New Function Annotation of PROSER2 in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to the absence of diagnostic markers and molecular targets. Here, we took an unconventional approach to identify new molecular targets for pancreatic cancer. We chose uncharacterized protein evidence level 1 without function annotation from extensive proteomic research on pancreatic cancer and focused on proline and serine-rich 2 (PROSER2), which ranked high in the cell membrane and cytoplasm. In our study using cell lines and patient-derived orthotopic xenograft cells, PROSER2 exhibited a higher expression in cells derived from primary tumors than in those from metastatic tissues. PROSER2 was localized in the cell membrane and cytosol by immunocytochemistry. PROSER2 overexpression significantly reduced the metastatic ability of cancer cells, whereas its suppression had the opposite effect. Proteomic analysis revealed that PROSER2 interacts with STK25 and PDCD10, and their binding was confirmed by immunoprecipitation and immunocytochemistry. STK25 knockdown enhanced metastasis by decreasing p-AMPK levels, whereas PROSER2-overexpressing cells increased the level of p-AMPK, indicating that PROSER2 suppresses invasion via the AMPK pathway by interacting with STK25. This is the first demonstration of the novel role of PROSER2 in antagonizing tumor progression via the STK25-AMPK pathway in PDAC. LC-MS/MS data are available at MassIVE (MSV000092953) and ProteomeXchange (PXD045646).

Evidence of the existence of multiple modules for the stroke-caused flexion synergy from Fugl-Meyer assessment scores.

Stroke-caused synergies may result from the preferential use of the reticulospinal tract (RST) due to damage to the corticospinal tract. The RST branches multiple motoneuron pools across the arm together resulting in gross motor control or abnormal synergies, and accordingly, the controllability of individual muscles decreases. However, it is not clear whether muscles involuntarily activated by abnormal synergy vary depending on the muscles voluntarily activated when motor commands descend through the RST. Studies showed that abnormal synergies may originate from the merging and reweighting of synergies in individuals without neurological deficits. This leads to a hypothesis that those abnormal synergies are still selectively excited depending on the context. In this study, we test this hypothesis, leveraging the Fugl-Meyer assessment that could characterize the neuroanatomical architecture in individuals with a wide range of impairments. We examine the ability to perform an out-of-synergy movement with the flexion synergy caused by either shoulder or elbow loading. The results reveal that about 14% [8/57, 95% confidence interval (5.0%, 23.1%)] of the participants with severe impairment (total Fugl-Meyer score <29) in the chronic phase (6 months after stroke) are able to keep the elbow extended during shoulder loading and keep the shoulder at neutral during elbow loading. Those participants underwent a different course of neural reorganization, which enhanced abnormal synergies in comparison with individuals with mild impairment (P < 0.05). These results provide evidence that separate routes and synergy modules to motoneuron pools across the arm might exist even if the motor command is mediated possibly via the RST.NEW & NOTEWORTHY We demonstrate that abnormal synergies are still selectively excited depending on the context.

Correlations in abnormal synergies between the upper and lower extremities across various phases of stroke.

The flexion synergy and extension synergy are a representative consequence of a stroke and appear in the upper extremity and the lower extremity. Since the ipsilesional corticospinal tract (CST) is the most influential neural pathway for both extremities in motor execution, damage by a stroke to this tract could lead to similar motor pathological features (e.g., abnormal synergies) in both extremities. However, less attention has been paid to the interlimb correlations in the flexion synergy and extension synergy across different recovery phases of a stroke. We used results of the Fugl-Meyer assessment (FMA) to characterize those correlations in a total of 512 participants with hemiparesis after stroke from the acute phase to 1 year. The FMA provides indirect indicators of the degrees of the flexion synergy and extension synergy after stroke. We found that, generally, strong interlimb correlations (r > 0.65 with all P values < 0.0001) between the flexion synergy and extension synergy appeared in the acute-to-subacute phase (<90 days). However, the correlations of the lower-extremity extension synergy with the upper-extremity flexion synergy and extension synergy decreased (down to r = 0.38) 360 days after stroke (P < 0.05). These results suggest that the preferential use of alternative neural pathways after damage by a stroke to the CST enhances the interlimb correlations between the flexion synergy and extension synergy. At the same time, the results imply that the recovery of CST integrity or/and the fragmentation (remodeling) of the alternative neural substrates in the chronic phase may contribute to diversity in neural pathways in motor execution, eventually leading to reduced interlimb correlations.NEW & NOTEWORTHY For the first time, this article addresses the asynchronous relationships in the strengths of flexion and extension synergy expressions between the paretic upper extremity and lower extremity across various phases of stroke.

Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor deoxyribonucleic acid (ctDNA) have been reported as representative noninvasive prognostic markers for pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to evaluate single KRAS mutations as prognostic and predictive biomarkers, with an emphasis on potential therapeutic approaches to PDAC. A total of 128 patients were analyzed for multiple or single KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D) in their tumors and plasma using droplet digital polymerase chain reaction (ddPCR). Overall, KRAS mutations were detected by multiplex ddPCR in 119 (93%) of tumor DNA and 68 (53.1%) of ctDNA, with a concordance rate of 80% between plasma ctDNA and tumor DNA in the metastatic stage, which was higher than the 44% in the resectable stage. Moreover, the prognostic prediction of both overall survival (OS) and progression-free survival (PFS) was more relevant using plasma ctDNA than tumor DNA. Further, we evaluated the selective tumor-suppressive efficacy of the KRAS G12C inhibitor sotorasib in a patient-derived organoid (PDO) from a KRAS G12C-mutated patient using a patient-derived xenograft (PDX) model. Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.

Refining Classification of Cholangiocarcinoma Subtypes via Proteogenomic Integration Reveals New Therapeutic Prospects.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinomas (iCCs) are characterized by their rarity, difficult diagnosis, and overall poor prognosis. The iCC molecular classification for developing precision medicine strategies was investigated. METHODS: Comprehensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses were performed on treatment-naïve tumor samples from 102 patients with iCC who underwent surgical resection with curative intent. An organoid model was constructed for testing therapeutic potential. RESULTS: Three clinically supported subtypes (stem-like, poorly immunogenic, and metabolism) were identified. NCT-501 (aldehyde dehydrogenase 1 family member A1 [ALDH1A1] inhibitor) exhibited synergism with nanoparticle albumin-bound-paclitaxel in the organoid model for the stem-like subtype. The oncometabolite dysregulations were associated with different clinical outcomes in the stem-like and metabolism subtypes. The poorly immunogenic subtype harbors the non-T-cell tumor infiltration. Integrated multiomics analysis not only reproduced the 3 subtypes but also showed heterogeneity in iCC. CONCLUSIONS: This large-scale proteogenomic analysis provides information beyond that obtained with genomic analysis, allowing the functional impact of genomic alterations to be discerned. These findings may assist in the stratification of patients with iCC and in developing rational therapeutic strategies.

Temporal Transcriptome Profiling of Pinus densiflora Infected with Pine Wood Nematode Reveals Genetically Programmed Changes upon Pine Wilt Disease.

Pine, an evergreen conifer, is widely distributed worldwide. It is economically, scientifically, and ecologically important. However, pine wilt disease (PWD) induced by the pine wood nematode (PWN) adversely affects pine trees. Many studies have been conducted on the PWN and its beetle vectors to prevent the spread of PWD. However, studies providing a comprehensive understanding of the pine tree transcriptome in response to PWN infection are lacking. Here, we performed temporal profiling of the pine tree transcriptome using PWD-infected red pine trees, Pinus densiflora, inoculated with the PWN by RNA sequencing. Our analysis revealed that defense-responsive genes involved in cell wall modification, jasmonic acid signaling, and phenylpropanoid-related processes were significantly enriched 2 weeks after PWD infection. Furthermore, some WRKY-type and MYB-type transcription factors were upregulated 2 weeks after PWD infection, suggesting that these transcription factors might be responsible for the genome-wide reprogramming of defense-responsive genes in the early PWD stage. Our comprehensive transcriptome analysis will assist in developing PWD-resistant pine trees and identifying genes to diagnose PWD at the early stage of infection, during which large-scale phenotypic changes are absent in PWD-infected pine trees.

