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PubMed1999

Place cells can flexibly terminate and develop their spatial firing. A new theory for their function.

In this study, hippocampal place cells were recorded in a behavioral paradigm previously not employed in place-cell research. Rats were exposed to the same fixed environment for as long as 8-24 h without interruption, while the firing of CA1 and CA3 place cells was monitored continuously. The first finding was that all place cells that were detected at the beginning of the recording sessions ceased to produce location-specific firing in their original firing fields within 2-12 h. This was observed despite the fact that the animals kept visiting the original firing fields, the hippocampal EEG was virtually unchanged, and the discriminated action potentials of the cells could be clearly recorded. The second finding was that some complex-spike cells that produced no spatially selective firing pattern at the beginning of the recording sessions developed location-specific discharges within 3-12 h. Thus, place cells can flexibly terminate and develop their spatial firing. even in a fixed environment and during similar behaviors, if that environment is explored continuously for a prolonged period. To explain this phenomenon, a new place-cell theory is outlined. Accordingly, the high-frequency discharges of these neurons may serve to create, under multiple extrahippocampal control and within limited periods, stable engrams for specific spatial sites in the association cortex where the cognitive map probably resides. After the creation of a stable engram, or in the absence of favorable extrahippocampal inputs, place cells may suspend their location-specific firing in the original field, and initiate the processing of another spatial site.

Animals↗

PubMedDate not supplied

Initiating a regional laboratory network.

Wherever we look--on television, in national and local newspapers, or within our own institutions and communities--the biggest issue facing health-care providers is integration. The Clinton plan virtually mandates integrated services, and many individual states are moving ahead rapidly with their own programs. Mandated purchasing alliances will require network services that are focused on cost savings and broad access to the medical system. The incentive to form collaborative medical networks defies our tradition of actively competing for patients and reimbursement dollars. Hospital and physician office laboratories, along with small independent laboratories, face both their greatest challenge and their best opportunity in the changing health-care environment. Those choosing to take up the gauntlet thrown down in the Clinton Administration's commitment to reform will be uniquely positioned to survive and thrive; those who dig their heels firmly into past paradigms will be swept away by the tide of economic change. Whether mandated by law or forged into being by the heat of economic pressure, the formation of integrated care networks positioned to vie for health-care dollars seems inevitable. Some states, including Florida, Washington, and Minnesota, have already passed legislation that anticipates national reform by virtually mandating integrated health-care services. Others are contemplating similar action, and the economic impact is already apparent in a lower-than-projected increase in health-care costs. How can community laboratories position themselves to participate in this rapidly changing environment? Most experts agree that laboratory services must roll themselves into total health-care programs and operate regionally to compete with the national, for-profit conglomerates.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost-Benefit Analysis↗

PubMed1997

Blocking gap junctional intercellular communication in myoblasts inhibits myogenin and MRF4 expression.

Cells rely heavily on cues from their extracellular environment and other cells to coordinate normal physiological processes, and the exchange of molecules via gap junctions has been suggested as on important avenue for cell-cell communication. Gap junctions are found in virtually all mammalian tissues with the notable exception of adult skeletal muscle. However, since functional gap junctions have been detected during the early stages of muscle development, gap junctional intercellular communication (GJIC) may play on important role in myogenesis. In this study, GJIC in normal 16 myoblasts was inhibited using the known blockers l-octanol and beta-glycyrrhetinic acid (beta-GA). Under differentiation promoting conditions, 16 cells fused to form multinucleated myotubes, but when treated with either octanol or beta-GA, no fusion was observed. The expression of two muscle regulatory factors (MRFs), myogenin and MRF4, was examined in both the blocked and control cells. As expected, the activation of both the myogenin and MRF4 genes coincided with the onset of differentiation in the control 16 cells. Neither of these genes were turned on in the blocked cells, even when grown under low serum conditions. This inhibition of differentiation by octanol and beta-GA was reversible, since the activation of both MRF genes as well as myoblast fusion were observed when the blocking medium was replaced with normal differentiating medium. These results suggest that intercellular communication via gap junctions plays an important role in skeletal muscle development and perhaps in the cell signaling events that trigger the activation of muscle-specific MRF genes.

