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PubMed1977

Enhancing effect of low dose cyclophosphamide treatment on the in vitro antibody response.

We have studied the effect of cyclophosphamide (CY) administration on the subsequent in vitro antibody response in the mouse. Treatment with a low dose (20 mg/kg) of CY four days before culture results in an increased IgM response to the T-independent antigen trinitrophenylated polyacrylamide (TNP-PAA), without affecting the background response of unstimulated cultures. This suggests that CY treatment eliminates a short-lived suppressor cell, involved in the regulation of the in vitro B cell response. In contrast, the same regimen decreases the ability of nude mouse spleen cells to respond to TNP-PAA, showing that the target of CY-enhancing effect is a mature T cell. The increased response observed in conventional mice should be the result of a balance between the direct suppressive effect of CY on B cells and the elimination of a suppresor T cell, the latter phenomenon being of predominant significance in our conditions. The target of CY-enhancing effect is nonadherent to plastic, but adherent to Sephadex G-10 columns.

Acrylamides↗

PubMed1997

Prolonged oxidative stress on actin.

Hydrogen peroxide, coming from polymorphonuclear leukocytes, causes severe oxidative injury on actin molecules with the disarrangement of cortical actin cytoskeleton followed by plasmalemma blebbing. In this paper we demonstrate that actin oxidation does not simply develop into denaturation, but oxidative injuries on actin are specific and related to the chemical characteristics of the oxidant. Experiments on purified actin in solution have shown that actin behavior to oxidation depends on (i) the amino acidic targets of the oxidant and (ii) on the structural plasticity of the actin molecule, which differently responds to different chemical modifications. Therefore, hydrogen peroxide (that presents a broad oxidative activity) affects actin dynamics by markedly inhibiting the assembly of actin monomers, by forcing the disassembly of actin polymers, and, moreover, by affecting the interaction between oxidant-stressed actin and DNase I. Diamide (a specific thiol oxidant), in contrast, mainly lowers the actin polymerization extent, while it slightly influences the polymerization rate and results uneffective on both F-actin disassembly and actin-related DNase I inhibition. Actin response to oxidative stresses likely depends on the "structural connectivity in actin," the property allowing it to finely modulate the actin filament architecture. The potential cellular relevance of the alterations in the interaction between oxidized actin and DNase I has been briefly discussed.

Actins↗

PubMed1996

The critical role of cholinergic basal forebrain neurons in morphological change and memory encoding: a hypothesis.

It has been known for a long time that cholinergic basal forebrain neurons which project to the cerebral cortex play a role in learning and memory. Behavioral studies following lesions, for example, repeatedly have suggested multiple learning-related roles for these neurons. Apart from behavioral studies, cholinergic neurons have been shown to possess extraordinarily plastic axons. This plasticity has not been related comprehensively to mnemonic devises, even though morphological changes in the CNS are prime candidates for the neural engram. In this paper, I propose a hypothesis that relates these two characteristics of cholinergic neurons. This hypothesis is that plastic cholinergic axon terminals induce structural reorganization in their targets during memory storage. Possible intracellular mechanisms are examined, whereby acetylcholine release in the cerebral cortex could cause postsynaptic structural changes. Finally, the characteristics of the overall cholinergic-cholinoceptive cell "engram" are elaborated with particular attention paid to the encoding of the stimulus properties along with the context and meaning of the stimulus.

Cholinergic Fibers↗

PubMed2001

Perinatal asphyxia: timing and mechanisms of injury in neonatal encephalopathy.

This article summarizes the recent medical literature regarding perinatal asphyxia with respect to timing and mechanisms of injury for neonates who were clinically diagnosed with an encephalopathy in the newborn period. Multiple mechanisms of injury are reviewed, including genetic vulnerability, acquired inflammatory responses, and clotting defects that can lead to ischemic-induced brain damage. Before effective treatments for fetal and neonatal brain disorders can be developed, accurate and timely diagnoses of fetal or neonatal brain injury must be achieved. Specific subsets of children can then benefit from neuroprotective strategies that can target the specific developmental aspects of brain adaptation or plasticity relative to the specific etiology and timing of injury after asphyxia.

Apoptosis↗

PubMed1989

A new colorimetric nucleic acid hybridization assay for Listeria in foods.

Non-isotopic colorimetric detection has been applied in a rapid nucleic acid dipstick hybridization assay for detection of Listeria spp. in food and environmental samples. The assay takes approximately 2.5-3 h following a two day broth and plate enrichment. Hybridization occurs between fluorescein labeled detector probes, poly(deoxyadenosine)-tailed capture probes, and Listeria-specific regions of 16 S ribosomal RNA. These target:probe complexes are captured on poly(deoxythymidine) coated plastic dipsticks. Detection is based on binding of horseradish peroxidase conjugated anti-fluorescein antibody to the hybridization complex, and enzyme-mediated color development. The colorimetric endpoint is read on a photometer at 450 nm. In these initial studies, 306 inoculated dairy, meat and seafood samples, and 200 environmental samples were tested. When compared with total culture results the hybridization assay had unconfirmed positive and false-negative rates of approximately 1.4-2.9% and 0.8-4.7%, respectively.

Colorimetry↗

PubMed1996

Gene expression of the transcription factor NF-kappa B in hippocampus: regulation by synaptic activity.

NF-kappa B is a potent transcriptional activator that resides in latent form in the cytoplasm complexed to its inhibitor I kappa B. Phosphorylation of I kappa B by protein kinase C (PKC) releases NF-kappa B, enabling its translocation to the nucleus. Since PKC can activate NF-kappa B and PKC is activated by long-term potentiation (LTP), we investigated NF-kappa B expression after hippocampal LTP induced in vivo. We first described the expression of the NF-kappa B subunits, p50 and p65, and I kappa B alpha mRNAs, in each cell field of the hippocampus. In other brain locations I kappa B alpha mRNA exhibited a more selective expression than p50 and p65. We then demonstrated specific NF-kappa B-like DNA-binding activity in hippocampal whole-cell extracts and in synaptosomes using electrophoretic mobility shift assays by the following criteria: (1) latent binding was revealed after deoxycholate treatment; (2) binding was competed off by unlabeled kappa B oligonucleotides; and (3) antibodies to either p50 or p65 blocked binding. Since p50 gene expression is auto-regulated by NF-kappa B, we used its expression as a reporter for NF-kappa B activity using quantitative in situ hybridization. Both p50 and p65 increased their expression in response to either LTP-inducing or low-frequency control stimulation, although the increase in p65 mRNA levels was greater after LTP than control stimulation. In contrast to p50 and p65, I kappa B alpha hybridization levels were not increased, but were inversely correlated with the magnitude of LTP. Since NF-kappa B subunit gene expression in the hippocampus is increased by augmented synaptic activity, NF-kappa B activation may contribute to alterations in target gene expression that accompany activity-dependent synaptic plasticity, but only in a combinatorial fashion with other transcription factors.

Animals↗

PubMed2002

Age-related and laminar-specific dendritic changes in the medial frontal cortex of the rat.

Early hypotheses that normal brain aging involves widespread loss of neurons have been revised in light of accumulating evidence that, in most regions of the brain, the number of neurons is stable throughout adulthood and senescence. It is not clear, however, that all aspects of neuronal structure are similarly maintained, and anatomical changes are likely to contribute to age-related declines in cognitive function. The extent and pattern of dendritic branches is one likely target for age-dependent regulation since dendrites remain plastic into adulthood and since dendrites, as the site of most synapses, critically regulate neuronal function. This study quantified the dendritic extent and geometry of superficial and deep pyramidal neurons in the medial frontal cortex of Brown Norway rats from young adulthood through senescence. This region of cortex is of specific interest given its involvement in a variety of cognitive functions that change with age. In the present study, age-related changes in dendritic extent were found to occur with remarkable specificity. Superficial, but not deep, pyramidal neurons exhibited ongoing dendritic growth after 2 months-of-age and then dendritic regression after 18 months-of-age. Apical and basal dendrites were similarly regulated; in each arbor adult growth and regression were limited to terminal dendritic segments. The focal specificity of age-related changes suggests several possible regulatory mechanisms, including regional changes in trophic support and in neuronal activity. Although restricted to specific neuronal populations, dendritic regression in aged animals is likely to contribute to cognitive changes associated with senescence.

