory T cells are maintained by continuous turnover, it is not clear how human regulatory CD4+ CD45RO+ CD25hi Foxp3+ T lymphocyte populations persist throughout life. We therefore used deuterium labeling of cycling cells in vivo to determine whether these cells could be replenished by proliferation. We found that CD4+ CD45RO+ Foxp3+ CD25hi T lymphocytes were highly proliferative, with a doubling time of 8 days, compared with memory CD4+ CD45RO+ Foxp3- CD25- (24 days) or naive CD4+ CD45RA+ Foxp3- CD25- populations (199 days). However, the regulatory population was susceptible to apoptosis and had critically short telomeres and low telomerase activity. It was therefore unlikely to be self regenerating. These data are consistent with continuous production from another population source. We found extremely close TCR clonal homology between regulatory and memory CD4+ T cells. Furthermore, antigen-related expansions within certain TCR Vbeta families were associated with parallel numerical increases of CD4+ CD45RO+ CD25hi Foxp3+ Tregs with the same Vbeta usage. It is therefore unlikely that all human CD4+ CD25+ Foxp3+ Tregs are generated as a separate functional lineage in the thymus. Instead, our data suggest that a proportion of this regulatory population is generated from rapidly dividing, highly differentiated memory CD4+ T cells; this has considerable implications for the therapeutic manipulation of these cells in vivo.

Adult↗

PubMed1999

Locus of control and the age difference in free recall from episodic memory.

The authors investigated the relation of locus of control (LOC) to age differences in free-recall memory performance. Older and younger participants completed P. C. Duttweiler's (1984) Internal Control Index (ICI) and subsequently performed free-recall memory tasks. Compared with the younger participants, the older participants exhibited poorer recall with more intrusions and uncorrected repetition errors as well as reduced categorical clustering. For the older participants with less internal LOC, recall proportion and item-pair associative recall clustering were lower than for the older participants with more internal LOC. By contrast, the younger participants did not exhibit any LOC effects in their recall performance. The results suggest that a differential memory organization deficit may underlie the age differences in free recall among individuals varying in LOC when they are performing an intentional learning task. This deficit is discussed in terms of a reduced-inhibition account of cognitive aging.

Adult↗

PubMed2005

The origins of life -- the 'protein interaction world' hypothesis: protein interactions were the first form of self-reproducing life and nucleic acids evolved later as memory molecules.

The 'protein interaction world' (PIW) hypothesis of the origins of life assumes that life emerged as a self-reproducing and expanding system of protein interactions. In mainstream molecular biology, 'replication' refers to the material copying of molecules such as nucleic acids. However, PIW is conceptualized as an abstract communication system constituted by the interactions between proteins, in which 'replication' happens at the level of self-reproduction of these interactions between proteins. Densely concentrated peptide interaction systems may have reproduced and expanded as 'protocell' vesicles surrounded by lipid bi-layer membranes. Protocells led to the emergence of proto-RNA molecules of greater chemical stability which served as chemically differentiated 'memories' of peptide interaction states, thereby facilitating the reproduction and expansion of protocells. Simplification-driven expansion led to the selection of biotic amino acids and the reduction of the typical RNA alphabet to the four usual bases (A, C, G and U). Dense interactions between RNA molecules led to the emergence of the RNA interaction subsystem of the cell, and to the emergence of 'memories' of RNA interactions in the form of DNA molecules with greater chemical stability. The expansion of DNA molecule interactions led to the dense clustering and encapsulation of DNA molecules within the cell nucleus. RNA molecules therefore serve as memories of protein interactions and DNA molecules are memories of RNA interactions. We believe that the PIW hypothesis is more evolutionarily plausible than the mainstream RNA world hypothesis, and has greater explanatory power.

Evolution, Molecular↗

PubMed2006

Over-expression of two different forms of the alpha-secretase ADAM10 affects learning and memory in mice.