Use of cortical hemodynamic responses in digital therapeutics for upper limb rehabilitation in patients with stroke.

BACKGROUND: Stroke causes long-term disabilities, highlighting the need for innovative rehabilitation strategies for reducing residual impairments. This study explored the potential of functional near-infrared spectroscopy (fNIRS) for monitoring cortical activation during rehabilitation using digital therapeutics. METHODS: This cross-sectional study included 18 patients with chronic stroke, of whom 13 were men. The mean age of the patients was 67.0 ± 7.1 years. Motor function was evaluated through various tests, including the Fugl-Meyer assessment for upper extremity (FMA-UE), grip and pinch strength test, and box and block test. All the patients completed the digital rehabilitation program (MotoCog®, Cybermedic Co., Ltd., Republic of Korea) while being monitored using fNIRS (NIRScout®, NIRx Inc., Germany). Statistical parametric mapping (SPM) was employed to analyze the cortical activation patterns from the fNIRS data. Furthermore, the K-nearest neighbor (K-NN) algorithm was used to analyze task performance and fNIRS data to classify the severity of motor impairment. RESULTS: The participants showed diverse task performances in the digital rehabilitation program, demonstrating distinct patterns of cortical activation that correlated with different motor function levels. Significant activation was observed in the ipsilesional primary motor area (M1), primary somatosensory area (S1), and contralateral prefrontal cortex. The activation patterns varied according to the FMA-UE scores. Positive correlations were observed between the FMA-UE scores and SPM t-values in the ipsilesional M1, whereas negative correlations were observed in the ipsilesional S1, frontal lobe, and parietal lobe. The incorporation of cortical hemodynamic responses with task scores in a digital rehabilitation program substantially improves the accuracy of the K-NN algorithm in classifying upper limb functional levels in patients with stroke. The accuracy for tasks, such as the gas stove-operation task, increased from 44.4% using only task scores to 83.3% when these scores were combined with oxy-Hb t-values from the ipsilesional M1. CONCLUSIONS: The results advocated the development of tailored digital rehabilitation strategies by combining the behavioral and cerebral hemodynamic data of patients with stroke. This approach aligns with the evolving paradigm of personalized rehabilitation in stroke recovery, highlighting the need for further extensive research to optimize rehabilitation outcomes.

Exposure to Radiofrequency Induces Synaptic Dysfunction in Cortical Neurons Causing Learning and Memory Alteration in Early Postnatal Mice.

The widespread use of wireless communication devices has necessitated unavoidable exposure to radiofrequency electromagnetic fields (RF-EMF). In particular, increasing RF-EMF exposure among children is primarily driven by mobile phone use. Therefore, this study investigated the effects of 1850 MHz RF-EMF exposure at a specific absorption rate of 4.0 W/kg on cortical neurons in mice at postnatal day 28. The results indicated a significant reduction in the number of mushroom-shaped dendritic spines in the prefrontal cortex after daily exposure for 4 weeks. Additionally, prolonged RF-EMF exposure over 9 days led to a gradual decrease in postsynaptic density 95 puncta and inhibited neurite outgrowth in developing cortical neurons. Moreover, the expression levels of genes associated with synapse formation, such as synaptic cell adhesion molecules and cyclin-dependent kinase 5, were reduced in the cerebral cortexes of RF-EMF-exposed mice. Behavioral assessments using the Morris water maze revealed altered spatial learning and memory after the 4-week exposure period. These findings underscore the potential of RF-EMF exposure during childhood to disrupt synaptic function in the cerebral cortex, thereby affecting the developmental stages of the nervous system and potentially influencing later cognitive function.

Predictors of Burden for First-Ever Stroke Survivor's Long-Term Caregivers: A Study of KOSCO.

Long-term changes in caregiver burden should be clarified considering that extended post-stroke disability can increase caregiver stress. We assessed long-term changes in caregiver burden severity and its predictors. This study was a retrospective analysis of the Korean Stroke Cohort for Functioning and Rehabilitation. Patients with an acute first-ever stroke were enrolled from August 2012 to May 2015. Data were collected at 6 months and 6 years after stroke onset. The caregiver burden was measured with a subjective caregiver burden questionnaire based on the Korean version of the Caregiver Burden Inventory. The caregivers' characteristics and patients' clinical and functional status were also examined at each follow-up. A high caregiver burden, which suggests a risk of burnout, was reported by 37.9% and 51.7% of caregivers at 6 months and 6 years post-stroke, respectively. Both the caregiver burden total score and proportion of caregivers at risk of burnout did not decrease between 6 months and 6 years. The patients' disability (OR = 11.60; 95% CI 1.58-85.08; p = 0.016), caregivers' self-rated stress (OR = 0.03; 95% CI 0.00-0.47; p = 0.013), and caregivers' quality of life (OR = 0.76; 95% CI 0.59-0.99; p = 0.042) were burden predictors at 6 months. At 6 years, only the patients' disability (OR = 5.88; 95% CI 2.19-15.82; p < 0.001) and caregivers' psychosocial stress (OR = 1.26; 95% CI 1.10-1.44; p = 0.001) showed significance. Nearly half of the caregivers were at risk of burnout, which lasted for 6 years after stroke onset. The patients' disability and caregivers' stress were burden predictors in both subacute and chronic phases of stroke. The findings suggest that consistent interventions, such as emotional support or counseling on stress relief strategies for caregivers of stroke survivors, may reduce caregiver burden. Further research is needed to establish specific strategies appropriate for Korean caregivers to alleviate their burden in caring for stroke patients.

Influenza vaccines: Past, present, and future.

Globally, infection by seasonal influenza viruses causes 3-5 million cases of severe illness and 290,000-650,000 respiratory deaths each year. Various influenza vaccines, including inactivated split- and subunit-type, recombinant and live attenuated vaccines, have been developed since the 1930s when it was discovered that influenza viruses could be cultivated in embryonated eggs. However, the protection rate offered by these vaccines is rather low, especially in very young children and the elderly. In this review, we describe the history of influenza vaccine development, the immune responses induced by the vaccines and the adjuvants applied. Further, we suggest future directions for improving the effectiveness of influenza vaccines in all age groups. This includes the development of an influenza vaccine that induces a balanced T helper cell type 1 and type 2 immune responses based on the understanding of the immune system, and the development of a broad-spectrum influenza vaccine that can increase effectiveness despite antigen shifts and drifts, which are characteristics of the influenza virus. A brighter future can be envisaged if the development of an adjuvant that is safe and effective is realized.

Comparative study of young-old and old-old people using functional evaluation, gait characteristics, and cardiopulmonary metabolic energy consumption.