Aging↗

PubMed1997

c-fos induction in sensory pathways of rats exploring a novel complex environment: shifts of active thalamic reticular sectors by predominant sensory cues.

In normal rats exploring a novel, complex environment, in comparison to control nonexploring rats, there is induction of the FOS protein, a marker of neuronal activity, in all layers of the striate visual cortex (particularly in the granular and supragranular layers), in the stratum griseum superficiale of the superior colliculus, and in the dorsal lateral geniculate nucleus, as well as in all layers of the whiskers barrel field in the somatosensory cortex. A surprising finding was a selective activation of the visual sector of the thalamic reticular nucleus, in dorsocaudal parts of the nucleus. To the contrary, in visually deprived rats exploring a novel environment which would depend critically on whiskers tactile clues for exploration there was instead a selective activation of the somatic sector in central parts of the thalamic reticular nucleus, in conjunction with activation of cortical whiskers barrel field. From these results it is concluded: (1) Different sensory sectors of the rat thalamic reticular nucleus are activated depending on prevalent sensory channels used in recognition of the environment, suggesting a role of thalamic reticular nucleus in optimizing thalamocortical transmission of essential external cues to guide adequate behaviour. (2) In the awake state, the granular and supragranular layers of the visual and somatosensory cortices are more active when attention is paid to sensory stimuli that are essential for recognition of the environment. (3) The selective induction of c-fos in the visual and somatosensory cortices, and in the stratum griseum superficiale of superior colliculus of rats exploring a novel, complex environment might be related to plastic changes that have been demonstrated in these centres in rats raised in complex environments. These plastic changes are likely to be the result of target late-response genes activated by c-fos.

Animals↗

PubMed2006

Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness.

Bidirectional cellular communication is integral to both cancer progression and embryological development. In addition, aggressive tumor cells are phenotypically plastic, sharing many properties with embryonic cells. Owing to the similarities between these two types of cells, the developing zebrafish can be used as a biosensor for tumor-derived signals. Using this system, we show that aggressive melanoma cells secrete Nodal (a potent embryonic morphogen) and consequently can induce ectopic formation of the embryonic axis. We further show that Nodal is present in human metastatic tumors, but not in normal skin, and thus may be involved in melanoma pathogenesis. Inhibition of Nodal signaling reduces melanoma cell invasiveness, colony formation and tumorigenicity. Nodal inhibition also promotes the reversion of melanoma cells toward a melanocytic phenotype. These data suggest that Nodal signaling has a key role in melanoma cell plasticity and tumorigenicity, thereby providing a previously unknown molecular target for regulating tumor progression.

Animals↗

PubMed2001

Neuroendocrine-immune (NEI) circuitry from neuron-glial interactions to function: Focus on gender and HPA-HPG interactions on early programming of the NEI system.

Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.

Animals↗

PubMed2005

Immunity to Aspergillus fumigatus: the basis for immunotherapy and vaccination.

