Scott Feldman

Pain, negative mood, and perceived support in chronic pain patients: a daily diary study of people with reflex sympathetic dystrophy syndrome.

Chronic pain patients show substantial psychological distress, including depressed mood, anxiety, and anger. Nevertheless, the causal role of negative mood in the course of chronic pain conditions remains unclear. This study prospectively investigated the relationship between daily pain, negative mood, and social support in 109 people with reflex sympathetic dystrophy syndrome. Participants completed 28 daily diaries that included questions about pain, mood, and perceived support. Time-lagged within-subject analyses indicated that pain led to increases in depressed, anxious, and angry mood. Depressed mood, but not anxiety or anger, contributed to increases in pain. Perceived support had both main and buffering (interaction) effects on negative mood and a main effect on pain.

Three-dimensional architecture of the IgH locus facilitates class switch recombination.

Immunoglobulin (Ig) class switch recombination (CSR) is responsible for diversification of antibody effector function during an immune response. This region‐specific recombination event, between repetitive switch (S) DNA elements, is unique to B lymphocytes and is induced by activationinduced deaminase (AID). CSR is critically dependent on transcription of noncoding RNAs across S regions. However, mechanistic insight regarding this process has remained unclear. New studies indicate that long‐range intrachromosomal interactions among IgH transcriptional elements organize the formation of the S/S synaptosome, as a prerequisite for CSR. This three‐dimensional chromatin architecture simultaneously brings promoters and enhancers into close proximity to facilitate transcription. Here, we recount how transcription across S DNA promotes accumulation of RNA polymerase II, leading to the introduction of activating chromatin modifications and hyperaccessible chromatin that is amenable to AID activity.

Chronic Airway Inflammation Provides a Unique Environment for B Cell Activation and Antibody Production

B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways.

Constraints Contributed by Chromatin Looping Limit Recombination Targeting during Ig Class Switch Recombination

Engagement of promoters with distal elements in long-range looping interactions has been implicated in regulation of Ig class switch recombination (CSR). The principles determining the spatial and regulatory relationships among Igh transcriptional elements remain poorly defined. We examined the chromosome conformation of C region (CH) loci that are targeted for CSR in a cytokine-dependent fashion in mature B lymphocytes. Germline transcription (GLT) of the γ1 and ε CH loci is controlled by two transcription factors, IL-4–inducible STAT6 and LPS-activated NF-κB. We showed that although STAT6 deficiency triggered loss of GLT, deletion of NF-κB p50 abolished both GLT and γ1 locus:enhancer looping. Thus, chromatin looping between CH loci and Igh enhancers is independent of GLT production and STAT6, whereas the establishment and maintenance of these chromatin contacts requires NF-κB p50. Comparative analysis of the endogenous γ1 locus and a knock-in heterologous promoter in mice identified the promoter per se as the interactive looping element and showed that transcription elongation is dispensable for promoter/enhancer interactions. Interposition of the LPS-responsive heterologous promoter between the LPS-inducible γ3 and γ2b loci altered GLT expression and essentially abolished direct IgG2b switching while maintaining a sequential μ→γ3→γ2b format. Our study provides evidence that promoter/enhancer looping interactions can introduce negative constraints on distal promoters and affect their ability to engage in germline transcription and determine CSR targeting.

53BP1 Contributes to Igh Locus Chromatin Topology during Class Switch Recombination

In B lymphocytes, Ig class switch recombination (CSR) is induced by activation-induced cytidine deaminase, which initiates a cascade of events leading to DNA double-strand break formation in switch (S) regions. Resolution of DNA double-strand breaks proceeds through formation of S–S synaptic complexes. S–S synapsis is mediated by a chromatin loop that spans the C region domain of the Igh locus. S–S junctions are joined via a nonhomologous end joining DNA repair process. CSR occurs via an intrachromosomal looping out and deletion mechanism that is 53BP1 dependent. However, the mechanism by which 53BP1 facilitates deletional CSR and inhibits inversional switching events remains unknown. We report a novel architectural role for 53BP1 in Igh chromatin looping in mouse B cells. Long-range interactions between the Eμ and 3′Eα enhancers are significantly diminished in the absence of 53BP1. In contrast, germline transcript promoter:3′Eα looping interactions are unaffected by 53BP1 deficiency. Furthermore, 53BP1 chromatin occupancy at sites in the Igh locus is B cell specific, is correlated with histone H4 lysine 20 marks, and is subject to chromatin spreading. Thus, 53BP1 is required for three-dimensional organization of the Igh locus and provides a plausible explanation for the link with 53BP1 enforcement of deletional CSR.

Using computer simulations to investigate individual differences: a look at an addition retrieval model

Abstract In this article the use of computer simulations as a research tool to investigate individual differences in performance will be discussed and illustrated. A computer simulation of the retrieval of addition facts is presented. The goal of this presentation is to illustrate the level of specificity of describing assumptions that goes into constructing a simulation model and the implications and understanding of individual differences in performance that can be derived from such simulation attempts.

S region sequence, RNA polymerase II, and histone modifications create chromatin accessibility during class switch recombination

1. 1. Wang, 2. et al . 2009. J. Exp. Med. doi: 10.1084/jem.20081678 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.20081678%26rft_id%253Dinfo%253Apmid%252F19596805%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%