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Abstract Among the three isoforms encoded by Rtn4, Nogo-A has been intensely investigated as a central nervous system inhibitor. Although Nogo-A expression is increased in muscles of patients with amyotrophic lateral sclerosis, its role in muscle homeostasis and regeneration is not well elucidated. In this study, we discovered a significant increase in Nogo-A expression in various muscle-related pathological conditions. Nogo−/− mice displayed dystrophic muscle structure, dysregulated muscle regeneration following injury, and altered gene expression involving lipid storage and muscle cell differentiation. We hypothesized that increased Nogo-A levels might regulate muscle regeneration. Differentiating myoblasts exhibited Nogo-A upregulation and silencing Nogo-A abrogated myoblast differentiation. Nogo-A interacted with filamin-C, suggesting a role for Nogo-A in cytoskeletal arrangement during myogenesis. In conclusion, Nogo-A maintains muscle homeostasis and integrity, and pathologically altered Nogo-A expression mediates muscle regeneration, suggesting Nogo-A as a novel target for the treatment of myopathies in clinical settings.

Abstract Individuals with myotonic dystrophy type 1 (DM1) reportedly have a higher risk of postoperative complications than those without DM1; however, factors related to perioperative complications in DM1 patients remain unclear. We aimed to identify the risk factors that may be associated with postoperative complications in DM1 patients. We reviewed medical records of 256 patients with DM1 from 1998 to 2018, among whom 42 (16.4%) had previously undergone 51 surgeries under general and regional anaesthesia. Among the 42 patients, 11 (21.5%) had 13 postoperative complications including respiratory complications, sustained hypotension, wound infection and dehiscence, artery thrombosis and occlusion, and delayed recovery from anaesthesia. There were significant inter-group differences between the non-complicated and complicated groups considering the following parameters: high-grade (≥ 3) muscular impairment rating scale (MIRS), extubation time, postoperative opioid use, and hospital length of stay. Furthermore, univariate analysis revealed that an MIRS score ≥ 3 (odds ratio [OR] 9.346, confidence interval [CI] 1.761–49.595, p = 0.009) and postoperative opioid use (OR 8.000, CI 1.772–36.127, p = 0.007) were the only statistically significant factors. Therefore, clinicians should be cautious in administering opioids, particularly in patients with a high-grade MIRS score during the perioperative period.

Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare neurological genetic disease caused by deletion of the peripheral myelin protein 22 gene and presents in childhood or young adulthood. We report four cases of HNPP with typical and rare presentations, reflecting the broad clinical spectrum of this disease. Two patients presented with mononeuropathies that are frequently observed in HNPP; the remaining two presented with bilateral neuropathy or mononeuropathy anatomically present in the deep layer. This reflects the broad clinical presentation of HNPP, and clinicians should differentiate these conditions in young patients with monoparesis or bilateral paresis. Although HNPP is currently untreatable, early diagnosis in the emergency department can lead to early detection, eventually resulting in less provocation and recurrence which may cause early motor nerve degeneration.

Abstract Background Citrus sunki Hort. ex Tanaka peel has been traditionally used as an ingredient in folk medicine due to its therapeutic effects on promotion of splenic health and diuresis as well as relief of gastrointestinal symptoms. Although a growing interest in health-promoting natural products and the development of highly concentrated products have facilitated consumption of C. sunki peel, its safety assessment has not been explored, posing a potential health risk. In this study, we carried out a series of systemic and genetic toxicity tests on fermented C. sunki peel extract (FCPE) to provide the essential information required for safe use in human. Methods We conducted acute and 90-day repeated oral toxicity studies in Sprague-Dawley rats to evaluate systemic toxicity, and three genotoxicity assays to measure bacterial mutation reversion, cellular chromosome aberration and in vivo micronucleus formation. Results Single oral administration of FCPE did not cause any clinical signs and lethality in all animals, establishing LD50 to be over 2000 mg/kg BW. Repeated administration of up to 2000 mg/kg BW FCPE for 90 days revealed no test substance-related toxicity as demonstrated in analysis of body weight gain, food/water intake, blood, serum biochemistry, organ weight and histopathology, collectively determining that the no-observable-adverse-effect-level of FCPE is over 2000 mg/kg BW. In addition, we detected no mutagenicity and clastogenicity in FCPE at 5000 μg/plate for the in vitro assays and 2000 mg/kg BW for the in vivo micronucleus test. Conclusion FCPE did not cause systemic and genetic toxicity in our model systems at the tested dose levels. These results suggest a guideline for safe consumption of C. sunki peel in human.

Abstract To test the hypothesis that aspirin, non-aspirin nonsteroidal anti-infammatory drugs (NA-NSAIDs), or acetaminophen can reduce the risk of ALS, we conducted a systematic review and meta-analysis of related previous studies. A comprehensive search was conducted on the PubMed, Embase, Cochrane Library and SCOPUS databases. It included studies published up to 29 February 2020 that fulfilled our inclusion criteria. Aspirin, acetaminophen and NA-NSAIDs use information, between the ALS and control groups, was collected for the meta-analysis. Rates of aspirin, NA-NSAID, and acetaminophen use in ALS group, compared with control group were investigated. In the results, only three studies that relate the risk of ALS to aspirin, NA-NSAIDs and acetaminophen use satisfied the inclusion criteria for the meta-analysis. Regarding aspirin, the studies did not show any statistically significant difference in aspirin use between the ALS and control groups (Odds ratio, 1.04 [95% confidence interval, 0.90–1.21]). NA-NSAIDs and acetaminophen use, however, did show up statistically significant differences in between the ALS and control groups. (Odds ratio, 0.82 [95% confidence interval, 0.73–0.91]) and (Odds ratio, 0.80 [95% confidence interval, 0.69–0.93]). However, our study has some limitations. Firstly, we only included a small number of studies. Secondly, the included studies did not control for past medical history, which may have confounded their results, and in turn, could have caused bias in our study. Thirdly, in this meta-analysis, the ALS patients were not subdivided into sporadic or familial type. Lastly, the studies also did not consider the types of NSAIDs and dosages used of each drug. For more convincing evidence regarding the effectiveness of aspirin, NA-NSAIDs and acetaminophen to reduce the risk of ALS occurrence, more qualified prospective studies are required. In conclusion, the use of NA-NSAIDs and acetaminophen is associated with a decreased risk for the development of ALS. In contrast, aspirin did not have any effect on the reduction of the risk of ALS occurrence.

Occupational safety and health is among the most challenging issues in many industrial workplaces, in that various factors can cause occupational illness and injury. Robotics, automation, and other state-of-the-art technologies represent risks that can cause further injuries and accidents. However, the tools currently used to assess risks in workplaces require manual work and are highly subjective. These tools include checklists and work assessments conducted by experts. Modern Industry 4.0 technologies such as a digital twin, a computerized representation in the digital world of a physical asset in the real world, can be used to provide a safe and healthy work environment to human workers and can reduce occupational injuries and accidents. These digital twins should be designed to collect, process, and analyze data about human workers. The problem is that building a human-focused digital twin is quite challenging and requires the integration of various modern hardware and software components. This paper aims to provide a brief survey of recent research papers on digital twins, focusing on occupational safety and health applications, which is considered an emerging research area. The authors focus on enabling technologies for human data acquisition and human representation in a virtual environment, on data processing procedures, and on the objectives of such applications. Additionally, this paper discusses the limitations of existing studies and proposes future research directions.

Purpose Pseudoarthrosis and metal failure at L5-S1 following long fusion surgery for adult spinal deformity (ASD) remain major issues. Few studies report on which anterior column support technique is better in terms of achieving fusion and avoiding metal failures. Our study aimed to evaluate the fusion status and metal failure rate at L5-S1 after anterior lumbar interbody fusion (ALIF) versus transforaminal lumbar interbody fusion (TLIF). Methods The study population included patients aged >50 years who underwent surgery for ASD. Anterior column supports at L5-S1 using ALIF and TLIF were compared with ≥ 2-year follow-up. Fusion status on 2-year computed tomography (CT) scan, metal failure, visual analog scale (VAS), and Oswestry disability index (ODI) were evaluated. Results 98 patients were included in this study (53 ALIF group and 45 TLIF group). We achieved solid fusion on 2-year CT scans in 88.9% and 69.8% patients in the TLIF and ALIF group, respectively. Metal failure developed in nine (17.0%) and six (13.3%) patients in the ALIF and TLIF group, respectively. The most common failure type was unilateral L5-S1 rod fracture (7 and five patients in the ALIF and TLIF group, respectively). Only one patient with bilateral rod fractures in the ALIF group required revision surgery. There were no differences in the VAS and ODI scores at the last follow-up. Conclusions TLIF showed a better fusion rate than ALIF at L5-S1 after long instrumented fusion for ASD. However, the capacity to restore sagittal parameters was greater in the ALIF group. There were no differences between the groups regarding metal failure rate, revision surgery, or clinical outcomes.

Abstract Background We report a rare case of an 18-year-old male with unilateral hand tremor who was finally diagnosed with Hirayama disease (HD). Case presentation An 18-year-old male presented with unilateral polymyoclonus that aggravated with neck flexion. The patient did not complain of muscle weakness or muscle atrophy. The needle electromyography showed giant motor unit potentials in right cervical 7 and 8 innervated muscles. The cervical magnetic resonance imaging on supine and flexion state showed prominent forward effacement of posterior dural sac that was compatible with HD. Conclusions HD usually presents with unilateral distal hand weakness, muscle atrophy and tremor. Although it is a benign and self-limiting disease, early diagnosis may lead to less clinical deterioration. Moreover, electromyography should be completed in the differentiation of young male patients who present with polymyoclonus without hand weakness or atrophy.

Abstract Hereditary spastic paraplegia (HSP) is a heterogeneous inherited disorder that manifests with lower extremity weakness and spasticity. HSP can be inherited by autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have shown that, although rare, mutations in a single gene can lead to multiple patterns of inheritance of HSP. We enrolled the HSP family showing autosomal dominant inheritance and performed genetic study to find the cause of phenotype in this family. We recruited five members of a Korean family as study participants. Four of the five family members had pure HSP. Part of the family members underwent whole-exome sequencing (WES) to identify the causative mutation. As the result of WES and Sanger sequencing analysis, a novel missense mutation (c.452 C > T, p.Ala151Val) of ERLIN2 gene was identified as the cause of the autosomal dominant HSP in the family. Our study suggests that the ERLIN2 gene leads to both autosomal recessive and autosomal dominant patterns of inheritance in HSP. Moreover, autosomal dominant HSP caused by ERLIN2 appears to cause pure HSP in contrast to autosomal recessive ERLIN2 related complicated HSP (SPG18).

Fibroblastic reticular cells (FRC) are important for lymph node (LN) structure and function. Here the authors show that the YAP/TAZ complex downstream of Hippo signalling regulates FRC commitment and maturation, with YAP/TAZ deficiency impairing FRC differentiation, while hyperactivation of YAZ/TAZ inducing myofibroblastic FRCs and LN fibrosis.

Background: Spinal and bulbar muscular atrophy (SBMA) is an X-lined motor neuron disease characterized by progressive muscle weakness, bulbar palsy, and dysphagia. Dysphagia is associated with tongue weakness, which is a common manifestation of SBMA. This study aimed to investigate the correlations between tongue pressure and dysphagia in patients with SBMA.Materials and Methods: Thirty-nine genetically confirmed SBMA patients underwent a videofluoroscopic swallowing study (VFSS) and tongue pressure assessment. Then, we analyzed the maximal tongue pressure (MTP), oral transit time, penetration-aspiration scale (PAS), videofluoroscopic dysphagia scale (VDS), amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and 6-min walk test (6MWT). Pearson and Spearman correlation coefficients were calculated to analyze the association of the MTP with clinical, swallowing, and functional parameters.Results: In the correlation analysis, MTP was negatively correlated with disease duration (r = −0.396, p = 0.013) and VDS (r = −0.426, p = 0.007), and positively correlated with ALSFRS-R (r = 0.483, p = 0.002) and 6MWT (r = 0.396, p = 0.013). The bulbar (r = 0.367, p = 0.022) and gross motor (r = 0.486, p = 0.002) domains of the ALSFRS-R were correlated with MTP.Conclusion: Tongue pressure assessment can be used as a safe and easy tool to assess swallowing function in SBMA patients. Moreover, MTP reflects functional states, including activities of daily living and gait performance, showing it to be a potential biomarker for physical performance in SBMA.

