Functional Consequences of Necdin Nucleocytoplasmic Localization

Background: Necdin, a MAGE family protein expressed primarily in the nervous system, has been shown to interact with both nuclear and cytoplasmic proteins, but the mechanism of its nucleocytoplasmic transport are unknown. Methodology/Principal Findings: We carried out a large-scale interaction screen using necdin as a bait in the yeast RRS system, and found a wide range of potential interactors with different subcellular localizations, including over 60 new candidates for direct binding to necdin. Integration of these interactions into a comprehensive network revealed a number of coherent interaction modules, including a cytoplasmic module connecting to necdin through huntingtin-associated protein 1 (Hap1), dynactin and hip-1 protein interactor (Hippi); a nuclear P53 and Creb-binding-protein (Crebbp) module, connecting through Crebbp and WW domain-containing transcription regulator protein 1 (Wwtr1); and a nucleocytoplasmic transport module, connecting through transportins 1 and 2. We validated the necdin-transportin1 interaction and characterized a sequence motif in necdin that modulates karyopherin interaction. Surprisingly, a D234P necdin mutant showed enhanced binding to both transportin1 and importin b1. Finally, exclusion of necdin from the nucleus triggered extensive cell death. Conclusions/Significance: These data suggest that necdin has multiple roles within protein complexes in different subcellular compartments, and indicate that it can utilize multiple karyopherin-dependent pathways to modulate its localization

On the effects of signal processing on sample entropy for postural control

<div><p>Sample entropy, a measure of time series regularity, has become increasingly popular in postural control research. We are developing a virtual reality assessment of sensory integration for postural control in people with vestibular dysfunction and wished to apply sample entropy as an outcome measure. However, despite the common use of sample entropy to quantify postural sway, we found lack of consistency in the literature regarding center-of-pressure signal manipulations prior to the computation of sample entropy. We therefore wished to investigate the effect of parameters choice and signal processing on participants’ sample entropy outcome. For that purpose, we compared center-of-pressure sample entropy data between patients with vestibular dysfunction and age-matched controls. Within our assessment, participants observed virtual reality scenes, while standing on floor or a compliant surface. We then analyzed the effect of: modification of the radius of similarity (<i>r</i>) and the embedding dimension (<i>m</i>); down-sampling or filtering and differencing or detrending. When analyzing the raw center-of-pressure data, we found a significant main effect of surface in medio-lateral and anterior-posterior directions across <i>r</i>’s and <i>m</i>’s. We also found a significant interaction group × surface in the medio-lateral direction when <i>r</i> was 0.05 or 0.1 with a monotonic increase in <i>p</i> value with increasing <i>r</i> in both <i>m</i>’s. These effects were maintained with down-sampling by 2, 3, and 4 and with detrending but not with filtering and differencing. Based on these findings, we suggest that for sample entropy to be compared across postural control studies, there needs to be increased consistency, particularly of signal handling prior to the calculation of sample entropy. Procedures such as filtering, differencing or detrending affect sample entropy values and could artificially alter the time series pattern. Therefore, if such procedures are performed they should be well justified.</p></div

On the effects of signal processing on sample entropy for postural control - Fig 4

<p>We used the raw anterior-posterior time series (top) from one scene (the park scene, 120 seconds long) performed by a patient when standing on the floor to demonstrate the effect of detrending (middle) and differencing (bottom). The corresponding sample entropy values in this scene are: Raw: 0.463, Detrended: 0.56, Differenced: 2.6.</p

Distributions of SampEn and e^−SampEn as a function of the radius of similarity <i>r</i> for the data samples of patients and controls on the floor and stability trainer.