Efficient responses to fungi require different mechanisms of immunity. Dendritic cells (DCs) are uniquely able to decode the fungus-associated information and translate it into qualitatively different T helper (Th) immune responses. Murine and human DCs phagocytose conidia and hyphae of Aspergillus fumigatus through distinct recognition receptors. The engagement of distinct receptors translates into disparate downstream signaling events, ultimately affecting cytokine production and co-stimulation. Adoptive transfer of different types of DCs activates protective and non-protective Th cells as well as regulatory T cells, ultimately affecting the outcome of the infection in mice with invasive aspergillosis. The infusion of fungus-pulsed or RNA-transfected DCs also accelerates recovery of functional antifungal Th 1 responses in mice with allogeneic hematopoietic stem cell transplantation. Patients receiving T cell-depleted allogeneic hematopoietic stem cell transplantation are unable to develop antigen-specific T cell responses soon after transplant due to defective DC functions. Our results suggest that the adoptive transfer of DCs may restore immunocompetence in hematopoietic stem cell transplantation by contributing to the educational program of T cells. Thus, the remarkable furictional plasticity of DCs can be exploited for the deliberate targeting of cells and pathways of cell-mediated immunity in response to the fungus.

Adoptive Transfer↗

PubMed2003

Influence of fragment reaction of relativistic heavy charged particles on heavy-ion radiotherapy.

The production of projectile fragments is one of the most important, but not yet perfectly understood, problems to be considered when planning for the utilization of high-energy heavy charged particles for radiotherapy. This paper reports our investigation of the fragments' fluence and linear energy transfer (LET) spectra produced from various incident ions using an experimental approach to reveal these physical qualities of the beams. Polymethyl methacrylate, as a substitute for the human body, was used as a target. A deltaE-E counter telescope with a plastic scintillator and a BGO scintillator made it possible to identify the species of fragments based on differences of various elements. By combining a gas-flow proportional counter with a counter telescope system, LET spectra as well as fluence spectra of the fragments were derived for each element down from the primary particles to hydrogen. Among them, the information on hydrogen and helium fragments was derived for the first time. The result revealed that the number of light fragments, such as hydrogen and helium, became larger than the number of primaries in the vicinity of the range end. However, the greater part of the dose delivered to a cell was still governed by the primaries. The calculated result of a simulation used for heavy-ion radiotherapy indicated room for improving the reaction model.

Ions↗

PubMed1994

Ultrastructural studies of diffuse axonal injury in humans.

Diffuse axonal injury (DAI) is observed commonly in traumatically brain injured humans. However, traditional histologic methods have proven of limited use in identifying reactive axonal change early (< 12 h) in the posttraumatic course. Recently, we have reported, in both humans and animals, that antibodies targeting neurofilament subunits are useful in the light microscopic recognition of early reactive change. In the present study, we extend our previous efforts in humans by analyzing the progression of traumatic brain injury (TBI)-induced axonal change at the ultrastructural level. This effort was initiated to follow the subcellular progression of reactive axonal change in humans and to determine whether this progression parallels that described in animals. Two commercially prepared antibodies were used to recognize reactive axonal change in patients surviving from 6 to 88 h. The NR4 antibody was used to target the light neurofilament subunit (NF-L), and the SMI32 antibody was used to target the heavy neurofilament subunit (NF-H). Plastic-embedded tissue sections were screened for evidence of reactive axonal change, and once identified, this reactive change was analyzed at the ultrastructural level. At 6 h survival, focally enlarged, immunoreactive axons with axolemmal infolding or disordered neurofilaments were seen within fields of axons exhibiting no apparent abnormality. By 12 h, some axons exhibited continued neurofilamentous misalignment, pronounced immunoreactivity, vacuolization, and, occasionally, disconnection. At later stages, specifically 30 and 60 h survival, further accumulation of neurofilaments and organelles had led to the further expansion of the axis cylinder, and clearly disconnected reactive swellings were recognized. These contained a dense core of disordered immunoreactive neurofilaments partially encompassed by a cap of less densely aggregated organelles. At 88 h, the reactive axons were larger and elongated, consistent with the continued delivery of organelles by axoplasmic transport. At the later time points, considerable heterogeneity was observed, with focally enlarged disconnected axons being observed in relation to axons showing less advanced reactive change. Our findings suggest that neurofilamentous disruption is a pivotal event in axonal injury.

Adult↗

PubMed1998

Constitutive activation of delayed-rectifier potassium channels by a src family tyrosine kinase in Schwann cells.

In the nervous system, Src family tyrosine kinases are thought to be involved in cell growth, migration, differentiation, apoptosis, as well as in myelination and synaptic plasticity. Emerging evidence indicates that K+ channels are crucial targets of Src tyrosine kinases. However, most of the data accumulated so far refer to heterologous expression, and native K+-channel substrates of Src or Fyn in neurons and glia remain to be elucidated. The present study shows that a Src family tyrosine kinase constitutively activates delayed-rectifier K+ channels (IK) in mouse Schwann cells (SCs). IK currents are markedly downregulated upon exposure of cells to the tyrosine kinase inhibitors herbimycin A and genistein, while a potent upregulation of IK is observed when recombinant Fyn kinase is introduced through the patch pipette. The Kv1.5 and Kv2.1 K+-channel alpha subunits are constitutively tyrosine phosphorylated and physically associate with Fyn both in cultured SCs and in the sciatic nerve in vivo. Kv2.1- channel subunits are found to interact with the Fyn SH2 domain. Inhibition of Schwann cell proliferation by herbimycin A and by K+-channel blockers suggests that the functional linkage between Src tyrosine kinases and IK channels could be important for Schwann cell proliferation and the onset of myelination.

Animals↗

PubMed2004

Oestradiol restores cell proliferation in dentate gyrus and subventricular zone of streptozotocin-diabetic mice.

Type 1 diabetes mellitus correlates with several brain disturbances, including hypersensitivity to stress, cognitive impairment, increased risk of stroke and dementia. Within the central nervous system, the hippocampus is considered a special target for alterations associated with diabetes. Neurogenesis is a plastic event restricted to few adult brain areas: the subgranular zone of the dentate gyrus and the subventricular zone (SVZ). First, we studied the ability for neurogenesis in the dentate gyrus and SVZ of chronic diabetic mice induced by streptozotocin (STZ). Using bromodeoxyuridine (BrdU) labelling of cells in the S-phase, we observed a strong reduction in cell proliferation rate in both brain regions of diabetic mice killed 20 days after STZ administration. Second, because oestrogens are active neuroprotective agents, we investigated whether 17beta-oestradiol (200 micro g pellet implant in cholesterol during 10 days) restored brain cell proliferation in the diabetic mouse brain. Our results demonstrated a complete reversibility of dentate gyrus cell proliferation in oestrogen-treated diabetic mice. This plasticity change was not exclusive to the hippocampus because oestrogen treatment restored BrdU incorporation into newborn cells of the SVZ region of diabetic animals. Oestrogen treatment did not alter the hyperglycemic status of STZ-diabetic mice. Moreover, oestrogen did not modify BrdU incorporation in control animals. These data show that oestrogen treatment strongly stimulates brain neurogenesis of diabetic mice and open up new venues for understanding the potential neuroprotective role of steroid hormones in diabetic encephalopathy.

Animals↗

PubMed2005

Atomic hydrogen emission induced by TEA CO(2) laser bombardment on solid samples at low pressure and its analytical application.

Hydrogen emission has been studied in laser plasmas by focusing a TEA CO(2) laser (10.6 microm, 500 mJ, 200 ns) on various types of samples, such as glass, quartz, black plastic sheet, and oil on copper plate sub-target. It was found that H(alpha) emission with a narrow spectral width occurs with high efficiency when the laser plasma is produced in the low-pressure region. On the contrary, the conventional well-known laser-induced breakdown spectroscopy (LIBS), which is usually carried out at atmospheric air pressure, cannot be applied to the analysis of hydrogen as an impurity. By combining low-pressure laser-induced plasma spectroscopy with laser surface cleaning, a preliminary quantitative analysis was made on zircaloy pipe samples intentionally doped with hydrogen. As a result, a good linear relationship was obtained between H(alpha) emission intensity and its concentration.

Chemistry Techniques, Analytical↗

PubMed2006

Perceptual learning directs auditory cortical map reorganization through top-down influences.

