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ABSTRACTThe pathological accumulation of the nuclear protein TDP-43 (TAR DNA-binding protein 43 kDa) in the cytoplasm is characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), and its spread through the brain and spinal cord is closely associated with the progression of these two diseases. However, the mechanisms through which the TDP-43 pathology propagates throughout the central nervous system remain unclear. We recently reported the role of (macro)autophagy in the secretion of TDP-43 via extracellular vesicles (EVs). We found that among the autophagy modulators, bafilomycin A1 (Baf) and GRN (granulin precursor) deficiency impair the formation of autolysosomes and promote the secretion of TDP-43 by EVs. TDP-43 loading on EVs involves autophagy-related proteins and the knockdown of TDP-43 augmented Baf-induced EV release. Thus, our results suggest that the loss-of-function of TDP-43 accelerates release of EVs possibly derived from autophagosomes, which may mediate cell-to-cell spread of the TDP-43 pathology.

(Macro)autophagy is a cellular degradation system for unnecessary materials, such as aggregate-prone TDP-43, a central molecule in neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Abemaciclib (Abe) and vacuolin-1 (Vac) treatments are known to induce vacuoles characterized by an autophagosome and a lysosome component, suggesting that they facilitate autophagosome-lysosome fusion. However, it remains unknown whether Abe and Vac suppress the accumulation of aggregate-prone TDP-43 by accelerating autophagic flux. In the present study, the Abe and Vac treatment dose-dependently reduced the GFP/RFP ratio in SH-SY5Y neuroblastoma cells stably expressing the autophagic flux marker GFP-LC3-RFP-LC3ΔG. Abe and Vac also increased the omegasome marker GFP-ATG13 signal and the autophagosome marker mCherry-LC3 localized to the lysosome marker LAMP1-GFP. The Abe and Vac treatment decreased the intracellular level of the lysosome marker LAMP1-GFP in SH-SY5Y cells stably expressing LAMP1-GFP, but did not increase the levels of LAMP1-GFP, the autophagosome marker LC3-II, or the multivesicular body marker TSG101 in the extracellular vesicle-enriched fraction. Moreover, Abe and Vac treatment autophagy-dependently inhibited GFP-tagged aggregate-prone TDP-43 accumulation. The results of a PI(3)P reporter assay using the fluorescent protein tagged-2 × FYVE and LAMP1-GFP indicated that Abe and Vac increased the intensity of the PI(3)P signal on lysosomes. A treatment with the VPS34 inhibitor wortmannin (WM) suppressed Abe-/Vac-facilitated autophagic flux and the degradation of GFP-tagged aggregate-prone TDP-43. Collectively, these results suggest that Abe and Vac degrade aggregate-prone TDP-43 by accelerating autophagosome formation and autophagosome-lysosome fusion through the formation of PI(3)P.

Abstract The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment.

Abstract Background Patients with Hodgkin lymphoma exhibit various clinical presentations. Needle biopsy of the lymph nodes is a minimally invasive procedure and a useful diagnostic method for malignant lymphomas. However, at times it is difficult to differentiate malignant lymphomas from reactive lymph node changes using a small amount of biopsy material. Case presentation A 77-year-old Japanese man was referred to the emergency department of our hospital owing to high fever and disturbance of consciousness. We diagnosed sepsis due to an acute biliary tract infection because he presented with Charcot’s triad—fever, jaundice, and right-sided abdominal pain. However, he did not respond well to antimicrobial therapy and his high fever persisted. Considering the swelling of the right cervical, mediastinal, and intraperitoneal lymph nodes and splenomegaly detected on computed tomography, a differential diagnosis of malignant lymphoma was needed. Hence, we performed a needle biopsy of the right cervical lymph node; however, the amount of sample obtained was insufficient in establishing a definitive diagnosis of malignant lymphoma. Furthermore, during hospitalization, the patient developed thrombocytopenia, anasarca, and renal insufficiency. These symptoms seemed to be the typical signs of the thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, and organomegaly syndrome. Next, an external incisional mass biopsy of the right cervical lymph node was performed, which helped identify Hodgkin and Reed–Sternberg cells. Collectively, we established a definitive diagnosis of Hodgkin lymphoma with lymphoma-associated hemophagocytic syndrome. Conclusions This case highlights the importance of performing an external incisional mass biopsy of the lymph nodes for the early diagnosis and treatment, if malignant lymphoma is strongly suspected.

Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin–proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed ERK1/2 hyperphosphorylation was attributable to an upregulation of Raf-1 expression, rather than an increase in Ras levels, Raf-1 Ser338 phosphorylation, or B-Raf levels. The elevated Raf-1 expression, stemming from PHI-1 knockdown, enhanced EGF-induced ERK1/2 phosphorylation through MEK. Moreover, PHI-1 knockdown significantly contributed to Raf-1 protein stability without affecting Raf-1 mRNA levels. Conversely, ectopic PHI-1 expression suppressed Raf-1 protein levels in a manner that correlated with PHI-1’s inhibitory potency. Inhibiting PP1 to mimic PHI-1’s function using tautomycin led to a reduction in Raf-1 expression. In summary, our findings highlight that the PHI-1-PP1 signaling axis selectively governs Raf-1 proteostasis and cell survival signals.

Abstract To implement precision oncology, analytical validity as well as clinical validity and utility are important. However, proficiency testing (PT) to assess validity has not yet been systematically performed in Japan. To investigate the quality of next-generation sequencing (NGS) platforms and cancer genome testing prevalent in laboratories, we performed pilot PT using patient samples. We prepared genomic DNA from the cancer tissue and peripheral blood of 5 cancer patients and distributed these to 15 laboratories. Most participating laboratories successfully identified the pathogenic variants, except for two closely located KRAS variants and 25 bp delins in EGFR. Conversely, the EGFR L858R variant was successfully identified, and the allele frequency was similar for all the laboratories. A high DNA integrity number led to excellent depth and reliable NGS results. By conducting this pilot study using patient samples, we were able to obtain a glimpse of the current status of cancer genome testing at participating laboratories. To enhance domestic cancer genome testing, it is important to conduct local PT and to involve the parties concerned as organizers and participants.

Purpose: This study investigated the effects of 1400 mL intake of alkaline electrolyzed water (AEW) or purified water (PW) into which carbohydrate-electrolyte (CE) was dissolved on improving physiological responses during exercise under heat stress. Methods: This double-blinded, crossover randomized controlled trial included 10 male participants who completed two exercise trials in a hot environment (35 °C, ambient temperature, and 50% relative humidity) after consuming CE-dissolved PW (P-CE) or CE-dissolved AEW (A-CE). The exercise trial consisted of running for 30 min on a treadmill (at an intensity corresponding to 65% of heart rate reserve adjusted for heat stress conditions) and repeated sprint cycling (10 × 7-s maximal sprint cycling), with a 35-min rest interval between the two exercises, followed by a 30-min post-exercise recovery period. Before and after running, and after cycling, the participants drank P-CE (hydrogen concentration of 0 ppm, pH 3.8) or A-CE (0.3 ppm, pH 4.1). Blood samples were obtained before, during (rest interval between running and cycling), and post-exercise. Results: Repeated sprint performance and oxidative stress response did not differ between the P-CE and A-CE trials. A-CE consumption significantly attenuated the increase in blood lactate concentration during the running exercise but not during repeated sprint cycling under heat stress conditions. Conclusion: Our findings suggested that A-CE did not significantly affect repeated sprint performance; however, the attenuated elevation in blood lactate by A-CE ingestion implies a partial enhancement of endurance performance during submaximal exercise under heat stress.

In our basic study that used a low water flow rate of 100 ml/min, the amount of dissolved hydrogen produced during water electrolysis varied according to the roughness factor of the electrode, which is thought to affect the state of supersaturation at the electrode surface. However, at a high-water flow rate of 500 ml/min, which is commonly used in commercial and industrial contexts, no change in the amount of dissolved hydrogen was observed as a function of electrode roughness factor. We observed that, at water flow rates used in commercial and industrial applications, increasing the electrode area made it possible to decrease the supersaturation state and increase the hydrogen dissolution efficiency.

Abstract Background An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. Methods Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as ‘early recurrence’, and recurrence more than 1 year after as ‘late recurrence’. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. Results Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026–1.087, p

Introduction: In lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) patients, prostate volume (PV) at baseline affects the improvement of International Prostate Symptom Score voiding symptoms (IPSS-VS) by naftopidil (NAF), but not total IPSS (IPSS-TS). To predict the efficacy of NAF, the PV cutoff point was examined using IPSS-VS. Materials and Methods: Seventy-seven patients with LUTS/BPH were administrated with NAF 50 mg/day for 4 weeks. Age, PV, IPSS, IPSS quality-of-life (IPSS-QoL), and maximum flow rate (MFR) were evaluated at baseline, and IPSS, IPSS-QoL, and MFR were evaluated after the treatment (at 4 weeks). Responders and nonresponders were divided by IPSS-VS at 4 weeks, and the PV cutoff point was calculated. Results: At baseline, the mean age and PV were 70.7 ± 8.2 years (range, 54–88 years) and 43.3 ± 24.5 mL (range, 20.6–141.7 mL), respectively. After 4 weeks, area under the receiver operating characteristic curve was largest in the patients with

Beam scanning lasers are required for systems for smart mobility, object recognition, and adaptive illuminations. The authors demonstrate dually modulated photonic crystals, wherein the positions and sizes of the photonic-crystal lattice points are modulated simultaneously, to achieve mechanical-free, 2D beam scanning.

Electron temperature is reconsidered for weakly-ionized oxygen and nitrogen plasmas with its discharge pressure of a few hundred Pa, with its electron density of the order of 1017m−3 and in a state of non-equilibrium, based on thermodynamics and statistical physics. The relationship between entropy and electron mean energy is focused on based on the electron energy distribution function (EEDF) calculated with the integro-differential Boltzmann equation for a given reduced electric field E/N. When the Boltzmann equation is solved, chemical kinetic equations are also simultaneously solved to determine essential excited species for the oxygen plasma, while vibrationally excited populations are solved for the nitrogen plasma, since the EEDF should be self-consistently found with the densities of collision counterparts of electrons. Next, the electron mean energy U and entropy S are calculated with the self-consistent EEDF obtained, where the entropy is calculated with the Gibbs’s formula. Then, the “statistical” electron temperature Test is calculated as Test=[∂S/∂U]−1. The difference between Test and the electron kinetic temperature Tekin is discussed, which is defined as [2/(3k)] times of the mean electron energy U=⟨ϵ⟩, as well as the temperature given as a slope of the EEDF for each value of E/N from the viewpoint of statistical physics as well as of elementary processes in the oxygen or nitrogen plasma.

Determining cellular activities of protein kinases is a fundamental step for characterizing pathophysiological cell signaling pathways. Here, we optimized a nonradioactive method that detects protein kinases in tissues or cells after separation by SDS-PAGE and transfer onto polyvinylidene fluoride membranes. The method, kinase activity-tagged western blotting (KAT-WB), consists of five steps: electrophoresis of cell extracts that contain protein kinases, electroblotting proteins onto polyvinylidene fluoride membrane, denaturation–renaturation, phosphorylation, with or without an added substrate protein and immunodetection using anti-phospho-specific antibodies. KAT-WB detected autophosphorylation of one Tyr-kinase and site-specific phosphorylation of added substrate by multiple kinases. KAT-WB assay enables us to interrogate multiple kinase signaling pathways without using radioactive ATP.

