Loss-of-function of kinesin-5 KIF11 causes microcephaly, chorioretinopathy, and developmental disorders through chromosome instability and cell cycle arrest.

Kinesin motors play a fundamental role in development by controlling intracellular transport, spindle assembly, and microtubule organization. In humans, patients carrying mutations in KIF11 suffer from an autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR). While mitotic functions of KIF11 proteins have been well documented in centrosome separation and spindle assembly, cellular mechanisms underlying KIF11 dysfunction and MCLMR remain unclear. In this study, we generate KIF11-inhibition chick and zebrafish models and find that KIF11 inhibition results in microcephaly, chorioretinopathy, and severe developmental defects in vivo. Notably, loss-of-function of KIF11 causes the formation of monopolar spindle and chromosome misalignment, which finally contribute to cell cycle arrest, chromosome instability, and cell death. Our results demonstrate that KIF11 is crucial for spindle assembly, chromosome alignment, and cell cycle progression of progenitor stem cells, indicating a potential link between polyploidy and MCLMR. Our data have revealed that KIF11 inhibition cause microcephaly, chorioretinopathy, and development disorders through the formation of monopolar spindle, polyploid, and cell cycle arrest.

Implementing technology enhanced real-time action observation therapy in persons with chronic stroke: A pilot study.

This pilot study examined a novel technology-enhanced real-time action observation therapy (TERTAOT) of symmetrical bilateral movements in survivors of chronic stroke regardless of their ability to move their paretic limb(s). The TERTAOT used a Kinect XBox One to project mirror images of non-paretic limbs as participants performed symmetrical bilateral motor tasks involving whole-body movements in sitting or standing. The participants received eight weeks of treatment consisting of 30-minutes of conventional physical therapy (balance training, gait training, neuromuscular reeducation, and generalized strength training) and 30-minutes of the TERTAOT protocol per session (three sessions per week for a total of 24 sessions). Ten Meter Walk Test (10MWT), Five Times Sit-to-Stand (5TSTS), Timed Up and Go (TUG), Motor Activity Log - Quality of Movement (QOM) and Amount of Use (AOU) were administered at baseline (pretest), 4 weeks (posttest 1) and 8 weeks (posttest 2) post-TERTAOT, and 3 months after TERTAOT ended (retention). A General Linear Model Repeated Measures (parametric test) or the Friedman Test (non-parametric test) was used to compare outcomes across time points, depending on the normality of data distribution. Bonferroni post-hoc corrections were applied. Seventeen participants completed >80% of TERTAOT sessions without adverse events. The effect of time was significant for 10MWT (p = .001), 5TSTS (p = .001), TUG (p = .005), QOM (p = .001), and AOU (p = .017). TERTAOT may be feasible to be implemented in an outpatient setting. Improvements in functional outcomes including gait, balance, and use of upper limbs were observed after eight weeks of conventional therapy and TERTAOT protocol in survivors of chronic stroke.

Predictors of positive outcomes following resistive inspiratory muscle training in non-ambulatory persons with advanced multiple sclerosis.

Background: Inspiratory muscle training (IMT) using a threshold device improves inspiratory muscle strength. What factors influence the IMT outcome has not been examined. Objective: To identify predictors of the positive outcome following IMT in persons with advanced multiple sclerosis (PwAMS). Methods: Inclusion criteria were non-ambulatory PwAMS, Expanded Disability Status Scale (EDSS) ≥6.5, age >18 years, no acute medical conditions, current non-smokers, and ability to consent. Participants (n = 38) performed daily inspiratory exercises using a resistive threshold device for 10 weeks. Baseline measurements included age, sex, body mass index, year post multiple sclerosis diagnosis, comorbidities, EDSS, Modified Fatigue Impact Scale-5, and oral Symbol Digit Modality Test. The percentage of completed prescribed exercise trials (Trials%) during the 10-week intervention was calculated. Age- and sex-adjusted predicted values of maximum inspiratory pressure (MIP%pred) and maximum expiratory pressure (MEP%pred) were obtained before and after the 10-week intervention. Backward multivariable regression analyses for the primary outcome (MIP%pred) were conducted. Results: After controlling for the initial MIP%pred, perceived fatigue at the baseline and Trial% were significant and independent predictors of MIP%pred after IMT. Conclusion: Less fatigue at the baseline and higher adherence to the prescribed exercise repetitions were positive predictors of the positive outcome following IMT in PwAMS.

Design of Fluorescence-Enhanced Silver Nanoisland Chips for High-Throughput and Rapid Arsenite Assay.

High-throughput and rapid arsenite (As(III)) monitoring is an urgent task to deal with the critical threat from As(III) contamination in the environment. In this study, an effective, portable, and sensitive As(III) assay was developed using the plasmonic silver (pAg) chips for As(III) detection. The pAg chips were fabricated by a simple seed-mediated method to grow the silver nanoisland films (Ag-NIFs) with the compact nanoislands and adjustable interisland gaps on the large-sized substrates. With appropriate surface functionalization and optimal chip manufacturing, Cy7.5 fluorescence dye can be immobilized on the surface of Ag-NIFs in the presence of As(III) to output the enhanced fluorescence signals up to 10-fold and improve the detection limit of As(III) less than 10 ppb. According to our results, the high-throughput detection measurements and wide dynamic range over 4 orders of magnitude implied the broad prospects of pAg chips in fluorescence-enhanced assays. The proposed As(III) assay has shown great opportunities for the practical application of ultratrace As(III) monitoring.

Retrospectively investigating the 12-year experience of prenatal diagnosis of small supernumerary marker chromosomes through array comparative genomic hybridization.

OBJECTIVE: This study retrospectively evaluated the incidences of small supernumerary marker chromosomes (sSMCs) in prenatal diagnoses and detected with gain of pathogenic copy number variation through array comparative genomic hybridization (CGH) in a laboratory in Taiwan. MATERIALS AND METHODS: We retrospectively searched and reviewed the sSMC cases detected during prenatal diagnoses in the Youthgene medical laboratory, between 2004 and 2015 and used array CGH to successfully analyze 45 of 47,XN,+mar or 47,XN + mar/46,XN. RESULTS: A total of 68,087 cases of amniocentesis were analyzed, of which 59 were identified as sSMCs. The overall frequency of sSMCs was 0.087%, and 7 of 45 sSMCs were identified with gain of pathogenic copy number variation (CNV). CONCLUSION: Array CGH offers useful tools that can be used to detect small fragments of chromosomal abnormalities and sSMC origins in prenatal diagnosis. In this study, we successfully used array CGH to detect 7 out of 45 sSMCs, which were identified with gain in pathogenic CNV.

Age differences in the control of postural stability during reaching tasks.

Reaching tasks are commonly performed during daily activities and require anticipatory postural adjustments (APAs) to ensure a stable posture during movement execution. Age-related changes in APAs may impact dynamic balance and cause postural instability during reaching tasks made from standing. The present study examined age differences in postural control during reaching to targets located at different heights. Fourteen young adults (aged 20.0±1.5 yrs) and 16 community-dwelling older adults (aged 73.4±5.3 yrs) participated in the study. The task involved reaching forward to grasp a cylinder, and returning to an upright position as fast and accurately as possible. Postural control was analyzed using the center of pressure (COP) during four phases of the task: COP displacement during APA production, COP trajectory smoothness during the reach and return phases, and COP path length during the recovery phase following movement. APA amplitude measured by COP displacement and COP path length during the recovery phase was larger in older compared to young adults. Dynamic balance represented by COP trajectory smoothness was reduced with age. In both age groups, APA amplitude was largest and COP trajectory smoothness the least during low target reaches. The results demonstrate that, while older adults can alter APAs in order to maintain postural stability, control of COP during movement execution, particularly during low target reaches, is compromised with aging. These findings have clinical implications for both the assessment of dynamic balance and the development of balance training programs.