Molecular connections between nuclear and ciliary import processes

Abstract As an organelle, the cilium contains a unique complement of protein and lipid. Recent work has begun to shed light on the mechanisms that regulate entry of ciliary proteins into the compartment. Here, we focus on the mechanisms that regulate ciliary entry of cytosolic molecules. Studies have revealed a size exclusion mechanism for ciliary entry that is similar to the barrier to nuclear entry. Active import into the ciliary compartment involves nuclear trafficking components including importins, a Ran-guanosine triphosphate gradient, and nucleoporins. Together, this work indicates that nuclei and cilia share molecular, structural and mechanistic components that regulate import into the compartments.http://deepblue.lib.umich.edu/bitstream/2027.42/134547/1/13630_2013_Article_193.pd

Alzheimer's disease pathology:pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD

Preparation for Hollow Cathode Testing for the Advanced Electric Propulsion System at NASA Glenn Research Center

NASA Glenn Research Center is performing activities to support the unique needs of hollow cathode development and testing for the Advanced Electric Propulsion System (AEPS). Three existing vacuum facilities have been outfitted as cathode test facilities, and each will serve a different role in upcoming testing. Vacuum Facility 67 is being developed to serve as a long-duration test facility for the Engineering Development Unit cathode, which is to be delivered by the AEPS contractor. It will feature a thruster-like magnetic field simulator and cold-cycle capability via a liquid nitrogen-cooled cold plate. Vacuum Facility 17 is being developed as a test facility for short- to medium-duration experiments in order to provide auxiliary support for the long-duration testing. It will feature a magnetic field simulator but not cold-cycling. Finally, Vacuum Facility 1 will be a high-pumping speed cathode development environment, and will feature an array of plasma and temperature diagnostics. In addition to the facility preparation work, a new cathode, referred to as the Mark II, has been designed. The Mark II is an evolution of the Technology Demonstration Unit cathodes that better evokes the geometry, fabrication, and construction of the forthcoming Engineering Development Unit. This cathode serves as a transition between the Technology Demonstration Unit cathodes used during early thruster development and the forthcoming Engineering Development Unit cathodes. It will be used as a means of verifying the new test facilities prior to arrival of Engineering Development Unit hardware. Details of the Mark II design and key features are presented, as well as details of future work to be performed

Dynamic concentration of motors in microtubule arrays

We present experimental and theoretical studies of the dynamics of molecular motors in microtubule arrays and asters. By solving a convection-diffusion equation we find that the density profile of motors in a two-dimensional aster is characterized by continuously varying exponents. Simulations are used to verify the assumptions of the continuum model. We observe the concentration profiles of kinesin moving in quasi two-dimensional artificial asters by fluorescent microscopy and compare with our theoretical results.Comment: 4pages, 4 figures revte

Elevated activity of the sympathetic nervous system is related to diminished practice effects in memory:A pilot study

BACKGROUND: Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load. OBJECTIVE: In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects. METHODS: Thirty cognitively healthy individuals aged 40–70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance. RESULTS: Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners. CONCLUSION: These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline

Prevalence and correlates of probable post-traumatic stress disorder and common mental disorders in a population with a high prevalence of HIV in Zimbabwe.

Background: We investigated the prevalence of and factors associated with post-traumatic stress disorder (PTSD) and common mental disorders (CMDs), which include depression and anxiety disorders, in a setting with a prevalence of high human immunodeficiency virus (HIV) within a primary care clinic, using the PTSD Checklist for DSM-5 and the 14-item Shona Symptom Questionnaire, both locally validated screening tools. Methods: A cross-sectional survey was carried out with adult patients (n = 204) from the largest primary care clinic facility in Harare, Zimbabwe, in June 2016. Results: A total of 83 patients (40.7%) met the criteria for probable PTSD, of whom 57 (69.5%) had comorbid CMDs. Among people living with HIV, 42 (55.3%) had PTSD. Probable PTSD was associated with having experienced a negative life event in the past 6 months [adjusted odds ratio (OR) 3.73, 95% confidence interval (CI) 1.49-9.34] or screening positive for one or more CMD (adjusted OR 6.48, 95% CI 3.35-2.54). Conclusion: People living with HIV showed a high prevalence of PTSD and CMD comorbidity. PTSD screening should be considered when the CMD screen is positive and there is a history of negative life events

Cost-Utility of Using Alzheimer's Disease Biomarkers in Cerebrospinal Fluid to Predict Progression from Mild Cognitive Impairment to Dementia

Background: Diagnostic research criteria for Alzheimer's disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI). Objective: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI. Methods: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon. Results: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416. Conclusion: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization