The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors.

VAP proteins (human VAPB/ALS8, Drosophila VAP33, and C. elegans VPR-1) are homologous proteins with an amino-terminal major sperm protein (MSP) domain and a transmembrane domain. The MSP domain is named for its similarity to the C. elegans MSP protein, a sperm-derived hormone that binds to the Eph receptor and induces oocyte maturation. A point mutation (P56S) in the MSP domain of human VAPB is associated with Amyotrophic lateral sclerosis (ALS), but the mechanisms underlying the pathogenesis are poorly understood. Here we show that the MSP domains of VAP proteins are cleaved and secreted ligands for Eph receptors. The P58S mutation in VAP33 leads to a failure to secrete the MSP domain as well as ubiquitination, accumulation of inclusions in the endoplasmic reticulum, and an unfolded protein response. We propose that VAP MSP domains are secreted and act as diffusible hormones for Eph receptors. This work provides insight into mechanisms that may impact the pathogenesis of ALS.

Second-order moiré method for accurate deformation measurement with a large field of view.

In this study, we propose a second-order moiré method by performing digital sampling at two stages to realize high-accuracy deformation measurement in a wide field of view, where a grid image is recorded at a low magnification. Simulations have verified that this method has high strain measurement accuracy when the grid pitch is close to or even smaller than two pixels for both parallel and oblique grids with random noise. As an application, the two-dimensional microscale strain distributions of a carbon fiber reinforced plastic specimen when the grid pitch was about 2.1 pixels were presented. Shear strain concentration was detected before an interlaminar crack emerged, and tensile strain concentration was found prior to the occurrence of a transverse crack. The proposed method makes the two-step phase-shifting technique achieved indirectly, not only enlarging the field of view, but also maintaining the measurement accuracy.

Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology.

OBJECTIVE: Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain. METHODS: Structural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes. RESULTS: We found that G51D α-syn fibrils have higher ß-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment. CONCLUSION: Our findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

A clinicopathological study of ALS with L126S mutation in the SOD1 gene presenting with isolated inferior olivary hypertrophy.

We report an autopsy case of amyotrophic lateral sclerosis with L126S mutation in the superoxide dismutase 1 (SOD1) gene (SOD1). The patient was a 69-year-old Japanese man without relevant family history, who initially presented with slow progressive muscle weakness of the lower extremities without upper motor neuron signs, and died of respiratory failure 6 years after the onset. Neuropathological examination revealed a loss of lower motor neurons and degeneration of Clarke's column commensurate with that of the posterior spinocerebellar tract and the middle root zone of the posterior column. The primary motor area was minimally affected. Characteristic SOD1-immunopositive neuronal intracytoplasmic inclusions, mixed with neurofilament accumulation, were present in the affected areas. Isolated inferior olivary hypertrophy was observed, but did not involve the contralateral dentate nucleus, or the ipsilateral red nucleus and central tegmental tract, where no neuronal inclusions were found. In combination with data from a previous autopsy case, this study suggests that the L126S mutation may cause focal neuronal degeneration in the brainstem.

Nanometer-order thermal deformation measurement by a calibrated phase-shifting digital holography system.

A thermal deformation measurement system based on calibrated phase-shifting digital holography is proposed. Two synchronized ordinary CMOS cameras are used in the calibrated phase-shifting digital holography system. One is to record the holograms including the object information, and the other is to record the interference fringes to evaluate phase-shifting errors. The calibrated phase-shifting digital holography can provide the high quality reconstructed images which are applied to calculate the thermal deformation of the object. Meanwhile, the thermal images of the object at different temperatures are recorded by a thermal camera. Nanometer-order thermal deformation measurement of an electronic device is achieved in a real experiment. Our measurement system could be useful for electric packaging materials development or the system design.

Computerized Hammer Sounding Interpretation for Concrete Assessment with Online Machine Learning.

Developing efficient Artificial Intelligence (AI)-enabled systems to substitute the human role in non-destructive testing is an emerging topic of considerable interest. In this study, we propose a novel hammering response analysis system using online machine learning, which aims at achieving near-human performance in assessment of concrete structures. Current computerized hammer sounding systems commonly employ lab-scale data to validate the models. In practice, however, the response signal patterns can be far more complicated due to varying geometric shapes and materials of structures. To deal with a large variety of unseen data, we propose a sequential treatment for response characterization. More specifically, the proposed system can adaptively update itself to approach human performance in hammering sounding data interpretation. To this end, a two-stage framework has been introduced, including feature extraction and the model updating scheme. Various state-of-the-art online learning algorithms have been reviewed and evaluated for the task. To conduct experimental validation, we collected 10,940 response instances from multiple inspection sites; each sample was annotated by human experts with healthy/defective condition labels. The results demonstrated that the proposed scheme achieved favorable assessment accuracy with high efficiency and low computation load.

Measurement of endometrial thickness in premenopausal women in office gynecology.

Purpose: To define the median endometrial thickness (ET) in office gynecology is thought to be important for clinical practice. However, there are few reports about ET that have included the general female population on a large scale. The median ET was determined prospectively in premenopausal women who attended office gynecology for cervical cancer screening. Methods: In total, 849 women were enrolled. The median ET was determined by using transvaginal ultrasound and the relationships between the ET and various clinical factors were analyzed. Results: The participants' median age was 38.5 years. The median ET was 8.6 mm (90% and 95% quantiles: 13.8 and 15.8 mm). The ET was not related to their age, symptoms, obstetric history, geographical location, or risk factors for endometrial cancer. In the women with a menstrual cycle length of 28-30 days, the ET was 7 mm on days 1-6, but it increased from 5.4 mm immediately after menstruation (day 7 or 8) to 9.2 mm on days 13-14. Subsequently, the ET increased further to 11.1 mm on day 18. Conclusion: In all the women, the upper limit of the ET was 13.8 mm and 15.8 mm in the 90% and 95% quantile, respectively, in office gynecology.

Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response.

Missense mutations (P56S) in Vapb are associated with autosomal dominant motor neuron diseases: amyotrophic lateral sclerosis and lower motor neuron disease. Although transgenic mice overexpressing the mutant vesicle-associated membrane protein-associated protein B (VAPB) protein with neuron-specific promoters have provided some insight into the toxic properties of the mutant proteins, their role in pathogenesis remains unclear. To identify pathological defects in animals expressing the P56S mutant VAPB protein at physiological levels in the appropriate tissues, we have generated Vapb knock-in mice replacing wild-type Vapb gene with P56S mutant Vapb gene and analyzed the resulting pathological phenotypes. Heterozygous P56S Vapb knock-in mice show mild age-dependent defects in motor behaviors as characteristic features of the disease. The homozygous P56S Vapb knock-in mice show more severe defects compared with heterozygous mice reflecting the dominant and dose-dependent effects of P56S mutation. Significantly, the knock-in mice demonstrate accumulation of P56S VAPB protein and ubiquitinated proteins in cytoplasmic inclusions, selectively in motor neurons. The mutant mice demonstrate induction of ER stress and autophagic response in motor neurons before obvious onset of behavioral defects, suggesting that these cellular biological defects might contribute to the initiation of the disease. The P56S Vapb knock-in mice could be a valuable tool to gain a better understanding of the mechanisms by which the disease arises.

Two-dimensional Moiré phase analysis for accurate strain distribution measurement and application in crack prediction.

Aimed at the low accuracy problem of shear strain measurement in Moiré methods, a two-dimensional (2D) Moiré phase analysis method is proposed for full-field deformation measurement with high accuracy. A grid image is first processed by the spatial phase-shifting sampling Moiré technique to get the Moiré phases in two directions, which are then conjointly analyzed for measuring 2D displacement and strain distributions. The strain especially the shear strain measurement accuracy is remarkably improved, and dynamic deformation is measurable from automatic batch processing of single-shot grid images. As an application, the 2D microscale strain distributions of a titanium alloy were measured, and the crack occurrence location was successfully predicted from strain concentration.

