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Papers by Daniel Car

IEEE Visualization, Oct 21, 2001

Recent advances in genomics and related fields have changed our understanding of how biological s... more Recent advances in genomics and related fields have changed our understanding of how biological systems work, and have brought forth new products and therapies. The human genome project, for example, will enable more effective ways of diagnosing and treating many ...

Journal of Biological Chemistry, 2001

We examined the phosphorylation and acetylation of histone H3 in ovarian granulosa cells stimulat... more We examined the phosphorylation and acetylation of histone H3 in ovarian granulosa cells stimulated to differentiate by follicle-stimulating hormone (FSH). We found that protein kinase A (PKA) mediates H3 phosphorylation on serine 10, based on inhibition exclusively by PKA inhibitors. FSH-stimulated H3 phosphorylation in granulosa cells is not downstream of mitogenactivated protein kinase/extracellular signal-regulated kinase, ribosomal S6 kinase-2, mitogen-and stressactivated protein kinase-1, p38 MAPK, phosphatidylinositol-3 kinase, or protein kinase C. Transcriptional activation-associated H3 phosphorylation on serine 10 and acetylation of lysine 14 leads to activation of serum glucocorticoid kinase, inhibin ␣, and c-fos genes. We propose that phosphorylation of histone H3 on serine 10 by PKA in coordination with acetylation of H3 on lysine 14 results in reorganization of the promoters of select FSH responsive genes into a more accessible configuration for activation. The unique role of PKA as the physiological histone H3 kinase is consistent with the central role of PKA in initiating granulosa cell differentiation.

Statistical Mining and Data Visualization in Atmospheric Sciences, 2000

The paper introduces linked micromap (LM) plots for presenting environmental summaries. The LM te... more The paper introduces linked micromap (LM) plots for presenting environmental summaries. The LM template includes parallel sequences of micromap, label, and statistical summary graphics panels with attention paid to perceptual grouping, sorting and linking of the summary components. The applications show LM plots for Omernik Level II Ecoregions. The summarized United States continental data includes USGS digital elevation, 30-year normal

Cell Motility and the Cytoskeleton, 2008

A-kinase anchoring proteins (AKAPs) bind to protein kinase A (PKA) via an amphipathic helix domai... more A-kinase anchoring proteins (AKAPs) bind to protein kinase A (PKA) via an amphipathic helix domain that interacts with a dimerization/docking domain on the regulatory (R) subunit of PKA. Four other mammalian proteins (ROPN1, ASP, SP17, and CABYR) also contain a highly conserved RII dimerization/docking (R2D2) domain, suggesting all four proteins may interact with all AKAPs in a manner similar to RII. All four of these proteins were originally detected in the flagellum of mammalian sperm. In this report, we demonstrate that all four R2D2 proteins are expressed in a wide variety of tissues and three of the proteins SP17, CABYR, and ASP are located in motile cilia of human bronchus and fallopian tubes. In addition, we detect SP17 in primary cilia. We also provide evidence that ROPN1 and ASP bind to a variety of AKAPs and this interaction can be disrupted with anchoring inhibitor peptides. The interaction of SP17 and CABYR with AKAPs appears to be much more limited. None of the R2D2 proteins appears to bind cAMP, a fundamental characteristic of the regulatory subunits of PKA. These observations suggest that R2D2 proteins utilize docking interactions with AKAPs to accomplish their function of regulating cilia and flagella. Based on location, affinity for AKAPs and lack of affinity for cAMP, it appears that each R2D2 protein has a unique role in this process.

