Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity

A randomized controlled trial to prevent glycemic relapse in longitudinal diabetes care: Study protocol (NCT00362193)

BACKGROUND: Diabetes is a common disease with self-management a key aspect of care. Large prospective trials have shown that maintaining glycated hemoglobin less than 7% greatly reduces complications but translating this level of control into everyday clinical practice can be difficult. Intensive improvement programs are successful in attaining control in patients with type 2 diabetes, however, many patients experience glycemic relapse once returned to routine care. This early relapse is, in part, due to decreased adherence in self-management behaviors. OBJECTIVE: This paper describes the design of the Glycemic Relapse Prevention study. The purpose of this study is to determine the optimal frequency of maintenance intervention needed to prevent glycemic relapse. The primary endpoint is glycemic relapse, which is defined as glycated hemoglobin greater than 8% and an increase of 1% from baseline. METHODS: The intervention consists of telephonic contact by a nurse practitioner with a referral to a dietitian if indicated. This intervention was designed to provide early identification of self-care problems, understanding the rationale behind the self-care lapse and problem solve to find a negotiated solution. A total of 164 patients were randomized to routine care (least intensive), routine care with phone contact every three months (moderate intensity) or routine care with phone contact every month (most intensive). CONCLUSION: The baseline patient characteristics are similar across the treatment arms. Intervention fidelity analysis showed excellent reproducibility. This study will provide insight into the important but poorly understood area of glycemic relapse prevention

Mechanisms Establishing TLR4-Responsive Activation States of Inflammatory Response Genes

Precise control of the innate immune response is required for resistance to microbial infections and maintenance of normal tissue homeostasis. Because this response involves coordinate regulation of hundreds of genes, it provides a powerful biological system to elucidate the molecular strategies that underlie signal- and time-dependent transitions of gene expression. Comprehensive genome-wide analysis of the epigenetic and transcription status of the TLR4-induced transcriptional program in macrophages suggests that Toll-like receptor 4 (TLR4)-dependent activation of nearly all immediate/early- (I/E) and late-response genes results from a sequential process in which signal-independent factors initially establish basal levels of gene expression that are then amplified by signal-dependent transcription factors. Promoters of I/E genes are distinguished from those of late genes by encoding a distinct set of signal-dependent transcription factor elements, including TATA boxes, which lead to preferential binding of TBP and basal enrichment for RNA polymerase II immediately downstream of transcriptional start sites. Global nuclear run-on (GRO) sequencing and total RNA sequencing further indicates that TLR4 signaling markedly increases the overall rates of both transcriptional initiation and the efficiency of transcriptional elongation of nearly all I/E genes, while RNA splicing is largely unaffected. Collectively, these findings reveal broadly utilized mechanisms underlying temporally distinct patterns of TLR4-dependent gene activation required for homeostasis and effective immune responses

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The Relationship Between Student Textbook Preferences and Learning and Grade Orientations

Introductory psychology is one of the most populated courses in psychology departments nationally. Given this important learning opportunity for so many students, it would be beneficial to understand how textbook use is related to student attitudes about learning and grades. A key question of interest was to understand how student preferences for textbooks are related to their learning orientation and grade orientation. Once enrolled in our study, students were provided a link to an online Qualtrics survey where the textbook preferences were provided. In addition, students completed the LOGO to measure orientation (Milton, Pollio, & Eison, 1982) as well as other demographic items. LOGO results were correlated with each of the 9 subscales yielded by the textbook preferences instrument. Our interest was in those subscales in which there were positive correlations for both learning oriented attitudes and grade oriented attitudes. By identifying this pattern of results, we can better understand those factors that most widely appeal to a greater number of students. For each of the following subscales, we provide the correlation coefficient for the learning oriented attitudes (LOA) score and the grade oriented attitudes (GOA) score, respectively: like the book due to applicability and convenience, 0.41, 0.28; like the book due to its accessibility, 0.22, 0.24; use book for study aids, 0.39, 0.28; use book because of instructor use, 0.24, 0.19; use book because it is easy to use, 0.44, 0.38. All correlations were significant at p ≤ .01. Based on the results of this research, a textbook which encompasses the five key factors from above is more likely to appeal to a greater number of students; developers of introductory psychology textbooks may want to hold these five subscales ideas as paramount as they think about how to reach the widest number of students

Dialogue or Narrative? Exploring Tensions between Interpretations of Genesis 38

We examine dialectical tensions between “dialogue” and “narrative” as these discourses supplant one another as the fundamental discourse of intelligibility, through juxtaposing two interpretations of Genesis 38 rooted in changing interpretative paradigms. Is dialogue properly understood as a narrative genre, or is narrative the content about which people are in dialogue? Is the divine–human relationship a narrative drama or is it a dialogue between a god and human beings? We work within parameters laid out by the philosophical hermeneutics of Gadamer (primarily representing dialogue) and Ricoeur (primarily representing narrative). On the one hand, a feminist approach can develop Tamar as a courageous hero in impossible circumstances, strategizing to overturn Judah’s patriarchal naïveté. On the other hand, Judah seems to be able to be read as a tragic hero, seeking to save Tamar. These readings challenge one another, where either Tamar’s or Judah’s autonomy is undermined. By putting these interpretations into dialogue, our aim is to show that neither dialogue nor narrative succeeds the other with finality, and that we can achieve a fragile integration of the two (dialogue and narrative) despite their propensity toward polarization

Assessments of Textbook Usage and the Relationship to Student Course Performance

The authors conducted two studies regarding student textbook preferences; the first developed an original measurement tool (the Collegiate Student Assessment of Textbooks [CSAT]), including an examination of the relationship between student textbook preferences with learning- and grade-oriented attitudes. The second study was a large-scale national study administering the CSAT and the Textbook Assessment and Usage Scale (TAUS; Gurung and Martin 2011) to introductory psychology students; a portion of the study includes actual student course performance data. CSAT and TAUS subscale comparisons indicate (a) converging validity, (b) significant relationships to percentage of textbook read, and (c) relationships between GPA and expected course grades. An indirect link appears between the effect of pedagogical aids, percentage of textbook read, and actual course outcomes. The authors discuss a possible moderating variable and the potential benefits from continued study of textbook pedagogical aids and student performance

Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4.

Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity