IκBɛ provides negative feedback to control NF-κB oscillations, signaling dynamics, and inflammatory gene expression

NF-κB signaling is known to be critically regulated by the NF-κB–inducible inhibitor protein IκBα. The resulting negative feedback has been shown to produce a propensity for oscillations in NF-κB activity. We report integrated experimental and computational studies that demonstrate that another IκB isoform, IκBɛ, also provides negative feedback on NF-κB activity, but with distinct functional consequences. Upon stimulation, NF-κB–induced transcription of IκBɛ is delayed, relative to that of IκBα, rendering the two negative feedback loops to be in antiphase. As a result, IκBɛ has a role in dampening IκBα-mediated oscillations during long-lasting NF-κB activity. Furthermore, we demonstrate the requirement of both of these distinct negative feedback regulators for the termination of NF-κB activity and NF-κB–mediated gene expression in response to transient stimulation. Our findings extend the capabilities of a computational model of IκB–NF-κB signaling and reveal a novel regulatory module of two antiphase negative feedback loops that allows for the fine-tuning of the dynamics of a mammalian signaling pathway

Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways.

The NF-κB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-κB pathway, but as a RelB-p50 dimer regulated by canonical IκBs, IκBα and IκBɛ. IκB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-κB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses

Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20

TNF-induced NF-κB activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two temporal amplification steps—one determined by the obligate negative feedback regulator IκBα—that define the duration of the first phase of NF-κB activity. The second phase is defined by A20, whose inducible expression provides for a rheostat function by which other inflammatory stimuli can regulate TNF responses. Our results delineate the nonredundant functions implied by the knockout phenotypes of iκbα and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Pervasiveness of Parasites in Pollinators

Many pollinator populations are declining, with large economic and ecological implications. Parasites are known to be an important factor in the some of the population declines of honey bees and bumblebees, but little is known about the parasites afflicting most other pollinators, or the extent of interspecific transmission or vectoring of parasites. Here we carry out a preliminary screening of pollinators (honey bees, five species of bumblebee, three species of wasp, four species of hoverfly and three genera of other bees) in the UK for parasites. We used molecular methods to screen for six honey bee viruses, Ascosphaera fungi, Microsporidia, and Wolbachia intracellular bacteria. We aimed simply to detect the presence of the parasites, encompassing vectoring as well as actual infections. Many pollinators of all types were positive for Ascosphaera fungi, while Microsporidia were rarer, being most frequently found in bumblebees. We also detected that most pollinators were positive for Wolbachia, most probably indicating infection with this intracellular symbiont, and raising the possibility that it may be an important factor in influencing host sex ratios or fitness in a diversity of pollinators. Importantly, we found that about a third of bumblebees (Bombus pascuorum and Bombus terrestris) and a third of wasps (Vespula vulgaris), as well as all honey bees, were positive for deformed wing virus, but that this virus was not present in other pollinators. Deformed wing virus therefore does not appear to be a general parasite of pollinators, but does interact significantly with at least three species of bumblebee and wasp. Further work is needed to establish the identity of some of the parasites, their spatiotemporal variation, and whether they are infecting the various pollinator species or being vectored. However, these results provide a first insight into the diversity, and potential exchange, of parasites in pollinator communities