Calibrated phase-shifting digital holography based on a dual-camera system.

A calibrated phase-shifting digital holography system based on the sampling Moiré technique is proposed. Two synchronized cameras are used in this system. One is to record the conventional holograms that include the object information, and the other is to record the interference fringes to analyze phase-shifting errors. An algorithm for improving the quality of the reconstructed images is proposed. In this Letter, the effectiveness of the proposed system and algorithm is demonstrated in four-step phase-shifting digital holography. The quality of the reconstructed images is greatly improved from both the numerical simulation and experiment.

Predictive factors for mortality in elderly Japanese patients with severe microscopic polyangiitis: A retrospective single-center study.

PURPOSE: To determine mortality and its predictive factors in elderly Japanese patients with severe microscopic polyangiitis (MPA). METHOD: This retrospective single-center study determined the mortality of 52 patients with MPA who were admitted to our geriatric medical center from 2002 to 2014. The variables at baseline, including patient demographics, clinical characteristics, and treatment, were analyzed for their association with mortality. RESULT: Mean age at onset of MPA was 73.2 years, and the one-year survival rate was 65.9%. Relapse was observed in 32.7%. Among variables at diagnosis, age, cardiomyopathy, central nervous system (CNS) involvement, alveolar hemorrhage, disease severity, the 1996 Five-Factor Score (FFS), and the 2009 FFS were associated with mortality in univariate analysis. Cardiomyopathy, CNS involvement, age >65 years, disease severity, Birmingham Vasculitis Activity Score, the 1996 FFS, and the 2009 FFS were associated with relapse-free survival in univariate analysis. CONCLUSION: We investigated mortality and relapse-free survival and their predictive factors in elderly Japanese patients with severe MPA. Age, disease severity, the 1996 FFS, and the 2009 FFS at diagnosis were prognostic factors for both mortality and relapse-free survival.

The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control.

A familial form of Amyotrophic lateral sclerosis (ALS8) is caused by a point mutation (P56S) in the vesicle-associated membrane protein associated protein B (VapB). Human VapB and Drosophila Vap-33-1 (Vap) are homologous type II transmembrane proteins that are localized to the ER. However, the precise consequences of the defects associated with the P56S mutation in the endoplasmic reticulum (ER) and its role in the pathology of ALS are not well understood. Here we show that Vap is required for ER protein quality control (ERQC). Loss of Vap in flies shows various ERQC associated defects, including protein accumulation, ER expansion, and ER stress. We also show that wild type Vap, but not the ALS8 mutant Vap, interacts with a lipid-binding protein, Oxysterol binding protein (Osbp), and that Vap is required for the proper localization of Osbp to the ER. Restoring the expression of Osbp in the ER suppresses the defects associated with loss of Vap and the ALS8 mutant Vap. Hence, we propose that the ALS8 mutation impairs the interaction of Vap with Osbp, resulting in hypomorphic defects that might contribute to the pathology of ALS8.

Safety and efficacy of the leukocytapheresis procedure in eighty-five patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory disease in which the predominant symptom is polyarthritis that follows a chronic and progressive clinical course characterized by destructive synovitis and various immune disorders. Striking progress in RA treatment was achieved with the emergence of monoclonal antibodies to target cytokines. However, drug choices are limited for many patients due to resistance to multidrug antirheumatic therapy, concomitant disease, and infection. We evaluated the efficacy of treatment in 85 patients with RA for whom leukocytapheresis (LCAP) was initiated at our hospital between 2006 and 2015. All patients continued drug therapy and were treated with LCAP once a week for up to 5 weeks. The clinical response was evaluated at the completion of LCAP series and 4 weeks later using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of European League Against Rheumatism (EULAR). The tender joint counts, swollen joint counts, and C-reactive protein (CRP) levels decreased remarkably. DAS28-CRP was significantly improved by LCAP. And furthermore, the efficacy lasted at least 4 weeks after the completion of LCAP. These results suggest that LCAP is a beneficial and are consistent with several trials' reported effect of LCAP. This treatment can contribute to improvements in activities of daily living (ADLs) and long-term outcome by improving swollen and tender joint counts and CRP levels even in refractory patients for whom the use of conventional disease-modifying antirheumatic drugs (DMARDs) and biopharmaceuticals is problematic. LCAP might be a promise therapy to refractory RA.

Digital sampling Moiré as a substitute for microscope scanning Moiré for high-sensitivity and full-field deformation measurement at micron/nano scales.

This study proposed to generate digital sampling Moiré fringes by two-pixel down-sampling as a substitute for microscope scanning Moiré fringes, and further reconstruct multiplication Moiré fringes for micron/nano-scale deformation measurement. The displacement and strain sensitivities of the proposed reconstructed multiplication Moiré method are 2 times higher in a wide field of view. Besides, two-dimensional deformation is easily measurable without rotating the sample stage or the scanning lines, no matter whether the scanning resolution is adjustable or not. As an example, the deformations of a carbon fiber reinforced plastic specimen were measured and analyzed. The proposed method effectively expands the application range of the Moiré technique to deformation measurement.

[A clinical analysis of elderly dementia patients with physical comorbidities].

AIM: To investigate the current status of elderly dementia patients with physical illnesses and identify optimal care strategies for this growing population. METHODS: This retrospective study included elderly dementia patients who (i) received in-patient treatment for a physical comorbidity at the dementia ward of the Juntendo Tokyo Koto Geriatric Medical Center, and (ii) who were discharged from April 2009 to March 2011. RESULTS: The study population was 390 patients (144 males, 246 females), with a mean [±SD] age of 80.5 [±8.1] years. Two hundred thirteen of the patients had Alzheimer's disease; the remaining 177 had other types of dementia. The comorbidities necessitating admission were: malignant neoplasms (n=65), respiratory conditions (n=57), genitourinary conditions (n=50), trauma or fracture (n=41), and other (n=177). Among the 239 subjects who were hospitalized from their homes and who were discharged alive, 157 (65.7%) returned to their homes. The hospital stays of patients who were discharged were significantly shorter (P<0.000) and their N-ADL scores were significantly better at admission (P<0.013) and at discharge (P<0.000). The proportion of subjects who were capable of oral ingestion was significantly higher among the patients who were discharged to their homes (P<0.025). The subjects who lived in their homes alone at the time of hospitalization were significantly less likely to be discharged to their homes (P<0.018). CONCLUSIONS: Elderly dementia patients should ideally return home after hospitalization for comorbid illnesses. This was facilitated by minimizing their hospital stay. During in-patient treatment, efforts should be made to maintain their N-ADL levels and support their oral intake.

100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future.

Discoveries in fruit flies have greatly contributed to our understanding of neuroscience. The use of an unparalleled wealth of tools, many of which originated between 1910­1960, has enabled milestone discoveries in nervous system development and function. Such findings have triggered and guided many research efforts in vertebrate neuroscience. After 100 years, fruit flies continue to be the choice model system for many neuroscientists. The combinational use of powerful research tools will ensure that this model organism will continue to lead to key discoveries that will impact vertebrate neuroscience.

Simultaneous analysis of the gene expression profiles of cancer and stromal cells in endometrial cancer.

To address the role of cancer-stroma interactions, we performed gene expression profiling of both cancer and stroma, using matching samples of endometrial cancer (EC), and analyzed the relationship between the gene expression pattern and prognosis in EC. Sixty EC cases were included in this study (38 nonrecurrent and 22 recurrent). Cancer and stroma were separated by performing laser capture microdissection, and microarray analysis was performed separately on cancer and stromal cells. Genes related with progression-free survival (PFS) in cancer and stroma were analyzed using the Cox regression model, and we established a formula, based on the gene expression pattern of cancer and stroma, to predict recurrence using logistic regression. We estimated the accuracy of the formula using the 0.632 method. All cases were classified based on the 79 selected genes of cancer and stroma related to PFS, based on unsupervised clustering. A total of 143 genes in cancer, and 79 genes in stroma were significantly related with PFS. The estimated area under the curve of receiver operating characteristics curve in cancer and stroma to predict recurrence were 0.800 and 0.758, respectively. Based on the 79 genes of cancer, the 22 recurrent cases were divided into two groups, which generally correlated with the histological grade. In contrast, based on the 79 genes of stroma, the 22 recurrent cases displayed homogeneous gene expression, unrelated to the histological grade. We conclude that gene expression profiles of cancer and stroma can predict the recurrence of EC and stromal that gene expression does not depend on the cancer grade.