Members of the ADAM family (adisintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid precursor protein within the region of the Abeta peptides preventing their aggregation in the brain. The increase of alpha-secretase activity in the brain provides a plausible strategy to prevent Abeta formation. Concerning this possibility two transgenic mouse lines (FVB/N) have been created: mice over-expressing the bovine form of the alpha-secretase (ADAM10) and mice over-expressing an inactive form of the alpha-secretase (ADAM10-E348A-HA; ADAM10-dn). For behavioral examination a F1 generation of transgenic mice (C57Bl/6 x FVB/N (tg)) was generated and compared to wild type F1 generation (C57Bl/6 x FVB/N). Behavior was characterized in the following tasks: standard open field, enriched open field, elevated plus-maze, and the Morris water maze hidden platform task. Concerning basal activity, exploration, and anxiety, transgenic mice behaved similar to controls. With respect to learning and memory both transgenic lines showed a significant deficit compared to controls. ADAM10 mice however, showed thigmotaxis with passive floating behavior in the Morris water maze indicating differences in motivation, whereas, ADAM10-dn mice displayed an inconspicuous but limited goal-directed search pattern. Thus variation of the enzymatic activity of alpha-secretase ADAM10 alters learning and memory differentially. Nevertheless, it could be concluded that both, ADAM10 and ADAM10-dn mice are suitable control mice for the assessment of alpha-secretase-related effects in animal models of Alzheimer's disease.

ADAM Proteins↗

PubMed2003

[Memory and brain--neurobiological correlates of memory disturbances].

A differentiation of memory is possible on the basis of chronological and contents-related aspects. Furthermore, it is possible to make process-specific subdivisions (encoding, transfer, consolidation, retrieval). The time-related division on the one hand refers to the general differentiation into short-term and long-term memory, and, on the other, to that between anterograde and retrograde memory ("new" and "old memory"; measured from a given time point, usually that when brain damage occurred). Anterograde memory means the successful encoding and storing of new information; retrograde the ability to retrieve successfully acquired and/or stored information. On the contents-based level, memory can be divided into five basic long-term systems--episodic memory, the knowledge system, perceptual, procedural and the priming form of memory. Neural correlates for these divisions are discussed with special emphasis of the episodic and the knowledge systems, based both on normal individuals and brain-damaged subjects. It is argued that structures of the limbic system are important for encoding of information and for its transfer into long-term memory. For this, two independent, but interacting memory circuits are proposed--one of them controlling and integrating primarily the emotional, and the other primarily the cognitive components of newly incoming information. For information storage principally neocortical structures are regarded as important and for the recall of information from the episodic and semantic memory systems the combined action of portions of prefrontal and anterior temporal regions is regarded as essential. Within this fronto-temporal agglomerate, a moderate hemispheric-specificity is assumed to exist with the right-hemispheric combination being mainly engaged in episodic memory retrieval and the left-hemispheric in that of semantic information. Evidence for this specialization comes from the results from focally brain-damaged patients as well as from that functional brain imaging in normal human subjects. Comparing results from imaging studies in memory disturbed patients with brain damage and from patients with a psychiatric diagnosis (e. g., psychogenic amnesia) revealed that both patient groups demonstrate comparable metabolic changes on the brain level. It can therefore be concluded that in neurological patients distinct, identifiable tissue damage is existent, while in psychiatric patients changes in the brain's biochemistry (release of stress hormones, and transmitters) constitute the physiological bases for the memory disturbances.

Amnesia, Anterograde↗

PubMedDate not supplied

The effects of telencephalic pallial lesions on spatial, temporal, and emotional learning in goldfish.

In mammals, the pallial amygdala is implicated in emotional learning and memory, whereas the hippocampus is involved in spatial, contextual, or relational memory. This review presents a set of experiments aimed to study the involvement of the dorsomedial and dorsolateral telencephalon of goldfish in spatial and active avoidance learning. Results showed that (1) medial lesions impaired both acquisition and retention of conditioned avoidance response in two-way active avoidance learning experiments with stimuli overlapping (emotional factor) and with an interstimuli gap (temporal and emotional factors), and (2) the medial lesion did not affect spatial learning (spatial, contextual, or relational factors). In contrast, lateral lesions did not impair conditioned avoidance response with stimuli overlapping, but affected conditioned avoidance response with an interstimuli gap and spatial learning. These results support the presence of two differentiated memory systems in teleost fish based on discrete pallial regions: emotional (dorsomedial telencephalon) and spatial/temporal or relational (dorsolateral telencephalon). Furthermore, these functional data support the homology between the medial pallium of the teleost and the pallial amygdala of land vertebrates, and between the teleost lateral pallium and the mammalian hippocampus.

Amygdala↗

PubMed1997

Ligation of CD2 provides a strong helper signal for the production of the type 2 cytokines interleukin-4 and -5 by memory T cells.

In this study, we investigated the efficiency of costimulatory signaling provided by anti-CD2 monoclonal antibodies (mAbs) for the production of type 1 (IL-2 and IFN-gamma) and type 2 (IL-4, IL-5, and IL-10) cytokines by human T cells. We cultured purified human T cells (freshly isolated from blood) with immobilized anti-CD3 mAb, either alone or in combination with anti-CD28 or anti-CD2 mAbs. When compared with the standard costimulatory signal anti-CD28, anti-CD2 mAbs (9-1 plus 9.6) were shown to be more potent costimulators of IL-4 production and to have similar activity for IL-5 production, but to be less potent for costimulation of IL-2, IL-10, and IFN-gamma production. IL-4 production was completely inhibited by cyclosporin A or by blocking IL-2 activity and its receptor. IL-4 and IL-5 were produced by CD45RO+ T cells but not by CD45RA+ T cells, indicating that anti-CD2 in this system costimulated type 2 cytokine production by differentiated memory cells. In the presence of IL-12, the cytokine profile was shifted to high IFN-gamma and IL-10 production and IL-4 and IL-5 production were slightly inhibited. Our data thus suggest that CD2 ligation plays an important role in the upregulation of Th2-like T cell activity (especially IL-4 production), but they also show that this effect is strongly modulated by IL-12, resulting in predominant IL-10 and IFN-gamma production instead.

Adult↗

PubMed1993

Changes in semantic memory in early stage Alzheimer's disease patients.

The types and number of exemplars of categories that are retrieved from semantic memory differentiate elderly normal controls and early stage Alzheimer's disease (AD) patients. Elderly normal controls generated more uncommon exemplars from closed semantic categories (fruits and vegetables) than did AD patients 2 1/2 years prior to the presumed onset of AD. AD patients, however, were just as productive as elderly normal controls in generating associations to open categories (letters). The findings suggest that one of the early cognitive symptoms of AD is changes in availability of uncommon exemplars of semantic networks.

Aged↗

PubMed2002

The proto-oncogene BCL-6 in normal and malignant B cell development.

BCL-6 is an important regulator of the immune system. It is required for GC formation and T cell dependent antibody responses. Mice deficient in BCL-6 fail to form GC and mount reduced levels of T cell-dependent antibody responses. BCL-6 (-/-) mice, in addition, develop a massive inflammatory response in many organs characterized by eosinophilic infiltration and hyper-IgE production, a typical Th2 hyperimmune response. This suggests a negative role of BCL-6 in Th2 pathway. The BCL-6 gene encodes a POZ/zinc finger transcription repressor highly expressed in GC B cells, but not in pre-GC B cells or in more differentiated memory or plasma cells. By functioning as a potent transcriptional repressor of various target genes, BCL-6 modulates IL-4, BCR, and CD40L signals for normal B cell development. In B cell lymphomas, structural alterations of the BCL-6 promoter region, including chromosome translocation and somatic hypermutation, represent the most frequent genetic lesions associated with non-Hodgkin lymphoma, especially of diffuse large cell lymphoma, a malignancy often derived from germinal centre (GC) B cells. This suggests that deregulated expression of BCL-6 may contribute to lymphomagenesis.

Animals↗

PubMed2006

Visual association memory test in differentiating early stage of Alzheimer's disease from vascular dementia.

We studied the results of the Visual Association Memory Test (VAMT) in differentiating Alzheimer's disease (AD) and vascular dementia (VaD). In addition, other basic neuropsychological tests, including the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) were also used. Generally, with the VAMT, AD patients had a worse performance than VaD patients. Particularly among patients with a CDR = 0.5, the AD patients had statistically significantly lower VAMT scores (score less than 3) (p = 0.026) compared to those of VaD patients. However, the VAMT could not predict clinical severity or disease progression. The VAMT, as revealed in this study, is a brief, simply administered, and less biased test, and may offer a diagnostic adjunct to differentiate AD from VaD especially in an early dementia state.

Aged↗

PubMed2000

Plasticity of cardiorespiratory neural processing: classification and computational functions.

