ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated ...in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein. We find that the previously studied "∆NES" mutant, in which conserved hydrophobic residues are mutated to alanines, disrupts both solubility and splicing function. We further show that nuclear export of TDP-43 is independent of the exportin XPO1. Finally, we provide evidence that nuclear egress of TDP-43 is size dependent; nuclear export of dTomato TDP-43 is significantly impaired compared to Flag TDP-43. Together, these results suggest nuclear export of TDP-43 is predominantly driven by passive diffusion.
Highlights • Pain catastrophizing is associated with altered neuromotor behavior during gait. • Catastrophizers had higher EMG activation in certain trunk muscles during gait. • Catastrophizers had ...less phasic modulation of other trunk muscles during gait. • Activation of most muscles was correlated with pain catastrophizing scores.
We systematically reviewed and analyzed the literature to find randomized controlled trials (RCTs) that employed robotic devices in upper-limb rehabilitation of people with stroke. Out of 574 ...studies, 12 matching the selection criteria were found. The Fugl-Meyer, Functional Independence Measure, Motor Power Scale, and Motor Status Scale outcome measures from the selected RCTs were pooled together, and the corresponding effect sizes were estimated. We found that when the duration/intensity of conventional therapy (CT) is matched with that of the robot-assisted therapy (RT), no difference exists between the intensive CT and RT groups in terms of motor recovery, activities of daily living, strength, and motor control. However, depending on the stage of recovery, extra sessions of RT in addition to regular CT are more beneficial than regular CT alone in motor recovery of the hemiparetic shoulder and elbow of patients with stroke; gains are similar to those that have been observed in intensive CT.
The sixth update of the Canadian Stroke Best Practice Recommendations: Rehabilitation, Recovery, and Reintegration following Stroke. Part one: Rehabilitation and Recovery Following Stroke is a ...comprehensive set of evidence-based guidelines addressing issues surrounding impairments, activity limitations, and participation restrictions following stroke. Rehabilitation is a critical component of recovery, essential for helping patients to regain lost skills, relearn tasks, and regain independence. Following a stroke, many people typically require rehabilitation for persisting deficits related to hemiparesis, upper-limb dysfunction, pain, impaired balance, swallowing, and vision, neglect, and limitations with mobility, activities of daily living, and communication. This module addresses interventions related to these issues as well as the structure in which they are provided, since rehabilitation can be provided on an inpatient, outpatient, or community basis. These guidelines also recognize that rehabilitation needs of people with stroke may change over time and therefore intermittent reassessment is important. Recommendations are appropriate for use by all healthcare providers and system planners who organize and provide care to patients following stroke across a broad range of settings. Unlike the previous set of recommendations, in which pediatric stroke was included, this set of recommendations includes primarily adult rehabilitation, recognizing many of these therapies may be applicable in children. Recommendations related to community reintegration, which were previously included within this rehabilitation module, can now be found in the companion module, Rehabilitation, Recovery, and Community Participation following Stroke. Part Two: Transitions and Community Participation Following Stroke.
Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung ...et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.
A Chinese version of the Online Self-Regulated Learning Questionnaire (OLSQ) was administered to 412 Hong Kong students of average ability and 374 students talented in mathematics (Grades 4-9, age ...9-15 years). Data indicated that the Chinese OLSQ provides valid and reliable scores when used with these students.
The aim of the current study was to examine the role of environment, whether virtual or physical, on robot-assisted reaching movements in chronic stroke and healthy individuals, within a single ...session. Twenty-three subjects participated in the current study divided into three groups: nine chronic stroke individuals able to perform a reaching task with no need for the robot assistance, nine chronic stroke individuals who needed robot assistance to complete the reaching task, and five healthy individuals. The task was to reach six target buttons in two identical physical and virtual environments. The outcomes consisted of specific kinematic measures (amount of movement completion without robot assistance, mean speed, peak speed, straightness, and shakiness) and a custom questionnaire to assess how the stroke subjects perceived and experienced the reaching task in both environments. The results showed no differences between the two environments in terms of the outcome measures in any of the groups. Our findings suggest that the choice of environment, whether physical or virtual, is not a key factor in designing a simple robot-assisted reaching task for stroke survivors. Further studies are required for more complex environments and tasks as well as robot-assisted training protocols.
Abstract CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as ...the transport receptor is overexpressed in many cancers where some of its cargos are misregulated and mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes structure–function studies that explain CRM1-cargo recognition, release and inhibition.
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