Purpose: The persistence of treatment with mirabegron and the reasons for withdrawal from the treatment among treatment-naïve Japanese female patients with overactive bladder (OAB) were prospectively investigated for 3 years in the real-world clinical setting. Materials and Methods: A total of 62 treatment-native Japanese female patients clinically diagnosed with OAB were treated with mirabegron and prospectively followed for 3 years. The persistence rate was estimated using the Kaplan-Meier method. If mirabegron had to be terminated or a patient did not come to the hospital to receive a prescription, the reasons for withdrawal from treatment were determined. Results: The 6-month, 1-year, 2-year, and 3-year persistence rates were 51.6%, 38.7%, 32.3%, and 25.8%, respectively. The most frequent reasons for withdrawal from treatment with mirabegron were symptom resolution (38.7%), deterioration of comorbidity unrelated to OAB (12.9%), lack of efficacy (8.1%), and adverse events (4.8%). Conclusions: The persistence rate of treatment with mirabegron among treatment-naïve Japanese female patients with OAB is low for 3 years in the real-world clinical setting. Many patients discontinue the treatment for various reasons, the most frequent of which is symptom resolution. These findings provide important considerations for clinicians whose patients are continuing medication for OAB.

Abstract Sulfide-based all-solid-state lithium batteries are a next-generation power source composed of the inorganic solid electrolytes which are incombustible and have high ionic conductivity. Positive electrode composites comprising LiNi1/3Mn1/3Co1/3O2 (NMC) and 75Li2S·25P2S5 (LPS) glass electrolytes exhibit excellent charge–discharge cycle performance and are promising candidates for realizing all-solid-state batteries. The thermal stabilities of NMC–LPS composites have been investigated by transmission electron microscopy (TEM), which indicated that an exothermal reaction could be attributed to the crystallization of the LPS glass. To further understand the origin of the exothermic reaction, in this study, the precipitated crystalline phase of LPS glass in the NMC–LPS composite was examined. In situ TEM observations revealed that the β-Li3PS4 precipitated at approximately 200 °C, and then Li4P2S6 and Li2S precipitated at approximately 400 °C. Because the Li4P2S6 and Li2S crystalline phases do not precipitate in the single LPS glass, the interfacial contact between LPS and NMC has a significant influence on both the LPS crystallization behavior and the exothermal reaction in the NMC–LPS composites.

Abstract Background The efficacy of chemotherapy for unresectable pancreatic cancer has improved. However, it is occasionally difficult to make treatment decisions for elderly patients. We reviewed the outcomes of elderly patients with unresectable pancreatic cancer by using a large cohort and evaluated whether they had received chemotherapy and the reason why. Methods Data for 895 pancreatic cancer patients who were treated using chemotherapy or best supportive care were analyzed considering demographics, clinical stage, treatment, and outcome. Data were analyzed using the chi-square test, Student t-test, or Mann-Whitney U-test, as appropriate. Outcomes were analyzed using the Kaplan-Meier method. Differences in survival were analyzed using the log-rank test. Results The median survival time was significantly shorter in elderly patients (≥65 years) than in younger patients (

Introduction: We evaluated the predictive factors which affect the efficacy of naftopidil 50 mg/day therapy and dose increase therapy to administration of 75 mg/day after an initial dose of 50 mg/day. Materials and Methods: A total of 92 patients with male lower urinary tract symptoms/benign prostatic hyperplasia were administrated naftopidil 50 mg/day for 4 weeks (50 mg therapy). At week 4, the patients were divided into an effective and an ineffective group (Group E and Group I, respectively). For further 4 weeks, the dosage of naftopidil was increased to 75 mg/day in all patients. At week 8, the patients of Group E and Group I were divided into an effective and an ineffective group (Group EE, Group EI, Group IE, and Group II, respectively). Results: Postvoid residual (PVR) urine volume at baseline was a predictive factor for efficacy of 50 mg therapy. In Group E, change in International Prostate Symptom Score storage symptoms subscore from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. In Group I, change in maximum flow rate from baseline to week 4 was a predictive factor for efficacy of this dose increase therapy. Conclusions: The short term of naftopidil 50 mg therapy was ineffective for the patients who had large PVR. The predictive factor of this dose increase therapy might be a dynamic variable in 50 mg/day of dose period, but not a baseline variable at the time of 75 mg/day dosage starts.