Acer tegmentosum Maxim., commonly known as Manchurian stripe maple, is a deciduous tree belonging to the family of Aceraceae and has been traditionally used in folk medicine for its remedial effects in liver diseases and traumatic bleedings. With a growing body of experimental evidence for its pharmacological efficacies, such as neuroprotective, hepatoprotective, antioxidant, and anti-inflammatory activities, A. tegmentosum has gradually gained popularity as a health supplement and functional food. However, the large part of essential toxicity information still remained lacking despite the possibility of mutagenic potentials as previously suggested, posing safety concerns for human consumption. In this study, we evaluated 90-day repeated oral toxicity of A. tegmentosum Maxim. water extract (ATWE) in SD rats with acute toxicity assessment in beagle dogs, and reevaluated genotoxicity using a combination of in vitro and in vivo assays. During the oral study period, ATWE did not cause toxicity-related clinical signs and mortality in rodents without adverse effects observed in the analysis of hematology, serum biochemistry, and histopathology, establishing >5,000 mg/kg BW as the NOAEL. In addition, doses up to 5,000 mg/kg BW did not cause acute toxicity in beagle dogs. When assessed for genotoxicity using bacterial reverse mutation, chromosome aberration, and micronucleus formation, ATWE showed lack of mutagenicity and clastogenicity. These results demonstrated that AWTE was safe in the present preclinical study for systemic toxicity and genotoxicity at the tested doses, providing a guideline for safe use in humans.

Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes. In this study, we clarify the functional role it plays in the morphological characteristics of intracellular vesicle formation as well as apoptosis in A549 human lung cancer cells. CBD treatment shows growth inhibition at concentrations above 20 μM, but FACS analysis shows low efficacy in terms of cell death. Microscopic observations suggest that multiple vesicles were detected in the cytoplasmic region of CBD-treated A549 cells. CBD treatment upregulates apoptosis-related proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin, indicating that CBD regulates several types of cell death. CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components. Treatment combining CBD with GW9662, a PPARγ inhibitor, reduced CBD-induced cytoplasmic vesicle formation. This indicates that PPARγ regulates the vesicle-formation mechanism. However, CBD-treated E-cad KO clones did not show this regulatory mechanism. These results elucidate the pharmacological and molecular networks associated with CBD in PPARγ-dependent vesicle formation and the induction of apoptosis.

Objective. Many patients with postpolio syndrome (PPS) experience pain. In this study, we aimed to review previous studies to investigate the effectiveness of intravenous immunoglobulin (IVIG) for managing pain in patients with PPS. We performed a narrative review. Methods. In PubMed, we searched for the keywords ((Immunoglobulin OR IVIG) AND (poliomyelitis OR poliomyelitis syndrome)). We included articles in which IVIG was infused in patients with PPS and pain severity was measured before and after treatment. Results. In the results, five articles (4 randomized controlled trials and 1 prospective observational study) were included in this review. Four of the studies reported that IVIG had a positive pain-reducing effect in patients with PPS. In addition, 4 studies evaluated the outcomes related to muscle strength and function. Of these studies, 3 showed some improvement in measurements for muscle strength and function. Conclusion. In conclusion, IVIG might be one of the beneficial options for managing pain in PPS. Pain reduction might be responsible for the improvement of muscle strength or function. To confirm the benefits of IVIG in reducing pain, more high-quality studies are required.

Background: Despite the high incidence of muscle weakness in patients with amyotrophic lateral sclerosis (ALS), the effects of therapeutic exercise on these individuals have not been clearly determined.Methods: A comprehensive database search was conducted on PubMed, Embase, Cochrane Library, and SCOPUS. We included studies published up to December 31, 2019 that fulfilled our inclusion and exclusion criteria. Functional status was determined as the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score (previous and revised versions) before and after a therapeutic exercise program for the meta-analysis. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used for the methodological quality assessments of included studies. The meta-analysis was performed using the RevMan v.5.3.Results: A total of 94 patients in the experimental group (who received therapeutic exercise) and 159 patients in the control group (who received conventional exercise or therapy) were included from five randomized controlled trials. The decrement of ALSFRS (previous version), ALSFRS-R (revised version), and ALSFRS-R-Respiratory scores at the 6-month evaluation were less for the therapeutic exercise group as compared to the control group. However, at the 6-month evaluation, the ALSFRS-R-Limb scores did not significantly differ between the two groups.Conclusions: Therapeutic exercise appears beneficial for patients with ALS. Further, it appears to exert more of a cardiopulmonary benefit, as opposed to preventing the progression of limb weakness. However, as the therapeutic exercises applied in each included study were not uniform, the result of our meta-analysis should be considered cautiously.

Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spasticity and paralysis of the lower limbs. Autosomal dominant mutations in SPAST gene account for ∼40% of adult-onset patients. We have previously shown that SPAST patient cells have reduced organelle transport and are therefore more sensitive to oxidative stress. To test whether these effects are present in neuronal cells, we first generated 11 induced pluripotent stem (iPS) cell lines from fibroblasts of three healthy controls and three HSP patients with different SPAST mutations. These cells were differentiated into FOXG1-positive forebrain neurons and then evaluated for multiple aspects of axonal transport and fragmentation. Patient neurons exhibited reduced levels of SPAST encoded spastin, as well as a range of axonal deficits, including reduced levels of stabilized microtubules, lower peroxisome transport speed as a consequence of reduced microtubule-dependent transport, reduced number of peroxisomes, and higher density of axon swellings. Patient axons fragmented significantly more than controls following hydrogen peroxide exposure, suggesting for the first time that the SPAST patient axons are more sensitive than controls to the deleterious effects of oxidative stress. Treatment of patient neurons with tubulin-binding drugs epothilone D and noscapine rescued axon peroxisome transport and protected them against axon fragmentation induced by oxidative stress, showing that SPAST patient axons are vulnerable to oxidative stress-induced degeneration as a consequence of reduced axonal transport.

Recent studies on Myotonic dystrophy type 1 (DM1) have shown profound impairments in gait, leading to falls. We analyzed functional ambulation profile (FAP) score that reflects the temporal and spatial gait characteristics and investigated correlations with the lower limb muscle magnetic resonance imaging (MRI) and 6 min walk test (6MWT). Twenty patients with DM1 and 20 controls participated in this study. The 6MWT and gait analysis including FAP scores via GAITRite were performed in all patients and controls. DM1 patients displayed slower gait, shorter stride length, shorter stance length, and lower FAP score. Among lower extremity muscles, the gastrocnemius, soleus and tibialis anterior showed the most severe fat infiltration and these crural muscles significantly correlated with FAP and 6MWT. Among crural muscles, tibialis anterior was the most important muscle affecting gait speed, whereas the gastrocnemius contributed substantially to gait instability. FAP score correlated with the muscle imaging and 6MWT in DM1. Therefore, FAP score maybe used as an non-invasive marker that reflects deterioration of gait and a possible surrogate biomarker in DM1.

Abstract Recombination activating gene-2 (RAG-2) plays a crucial role in the development of lymphocytes by mediating recombination of T cell receptors and immunoglobulins, and loss of RAG-2 causes severe combined immunodeficiency (SCID) in humans. Rag-2 knockout mice created using homologous recombination in ES cells have served as a valuable immunodeficient platform, but concerns have persisted on the specificity of Rag-2-related phenotypes in these animals due to the limitations associated with the genome engineering method used. To precisely investigate the function of Rag-2, we recently established a new Rag-2 knockout FVB mouse line (Rag-2-/-) manifesting lymphopenia by employing a CRISPR/Cas9 system at Center for Mouse Models of Human Disease. In this study, we further characterized their phenotypes focusing on histopathological analysis of lymphoid organs. Rag-2-/- mice showed no abnormality in development compared to their WT littermates for 26 weeks. At necropsy, gross examination revealed significantly smaller spleens and thymuses in Rag-2-/- mice, while histopathological investigation revealed hypoplastic white pulps with intact red pulps in the spleen, severe atrophy of the thymic cortex and disappearance of follicles in lymph nodes. However, no perceivable change was observed in the bone marrow. Moreover, our analyses showed a specific reduction of lymphocytes with a complete loss of mature T cells and B cells in the lymphoid organs, while natural killer cells and splenic megakaryocytes were increased in Rag-2-/- mice. These findings indicate that our Rag-2-/- mice show systemic lymphopenia with the relevant histopathological changes in the lymphoid organs, suggesting them as an improved Rag-2-related immunodeficient model.