<p>Distributions of SampEn and e^−SampEn as a function of the radius of similarity <i>r</i> for the data samples of patients and controls on the floor and stability trainer.</p

On the effects of signal processing on sample entropy for postural control - Fig 2

<p>Top: comparison of sample entropy values derived from tasks performed on the stability trainer (ST) or floor (Fl) in the medio-lateral (ML) plane (left) and anterior-posterior (AP) plane (right). This comparison is shown for <i>m</i> = 2 and <i>r</i> = 0.1 across different levels of down-sampling (DS) by 1, 2, 3 and 4 or when applying a 4^th order low-pass Butterworth filter with a cutoff frequency at 10 Hz. Sample entropy was significantly higher on the floor for all DS levels in both planes but not when applying the filter. Bottom: A between-group comparison of sample entropy for tasks performed on the floor given DS or filter in the ML (left side) or AP (right side) plane.</p

On the effects of signal processing on sample entropy for postural control - Fig 3

<p>Sample entropy between surfaces (top) and between groups on the floor (bottom) in the ML direction (left hand side) and AP direction (right hand side) for original data, detrended data and differenced data when <i>m</i> = 2 and <i>r</i> = 0.1.</p

Cognitive function in multiple sclerosis: A long-term look on the bright side.

BackgroundMultiple sclerosis (MS) may lead to cognitive decline over-time.ObjectivesCharacterize cognitive performance in MS patients with long disease duration treated with disease modifying drugs (DMD) in relation to disability and determine the prevalence of cognitive resilience.MethodsCognitive and functional outcomes were assessed in 1010 DMD-treated MS patients at least 10 years from onset. Cognitive performance was categorized as high, moderate or low, and neurological disability was classified according to the Expanded Disability Status Scale (EDSS) as mild, moderate or severe. Relationship between cognitive performance and disability was examined.ResultsAfter a mean disease duration of 19.6 (SD = 7.7) years, low cognitive performance was observed in 23.7% (N = 239), moderate performance in 42.7% (N = 431), and 33.7% (N = 340) had high cognitive performance, meeting the definition of cognitively resilient patients. Within the group of patients with low cognitive performance, severe disability was observed in 50.6% (121/239), while in the group of patients with high cognitive performance, mild disability was observed in 64.4% (219/340). Differences between the group of patients with high cognitive performance and severe disability (4.5%) and the group of patients with low cognitive performance and mild disability (5.0%) were not accounted for by DMD treatment duration.ConclusionsThe majority of DMD treated MS patients did not have cognitive decline that could impair their quality of life after disease of extended duration

Contextual sensory integration training vs. traditional vestibular rehabilitation: a pilot randomized controlled trial

Abstract Background We created a clinical virtual reality application for vestibular rehabilitation. Our app targets contextual sensory integration (C.S.I.) where patients are immersed in safe, increasingly challenging environments while practicing various tasks (e.g., turning, walking). The purpose of this pilot study was to establish the feasibility of a randomized controlled trial comparing C.S.I. training to traditional vestibular rehabilitation. Methods Thirty patients with vestibular dysfunction completed the Dizziness Handicap Inventory (DHI), Activities-Specific Balance Confidence Scale (ABC), Visual Vertigo Analog Scale (VVAS), Functional Gait Assessment (FGA), Timed-Up-and-Go (TUG), and Four-Square Step Test (FSST). Following initial assessment, the patients were randomized into 8 weeks (once per week in clinic + home exercise program) of traditional vestibular rehabilitation or C.S.I. training. Six patients had to stop participation due to the covid-19 pandemic, 6 dropped out for other reasons (3 from each group). Ten patients in the traditional group and 8 in the C.S.I group completed the study. We applied an intention to treat analysis. Results Following intervention, we observed a significant main effect of time with no main effect of group or group by time interaction for the DHI (mean difference − 18.703, 95% CI [-28.235, -9.172], p = 0.0002), ABC (8.556, [0.938, 16.174], p = 0.028), VVAS, (-13.603, [-25.634, -1.573], p = 0.027) and the FGA (6.405, [4.474, 8.335], p < 0.0001). No changes were observed for TUG and FSST. Conclusion Patients’ symptoms and function improved following either vestibular rehabilitation method. C.S.I training appeared comparable but not superior to traditional rehabilitation. Trial registration This study (NCT04268745) was registered on clincaltrials.gov and can be found at https://clinicaltrials.gov/ct2/show/NCT04268745