1-Octanol↗

PubMed1988

Lung lamellar body amphiphilic topography: a morphological evaluation using the continuum theory of liquid crystals: I. Closed surfaces: closed spheres, concentric tori, and Dupin cyclides.

The structure and symmetry of the bilayers of in vivo phospholipid lung lamellar bodies is shown to be analogous to thermotropic smectic-A liquid crystals and in vitro lyotropic multilamellar liquid crystalline liposomes. This structural similarity has led us to extend biophysical and geometrical principles that have long been used to predict the layer conformation in these in vitro systems to in vivo lung lamellar bodies. These configurations were demonstrated by electron micrographs of thin sections of rodent, monkey, and human lung lamellar bodies prepared by lipid-retaining embedment procedures. The bilayer configurations in all species were consistent with the two geometries predicted by minimal energy solutions of a continuum theory of liquid crystals subject to the boundary conditions imposed by the amphiphilic nature of lung surfactant lipid: concentric (either closed or partially closed) spheres and Dupin cyclides. These bilayer arrangements in lung lamellar bodies were virtually identical to the bilayer configuration of in vitro multilamellar liposomes. The agreement between the two predicted configurations and our observations shows that multilamellar liquid crystalline bilayer aggregate organization is universal in any aqueous environment.

Animals↗

PubMed1985

Differential regulation of peptide and catecholamine characters in cultured sympathetic neurons.

Mechanisms regulating peptidergic, noradrenergic and cholinergic development were compared in dissociated cell cultures of neonatal rat sympathetic ganglia. The majority of cultured neurons contained at least two neurotransmitters and many neurons contained three or more. These studies were undertaken to determine whether co-existing transmitters were co-ordinately regulated by the environment. Co-culture of sympathetic neurons with ganglion non-neuronal cells increased substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity. Conversely, elimination of non-neuronal cells virtually abolished neuronal expression of substance P and choline acetyltransferase and increased somatostatin and tyrosine hydroxylase. Consequently, under these conditions, somatostatin and tyrosine hydroxylase were similarly regulated, whereas substance P was associated with choline acetyltransferase. By contrast, stimulation of adenylate cyclase or treatment with membrane-permeable adenosine 3',5'-phosphate analogs increased tyrosine hydroxylase and decreased choline acetyltransferase, but had no effect on substance P or somatostatin levels. Moreover, potassium- or veratridine-induced membrane depolarization increased tyrosine hydroxylase but decreased substance P, somatostatin and norepinephrine levels. However, inhibition of neurotransmitter release with magnesium or calcium-free medium prevented the decrease in norepinephrine levels but not the decrease in substance P and somatostatin. Consequently, the effects of membrane depolarization on peptide levels cannot be ascribed to release and subsequent depletion of substance P and somatostatin and must result from decreased net synthesis (synthesis minus catabolism) of the transmitters. Nerve growth-factor treatment also differentially regulated transmitter metabolism; nerve growth factor increased protein-specific activities of tyrosine hydroxylase and choline acetyltransferase but did not increase the protein-specific content of substance P and somatostatin. Quantitative transmitter expression was also influenced by neuron density; increasing density elevated substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity per neuron. Finally, culture of sympathetic neurons in a defined (serum-free) medium also altered some but not all traits, decreasing substance P, somatostatin and choline acetyltransferase without any change in tyrosine hydroxylase.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Virtual and biomolecular screening converge on a selective agonist for GPR30.

Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. We have recently shown that the seven-transmembrane G protein-coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.

Animals↗

PubMed2003

A platform for combining virtual reality experiments with functional magnetic resonance imaging.

How the brain functions during behavioural tasks conducted in virtual reality (VR) remains largely unresolved. This issue is extremely important both in terms of establishing the benefits of VR through basic science, as well as for future optimization of tasks conducted in VR environments. Here, the authors describe their current work to develop a testing platform for conducting VR experiments that can be probed by functional magnetic resonance imaging (fMRI) to measure brain activity. Examples involving human spatial navigation and data glove operation illustrate the technical feasibility of the approach and introduce thought-provoking observations of brain activation patterns. Future research directions for combined use of VR and fMRI are also discussed.

