Disruption of the NF-κB/IκBα Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons

<p>Abstract</p> <p>Background</p> <p>Though originally discovered in the immune system as an important mediator of inflammation, NF-κB has recently been shown to play key roles in the central nervous system, such as synaptogenesis, synaptic plasticity, and cognition. NF-κB activity is normally tightly regulated by its primary inhibitor, IκBα, through a unique autoinhibitory loop. In this study, we tested the hypothesis that the IκBα autoinhibitory loop ensures optimal levels of NF-κB activity to promote proper brain development and function. To do so, we utilized knock-in mice which possess mutations in the IκBα promoter to disrupt the autoinhibitory loop (IκBα^M/MKI mice).</p> <p>Results</p> <p>Here, we show that these mutations delay IκBα resynthesis and enhance NF-κB activation in neurons following acute activating stimuli. This leads to improved cognitive ability on tests of hippocampal-dependent learning and memory but no change in hippocampal synaptic plasticity. Instead, hippocampal neurons from IκBα^M/MKI mice form more excitatory and less inhibitory synapses in dissociated cultures and are hyperexcitable. This leads to increased burst firing of action potentials and the development of abnormal hypersynchronous discharges <it>in vivo</it>.</p> <p>Conclusions</p> <p>These results demonstrate that the IκBα autoinhibitory loop is critical for titrating appropriate levels of endogenous NF-κB activity to maintain proper neuronal function.</p

Development of a clinical risk score for pain and function following total knee arthroplasty: results from the TRIO study

ObjectivesThe aim was to develop and validate a simple clinical prediction model, based on easily collected preoperative information, to identify patients at high risk of pain and functional disability 6 months after total knee arthroplasty (TKA).MethodsThis was a multicentre cohort study of patients from nine centres across the UK, who were undergoing a primary TKA for OA. Information on sociodemographic, psychosocial, clinical and quality-of-life measures were collected at recruitment. The primary outcome measure for this analysis was the Oxford knee score (OKS), measured 6 months postoperatively by postal questionnaire. Multivariable logistic regression was used to develop the model. Model performance (discrimination and calibration) and internal validity were assessed, and a simple clinical risk score was developed.ResultsSeven hundred and twenty-one participants (mean age 68.3 years; 53% female) provided data for the present analysis, and 14% had a poor outcome at 6 months. Key predictors were poor clinical status, widespread body pain, high expectation of postoperative pain and lack of active coping. The developed model based on these variables demonstrated good discrimination. At the optimal cut-off, the final model had a sensitivity of 83%, specificity of 61% and positive likelihood ratio of 2.11. Excellent agreement was found between observed and predicted outcomes, and there was no evidence of overfitting in the model.ConclusionWe have developed and validated a clinical prediction model that can be used to identify patients at high risk of a poor outcome after TKA. This clinical risk score may be an aid to shared decision-making between patient and clinician

Long-term adverse effects and healthcare burden of rectal cancer radiotherapy: systematic review and meta-analysis

BackgroundAs rectal cancer survival increases, more patients survive with potentially severe, long-term gastrointestinal and genitourinary complications from radiotherapy. The burden of these complications for patients and healthcare services is unclear, which this review aims to quantify.MethodsSystematic search of Medline and Embase for randomized-controlled trials (RCTs) and multicentre observational studies published since 2000, reporting hospitalization/procedural intervention for long-term (>6 months post-treatment) gastrointestinal or genitourinary complications after radiotherapy and surgery for rectal cancer. Prevalence values were pooled in a meta-analysis assuming random effects. Organ-preservation patients were excluded.Results4044 records screened; 24 reports from 23 studies included (15 RCTs, 8 Observational), encompassing 15 438 patients. Twenty-one studies (median follow-up 60 months) reported gastrointestinal complications post-radiotherapy: pooled prevalence 11% (95% confidence interval (95% CI) 8–14%). Thirteen reported small bowel obstruction: prevalence 9% (95% CI 6–12%), a 58% increased risk compared with surgery alone (RR 1.58, 95% CI 1.26–1.98, n = 5 studies). Seven reported fistulas: prevalence 1% (95% CI 1–2%). Thirteen reported genitourinary complications: prevalence 4% (95% CI 1–6%); RR 1.10 (95% CI 0.88–1.38, n = 3 studies) compared with surgery alone.ConclusionsOver 10% of patients are hospitalized for long-term complications following rectal cancer radiotherapy. Serious gastrointestinal complications are commonplace; late small bowel obstruction is more common in patients having radiotherapy and surgery compared with surgery alone. Patients and clinicians need to be aware of these risks

Polyubiquitin binding to ABIN1 is required to prevent autoimmunity

The protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappa B (NF-kappa B) essential modulator (NEMO), a component of the inhibitor of NF-kappa B (I kappa B) kinase (IKK) complex. To address the physiological significance of polyubiquitin binding, we generated knockin mice expressing the ABIN1[D485N] mutant instead of the wild-type (WT) protein. These mice developed all the hallmarks of autoimmunity, including spontaneous formation of germinal centers, isotype switching, and production of autoreactive antibodies. Autoimmunity was suppressed by crossing to MyD88(-/-) mice, demonstrating that toll-like receptor (TLR)-MyD88 signaling pathways are needed for the phenotype to develop. The B cells and myeloid cells of the ABIN1[D485N] mice showed enhanced activation of the protein kinases TAK, IKK-alpha/beta, c-Jun N-terminal kinases, and p38 alpha mitogen-activated protein kinase and produced more IL-6 and IL-12 than WT. The mutant B cells also proliferated more rapidly in response to TLR ligands. Our results indicate that the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR-MyD88 pathways and prevent autoimmunity

A quick approach for rheological evaluation of warm asphalt binders using response surface method

This paper describes a quick approach for quantification of the effects of a chemical warm named Rediset, and its interactions with temperature and aging on the rheological properties of asphalt binders using Response Sur-face Method. The central composite method was applied to design experimental programs for three test temperature conditions, namely; very high temperature (120–180 °C), high temperature (46–82 °C), and intermediate temperature (19–31 °C). Rotational viscosity, G*/sin δ and G*sin δ were selected as parameters to assess the effects of the chemical warm additive on the rheological properties of asphalt binders for different aging conditions. Evaluation of the effects of this additive on the transformed value of G*/sin δ at high temperatures indicates that additive content has significant effect on Ln(G*/sin δ). The results for intermediate temperatures show that this additive has a positive effect on G*sin δ of asphalt binders

Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src–mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL

A Survey of Air-to-Ground Propagation Channel Modeling for Unmanned Aerial Vehicles

In recent years, there has been a dramatic increase in the use of unmanned aerial vehicles (UAVs), particularly for small UAVs, due to their affordable prices, ease of availability, and ease of operability. Existing and future applications of UAVs include remote surveillance and monitoring, relief operations, package delivery, and communication backhaul infrastructure. Additionally, UAVs are envisioned as an important component of 5G wireless technology and beyond. The unique application scenarios for UAVs necessitate accurate air-to-ground (AG) propagation channel models for designing and evaluating UAV communication links for control/non-payload as well as payload data transmissions. These AG propagation models have not been investigated in detail when compared to terrestrial propagation models. In this paper, a comprehensive survey is provided on available AG channel measurement campaigns, large and small scale fading channel models, their limitations, and future research directions for UAV communication scenarios