Neural plasticity, or malleability of neuronal structure and function, is an important attribute of the mammalian forebrain and is generally thought to be a kernel of biological intelligence. In this review, we examine some reported manifestations of neural plasticity in the cardiorespiratory system and classify them into four functional categories, integral; differential; memory; and statistical-type plasticity. At the cellular and systems level the myriad forms of cardiorespiratory plasticity display emergent and self-organization properties, use- and disuse-dependent and pairing-specific properties, short-term and long-term potentiation or depression, as well as redundancy in series or parallel structures, convergent pathways or backup and fail-safe surrogate pathways. At the behavioral level, the cardiorespiratory system demonstrates the capability of associative and nonassociative learning, classical and operant conditioning as well as short-term and long-term memory. The remarkable similarity and consistency of the various types of plasticity exhibited at all levels of organization suggest that neural plasticity is integral to cardiorespiratory control and may subserve important physiological functions.

Animals↗

PubMed2001

How golden hamsters (Mesocricetus auratus) discriminate top from bottom flank scents in over-marks.

Using a habituation-discrimination paradigm, the authors investigated what cues male golden hamsters (Mesocricetus auratus) use to determine the top and bottom positions in flank gland over-marks. A difference in the ages of 2 hamsters' marks did not, by itself, produce differential memory or evaluation of the 2 scents. A spatial configuration of marks suggestive of an overlap was sufficient for the apparently overlapping scent to be remembered or valued more than the apparently underlying scent. Cues from the overlap of 2 hamsters' marks were also sufficient. These results, consistent with those previously found for responses to hamster vaginal scent over-marks, suggest that hamsters use similar cues to analyze scent over-marks that are different in chemical composition and in social functions.

Animals↗

PubMed1998

Variation in gut-homing CD27-negative lymphocytes in inflammatory colon disease.

Prolonged antigenic stimulation results in lymphocyte shedding of CD27, a member of the tumour necrosis factor receptor (TNFR) family, and transformation to a stable phenotype capable of synthesizing interleukin-4 (IL-4). Co-expression of alpha4beta7 identifies those cells with gut-homing potential. We have investigated these cell populations in patients with inflammatory colonic disease. Circulating and lamina propria mononuclear cells were isolated from patients with Crohn's disease (CD), ulcerative colitis (UC), non-inflammatory bowel disease (non-IBD) colonic inflammation and healthy controls. Double and triple colour flow cytometry for CD3, CD4, CD27, alpha4beta7 and intracellular cytokines was performed. Circulating CD4+ CD27- populations were increased in patients with CD (8.8 +/- 0.8%, P < 0.001), UC (12.2 +/- 1.9%, P < 0.001) and non-IBD colitis (10.5 +/- 1.3%, P < 0.01) as compared with controls (6.1 +/- 0.5%). CD4+ CD27- alpha4beta7+ cells were increased in CD (P < 0.01). Lamina propria CD4+ CD27- populations were depressed significantly in CD (P < 0.05), UC (P < 0.02) and non-IBD colitis (P < 0.03). Mucosal CD4+ CD27- cells synthesized IL-4 in preference to interferon-gamma. Thus, colonic inflammation is associated with alterations in gut-tropic circulating and mucosal populations of differentiated memory T cells with the phenotype of predominantly IL-4-synthesizing cells.

CD4-Positive T-Lymphocytes↗

PubMed2005

Patterns of premorbid functioning in first episode psychosis: relationship to 2-year outcome.

OBJECTIVE: To determine how different patterns of premorbid functioning relate to outcome longitudinally. METHOD: Premorbid adjustment was assessed in 194 first-episode of psychosis subjects. Positive and negative symptoms, depression, substance misuse and social and cognitive functioning were assessed over 2 years. RESULTS: Four patterns of premorbid adjustment: stable-good, stable-intermediate, poor-deteriorating and deteriorating were identified. Relative to the stable-good group, the deteriorating and poor-deteriorating groups had significantly more positive symptoms at 1-year follow-up but not at 2-year follow-up and significantly more negative symptoms and significantly poorer social functioning at both 1 and 2-years. Only verbal fluency and memory differentiated between the groups with the stable-good group having a superior performance. CONCLUSION: Those who demonstrated poor or deteriorating functioning prior to the onset of acute psychosis have a poorer outcome up to at least 2 years in terms of negative symptoms and social functioning.

Adolescent↗

PubMed1989

Lymphocyte migration patterns in organ allograft recipients.