Abstract Atomic force microscopy (AFM) nanomanipulation has been viewed as a deterministic method for the assembly of plasmonic metamolecules because it enables unprecedented engineering of clusters with exquisite control over particle number and geometry. Nevertheless, the dimensionality of plasmonic metamolecules via AFM nanomanipulation is limited to 2D, so as to restrict the design space of available artificial electromagnetisms. Here, we show that “2D” nanomanipulation of the AFM tip can be used to assemble “3D” plasmonic metamolecules in a versatile and deterministic way by dribbling highly spherical and smooth gold nanospheres (NSs) on a nanohole template rather than on a flat surface. Various 3D plasmonic clusters with controlled symmetry were successfully assembled with nanometer precision; the relevant 3D plasmonic modes (i.e., artificial magnetism and magnetic-based Fano resonance) were fully rationalized by both numerical calculation and dark-field spectroscopy. This templating strategy for advancing AFM nanomanipulation can be generalized to exploit the fundamental understanding of various electromagnetic 3D couplings and can serve as the basis for the design of metamolecules, metafluids, and metamaterials.

No studies of the current status of treatment options are available for ankylosing spondylitis (AS) patients in South Korea. This study assesses the current status of AS treatment trends using a nationwide database. This study was conducted using a Korean National Health Insurance System (KNHIS) dataset from 2006 to 2016. We randomly extracted 50% of the total number of patients registered as As patients in the KNHIS. The distribution of the number of patients according to age and gender was analyzed each year. The types and combination methods of drugs used during the study period were estimated yearly. Between 2006 and 2016, the number of AS patients increased linearly by an average of 9% annually, 6372 in 2006 to 15188 in 2016. The study found that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was the most commonly prescribed pharmacological treatment option, followed by disease-modifying anti-rheumatic drugs (DMARDs) and then biologics. Biologics such as tumor necrosis factor alpha (TNF-α) inhibitors increased from 10% to 35% consistently for 10 years. In terms of combination therapy, DMARDs + NSAIDs accounted for almost 90% of treatments in 2006, but decreased by 65% in 2016. The use of biologics and NSAIDs increased from 3% to 28%. Prescriptions for dual therapies and mono therapies largely dominated prescription habits, accounted for up to approximately 80% of treatments. Among 10- to 14-year-old patients, there was no triple therapy, dual and triple therapies decreased gradually for those 60 and older, and the ratio of conservative treatments has increased. This study shows how South Korea reflects changes in AS treatment trends, along with the emergence of TNF-α inhibitors that are effective in treating AS. Research on clinical outcomes for AS treatments will be needed on following these drug changes.

[This corrects the article DOI: 10.1371/journal.pone.0222692.].

This paper proposes a novel genetic algorithm (GA) approach that utilizes a multichromosome to solve the flexible job-shop scheduling problem (FJSP), which involves two kinds of decisions: machine selection and operation sequencing. Typically, the former is represented by a string of categorical values, whereas the latter forms a sequence of operations. Consequently, the chromosome of conventional GAs for solving FJSP consists of a categorical part and a sequential part. Since these two parts are different from each other, different kinds of genetic operators are required to solve the FJSP using conventional GAs. In contrast, this paper proposes a unified GA approach that enables the application of an identical crossover strategy in both the categorical and sequential parts. In order to implement the unified approach, the sequential part is evolved by applying a candidate order-based GA (COGA), which can use traditional crossover strategies such as one-point or two-point crossovers. Such crossover strategies can also be used to evolve the categorical part. Thus, we can handle the categorical and sequential parts in an identical manner if identical crossover points are used for both. In this study, the unified approach was used to extend the existing COGA to a unified COGA (u-COGA), which can be used to solve FJSPs. Numerical experiments reveal that the u-COGA is useful for solving FJSPs with complex structures.

Background: This study was done to compare the efficacy of a recently developed eosinophil-derived neurotoxin (EDN) ELISA kit (“BioTracer™ K® EDN ELISA Kit”) to a commercially available EDN ELISA kit (“MBL EDN ELISA Kit”) and demonstrate the usefulness of serum EDN measurement in young asthmatic children. Methods: Forty-eight children with physician-diagnosed asthma (Asthma group) and 31 age-matched normal controls (Control group) were recruited from the Asthma and Allergy Center at Inje University Sanggye Paik Hospital, Seoul, Korea from January 2010 to September of 2012. EDN levels in each serum specimen were measured 2 times using the: 1) BioTracer™ K® EDN ELISA Kit and 2) MBL EDN ELISA Kit at the Inje University Sanggye Paik Hospital laboratory. EDN level measurements in each serum specimen were compared. Results: EDN measurements from the BioTracer™ K® EDN ELISA Kit correlated well with those from the MBL EDN ELISA Kit: r = 0.9472 at the Inje University Sanggye Paik Hospital laboratory. These r values were considered both clinically relevant (i.e., r > 0.85) and statistically significant (p

[This corrects the article DOI: 10.1371/journal.pone.0220810.].

