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Search Results: 1 - 10 of 330382 matches for " Jeffrey S Mogil "
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Distinguishing between Exploratory and Confirmatory Preclinical Research Will Improve Translation
Jonathan Kimmelman ,Jeffrey S. Mogil,Ulrich Dirnagl
PLOS Biology , 2014, DOI: 10.1371/journal.pbio.1001863
Abstract: Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.
Expression genetics identifies spinal mechanisms supporting formalin late phase behaviors
Xiangqi Li, Peyman Sahbaie, Ming Zheng, Jennifer Ritchie, Gary Peltz, Jeffrey S Mogil, J David Clark
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-11
Abstract: Late phase formalin behavior scores among 10 inbred mouse strains were correlated with a spinal cord gene expression database constructed using expression arrays. Messenger RNA levels for several genes were highly correlated with the late phase behavioral responses. Most of these genes had already been implicated in mechanisms regulating pain and analgesia. One of the most strongly correlated genes, Mapk8 coding for c-Jun N-terminal kinase 1 (JNK1), was chosen for further analysis. Studies using additional strains of mice confirmed that spinal cord mRNA expression levels of Mapk8 followed the pattern predicted by strain-specific levels of formalin behavior. Interestingly, spinal cord JNK1 protein levels displayed an inverse relationship with mRNA measurements. Finally, intrathecal injections of the selective JNK inhibitor, SP600125, selectively reduced late phase licking behavior.Wide differences in pain behaviors, including those resulting from the injection of formalin, can be observed in inbred strains of mice suggesting strong genetic influences. Correlating levels of gene expression in tissues established to be mechanistically implicated in the expression of specific behaviors can identify genes involved in the behaviors of interest. Comparing formalin late phase behavior levels with spinal cord gene expression yielded several plausible gene candidates, including the Mapk8 gene. Additional molecular and pharmacologic evidence confirmed a functional role for this gene in supporting formalin late phase responses.The injection of formalin into the skin of rodent hind paws to cause spontaneous pain-related (nocifensive) behaviors is one of the most commonly used animal pain assays [1]. This test was introduced in 1977 as a method that allowed nocifensive behaviors to be studied without restraint, and with a continuous rather than transient source of stimulation [2]. This model can be distinguished from many other irritant pain models--for example, ones involving th
Imputation of truncated p-values for meta-analysis methods and its genomic application
Shaowu Tang,Ying Ding,Etienne Sibille,Jeffrey S. Mogil,William R. Lariviere,George C. Tseng
Quantitative Biology , 2015, DOI: 10.1214/14-AOAS747
Abstract: Microarray analysis to monitor expression activities in thousands of genes simultaneously has become routine in biomedical research during the past decade. A tremendous amount of expression profiles are generated and stored in the public domain and information integration by meta-analysis to detect differentially expressed (DE) genes has become popular to obtain increased statistical power and validated findings. Methods that aggregate transformed $p$-value evidence have been widely used in genomic settings, among which Fisher's and Stouffer's methods are the most popular ones. In practice, raw data and $p$-values of DE evidence are often not available in genomic studies that are to be combined. Instead, only the detected DE gene lists under a certain $p$-value threshold (e.g., DE genes with $p$-value${}<0.001$) are reported in journal publications. The truncated $p$-value information makes the aforementioned meta-analysis methods inapplicable and researchers are forced to apply a less efficient vote counting method or na\"{i}vely drop the studies with incomplete information. The purpose of this paper is to develop effective meta-analysis methods for such situations with partially censored $p$-values. We developed and compared three imputation methods - mean imputation, single random imputation and multiple imputation - for a general class of evidence aggregation methods of which Fisher's and Stouffer's methods are special examples. The null distribution of each method was analytically derived and subsequent inference and genomic analysis frameworks were established. Simulations were performed to investigate the type I error, power and the control of false discovery rate (FDR) for (correlated) gene expression data. The proposed methods were applied to several genomic applications in colorectal cancer, pain and liquid association analysis of major depressive disorder (MDD). The results showed that imputation methods outperformed existing na\"{i}ve approaches. Mean imputation and multiple imputation methods performed the best and are recommended for future applications.
Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity
Douglas Tsao, Jeffrey S Wieskopf, Naim Rashid, Robert E Sorge, Rachel L Redler, Samantha K Segall, Jeffrey S Mogil, William Maixner, Nikolay V Dokholyan, Luda Diatchenko
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-25
Hypolocomotion, asymmetrically directed behaviors (licking, lifting, flinching, and shaking) and dynamic weight bearing (gait) changes are not measures of neuropathic pain in mice
Jeffrey S Mogil, Allyson C Graham, Jennifer Ritchie, Sara F Hughes, Jean-Sebastien Austin, Ara Schorscher-Petcu, Dale J Langford, Gary J Bennett
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-34
Abstract: We found no deficits in locomotor activity or rearing associated with neuropathic injury. The frequency of asymmetric (ipsilaterally directed) behaviors were too rare to be seriously considered as representing spontaneous pain, and in any case did not statistically exceed what was blindly observed on the contralateral hind paw and in control (sham operated and unoperated) mice. Changes in dynamic weight bearing, on the other hand, were robust and ipsilateral after spared nerve injury (but not chronic constriction injury). However, we observed timing, pharmacological, and genetic dissociation of mechanical allodynia and gait alterations.We conclude that spontaneous neuropathic pain in mice cannot be assessed using any of these measures, and thus caution is warranted in making such assertions.The perception that basic pain research over the last two decades has not always resulted in clinical advances has encouraged reflection as to how animal models of pain may be improved [1]. Proposals include the use of operant instead of reflexive dependent measures [2], the collection of a broader range of measurements besides pain behaviors per se [3], and the measurement of behaviors spontaneously emitted by the rodent subject [4]. The latter is important because in neuropathic pain patients, spontaneous (continuous or paroxysmal) pain is thought to be the most prevalent pain related symptom, the most bothersome, and the most highly correlated with overall pain ratings [5,6]. Whether or not drugs differentially affect spontaneous and stimulus-evoked pain in the clinical setting is a subject deserving of much more attention than it has received (e.g., [7]).Various behaviors following injuries in rodents are purported to be real time measures of spontaneous pain. For example, there are a few published reports of ultrasonic vocalizations during inflammatory pain [8,9], but two systematic investigations including nerve injuries concluded that ultrasonic vocalization is not specifi
The Rat Grimace Scale: A partially automated method for quantifying pain in the laboratory rat via facial expressions
Susana G Sotocinal, Robert E Sorge, Austin Zaloum, Alexander H Tuttle, Loren J Martin, Jeffrey S Wieskopf, Josiane CS Mapplebeck, Peng Wei, Shu Zhan, Shuren Zhang, Jason J McDougall, Oliver D King, Jeffrey S Mogil
Molecular Pain , 2011, DOI: 10.1186/1744-8069-7-55
Abstract: Despite great advances in basic understanding of molecular pain mechanisms and considerable investment by industry, translational achievements in analgesic drug development have been extremely limited. Many believe that the high attrition is due, at least in part, to the poor predictivity of current animal models of pain [1]. As in vivo animal research remains the mainstay of analgesic drug development [2,3], much recent effort has been devoted to reexamining pain testing paradigms in laboratory animals. Of the criticisms directed at the status quo in rodent algesiometry, one of the most common is that the vast majority of preclinical studies measure withdrawal responses to evoking thermal and mechanical stimuli instead of the more clinically important spontaneous pain [4]. Although a number of rodent behaviors are correlated in time with injuries that presumably also produce spontaneous pain, in many cases it has been difficult to demonstrate that these behaviors display specificity and sensitivity as measures of pain [5].Because of the known utility of facial coding scales (based on the facial action coding system; FACS) [6] for the quantification of pain in non-verbal human populations [see [7]], and the prediction by Darwin that nonhuman animals exhibit similar facial expressions to emotional states as do humans [8], we recently developed and characterized the Mouse Grimace Scale (MGS) [9]. It consists of five facial "action units" (orbital tightening, nose bulge, cheek bulge, ear position, and whisker change) scored on a 0-2 scale for their prominence in still photographs taken from digital video of mice in either a baseline or pain condition. We demonstrated that the MGS displays high accuracy and reliability, is useful for quantifying pain of moderate duration (from several minutes to approximately 1 day), is sensitive to detecting weak analgesic effects, and may represent a measure of the animal's affective response to pain [9].The purpose of the present wor
An analysis of NK and generalized NK landscapes
Jeffrey S. Buzas,Jeffrey Dinitz
Computer Science , 2013,
Abstract: Simulated landscapes have been used for decades to evaluate search strategies whose goal is to find the landscape location with maximum fitness. Applications include modeling the capacity of enzymes to catalyze reactions and the clinical effectiveness of medical treatments. Understanding properties of landscapes is important for understanding search difficulty. This paper presents a novel and transparent characterization of NK landscapes. We prove that NK landscapes can be represented by parametric linear interaction models where model coefficients have meaningful interpretations. We derive the statistical properties of the model coefficients, providing insight into how the NK algorithm parses importance to main effects and interactions. An important insight derived from the linear model representation is that the rank of the linear model defined by the NK algorithm is correlated with the number of local optima, a strong determinant of landscape complexity and search difficulty. We show that the maximal rank for an NK landscape is achieved through epistatic interactions that form partially balanced incomplete block designs. Finally, an analytic expression representing the expected number of local optima on the landscape is derived, providing a way to quickly compute the expected number of local optima for very large landscapes.