BACKGROUND: Walking is an important factor in daily life. Among older adults, gait function declines with age. In contrast to the many studies revealing gait differences between young adults and older adults, few studies have further divided older adults into groups. The purpose of this study was to subdivide an older adult population by age to identify age-related differences in functional evaluation, gait characteristics and cardiopulmonary metabolic energy consumption while walking. METHODS: This was a cross-sectional study of 62 old adult participants who were classified into two age groups of 31 participants each as follows: young-old (65-74 years) and old-old (75-84 years) group. Physical functions, activities of daily living, mood state, cognitive function, quality of life, and fall efficacy were evaluated using the Short Physical Performance Battery (SPPB), Four-square Step Test (FSST), Timed Up and Go Test (TUG), Korean Version of the Modified Barthel Index, Geriatric Depression Scale (GDS), Korean Mini-mental State Examination, EuroQol-5 Dimensions (EQ-5D) questionnaire, and the Korean version of the Fall Efficacy Scale. A three-dimensional motion capture system (Kestrel Digital RealTime System®; Motion Analysis Corporation, Santa Rosa, CA, USA) and two force plates (TF-4060-B; Tec Gihan, Kyoto, Japan) were used to investigate spatiotemporal gait parameters (velocity, cadence, stride length, stride width, step length, single support, stance phase, and swing phase), kinematic variables (hip, knee, and ankle joint angles), and kinetic variables (hip, knee, and ankle joint moment and power) of gait. A portable cardiopulmonary metabolic system (K5; Cosmed, Rome, Italy) was used to measure cardiopulmonary energy consumption. RESULTS: The old-old group showed significantly lower SPPB, FSST, TUG, GDS-SF, and EQ-5D scores (p < 0.05). Among spatiotemporal gait parameters, velocity, stride length, and step length were significantly lower in the old-old group than in the young-old group (p < 0.05). Among the kinematic variables, the knee joint flexion angles during initial contact and terminal swing phase were significantly higher in the old-old than the young-old group (P < 0.05). The old-old group also showed a significantly lower ankle joint plantarflexion angle during the pre- and initial swing phases (P < 0.05). Among the kinetic variables, the hip joint flexion moment and knee joint absorption power in the pre-swing phase were significantly lower in the old-old than the young-old group (P < 0.05). CONCLUSION: This study demonstrated that participants 75-84 years of age had less functional gaits than their young-old counterparts (65-74 years old). As the walking pace of old-old people diminishes, driving strength to move ahead and pressure on the knee joint also tend to decrease together with stride length. These differences in gait characteristics according to age among older adults could improve our understanding of how aging causes variations in gait that increase the risk of falls. Older adults of different ages may require customized intervention plans, such as gait training methods, to prevent age-related falls. TRIAL REGISTRATION: Clinical trials registration information: ClinicalTrials.gov Identifier: NCT04723927 (26/01/2021).

Predictors of quality of life at 6 months in patients with mild stroke: A prospective observational cohort study.

OBJECTIVES: This study aimed to analyze the factors affecting the long-term quality of life of patients with mild stroke and evaluate the differences according to age and sex. MATERIALS AND METHODS: The Korean Stroke Cohort for functioning and rehabilitation data was used, and patients with mild stroke with a National Institute of Health Stroke Scale score of < 5 were included. Quality of life after 6 months was analyzed using EuroQol-5 dimensions. Demographic and clinical characteristics were evaluated, and factors affecting the quality of life at 6 months were analyzed. RESULTS: Age, current drinking, marital status, length of stay, and modified Rankin Scale, Fugl-Meyer assessment, Functional Independence Measure, and Geriatric Depression Scale scores affected the quality of life at 6 months in patients with mild stroke. Fugl-Meyer assessment score was a predictor for those aged < 65 years, while the functional ambulatory category was a predictor for those aged ≥ 65 years. Predictors of quality of life, excluding alcohol consumption, were comparable between male and female. CONCLUSIONS: Among patients aged <65 years, individuals who consumed alcohol, and those who showed better motor function and fewer comorbidities had a higher quality of life. Among patients aged ≥65 years, quality of life was higher in males, younger age, married individuals, those with diabetes, and those with a better walking ability. Among male, individuals who consumed alcohol had a higher quality of life. Rehabilitation treatment should prioritize improving modifiable factors to enhance the quality of life in patients with mild stroke.

Comparative Analysis of the Prevalence of Dysphagia in Patients with Mild COVID-19 and Those with Aspiration Pneumonia Alone: Findings of the Videofluoroscopic Swallowing Study.

