Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome

Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR-Hdac3-deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR-Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome.     

Platelet reactivity in type 2 diabetes mellitus: a comparative analysis with survivors of myocardial infarction and the role of glycaemic control

Patients with type 2 diabetes mellitus exhibit considerable platelet dysfunction, though this is poorly characterized in patients with diabetes taking aspirin for the primary prevention of cardiovascular events. We sought to compare platelet function in this patient population with that of a high-risk group of non-diabetic subjects with a history of previous myocardial infarction (MI), and to assess whether glycaemic control impacts on platelet function. Methods: Platelet aggregation was measured in response to incremental concentrations of five platelet agonists using light transmission aggregometry. All patients were taking aspirin, and aspirin insensitivity was defined as ≥ 20% arachidonic acid (AA) mediated aggregation. Patients with diabetes were divided according to glycaemic control (HbA(1c)): optimal ≤ 6.5, good 6.6-7.4 and suboptimal ≥ 7.5%. Results: In total, 85 patients with type 2 diabetes and 35 non-diabetic patients with previous MI were recruited. Compared to MI patients, diabetes patients had increased aggregation in response to multiple concentrations of epinephrine, collagen, adenosine diphosphate and AA. Aspirin insensitivity was more common in type 2 diabetes (15% vs. 0%, p=0.037). Platelet aggregation was increased in response to several agonists patients with suboptimal glycaemic control compared to patients with optimal control. Aspirin insensitivity was also more common in patients with suboptimal glycaemic control compared to those with good or optimal control (26.0% vs. 8.3% vs. 4%, p=0.04). Conclusion: Patients with type 2 diabetes mellitus, without proven vascular disease, exhibit platelet dysfunction and have increased platelet aggregation and aspirin insensitivity compared to non-diabetic patients with previous MI. Platelet dysfunction in diabetes is more severe in patients with suboptimal glycaemic control.     

The genetics of phaeochromocytoma: using clinical features to guide genetic testing

Phaeochromocytoma is a rare, usually benign, tumour predominantly managed by endocrinologists. Over the last decade, major advances have been made in understanding the molecular genetic basis of adrenal and extra-adrenal phaeochromocytoma (also referred to as adrenal phaeochromocytoma (aPCA) and extra-adrenal functional paraganglioma (eFPGL)). In contrast to the previously held belief that only 10% of cases had a genetic component, currently about one-third of all aPCA/eFPGL cases are thought to be attributable to germline mutations in at least nine genes (NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, MAX and VHL). Recognition of inherited cases of aPCA/eFPGL is critical for optimal patient management. Thus, the identification of a germline mutation can predict risks of malignancy, recurrent disease, associated non-chromaffin tumours and risks to other family members. Mutation carriers should be offered specific surveillance programmes (according to the relevant gene). In this review, we will describe the genetics of aPCA/eFPGL and strategies for genetic testing.     

Cue-Induced Smoking Urges Deplete Cigarette Smokers’ Self-Control Resources

Background

Exposure to smoking-related cues leads to increased urge to smoke in regular cigarette smokers and resisting these urges requires considerable self-control.

Purpose

Adopting a resource depletion model, two studies tested the hypothesis that resisting smoking urges depletes self-control resources.

Methods

Adopting a within-participants randomized cross-over design, participants (study 1, N?=?19; study 2, N?=?32) were exposed to smoking-related (study 1: smoking images; study 2: cigarette cue-exposure task) and neutral (study 1: neutral images; study 2: drinking-straw task) cues with presentation order randomized. After each cue set, participants completed self-control tasks (study 1: handgrip task; study 2: handgrip and Stroop tasks), performance on which constituted dependent measures of self-control.

Results

Self-control task performance was significantly impaired when exposed to smoking-related cues compared to neutral cues. No significant presentation-order effects, or interaction effects between stimulus and presentation order, were found.

Conclusions

Findings corroborate our hypothesis that resisting smoking urges depletes cigarette smokers’ self-control resources and suggests that self-control capacity is governed by a limited resource.     

Improving blood donor recruitment and retention: integrating theoretical advances from social and behavioral science research agendas

BACKGROUND: Increasing blood donor recruitment and retention is of key importance to transfusion services. Research within the social and behavioral science traditions has adopted separate but complementary approaches to addressing these issues. This article aims to review both of these types of literature, examine theoretical developments, identify commonalities, and offer a means to integrate these within a single intervention approach. STUDY DESIGN AND METHODS: The social and behavioral science literature on blood donor recruitment and retention focusing on theory, interventions, and integration is reviewed. RESULTS: The role of emotional regulation (anticipated anxiety and vasovagal reactions) is central to both the behavioral and the social science approaches to enhancing donor motivation, yet although intentions are the best predictor of donor behavior, interventions targeting enactment of intentions have not been used to increase donation. Implementation intentions (that is, if-then plans formed in advance of acting) provide a useful technique to integrate findings from social and behavioral sciences to increase donor recruitment and retention. CONCLUSION: After reviewing the literature, implementation intention formation is proposed as a technique to integrate the key findings and theories from the behavioral and social science literature on blood donor recruitment and retention.