Pain, 1999

Recent animal models of experimental nerve injury have proven useful in evaluating potential symp... more Recent animal models of experimental nerve injury have proven useful in evaluating potential sympathetic involvement in neuropathic pain syndromes. We have employed a widely adopted unilateral L 5 /L 6 spinal nerve ligation model to compare the development of mechanical allodynia with neurochemical changes both at the site of peripheral nerve injury and in the dorsal root ganglia (DRG). We have focused on the expression of neuropeptide Y (NPY), a well-studied regulatory peptide and phenotypic marker of sympathetic neurons, and functionally related Y-receptor binding sites following nerve injury. In sympathetic neurons, NPY is colocalized and coreleased with norepinephrine (NE) at peripheral sites of action. Furthermore, NPY gene expression is induced within the population of medium-and large-diameter DRG neurons of the Ab-fiber class after experimental nerve injury. We therefore hypothesized that concurrent alterations in NPY and NE expression by sympathetic and sensory neurons may be a contributing factor to sympathetically-maintained neuropathic conditions. Animals with unilateral L 5 /L 6 spinal nerve ligation developed mechanical allodynia of the hind paw ipsilateral to the site of injury that persisted until sacrifice at postoperative day 10. A significant induction of preproneuropeptide Y-encoding (PPNPY) mRNA, as detected by in situ hybridization histochemistry (ISHH), occurred in populations of medium-and large-diameter DRG neurons ipsilateral to the site of injury. Immunohistochemical analysis indicated a marked decline in the number of labeled sympathetic axons positive for tyrosine hydroxylase-like and NPY-like immunoreactivities (TH-Ll and NPY-LI, respectively) proximal to the site of nerve injury and almost complete elimination of immunopositive fibers distal to the site of ligation. Whereas, the extent of colocalization of NPY-LI to TH-LI-positive sympathetic axons in unaffected L 4 or L 5 nerve segments exceeded 80%, this figure declined to approximately 50% in regenerating axons of ligated spinal nerve L 5. The portion of NPY-LI that was not colocalized to sympathetic TH-LI-positive fibers was most likely contributed by regenerating sensory axons, consistent with marked de novo synthesis of NPY by DRG neurons. In end bulb axon terminals, i.e. morphological profiles characteristic of neuromas, NPY-LI-positive elements that were not colocalized to TH-LI-positive sympathetic elements appeared to be spatially segregated from those of sympathetic origin with colocalized TH-LI and NPY-LI. Receptor autoradiography indicated that smalland medium-diameter DRG somata of the C-fiber class normally express both Y 1 and Y 2 receptor subtypes. The pattern of the distribution of Y-receptor binding sites appeared to be relatively unaffected by spinal nerve ligation. In contrast, there was a marked increase in the density of Y 2 receptor binding sites in the proximal segment of ligated spinal nerve L 5 , consistent with previously published data indicating differential transport of the Y 2 autoregulatory receptor subtype to nerve terminals. Induction of NPY gene expression in injured DRG neurons is consistent with appearance of NPY-LI-positive end bulbs derived from regenerating sensory axons that are found in developing neuromas containing a relatively high density of transported prejunctional Y 2 receptors. Newly established functional interactions of spatially segregated sensory-and sympathetically-derived end bulbs in developing neuromas may enhance neuronal hyperexcitability engendered by aberrant electrical activity at the site of injury. Injury-related alterations in the regulatory activities of NPY released within the DRG at somally-distributed Y-receptors may also contribute to the development and/or persistence of symptoms characteristic of sympatheticallymaintained pain. Finally, at later times NPY-mediated modulation of NE release from invading sympathetic axon terminals within the DRG may affect the extent of a 2 receptor-mediated neuronal hyperexcitability associated with neuropathic pain.

Analyst tasks vary substantially from application to application. The tasks often include finding... more Analyst tasks vary substantially from application to application. The tasks often include finding and evaluating patterns in different views of data. Two generic tasks include looking for density patterns (such as contours, ridges and valleys, holes, internal and external domain limits, and outliers) and functional relationships patterns. As we think about representing more than two variables it is reasonable to consider which encodings are most helpful in revealing patterns and their limitations. What was have learned about perceptual accuracy of extraction for a single continuous variables remains or relevance, but of course is not the whole story.

Statistics in Medicine, 2000

This paper describes two interactive templates for representing spatially indexed estimates. Both... more This paper describes two interactive templates for representing spatially indexed estimates. Both templates use a matrix layout of small panels. The ÿrst template, called linked micromap plots, can represent multivariate estimates associated with each spatially indexed study unit. The second template, called conditioned choropleth maps, shows the connection between a dependent variable, as represented in a classed choropleth map, and two explanatory variables. The paper describes the cognitive considerations that motivate the layouts and representation details. The discussion also addresses topics of data quality and access, hypothesis generation, and interactive features such as pan and zoom and dynamic conditioning via sliders. The examples show epidemiological (mortality rates) and environmental (toxic concentrations) applications. Copyright ? 2000 John Wiley & Sons, Ltd.

PLoS Genetics, 2011

Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining... more Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/ proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS-related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.