Brain↗

PubMed2001

Plants as de-worming agents of livestock in the Nordic countries: historical perspective, popular beliefs and prospects for the future.

Preparations derived from plants were the original therapeutic interventions used by man to control diseases (including parasites), both within humans and livestock. Development of herbal products depended upon local botanical flora with the result that different remedies tended to develop in different parts of the world. Nevertheless, in some instances, the same or related plants were used over wide geographic regions, which also was the result of communication and/or the importation of plant material of high repute. Thus, the Nordic countries have an ancient, rich and diverse history of plant derived anthelmintic medications for human and animal use. Although some of the more commonly used herbal de-wormers were derived from imported plants, or their products, many are from endemic plants or those that thrive in the Scandinavian environment. With the advent of the modern chemotherapeutic era, and the discovery, development and marketing of a seemingly unlimited variety of highly efficacious, safe synthetic chemicals with very wide spectra of activities, herbal remedies virtually disappeared from the consciousness--at least in the Western world. This attitude is now rapidly changing. There is a widespread resurgence in natural product medication, driven by major threats posed by multi-resistant pest, or disease, organisms and the diminishing public perceptions that synthetic chemicals are the panacea to health and disease control. This review attempts to provide a comprehensive account of the depth of historical Nordic information available on herbal de-wormers, with emphasis on livestock and to provide some insights on potentially rewarding areas of "re-discovery" and scientific evaluation in this field.

Animals↗

PubMed2004

Asked and answered--online: how two medical libraries are using OCLC's QuestionPoint to answer reference questions.

This paper imparts the experiences of two similar but unaffiliated medical libraries that use QuestionPoint, OCLC's collaborative virtual reference product. The authors introduce the major features of QuestionPoint, with particular emphasis on its asynchronous e-mail reference service. After presenting how both libraries have employed this service in their respective environments, the paper examines the quantity and quality of reference questions submitted via QuestionPoint. The types of questions are explicated, and statistical trends are compared.

Cooperative Behavior↗

PubMed2002

Virtual universities--the reality of e-learning?

With the growth of the internet and world wide web new ways of exchanging information are emerging, barriers are being overcome, new partnerships and ways of working are emerging. Amongst the hype is the notion of a Virtual University; it is hype or reality? What are the issues? A description of a University will not just include the programmes that it delivers but would no doubt include research and the academic environment. This paper raises some of the issues for Health Informatics.

Computer-Assisted Instruction↗

PubMedDate not supplied

A database-centric virtual chemistry system.

We describe an Oracle database application for general use within virtual chemistry. The application functions as a central hub and repository for chemical data with interfaces to external calculators. It deals with the general problems of merging data from disparate sources and with scheduling of computational tasks for parallel or sequential execution in a mixed environment. The central database is used for the storage of input, intermediary, and final data as well as for job control. A calculation job is split into distinct tasks, or units of work, which are put in a queue. Tasks are dequeued and handled by specialized calculators. These calculators are in-house or commercial programs for which adaptor modules for connection to the database must be written. Tasks are handled in a transactional fashion, so that uncompleted or failed tasks are left in the queue. This makes the system stable to many types of disturbances. Sorting, filtering, and merging operations are handled by the database itself. Usage is very general, but some specific examples are (1) as a back end for a chemical property calculator Web page, (2) in an automated quantitative structure-activity relationship system, and (3) in virtual screens.

Journal Article↗

PubMed1985

Time resolved fluorescence of bacteriophage Pfl DNA binding protein and its complex with DNA.