Distinct functions of negative regulators of NF-kappaB

The Nuclear Factor kappaB (NF-$$kappa$$B) signaling pathway is central to cellular responses to a diverse set of stimuli and stresses. It has been shown that much of this pleiotropic capacity is encoded within the activation dynamics of the upstream I$$kappa$$B Kinase (IKK), which acts as a central hub for NF-$$kappa$$B signaling. To account for how regulatory mechanisms impart specific NF- $$kappa$$B dynamics in response to IKK activity, I utilized a multidisciplinary approach that integrated mechanistic mathematical modeling with laboratory experimentation. Herein, I describe four pair wise comparisons between NF- $$kappa$$B inducible IκBα protein, the predominant regulatory mechanism, with others mediated by I$$kappa$$B$$beta$$, I$$kappa$$B$$epsilon$$, I$$kappa$$B$$delta$$ and A20. I$$kappa$$B$$epsilon$$and A20 are shown to primarily regulate the second phase of TNF responsive NF-$$kappa$$B activity by dampening oscillatory behavior and tuning the amplitude, respectively. Differences in inducible synthesis and stimulus-responsive degradation kinetics are determined to impart specific functionalities for I$$kappa$$B$$alpha$$ and I$$kappa$$B$$delta$$ negative feedback in acute/inflammatory versus chronic/pathogenic NF-$$kappa$$B signaling. In the final study, the role of I$$kappa$$B$$beta$$, a constitutive regulator, is delineated as mediating the distribution of RelA/NF-$$kappa$$B dimers in the resting cell but not their dynamics following cellular stimulation. These studies reveal the individual role of each mechanism, and collectively, the sources and functionalities of the emergent systems properties observed in cells in which these regulators act combinatorially

Wireless telesurveillance system for detecting dementia

Objective We hypothesized path tortuosity (an index of casual locomotor variability) measured by a movement telesurveillance system would be suitable for assisted living facility residents clinically diagnosed with dementia. Background We examined the relationship of dementia to path tortuosity and to movement speed and path length variability, both of which increase in dementia. Methods Daytime movements of 25 elders (19 female; 14 with dementia; average age 80.6) were monitored for 30 days using radio transponders measuring location with a maximum accuracy of 20 cm. After 30 days, the Mini Mental State Exam (MMSE) and Revised Algase Wandering Scale-Community Version (RAWS-CV) were administered. Results Fractal Dimension (Fractal D), a measure of path tortuosity, correctly classified all but 2 residents with dementia; sensitivity 0.857, specificity 0.818 while the MMSE had 6 misclassifications, a sensitivity of 0.857 and a specificity of 0.727. Individual logistic regressions of dementia diagnosis on predictors MMSE and Fractal D were significant, but a logistic regression using both predictors found Fractal D marginally predictive of dementia (p=0.055) while the MMSE was not (p=0.168). Although significantly correlated with Fractal D, rate of travel and mean path distance were not predictive of dementia. Fractal D correlated negatively with overall MMSE (r= -0.44, n=25, p \u3c 0.05) but the relationship was mediated by MMSE Geographical Orientation items. Fractal D was unrelated to the RAWS-CV. Conclusions Telesurveillance-measured path tortuosity is greater in persons diagnosed with dementia. Persons with dementia have relatively more impaired spatial memory which is required for successful navigation. Application Automatic monitoring of direction, length and speed of unconstrained movements

Real-Time Locating Systems (RTLS) to Improve Fall Detection

Objective To determine whether a Real Time Locating System (RTLS) can be used to accurately detect a fall and discuss the application of RTLS as a fall detection system in the home and health care environments. Methods Phase I used a mannequin to determine the feasibility of RTLS to detect a fall from three positional conditions of: standing, seated in a wheelchair, and laying on a bed. Phase II used a human subject to be an ecologically valid simulation of a fall from these conditions. Ten trials of each of these three conditions were conducted across subjects. The observed time of the fall (the \u27gold standard\u27) was compared with the RTLS tag position. A Receiver Operating Characteristic (ROC) curve was used to report the Area Under the Curve (AUC) with 95% confidence intervals (CI) and Cohen\u27s kappa (ϰ) was used to examine inter-rater reliability between the observed fall and the fall detected by the RTLS. Results RTLS accurately identified 89% (p\u3c0.001) of the mannequin falls and 80% (p\u3c0.001) of the human falls. Across subjects there were low false positive rates (specificity); 17% for the mannequin and 16% for the human. Interrater reliability was very good (ϰ=0.82; CI: 0.80-0.84) for mannequin falls and good (ϰ =0.72; CI: 0.69-0.74) for human falls. Implications RTLS technology may be used to improve caregiver and staff response times, patient-care, and reduce health care costs associated with falls in later life