PharmacoEconomics, 1997

Patient-controlled analgesia (PCA) is the use of a portable infusion pump activated by the patien... more Patient-controlled analgesia (PCA) is the use of a portable infusion pump activated by the patient to inject an analgesic drug intravenously, subcutaneously or epidurally. PCA permits a patient to deliver a small bolus of opioid to achieve prompt relief without over sedation. Use of PCA for pain management is increasing in hospitals and home settings, largely because it can provide equivalent or better analgesia than conventional methods, and patients are more satisfied with its use. This article reports on studies published between January 1984 and December 1995 which considered cost aspects of PCA. Most studies compared the

Pain, 2003

The use of percentage pain reduction is increasingly used to evaluate the effectiveness of pain t... more The use of percentage pain reduction is increasingly used to evaluate the effectiveness of pain treatments, but the degree of agreement between calculated percentage pain reduction (CPPR) as calculated from pre- and post-treatment levels of pain intensity and those reported directly by patients is unknown. Lack of agreement between these two measures could lead to errors in the determination of treatment effectiveness. We aimed to determine the agreement between CPPR and patient-reported percentage pain reduction (PRPPR). Patients with acute or cancer pain were asked to rate their pain intensity on a 0-10 verbal numerical rating scale (NRS) and to estimate the percent pain reduction from baseline pain after analgesic administration. They then received analgesics every 10 min until pain intensity declined to 4/10 or less. To evaluate agreement between CPPR and PRPPR, we computed the concordance correlation coefficient (CCC), which measures both accuracy and precision, and estimated the 95% limits of agreement for the differences between these two measures. 761 adult patients were enrolled. Female, healthy patients with acute pain of severe intensity and high levels of education predominated in the sample. The mean difference between CPPR and PRPPR was -2.6% (95% limits of agreement -12 to 17%). The CCC was 0.56 (accuracy was 0.9 and precision was 0.6). Although CPPR appeared to underestimate PRPPR in the higher range, this trend was not clinically important. The agreement between percentage pain reductions calculated from NRS scores and those estimated by patients did not vary according to gender or age. The good overall agreement between percentage pain reductions calculated from NRS scores and those estimated by patients suggests that these indices may be used interchangeably. The findings of this study extend existing patient-centered pain research and may be applied for the evaluation and comparison of pain treatments.

New England Journal of Medicine, 1981

Medical Intelligence from The New England Journal of Medicine Physical Conditioning Facilitates... more Medical Intelligence from The New England Journal of Medicine Physical Conditioning Facilitates the Exercise-Induced Secretion of Beta-Endorphin and Beta-Lipotropin in Women.

Medicine & Science in Sports & Exercise, 1993

Life Sciences, 2002

The structural similarity between substance P (SP, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH... more The structural similarity between substance P (SP, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2) and Arg/Pro rich bactericidal peptides suggests a possible direct effect of SP on invasive microbes. We now present evidence that substance P possesses direct antimicrobial activity, highest against S. aureus. A substance P antagonist also possesses such activity but while less potent than substance P agonist S. aureus, is more potent than substance P against C. albicans. Our data also show that the endogenous peptides bradykinin and neurotensin, that also play role in modulation of the host-defense system in situ, have antimicrobial properties but are less potent than substance P.

Journal Of Pain & Palliative Care Pharmacotherapy, 2005

Journal Of Pain & Palliative Care Pharmacotherapy, 2001

An international panel of pain specialists including physicians and health policy scholars met to... more An international panel of pain specialists including physicians and health policy scholars met to discuss the impact of fear of opioids on the clinical use of these strong analgesics. Recognizing potential risk from opioids, the panel members concluded that irrational fear of the drugs often impedes their appropriate use. The need for education among clinicians was recognized and the panel concluded that while progress has been made, much remains to be done to correct unfounded fears and misconceptions that impede provision of opioid analgesia when it is indicated.

The Journal of Pain, 2003

Side effects can limit opioid dosage and reduce quality of life. The purpose of this systematic r... more Side effects can limit opioid dosage and reduce quality of life. The purpose of this systematic review was to assess the management of opioid side effects in the context of cancer pain management or, in the event that no evidence was available for cancer pain, for chronic noncancer pain. The side effects studied were constipation, pruritus, nausea and vomiting, myoclonus, sedation, respiratory depression, and delirium. Opioid rotation to manage side effects was also studied. For each side effect, we searched MEDLINE and the Cochrane Controlled Trials Register and identified 657 possible titles for inclusion. Of these, 67 studies met inclusion criteria for analysis. The lack of well-designed, randomized controlled trials and the heterogeneity of populations and study designs made the drawing of firm conclusions difficult and precluded performance of meta-analysis. The type, strength, and consistency of evidence for available interventions to manage opioid side effects vary from strong (eg, on the use of naloxone to reverse respiratory depression or constipation) to weak (eg, changing from the oral to epidural route of morphine administration to manage sedation). Well-designed trials in the specified populations are required to furnish clinicians with secure evidence on managing opioid side effects successfully.