Among a variety of comorbidities of ankylosing spondylitis (AS), the association between dementia and AS by using an extensive dataset from the Korean National Health Insurance System was evaluated in this study. We extracted 15,547 newly diagnosed AS subjects among the entire Korean population and excluded wash-out patients (n = 162) and patients that were inappropriate for cohort match (n = 1192). Finally, 14,193 subjects were chosen as the AS group, and through 1:5 age- and sex-stratified matching, 70,965 subjects were chosen as the control group. We evaluated patient demographics, household incomes, and comorbidities, including hypertension, diabetes, and dyslipidemia. The prevalence of overall dementia (1.37%) and Alzheimer's dementia (AD) (0.99%) in the AS group was significantly higher than in the control group (0.87% and 0.63%), respectively. The adjusted hazard ratio of the AS group for overall dementia (1.758) and AD (1.782) showed statistical significance also. On the other hand, the prevalence of vascular dementia did not differ significantly between the two groups. Subgroup analyses revealed the following risk factors for dementia in the AS group: male gender, greater than 65 years in age, fair income (household income greater than 20% of the median), urban residency, no diabetes, and no hypertension. From the nationwide, population-based, retrospective, longitudinal cohort study, AS patients showed a significantly higher prevalence of overall dementia and Alzheimer's dementia. Comprehensive patient assessment using our subgroup analysis could help to prevent dementia in patients suffering from AS.

Freely crawling cells are often viewed as randomly moving Brownian particles but they generally exhibit some directional persistence. This property is often related to their zigzag motile behaviors that can be described as a noisy but temporally structured sequence of "runs" and "turns." However, its underlying biophysical mechanism is largely unexplored. Here, we carefully investigate the collective actin wave dynamics associated with the zigzag-crawling movements of microglia (as primary brain immune cells) employing a number of different quantitative imaging modalities including synthetic aperture microscopy and optical diffraction tomography, as well as conventional fluorescence imaging and scanning electron microscopy. Interestingly, we find that microglia exhibit two distinct types of actin waves working at two quite different time scales and locations, and they seem to serve different purposes. One type of actin waves is fast "peripheral ruffles" arising spontaneously with an oscillating period of about 6 seconds at some portion of the leading edge of crawling microglia, where the vigorously biased peripheral ruffles seem to set the direction of a new turn (in 2-D free space). When the cell turning events are inhibited with a physical confinement (in 1-D track), the peripheral ruffles still exist at the leading edge with no bias but showing phase coherence in the cell crawling direction. The other type is "dorsal actin waves" which also exhibits an oscillatory behavior but with a much longer period of around 2 minutes compared to the fast "peripheral ruffles". Dorsal actin waves (whether the cell turning events are inhibited or not) initiate in the lamellipodium just behind the leading edge, travelling down toward the core region of the cell and disappear. Such dorsal wave propagations seem to be correlated with migration of the cell. Thus, we may view the dorsal actin waves are connected with the "run" stage of cell body, whereas the fast ruffles at the leading front are involved in the "turn" stage.

Acquired myasthenia gravis (MG) is a prototype autoimmune disease of the neuromuscular junction, caused in most patients by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). There seem to be ethnic and regional differences in the frequency and clinical features of MG seronegative for the AChR antibody. This study aimed to describe the autoantibody profiles and clinical features of Korean patients with generalized MG seronegative for the AChR antibody. A total of 62 patients with a high index of clinical suspicion of seronegative generalized MG were identified from 18 centers, and we examined their sera for antibodies to clustered AChR, muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) by cell-based assays (CBA) and to MuSK by radioimmunoprecipitation assay (RIPA). We also included 8 patients with ocular MG, 3 with Lambert-Eaton myasthenic syndrome, 5 with motor neuron disease, and 9 with other diagnoses as comparators for the serological testing. Antibodies were identified in 25/62 (40.3%) patients: 7 had antibodies to clustered AChR, 17 to MuSK, and 2 to LRP4. Three patients were double seropositive: 1 for MuSK and LRP4, and 2 for MuSK and clustered AChR. The patients with MuSK antibodies were mostly female (88.2%) and characterized by predominantly bulbar involvement (70%) and frequent myasthenic crises (58.3%). The patients with antibodies to clustered AChR, including 2 with ocular MG, tended to have a mild phenotype and good prognosis.