Background and Objectives: Patients recovering from mild coronavirus disease (COVID-19) reportedly have dysphagia or difficulty in swallowing. We compared the prevalence of dysphagia between patients diagnosed with mild COVID-19 and those diagnosed with aspiration pneumonia alone. Materials and Methods: A retrospective study was conducted from January 2020 to June 2023 in 160 patients referred for a videofluoroscopic swallowing study (VFSS) to assess for dysphagia. The cohort included 24 patients with mild COVID-19 and aspiration pneumonia, 30 with mild COVID-19 without aspiration pneumonia, and 106 with aspiration pneumonia alone. We reviewed the demographic data, comorbidities, and VFSS results using the penetration-aspiration scale (PAS) and functional dysphagia scale (FDS). Results: In a study comparing patients with mild COVID-19 (Group A) and those with aspiration pneumonia alone (Group B), no significant differences were observed in the baseline characteristics, including the prevalence of dysphagia-related comorbidities between the groups. Group A showed milder dysphagia, as evidenced by lower PAS and FDS scores, shorter oral and pharyngeal transit times (p = 0.001 and p = 0.003, respectively), and fewer residues in the vallecula and pyriform sinuses (p < 0.001 and p < 0.03, respectively). When Group A was subdivided into those with COVID-19 with (Group A1) and without aspiration pneumonia (Group A2), both subgroups outperformed Group B in terms of specific VFSS metrics, such as oral transit time (p = 0.01), pharyngeal transit time (p = 0.04 and p = 0.02, respectively), and residue in the vallecula (p = 0.04 and p = 0.02, respectively). However, Group B showed improved triggering of the pharyngeal swallowing reflex compared with Group A2 (p = 0.02). Conclusion: Mild COVID-19 patients showed less severe dysphagia than those with aspiration pneumonia alone. This finding was consistent across VFSS parameters, even when the COVID-19 group was subdivided based on the status of aspiration pneumonia.

Home-Based Transcranial Direct Current Stimulation to Enhance Cognition in Stroke: Randomized Controlled Trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a promising tool for improving poststroke cognitive function. Home-based rehabilitation is increasingly required for patients with stroke, and additional benefits are expected if supplemented with remotely supervised tDCS (RS-tDCS). We evaluated the cognitive improvement effect and feasibility of RS-tDCS in patients with chronic stroke. METHODS: Twenty-six patients with chronic stroke and cognitive impairment (Korean version of the Montreal Cognitive Assessment [K-MoCA] score <26) were randomized into real and sham RS-tDCS groups and underwent concurrent computerized cognitive training and RS-tDCS. Patients and caregivers underwent training to ensure correct tDCS self-application, were monitored, and treated 5 d/wk for 4 weeks. We investigated several cognition tests including K-MoCA, Korean version of the Dementia Rating Scale-2, Korean-Boston Naming Test, Trail Making Test, Go/No Go, and Controlled Oral Word Association Test at the end of the training sessions and one month later. Repeated-measures ANOVA was used for comparison between the groups and within each group. The adherence rate of the appropriate RS-tDCS session was also investigated. RESULTS: In within-group comparison, unlike the sham group, the real group showed significant improvement in K-MoCA (Preal=0.004 versus Psham=0.132), particularly in patients with lower baseline K-MoCA (K-MoCA10-17; Preal=0.001 versus Psham=0.835, K-MoCA18-25; Preal=0.060 versus Psham=0.064) or with left hemispheric lesions (left; Preal=0.010 versus Psham=0.454, right; Preal=0.106 versus Psham=0.128). In between-group comparison, a significant difference was observed in K-MoCA in the lower baseline K-MoCA subgroup (K-MoCA10-17; Ptime×group=0.048), but no significant difference was found in other cognitive tests. The adherence rate of successful application of the RS-tDCS was 98.4%, and no serious adverse effects were detected. CONCLUSIONS: RS-tDCS is a safe and feasible rehabilitation modality for poststroke cognitive dysfunction. Specifically, RS-tDCS is effective in patients with moderate cognitive decline. Additionally, these data demonstrate the potential to enhance home-based cognitive training, although significant differences were not consistently found in between-group comparisons; therefore, further larger studies are needed. REGISTRATION: URL: https://cris.nih.go.kr; Unique identifier: KCT0003427.

Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study.

BACKGROUND AND PURPOSE: Stem cell-based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell-based therapy in patients with ischemic stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging. RESULTS: For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference. CONCLUSIONS: Stem cell-based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01716481.

Circulating Extracellular Vesicles in Stroke Patients Treated With Mesenchymal Stem Cells: A Biomarker Analysis of a Randomized Trial.

BACKGROUND: Mesenchymal stem cells (MSCs) secrete trophic factors and extracellular vesicles (EVs). However, the level and role of EVs after MSC therapy in patients with stroke are unknown. We investigated whether circulating EVs and trophic factors are increased after MSCs and are related to the therapeutic benefits in the STARTING-2 trial (Stem Cell Application Researches and Trials in Neurology-2) participants. METHODS: In this prospective randomized controlled trial, patients with chronic major stroke were assigned, in a 2:1 ratio, to receive autologous MSC intravenous injection (MSC group, n=39) or standard treatment (control group, n=15) and followed for 3 months. Detailed clinical assessment and neuroplasticity on diffusion tensor image and resting-state functional magnetic resonance imaging were evaluated. Serial samples were collected, before/after MSCs therapy. The primary outcome measure was circulating factors that are associated with the clinical improvement in the Fugl-Meyer Assessment (secondary end point of the trial) and neuroplasticity on diffusion tensor image and resting-state functional magnetic resonance imaging. Additional outcome measures were microRNAs and trophic factors enriched in the plasma EVs, obtained using quantitative polymerase chain reaction and ELISA, respectively. RESULTS: Circulating EV levels were increased ≈5-fold (mean±SD, from 2.7×109±2.2×109 to 1.3×1010±1.7×1010 EVs/mL) within 24 hours after injection of MSCs (P=0.001). After adjustment of age, sex, baseline stroke severity, and the time interval from stroke onset to treatment, only the EV number was independently associated with improvement in motor function (odds ratio, 5.718 for EV numberLog [95% CI, 1.144-28.589]; P=0.034). Diffusion tensor image and resting-state functional magnetic resonance imaging showed that integrity of the ipsilesional corticospinal tract and intrahemispheric motor network were significantly correlated with circulating EV levels, respectively (P<0.05). MicroRNAs related to neurogenesis/neuroplasticity (eg, microRNA-18a-5p) were significantly increased in circulating EVs after MSC therapy (P=0.0479). In contrast, trophic factor levels were not changed after MSC therapy. CONCLUSIONS: This trial is the first to show that treatment of ischemic stroke patients with MSCs significantly increases circulating EVs, which were significantly correlated with improvement in motor function and magnetic resonance imaging indices of plasticity. REGISTRATION: URL: https://www. CLINICAL TRIALS: gov; Unique identifier: NCT01716481.

Understanding of the Lower Extremity Motor Recovery After First-Ever Ischemic Stroke.

BACKGROUND: We aimed to verify the validity of the proportional recovery model for the lower extremity. METHODS: We reviewed clinical data of patients enrolled in the Korean Stroke Cohort for Functioning and Rehabilitation between August 2012 and May 2015. Recovery proportion was calculated as the amount of motor recovery over initial motor impairment, measured as the Fugl-Meyer Assessment of Lower Extremity score. We used the logistic regression method to model the probability of achieving the full Fugl-Meyer Assessment of Lower Extremity score, whereby we considered the ceiling effect of the score. To show the difference in the prevalence of achieving the full Fugl-Meyer Assessment of Lower Extremity score between 3 and 6 months poststroke, we constructed a marginal model through the generalized estimating equation method. We also performed the propensity score matching analysis to show the dependency of recovery proportion on the initial motor deficit at 3 and 6 months poststroke. RESULTS: We evaluated 1085 patients. The recovery proportions at 3 and 6 months poststroke were 0.67±0.42 and 0.75±0.39, respectively. A 1-unit decrease in the initial neurological impairment and the age at stroke onset increased the probability of achieving the full Fugl-Meyer Assessment of Lower Extremity score, which occurred at both 3 and 6 months poststroke. The prevalence of those who reach full lower limb motor recovery differs significantly between 3 and 6 months poststroke. We also found out that the recovery proportion at both 3 and 6 months poststroke is determined by the initial motor deficits of the lower limb. These results are not consistent with the proportional recovery model. CONCLUSIONS: Our results demonstrated that the proportional recovery model for the lower limb is invalid.