A central tenet of immunology is the observation, made 30 years ago, that lymphocytes recirculate continuously between peripheral blood and lymphoid tissues. In recent years, the subject of lymphocyte migration, both under physiological conditions and in states of alloresponsiveness, has become more enigmatic. It lies outside most current topics of immunological investigations, labelling and tracing techniques are problematic, and many experimental findings are phenomenological and difficult to interpret. Indeed, our overall knowledge of the functional differences between the various host lymphoid compartments and their constituent cell populations remains rudimentary. However, as understanding increases regarding the host immunological events responding to an antigenic stimulus such as a graft, with growing definition of the distinctive and interconnecting roles of lymphocyte subpopulations and their products acting on each other to produce graft destruction, the conceptual importance of lymphocyte migration again is becoming obvious. This role includes many facets of immunity such as the effects of antigen specificity, immunologic memory, differential behavior of recirculating or sessile populations, and local and systemic contact between antigen and effector cells. It has become evident that lymphocytes migrate in a non-random and highly dynamic fashion determined by a range of specific and non-specific factors; in the setting of organ transplantation, patterns are profoundly affected by the interrelated cellular and humoral components of the immunological cascade which may lead either to graft rejection or to its prolongation in untreated and immunologically modified recipients, respectively. Thus, the traffic of lymphocytes throughout host lymphoid and non-lymphoid compartments and their activity within these compartments should be considered an integral part of the host immunomodulation triggered by transplantation of histoincompatible tissue. Gradual filling of the gaps in our current knowledge on the mechanistic aspects of this phenomenon will not only contribute to basic science itself, but also should lead to the development of innovative therapeutic approaches to treat graft rejection.

Animals↗

PubMedDate not supplied

An analysis of contemporary morphological concepts of synaptic remodelling in the CNS: perforated synapses revisited.

Perforated synapses refer to a synaptic type found in the central nervous system. They are characterized by their large size and by a discontinuity of the postsynaptic density when viewed in transverse sections, and by a doughnut or horseshoe shape when viewed in en face views. Of recent morphological studies, one approach has followed their characteristics throughout development and maturity, while others have concentrated on their probable roles in activities including kindling, long-term potentiation, spatial working memory, differential rearing, and the functioning of neuroleptics. An assessment is made of the hypotheses and models that have proved determinative in the emergence of perforated synapses as being significant in synaptic plasticity. Their distribution and frequency are summarized, with emphasis on the importance of unbiased stereological procedures in their analysis. Using three-dimensional approaches various subtypes are recognized. Of these, a complex or fragmented subtype appears of especial significance in synaptic plasticity. Ideas regarding the life-cycle of perforated synapses are examined. The view that they originate from conventional, non-perforated synapses, enlarge, and subsequently split to give rise to a new generation of non-perforated synapses, is critically assessed. According to an alternative model, perforated and non-perforated synapses constitute separate populations from early in their development, each representing complementary forms of synaptic plasticity. An attempt is also made to discover whether synaptic studies on the human brain in normal aging and in Alzheimer's disease throw light on the role of perforated synapses in synaptic plasticity. The loss of synapses in Alzheimer's disease may include a loss of perforated synapses - of particular relevance for an understanding of certain neuropathological conditions.

Aging↗

PubMed1990

Underage gambling in Atlantic City casinos.

A three-year survey of college students was conducted to ascertain the frequency and preferences of student gambling at nearby casinos in Atlantic City, New Jersey. The data suggest that gambling by underage college students is common and indicates that age control at casino entrances is quite poor. An additional finding of differential memory for wins and losses suggests the need for an information processing analysis of memory for gambling outcomes.

Adolescent↗

PubMed2004

Processing strategies and the generation effect: implications for making a better reader.

When presented with items that must be generated versus read at encoding, individuals typically remember better those items that they generated versus those that they only read. We examined whether--given the opportunity to experience such differential memorial consequences of generating versus reading--participants might change how they processed future to-be-read information. In a first set of two experiments, participants were able to profit from such an experience to the extent that a generation advantage was eliminated on subsequent memory tests of generated and read items. Two additional experiments demonstrated the critical nature of this experience in leading to improved processing of future to-be-read information and elimination of a generation advantage. We believe that these results relate to the characterization of the learner emerging from recent metacognitive research and have possible implications for how learners might be induced to process information more effectively.

Cognition↗