Transplantation of mesenchymal stem cells (MSCs) has been shown to enhance the recovery of brain functions following ischemic injury. Although immune modulation has been suggested to be one of the mechanisms, the molecular mechanisms underlying improved recovery has not been clearly identified. Here, we report that MSCs secrete transforming growth factor-beta (TGF-β) to suppress immune propagation in the ischemic rat brain. Ischemic stroke caused global death of resident cells in the infarcted area, elevated the monocyte chemoattractant protein-1 (MCP-1) level, and evoked massive infiltration of circulating CD68+ immune cells through the impaired blood–brain barrier. Transplantation of MSCs at day 3 post-ischemia blocked the subsequent upregulation of MCP-1 in the ischemic area and the infiltration of additional CD68+ immune cells. MSC-conditioned media decreased the migration and MCP-1 production of freshly isolated immune cells in vitro, and this effect was blocked by an inhibitor of TGF-β signaling or an anti-TGF-β neutralizing antibody. Finally, transplantation of TGF-β1-silenced MSCs failed to attenuate the infiltration of CD68+ cells into the ischemic brain, and was associated with only minor improvements in motor function. These results indicate that TGF-β is key to the ability of MSCs to beneficially attenuate immune reactions in the ischemic brain. Our findings offer insight into the interactions between allogeneic MSCs and the host immune system, reinforcing the prospective clinical value of using MSCs in the treatment of neurological disorders involving inflammation-mediated secondary damage.

Introduction: A glomus tumor is a rare, benign tumor with atypical clinical symptoms. Because of its small size, it is difficult to diagnose and treat early; therefore, it leads to poor quality of life. Glomus tumors are known to commonly affect the hand and rarely manifest in other areas. Because they simulate neuromas, hemangiomas, and neurofibromatosis, the differential diagnosis is difficult. We performed marginal resection of a solitary forearm mass previously suspected to be a hemangioma or glomus tumor on the basis of ultrasound findings and histologically diagnosed to be a glomus tumor afterward. We report this case to demonstrate the good prognosis of the procedure we used, and we review the relevant literature.Case Presentation: A 68-year-old Asian man without a particular medical history visited our hospital with a mass with focal tenderness in his left distal forearm that had developed 8 years earlier. The tumor was observed with suspicion of being a hemangioma or glomus tumor based on the location, clinical symptoms, and ultrasound findings taken into consideration together. The biopsy results led us to conclude that the lesion was a glomus tumor.Conclusions: A glomus tumor located in the forearm is very rare. It is often clinically overlooked and is likely to be misdiagnosed as another disease. The patient's quality of life deteriorates, and, though the disease is rare, it has serious sequelae. Therefore, a quick diagnosis and appropriate treatment must be conducted early. If a mass occurs with serious pain in subcutaneous soft tissue of not the hands but the limbs, it is important to conduct examinations with suspicion of a glomus tumor. Ultrasonography performed quickly may be useful for making the differential diagnosis. [ABSTRACT FROM AUTHOR]

Populations of biological cells that communicate with each other can organize themselves to generate large-scale patterns. Examples can be found in diverse systems, ranging from developing embryos, cardiac tissues, chemotaxing ameba and swirling bacteria. The similarity, often shared by the patterns, suggests the existence of some general governing principle. On the other hand, rich diversity and system-specific properties are exhibited, depending on the type of involved cells and the nature of their interactions. The study on the similarity and the diversity constitutes a rapidly growing field of research. Here, we introduce a new class of self-organized patterns of cell populations that we term as ‘cellular trail networks’. They were observed with populations of rat microglia, the immune cells of the brain and the experimental evidence suggested that haptotaxis is the key element responsible for them. The essential features of the observed patterns are well captured by the mathematical model cells that actively crawl and interact with each other through a decomposing but non-diffusing chemical attractant laid down by the cells. Our finding suggests an unusual mechanism of socially cooperative long-range signaling for the crawling immune cells.