Design of a three-phase amplitude macro-pixel full-color complex spatial light modulator with an in-cell geometric phase retardation layer.

Complex spatial light modulation, which can simultaneously control the amplitude and phase of light, is an essential optical technology for holographic display. We propose a twisted nematic liquid crystal (TNLC) mode with an in-cell type embedded geometric phase (GP) plate for full-color complex spatial light modulation. The proposed architecture provides an achromatic full-color complex light modulation capability in the far-field plane. The feasibility and working characteristics of the design are validated through numerical simulation.

The structural connectome and motor recovery after stroke: predicting natural recovery.

Stroke patients vary considerably in terms of outcomes: some patients present 'natural' recovery proportional to their initial impairment (fitters), while others do not (non-fitters). Thus, a key challenge in stroke rehabilitation is to identify individual recovery potential to make personalized decisions for neuro-rehabilitation, obviating the 'one-size-fits-all' approach. This goal requires (i) the prediction of individual courses of recovery in the acute stage; and (ii) an understanding of underlying neuronal network mechanisms. 'Natural' recovery is especially variable in severely impaired patients, underscoring the special clinical importance of prediction for this subgroup. Fractional anisotropy connectomes based on individual tractography of 92 patients were analysed 2 weeks after stroke (TA) and their changes to 3 months after stroke (TC - TA). Motor impairment was assessed using the Fugl-Meyer Upper Extremity (FMUE) scale. Support vector machine classifiers were trained to separate patients with natural recovery from patients without natural recovery based on their whole-brain structural connectomes and to define their respective underlying network patterns, focusing on severely impaired patients (FMUE < 20). Prediction accuracies were cross-validated internally, in one independent dataset and generalized in two independent datasets. The initial connectome 2 weeks after stroke was capable of segregating fitters from non-fitters, most importantly among severely impaired patients (TA: accuracy = 0.92, precision = 0.93). Secondary analyses studying recovery-relevant network characteristics based on the selected features revealed (i) relevant differences between networks contributing to recovery at 2 weeks and network changes over time (TC - TA); and (ii) network properties specific to severely impaired patients. Important features included the parietofrontal motor network including the intraparietal sulcus, premotor and primary motor cortices and beyond them also attentional, somatosensory or multimodal areas (e.g. the insula), strongly underscoring the importance of whole-brain connectome analyses for better predicting and understanding recovery from stroke. Computational approaches based on structural connectomes allowed the individual prediction of natural recovery 2 weeks after stroke onset, especially in the difficult to predict group of severely impaired patients, and identified the relevant underlying neuronal networks. This information will permit patients to be stratified into different recovery groups in clinical settings and will pave the way towards personalized precision neurorehabilitative treatment.

Flashlight into the Function of Unannotated C11orf52 using Affinity Purification Mass Spectrometry.

For an enhanced understanding of the biological mechanisms of human disease, it is essential to investigate protein functions. In a previous study, we developed a prediction method of gene ontology (GO) terms by the I-TASSER/COFACTOR result, and we applied this to uPE1 in chromosome 11. Here, to validate the bioinformatics prediction of C11orf52, we utilized affinity purification and mass spectrometry to identify interacting partners of C11orf52. Using immunoprecipitation methods with three different peptide tags (Myc, Flag, and 2B8) in HEK 293T cell lines, we identified 79 candidate proteins that are expected to interact with C11orf52. The results of a pathway analysis of the GO and STRING database with candidate proteins showed that C11orf52 could be related to signaling receptor binding, cell-cell adhesion, and ribosome biogenesis. Then, we selected three partner candidates of DSG1, JUP, and PTPN11 for verification of the interaction with C11orf52 and confirmed them by colocalization at the cell-cell junctions by coimmunofluorescence experiments. On the basis of this study, we expect that C11orf52 is related to the Wnt signaling pathway via DSG1 from the protein-protein interactions, given the results of a comprehensive analysis of the bioinformatic predictions. The data set is available at the ProteomeXchange consortium via PRIDE repository (PXD026986).