[Blood culture results in elderly febrile patients].

AIM: We retrospectively evaluated blood culture results in elderly patients (≥65 years) with a fever due to infection. METHODS: We examined the bacteria isolated from blood cultures and compared them to bacteria detected in infected lesions that caused bacteremia. We compared the types of bacteria isolated in the two groups (the community-acquired group and the hospital-acquired group). RESULTS: Blood cultures were obtained from 638 patients. Bacteria were detected in 182 patients (28.5%), including 66 (36.3%) patients in the community-acquired group and 116 (63.7%) patients in the hospital-acquired group. There were 259 positive samples (25.1%). In arterial blood specimens, 153 (30.9%) samples were positive, while in venous blood specimens, there were 106 (19.8%) positive samples (P<0.001). In the community-acquired group, the most common bacteria identified were E. coli compared to S. epidermidis in the hospital-acquired group. More than 50% of the bacteria identified in the blood cultures were of the same species identified in the respective urine samples and central venous catheter tips. CONCLUSIONS: The bacteria detection rate in this study was 28.5% for blood cultures, which is higher than the 17.5% reported by the Japan Nosocomial Infections Surveillance Program conducted by the Japanese Ministry of Health, Labour and Welfare. These results suggest that in elderly patients from whom an insufficient volume of blood can be drawn from a vein, an arterial sample may increase the detection rate. A high percentage of bacterial species isolated from the blood cultures was also detected in urinary tract infections and central venous catheter-related infections, indicating that a blood culture is useful for detecting various infectious diseases, even in elderly febrile patients.

Accurate full-field optical displacement measurement technique using a digital camera and repeated patterns.

In this study, a novel, fast, and accurate in-plane displacement distribution measurement method is proposed that uses a digital camera and arbitrary repeated patterns based on the moiré methodology. The key aspect of this method is the use of phase information of both the fundamental frequency and the high-order frequency components of the moiré fringe before and after deformations. Compared with conventional displacement methods and sensors, the main advantages of the method developed herein are its high resolution, accuracy, speed, low cost, and easy implementation. The effectiveness is confirmed by a simple in-plane displacement measurement experiment, and the experimental results indicate that an accuracy of 1/1000 of the pitch can be achieved for various repeated patterns. This method is useful for various applications ranging from the study of displacement and strain distributions in materials science, the biomimetics field, and mechanical material testing, to secure the integrity of infrastructures.

Reduction in bradykinin generation during leukocytapheresis using novel cellsorba(TM) CS-180S: Effects of changing the filling solution.

We evaluated the bradykinin generation level during leukocytapheresis (LCAP) using novel Cellsorba(TM) CS-180S, which has sodium pyrosulfite and sodium carbonate as a filling solution. Subjects of this study were 14 rheumatoid arthritis patients. Regardless of the type of anticoagulant used, bradykinin levels were lower with the novel CS-180S than with the conventional CS-180S (28.7 ± 53.3 vs. 8.0 ± 2.7 as the mean ± standard deviation). When anticoagulants other than nafamostat mesilate were used with the conventional CS-180S, bradykinin levels increased at the column outlet compared with the column inlet, and adverse effects of bradykinin were seen in several cases. In contrast, bradykinin levels remained low and no bradykinin-associated adverse events were observed with the novel CS-180S. We recommend using the novel column instead of the conventional column in the treatment of LCAP.