Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury. Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived (...) from lipopolysaccharide. Additionally, -naltrexone, -naloxone, and -naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by -naloxone and -naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists -naloxone and -naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with -naloxone is of potential clinical relevance. This is because -naloxone is an antagonist that is inactive at the -opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that -opioid antagonists such as -naloxone may be useful clinically to suppress glial activation, yet -opioid agonists suppress pain. (shrink)

While N6‐methyladenosine (m6A) is a well‐known epigenetic modification in bacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well‐studied 5‐methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction‐modification and counter‐restriction systems. On at least four to five instances, these methyltransferases were recruited as RNA methylases. Thus, (...) m6A marks in eukaryotic DNA and RNA might be more widespread and diversified than previously believed. Several m6A‐binding protein domains from prokaryotes were also acquired by eukaryotes, facilitating prediction of potential readers for these marks. Further, multiple lineages of the AlkB family of dioxygenases have been recruited as m6A demethylases. Although members of the TET/JBP family of dioxygenases have also been suggested to be m6A demethylases, this proposal needs more careful evaluation. (shrink)

Previous studies have identified the critical role of the left fusiform cortex in visual word form processing, learning, and memory. However, this so-called visual word form area's other functions are not clear. In this study, we used fMRI and the subsequent memory paradigm to examine whether the putative VWFA was involved in the processing and successful memory encoding of faces as well as words. Twenty-two native Chinese speakers were recruited to memorize the visual forms of faces and Chinese words. Episodic (...) memory for the studied material was tested 3. h after the scan with a recognition test. The fusiform face area and the VWFA were functionally defined using separate localizer tasks. We found that, both within and across subjects, stronger activity in the VWFA was associated with better recognition memory of both words and faces. Furthermore, activation in the VWFA did not differ significantly during the encoding of faces and words. Our results revealed the important role of the so-called VWFA in face processing and memory and supported the view that the left mid-fusiform cortex plays a general role in the successful processing and memory of different types of visual objects. © 2010 Elsevier Inc. (shrink)

There are differences in caregivers’ literacy and health literacy levels that may affect their ability to consent to children participating in clinical research trials. This study aimed to explore the effectiveness, and caregivers’ understandings, of the process of informed consent that accompanied their child’s participation in a dental randomized control trial (RCT). Telephone interviews were conducted with a convenience sample of ten caregivers who each had a child participating in the RCT. Pre-tested closed and open-ended questions were used, and the (...) findings were produced from an inductive analysis of the latter and a descriptive analysis of the former. Participants had limited understanding of the purpose of the RCT and rated the readability of the consent form more highly than they rated their understanding of the research. All felt that informed consent was vital, but some caregivers had not read the consent documents. Some caregivers enrolled their child in the RCT because they trusted the researchers, and the majority wanted to improve dental care for children. The informed consent process was not always effective despite high readability of the informed consent documents. Researchers must consider the health literacy of the study group, and actively engaging with caregivers to achieve meaningful informed consent may be challenging. Future research could explore participants’ perspectives of informed consent in populations with low health literacy and assess whether an underlying expectation not to comprehend health-related information may be a barrier to informed consent. (shrink)

© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the frequency (...) of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (shrink)

The hematopoietic system consists of more than ten differentiated cell types, all of which are derived from a single type of hematopoietic stem cell. The accessibility and interest of this system have made it a model for understanding normal and abnormal differentiation of mammalian cells. Newer techniques have generated a mass of data that requires integrative approaches for analysis and interpretation. The traditional view of the differentiation program holds that a small number of regulators are involved in each stage of (...) cell specification. However, this may not be the case. Recent analyses have shown that almost all substantial subsets of genes, including the set of broadly expressed transcription factors, are expressed in patterns that are unique for each lineage. Further, much of this difference between lineages can be captured in two‐dimensional graphs. Understanding the biologic significance, mechanisms and constraints underlying these differences is a challenge for experimentalists and computational biologists alike. BioEssays 26:1276–1287, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