The DNA binding protein of the filamentous bacteriophage Pfl exhibits fluorescence from a single tryptophan residue. The location of the emission maximum at 340 nm ist quite common for proteins, but the single lifetime of 7.8 ns is one of the longest yet reported. Protein fluorescence is quenched more efficiently by Cs+ than by I-; the Trp is located in a partially exposed pocket, in the vicinity of a negative charge. In the native complex of the binding protein with Pfl DNA the fluorescence emission maximum is at 330 nm, indicating a more apolar environment for Trp 14. The native nucleoprotein complex exhibits a similar fluorescence lifetime (6.5 ns) and an approximately equal fluorescence yield, indicating the absence of Trp-DNA stacking. The tryptophan in the complex is virtually inaccessible to ionic quenchers, and thus appears to be buried. Fluorescence depolarisation measurements have been used to examine the rotational mobility of the tryptophan in the protein and in the nucleoprotein complex. In the protein alone a single rotational correlation time (phi) of approximately 19 ns is observed, corresponding to rotation of the entire dimeric molecule; in the native nucleoprotein complex with Pfl DNA, a phi of approximately 500 ns is observed, corresponding to a rigid unit of at least 50 subunits. In neither case does the tryptophan exhibit any detectable flexibility on the subnanosecond time scale.

Bacteriophages↗

PubMed2004

Olfactory receptors.

Olfaction is an ancient sensory system allowing an organism to detect chemicals in its environment. The first step in odor transduction is mediated by binding odorants to olfactory receptors (ORs) which belong to the heptahelical G-protein-coupled receptor (GPCR) superfamily. Mammalian ORs are disposed in clusters on virtually all chromosomes. They are encoded by the largest multigene family (approximately 1000 members) in the genome of mammals and Caenorhabditis elegans, whereas Drosophila contains only 60 genes. Each OR specifically recognizes a set of odorous molecules that share common molecular features. In mammals, signal transduces through the G-protein-dependent signal pathway in the olfactory sensory neurons that synapse ultimately in the glomeruli of the olfactory bulb, and is finally processed in higher brain structures. The expression of a given OR conditions neuron and glomerulus choices. To date, the processes which monitor OR expression and axon wiring have emerged but are not completely elucidated.

Animals↗

PubMed1990

Solubility properties of the alkylmethylglucamide surfactants.

The critical micelle concentration (CMC) and the ability to solubilize and form vesicles from phospholipids are important criteria for the selection of a surfactant for reconstitution protocols. The CMC and its temperature dependence were determined for an homologous series of alkylmethylglucamides (MEGA-8, MEGA-9, MEGA-10). Each detergent was added continuously from a concentrated solution to a saline buffer with the environment-sensitive fluorescent probe ANS, held in a thermojacketed cuvette; ANS fluorescence increases at the CMC. The CMCs at 25 degrees C were 51.3, 16.0 and 4.8 mM for MEGA-8, MEGA-9 and MEGA-10. The free energy change for transfer to a micellar environment per -CH2- was -740 cal/mol, similar to other alkyl series. The CMCs decreased slightly with increasing temperature (T = 5-40 degrees C) for MEGA-9 and MEGA-10 while that of MEGA-8 was virtually insensitive to temperature in this range. MEGA-9 solubilization of egg PC in aqueous solutions was determined as a function of [PC] and temperature. The lamellar-micellar phase boundaries were determined by simultaneous 90 degrees light scattering and the resonance energy transfer using the headgroup labeled lipid probes NBD-PE and Rho-PE. The [MEGA-9] at solubilization was linear with [PC]; the MEGA-9 to egg PC ratio in the structures at optical clarity was 2.3 while the monomeric [MEGA-9] was 14.3 mM or slightly lower than the CMC at 25 degrees C. Solubilization of egg PC by MEGA-9 was somewhat more temperature-dependent than the CMC of this detergent. Vesicles formed from MEGA-9 tended to be multilamellar. MEGA-9 is clearly different from octyl glucoside, despite its chemical similarity, in terms of its temperature sensitivity and vesicle forming characteristics.

Fatty Acids↗

PubMed2004

The perceptual support of goal-directed displacement is context-dependent.

This study investigates the perceptual-motor organisation underlying the control of goal-directed displacement. We used a virtual reality set-up to study the locomotor interception of a moving ball. Subjects had to intercept moving balls by modifying displacement velocity if necessary, while the ball's place of arrival and the environment were manipulated. The results showed that subjects simultaneously managed multiple sources of information and placed priority on the most salient variables, depending on the task and environmental constraints.

Goals↗

PubMedDate not supplied

Impact of ovarian stimulation on corpus luteum function and embryonic implantation.