Green Tea Polyphenols Mediated Apoptosis in Intestinal Epithelial Cells by a Fadd-Dependent Pathway  [PDF]
Helieh S. Oz, Jeffrey L. Ebersole
Journal of Cancer Therapy (JCT) , 2010, DOI: 10.4236/jct.2010.13018
Abstract: Colorectal cancer is the most common malignant complication in patients with chronic inflammatory bowel disease (IBD). In addition, these patients are at risk for developing painful complications during chemotherapy due to cytotoxic effects of drugs currently in use. Past studies have suggested a protective effect of tea consumption on gastrointestinal (GI) malignancies. Green tea polyphenols (GrTP) inhibited carcinogen-induced GI tumors in rodents and induced apoptosis in various carcinoma cell lines. We hypothesized that GrTP and its polyphenolic compounds regulate apoptosis in the intestinal epithelia. In this study, the effects of GrTP and its polyphenolics on apoptosis was evaluated in intestinal epithelial, IEC-6, cells grown to 85% confluency. GrTP (400-800 mg/ml) induced DNA fragmentation in a dose dependent fashion. Higher concentrations (> 800 mg/ml) induced a mixed apoptosis and cytolysis. Epithelial cells exposed to GrTP and a major polyphenol, EGCG, but not EGC or EC, increased caspase activities in a time and dose dependent manner. The caspase inhibitors rescued cells from GrTP and EGCG-induced cell death. Concomitantly, GrTP resulted in activation of fatty acid synthase (Fas)-associated protein with death domain (FADD) and recruitment to Fas/CD95 domain 30 minutes following treatment. While GrTP also blocked NF-?B activation, an NF-?B inhibitor (MG132) only promoted cytolysis. In conclusion, these data demonstrated GrTP and EGCG induced apoptosis in intestinal epithelia mediated by caspase-8 through a FADD dependent pathway. Future investigation may warrant preventive as well as therapeutic strategies for GrTP in GI malignancy.
Do Credit Rating Agencies Sacrifice Timeliness by Pursuing Rating Stability? Evidence from Equity Market Reactions to CreditWatch Events  [PDF]
Jenny Gu, Jeffrey S. Jones, Pu Liu
Theoretical Economics Letters (TEL) , 2014, DOI: 10.4236/tel.2014.45042

In this paper we examine how well CreditWatch is used by credit rating agencies to balance two conflicting goals: rating timeliness and rating stability. Examining equity market reactions around CreditWatch events in 2002-2005, we find evidence that while CreditWatch has improved rating timeliness, its intended purpose has not been completely achieved. Equity prices start to change days before companies are listed on CreditWatch and abnormal equity returns of firms prior to being listed on CreditWatch are effective predictors of the ultimate change in ratings. The findings in the study suggest that in the pursuit of rating stability, rating agencies may have sacrificed rating timeliness.

Black Sun: Ocular Invisibility of Relativistic Luminous Astrophysical Bodies  [PDF]
Jeffrey S. Lee, Gerald B. Cleaver
Journal of High Energy Physics, Gravitation and Cosmology (JHEPGC) , 2016, DOI: 10.4236/jhepgc.2016.24048
Abstract: Considered as a gedanken experiment are the conditions under which the relativistic Doppler shifting of visible electromagnetic radiation to beyond the human ocular range could reduce the incident radiance of the source, and render a luminous astrophysical body (LAB) invisible to a naked eye. This paper determines the proper distance as a function of relativistic velocity at which a luminous object attains ocular invisibility.
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