The Journal of Pain, 2005

OBJECTIVES 1) To investigate health status of older (>or=60 years) and younger adults (<60 ... more OBJECTIVES 1) To investigate health status of older (>or=60 years) and younger adults (<60 years) with chronic pain and to separately compare that with existing normative data; and 2) to examine more fully differences in health status between younger and older adults with chronic pain and explore their geographic variation across three multidisciplinary pain programs in the Pacific, Mountain, and New England regions of the United States. DESIGN We performed a cross-sectional analysis. PATIENTS Initial assessments of 6,147 patients dating from January 1998 to January 2003 were used. OUTCOMES MEASURES We used the Treatment Outcomes of Pain Survey (TOPS), a disease-specific instrument that includes the Short Form-36. RESULTS The health status of the older pain patients in terms of their actual scores was comparable with that of younger pain patients across the three sites. Health status is impaired to a lesser degree in older than in younger adults with chronic pain as compared with normative adults. Statistically significant differences were found in a number of domains of the TOPS. Older adults with chronic pain present with pain intensity similar to that of younger patients with chronic pain, but report better mental health (P < 0.002), less fear-avoidance (P < 0.05), less passive coping (P < 0.0001), more life control (P < 0.05), and more lower body physical limitations (P < 0.005) than younger patients with chronic pain. CONCLUSIONS Older adults with chronic pain differ in a number of important domains from younger adults with chronic pain: overall the former present with greater physical, and less psychosocial impairment.

Pain medicine (Malden, Mass.)

IEEE Computer Graphics and Applications, 2002

L ife-science research is increasingly reliant on computation, as affirmed by the recent mapping ... more L ife-science research is increasingly reliant on computation, as affirmed by the recent mapping of the human genome and the analysis questions it poses. Our task is to make sense of these genetic blueprints to develop treatments and therapies for disease. This market is huge, as is the commitment by pharmaceutical companies, biotech firms, and the investment community. The stage is set for scientific discovery and technology advances, the stakes are high, and researchers have many analysis alternatives. The question is whether visualization can be a player in this market and whether it's up to the challenges. This is the question we attempted to answer as panelists at the Visualization 2001 conference. 1 As a group of researchers and practitioners in this burgeoning field, we've noticed three broad problem-solving themes: I the visual integration of analyses, I high-dimensional analytic visualization, and I the emergence of new visualization designs to solve problems. Analytical high-dimensional visualizations, tightly couple analytical substance with high-dimensional visualization. We can think of this new breed of analytical tool as an intelligent computational probe or query. To review a few other key terms before reading further, see the sidebar "Bio-and Cheminformatics."

FEBS Letters, 2010

The myeloid translocation gene (MTG) homologue Nervy associates with PlexinA on the plasma membra... more The myeloid translocation gene (MTG) homologue Nervy associates with PlexinA on the plasma membrane, where it functions as an A-kinase anchoring protein (AKAP) to modulate plexin-mediated semaphorin signaling in Drosophila. Mammalian MTG16b is an AKAP found in immune cells where plexin-mediated semaphorin signaling regulates immune responses. This study provides the first evidence that MTG16b is a dual AKAP capable of binding plexins. These interactions are selective (PlexinA1 and A3 bind MTG, while PlexinB1 does not) and can be regulated by PKA-phosphorylation. Collectively, these data suggest a possible mechanism for the targeting and integration of adenosine 3 0 ,5 0-cyclic monophosphate (cAMP) and semaphorin signaling in immune cells. Structured summary: MINT-7556975: PlexinA3 (uniprotkb:P51805) physically interacts (MI:0915) with MTG 16b (uniprotkb:O75081) by anti tag coimmunoprecipitation (MI:0007) MINT-7557008: RI alpha (uniprotkb:Q9DBC7) physically interacts (MI:0915) with MTG 16b (uniprotkb:O75081) by anti bait coimmunoprecipitation (MI:0006) MINT-7556989: MTG 16b (uniprotkb:O75081) physically interacts (MI:0915) with PlexinA3 (uniprotkb:P51805) by pull down (MI:0096)