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)

Success in online and blended courses requires engaging in self-regulated learning, 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 college introductory level physics course taught online. Students’ achievement goal orientation was measured by repeated administration of the achievement goals questionnaire-revised. Students’ SRL behavior was measured by analyzing their clickstream event traces interacting with online learning modules via a 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 traces via process 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)

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)

Catalexis was the subject of an important recent article by L. P. E. Parker. There is one particular aspect of it that she does not touch, and that ought not to be left out of account: its presumable Indo-European origins. Consideration of this aspect leads to the drawing of distinctions which otherwise tend to escape notice.

Drawing on conservation of resources theory, we contribute to the behavioral ethics literature by examining how and why organizational socialization processes can affect newcomers’ adoption of unethical behaviors. Specifically, we contend that quality peer coaching provides newcomers with enhanced self-resources that diminishes emotional exhaustion and thus indirectly reduces newcomer unethical conduct. Conversely, peer coach unethical conduct increases newcomers’ emotional exhaustion, and thus indirectly increases newcomers’ own unethical acts. Our research also identifies newcomers’ goal orientations as important individual differences that moderate (...) the proposed mediation effects. Newcomers with high mastery orientations respond to high emotional exhaustion by harnessing more resources and identifying new work strategies, thereby engaging in less unethical conduct. Conversely, newcomers with high performance orientations give into emotional exhaustion and engage in unethical conduct as a way of outperforming others while conserving resources. We tested our theoretical model using a sample of peer coaches and newcomers from the Real Estate industry, using objective reporting of peer coaches’ and newcomers’ unethical conduct over a nine-month period. (shrink)

Pickering & Garrod's (P&G's) integrated model of production and comprehension includes no explicit role for nonlinguistic cognitive processes. Yet, how domain-general cognitive functions contribute to language processing has become clearer with well-specified theories and supporting data. We therefore believe that their account can benefit by incorporating functions like working memory and cognitive control into a unified model of language processing.

The work of many scholars in the last hundred years has helped us to understand the nature and origins of the treatise which we know for short as the Contest of Homer and Hesiod. The present state of knowledge may be summed up as follows. The work in its extant form dates from the Antonine period, but much of it was taken over bodily from an earlier source, thought to be the Movaelov of Alcidamas. Some of the verses exchanged in (...) the contest were current even earlier, and some scholars have supposed that the story of a contest went back to the fifth, sixth, or even eighth century; but this is now much doubted. (shrink)