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Success in online and blended courses requires engaging in self-regulated learning (SRL), especially for challenging STEM disciplines, such as physics. This involves students planning how they will navigate course assignments and activities, setting goals for completion, monitoring their progress and content understanding, and reflecting on how they completed each assignment. Based on Winne & Hadwin’s COPES model, SRL is a series of events that temporally unfold during learning, impacted by changing internal and external factors, such as goal orientation and content (...) difficulty. Thus, as goal orientation and content difficulty change throughout a course, so might students’ use of SRL processes. This paper studies how students’ SRL behavior and achievement goal orientation change over time in a large (N = 250) college introductory level physics course taught online. Students’ achievement goal orientation was measured by repeated administration of the achievement goals questionnaire-revised (AGQ-R). Students’ SRL behavior was measured by analyzing their clickstream event traces interacting with online learning modulesviaa combination of trace clustering and process mining. Event traces were first divided into groups similar in nature using agglomerative clustering, with similarity between traces determined based on a set of derived characteristics most reflective of students’ SRL processes. We then generated causal nets for each cluster of tracesviaprocess mining and interpreted the underlying behavior and strategy of each causal net according to the COPES SRL framework. We then measured the frequency at which students adopted each causal net and assessed whether the adoption of different causal nets was associated with responses to the AGQ-R. By repeating the analysis for three sets of online learning modules assigned at the beginning, middle, and end of the semester, we examined how the frequency of each causal net changed over time, and how the change correlated with changes to the AGQ-R responses. Results have implications for measuring the temporal nature of SRL during online learning, as well as the factors impacting the use of SRL processes in an online physics course. Results also provide guidance for developing online instructional materials that foster effective SRL for students with different motivational profiles. (shrink)

Mishel Fuco not only influenced the consciousness of modern West, but changed the modus of thinking, the way of perception of many traditional notions, transformed the opinions about the reality, history, person. Philosopher’s principle research programme which attaches the entirety to his works is “archeology of knowledge” programme, the search of human knowledge’s original layers. Let us mark that all Fuco’s works in 1960s are devoted to main aim: to clear up the conditions of historical origin of different mental aims (...) and social institutions in the culture of the Modern Time. Though in the whole this common aim remained for Fuco invariable, but the level on which he realizes his research search is changing constantly and rather logically. Relations of power, and to be more exact,accumulations of power and knowledge, social and cognitive which define all the aggregate of specific possibilities of culture in each given historical period. More than that the philosopher offers the particular prospects of sight of modern society and precisely totality of power relations, its ubiquitous nature and specific productivity which produces itself in each moment in any point or rather in any attitude from one point to another. From Fuco’s point of view the power is everywhere and not because it involves everything but because it comes from everywhere. The power is productive in that degree in which it is not associated with one definite imperious instance but pierces all kinds of activity in society, putting on its indelible stamp, developing under definite angle and due to this factit causes products, produced by them. The power induces and at the same time determines the fact which appears as a result of its inducement. The thirst of supremacy, which surrounds the individual and is focused on it as on the center of its use of force, comes out as a defining sign. It should be noticed that Fuco’s conception of power is not reduced to the understanding it as anonymous impersonal net of relations, piercing all society. It is supplemented by power treatment,coming out in “designed” look of definite imperious structure or imperious institute. (shrink)

The best-interests standard is a widely used ethical, legal, and social basis for policy and decision-making involving children and other incompetent persons. It is under attack, however, as self-defeating, individualistic, unknowable, vague, dangerous, and open to abuse. The author defends this standard by identifying its employment, first, as a threshold for intervention and judgment (as in child abuse and neglect rulings), second, as an ideal to establish policies or prima facie duties, and, third, as a standard of reasonableness. Criticisms of (...) the best-interests standard are reconsidered after clarifying these different meanings. (shrink)

In many ways the twentieth century was a turning point in the history of mankind. Rebellious social forces defied any reasonable explanation. Philosophical theories of society that had previously been considered true turned out to be inapplicable to the analysis of new historical processes. To an even greater extent than before, religion began to be used by its ministers in the service of corporate and political interests. The hope of solving the problems of human existence and social development with the (...) help of science was also shaken, for many phenomena of human life and cosmic processes were not amenable to scientific explanation. In spite of the impressive successes of science, which changed the face of the world, a critical, even negative, attitude towards science increasingly took hold of public opinion, for the negative features of the technogenic civilization that science helped to create became more and more visible. There were also cultural crises. Alongside beautiful examples of painting, poetry, literature, music, and architecture, a mass culture ruled by the dark spirit of consumerism, banality, and violence sprang up and entrenched itself. The moral sphere is in serious crisis. First the West and, following it, Russia tasted the bitter fruits of the sexual revolution. All of this was the reflection of a deep spiritual crisis that enveloped mankind, a crisis that became obvious in the twentieth century. (shrink)

A veritable cookbook for individuals or corporations seeking funding from the federal government, The Complete Writing Guide to NIH Behavioral Science Grants contains the latest in technical information on NIH grants, including the new electronic submission process. Some of the most successful grant writers in history have contributed to this volume, offering key strategies as well as tips and suggestions in areas that are normally hard to find in grant writing guides, such as budgeting, human subjects, and power analysis. A (...) "who's who" among grant reviewers, this guidebook provides "inside" information as to why some grants are scored well while others flounder during review. A must-read for both entry level grant writers making headway in the complex NIH grant system for the first time as well as more seasoned investigators who can't seem to break the barrier to funded research grants, Drs. Scheier and Dewey's comprehensive volume provides simple and clear explanations into the reasons why some grants get funded, and a step-by-step guide to writing those grants. (shrink)