The primary sensory cortex is positioned at a confluence of bottom-up dedicated sensory inputs and top-down inputs related to higher-order sensory features, attentional state, and behavioral reinforcement. We tested whether topographic map plasticity in the adult primary auditory cortex and a secondary auditory area, the suprarhinal auditory field, was controlled by the statistics of bottom-up sensory inputs or by top-down task-dependent influences. Rats were trained to attend to independent parameters, either frequency or intensity, within an identical set of auditory stimuli, allowing us to vary task demands while holding the bottom-up sensory inputs constant. We observed a clear double-dissociation in map plasticity in both cortical fields. Rats trained to attend to frequency cues exhibited an expanded representation of the target frequency range within the tonotopic map but no change in sound intensity encoding compared with controls. Rats trained to attend to intensity cues expressed an increased proportion of nonmonotonic intensity response profiles preferentially tuned to the target intensity range but no change in tonotopic map organization relative to controls. The degree of topographic map plasticity within the task-relevant stimulus dimension was correlated with the degree of perceptual learning for rats in both tasks. These data suggest that enduring receptive field plasticity in the adult auditory cortex may be shaped by task-specific top-down inputs that interact with bottom-up sensory inputs and reinforcement-based neuromodulator release. Top-down inputs might confer the selectivity necessary to modify a single feature representation without affecting other spatially organized feature representations embedded within the same neural circuitry.

Acoustic Stimulation↗

PubMed1998

Investment in Research as a National Priority.

The first time a nation made research a national priority was probably in 15th Century Portugal. While the Spanish built large galleons to ferry gold from the New World to Madrid, the Portuguese built small caravels to return with something more valuable: information. A National Navigational Institute was established in Sagres, where Prince Henry collated the raw data being delivered by the caravels: latitude, longitude, ocean depths, coastal landmarks, and current. Slowly, the caravels moved down the western coast of Africa, overcame the nautical and psychological obstacle of rounding the Horn, and slowly pushed up the Eastern coast. Each new voyage built on the incremental knowledge gleaned from the last and the certain knowledge of the ultimate goal. When Vasco DiGama reached India, the price of pepper in Venice plunged. A new route to the spice trade had been established, a route which did not require the payment of costly tributes at regular intervals along the land route, and a wealthy Empire which would last two centuries was established. The National Institutes of Health represent this nation's commitment to the importance of basic research. In the history of all mankind there has never been a greater, more consistent, and publically funded investment to understand the biology of human disease. Like the caravels, research laboratories and clinical trials have steadily moved forward with incremental progress toward a clearly visualized goal-the prevention and treatment of human disease. In the area of cancer research, we have clearly rounded the horn. The understanding of cancer at a basic level has now brought new targets for cancer treatment into sharper focus. We now understand cancer as a genetic disease. No longer do our therapies target a single cancer feature, uncontrolled growth. Instead, new vaccines like MART-1, gp100, p53 and ras peptides are targeting the cancer cell's ability to evade immune surveillance. Anti-angiogenesis agents like endostatin, Col-3, and angiostatin promise to inhibit the tumor's ability to make new blood vessels and convert cancer to a static, chronic disease. One advantage to these new angiogenesis inhibitors is their action against normal endothelial cells, rather than targeting the cancer itself. For this reason, the genetic plasticity of tumor cells, and their ability to develop drug resistance, is no longer relevant. The Clinton administration has recently announced its intention to add $4.7 billion to cancer research, essentially reaffirming the nation's initial investment of the National Cancer Act. The commitment could not have been better timed. When grants are funded at the 20th percentile, peer review does not work well. And when managed care makes clinical research nearly impossible, we erode the purpose of basic research and undermine the essence of our mission: the prevention and cure of human disease. The Administration's investment will prove to be wise. With the knowledge at hand, and the ability to translate this knowledge into new diagnostic, preventive and treatment approaches, we can begin to realistically vision cancer cures. A new era is at hand.

Journal Article↗