The luteal phase has been found to be defective in virtually all the stimulation protocols used in in-vitro fertilization (IVF), indicating that common mechanisms might be involved despite the use of different drugs. A normal luteal phase is characterised by a normal hormonal environment, normal progesterone secretion by the corpus luteum and adequate endometrial secretory transformation. Luteinizing hormone supports the corpus luteum and luteal luteinizing hormone (LH) levels have been found to be reduced in human menopausal gonadotrophin (HMG), gonadotrophin-releasing hormone (GnRH)-agonist/HMG and GnRH-antagonist/HMG protocols, probably leading to an insufficient corpus luteum function. Supraphysiological steroid serum concentrations routinely observed in stimulated cycles may adversely affect LH secretion and induce a luteal-phase defect. In turn, these high steroid serum concentrations may advance early luteal-phase endometrial development leading to embryo-endometrial asynchrony and decreased pregnancy rates in IVF cycles.

Chorionic Gonadotropin↗

PubMed2002

Optimization of bacteriorhodopsin for bioelectronic devices.

Bacteriorhodopsin (BR) is the photoactive proton pump found in the purple membrane of the salt marsh archaeon Halobacterium salinarum. Evolution has optimized this protein for high photochemical efficiency, thermal stability and cyclicity, as the organism must be able to function in a hot, stagnant and resource-limited environment. Photonic materials generated via organic chemistry have yet to surpass the native protein in terms of quantum efficiency or cyclicity. However, the native protein still lacks the overall efficiency necessary for commercial viability and virtually all successful photonic devices using bacteriorhodopsin are based on chemical or genetic variants of the native protein. We show that genetic engineering can provide significant improvement in the device capabilities of proteins and, in the case of bacteriorhodopsin, a 700-fold improvement has been realized in volumetric data storage. We conclude that semi-random mutagenesis and directed evolution will play a prominent role in future efforts in bioelectronic optimization.

Bacteriorhodopsins↗

PubMed2006

Nitroxidative, nitrosative, and nitrative stress: kinetic predictions of reactive nitrogen species chemistry under biological conditions.

A freely available Windows-based program, RNSim1A, is utilized to predict metal-independent reactive nitrogen species (RNS) chemistry (oxidation, nitrosation, and nitration) under simulated biological conditions and make the following specific predictions. (1) The peak in oxidative reactions that occurs in vitro with 1:1 fluxes of (*)NO and O(2)(*)(-) does not occur under biological conditions. (2) By far, the quantitatively dominant (92-99.6%) process in vivo is oxidation, compared to nitrosation and nitration. (3) Only five of the many possible RNS reactions involving thiol (glutathione, GSH) and tyrosine are quantitatively important biologically. (4) Under inflammatory conditions, approximately 1% of O(2)(*)(-) reacts with (*)NO to produce ONOO(-), with the remainder reacting with SOD. (5) The dominant reaction of tyrosyl radical is a radical swap with GSH, producing the glutathiyl radical and regenerating tyrosine. (6) Nitrosothiol is formed virtually exclusively via radical recombination (RS(*) + (*)NO) as opposed to reaction with nitrous anhydride (N(2)O(3)). (7) Nitrosothiol is an intermediate, not an endproduct, and responds dynamically to changes in the immediate chemical environment. (8) The formation of a nitroso group on a particular thiol can be considered a marker of increased reactivity of that thiol, and it is likely that other modifications of that thiol (oxidation, glutathiolation) are more abundant than nitrosation and may be the functionally significant modification. (9) Specific chemical mechanisms are proposed for posttranslational protein modification via nitrosation, nitration, glutathiolation, and also dithiol/disulfide exchange, with important roles for the thiolate anion and O(2) (suggesting possible mechanisms for O(2) sensing) and variable degrees of exposure of cysteine thiol and tyrosine phenolate. (10) Patterns of reactivity are similar for low (20 nM) and high (500 nM) steady-state levels of NO. (11) The dominant reactions are those involving reactants at the highest concentrations (CO(2), thiol, O(2)). Because of the dominance of oxidative processes caused by RNS, the term nitroxidative stress is proposed, emphasizing the oxidative (as opposed to nitrosative or nitrative) stress that dominates RNS actions under biological conditions.

Kinetics↗