Modulated photonic-crystal surface-emitting lasers (M-PCSELs) are new semiconductor lasers that can emit a laser beam in arbitrary directions. Therefore, they can be regarded as a next-generation light source for light detection and ranging. In this manuscript, we numerically investigate the characteristics of M-PCSELs, including one- and two-dimensional optical coupling constants and radiation constants, by using three-dimensional coupled wave theory. We also carry out lattice point designs and show that the two-dimensional optical coupling can be enhanced by more than four times over our previous M-PCSEL devices by employing elliptical lattice points. Moreover, we find that two-dimensional optical coupling can be maintained even when large lattice point position modulations are introduced for large radiation constants. These results indicate that more stable two-dimensional oscillation and a higher slope efficiency are expected in M-PCSELs with elliptical lattice points.

Introduction: There have been reports that one of the factors affecting the efficacy of α1-adrenoceptor antagonists (α1-blocker; α1-B) was prostate volume (PV). However, there are few reports of short-term prospective trials comparing the efficacy of α1-B by PV. We examined the influence of PV on the short-term efficacy of naftopidil dose increase therapy to administration of 75 mg/day after an initial dose of 50 mg/day. Materials and Methods: A total of 85 patients with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) received 50 mg/day of naftopidil for 4 weeks. After 4 weeks, the dosage of naftopidil was increased to 75 mg/day for a further 4 weeks. We divided the patients into two groups of PV ≥40 mL at baseline (Group L) and PV

Abstract Spinal anesthesia is popular for endoscopic urological surgery. Many patients undergoing urological surgery are elderly. It is important to limit the dose to reduce any resultant hemodynamic effect. We present a case in which incremental administration of 0.1 % bupivacaine up to 1.5 mg was sufficient to produce satisfactory spinal anesthesia for transurethral resection of bladder tumor (TURBT).

Objectives. The persistence of silodosin and the reasons for withdrawal from treatment of previously untreated Japanese patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) were evaluated in real-life clinical practice. Methods. A total of 81 previously untreated Japanese patients diagnosed with LUTS/BPH were treated with silodosin monotherapy and prospectively followed for 4 years. The persistence rate was estimated using the Kaplan-Meier method. If silodosin had to be terminated or a patient did not come to the hospital, the reason was determined. Results. The 6-month, 1-year, 2-year, 3-year, and 4-year persistence rates were 63.0%, 56.8%, 50.6%, 44.4%, and 35.8%, respectively. The most frequent reason (22.2%) for withdrawal was symptom resolution. After silodosin treatment, the international prostate symptom score and the quality of life index were significantly improved and maintained for 4 years. Conclusions. 35.8% of previously untreated Japanese patients continued silodosin for 4 years. Many patients terminated silodosin for various reasons, the most frequent of which was symptom resolution. The effects of silodosin were maintained when the patients continued treatment. Trial Registration. This study was approved by the institutional review board of Hokkaido Prefectural Esashi Hospital (number 2007-2) and was registered in a public trial registry (UMIN000026910).

We carry out the structural design of photonic crystals to enhance the optical absorption of thin-film microcrystalline silicon (μc-Si) solar cells using two methods. First, by exhaustive search, we choose a structure with the largest absorption within the investigated patterns. Then we employ a sensitivity analysis to finely modulate the structure for further increase of the optical absorption. The obtained μc-Si solar cell structure with a photonic crystal in this work has more than twice as much optical absorption as that without a photonic crystal.

Days from full maturity to combine harvest maturity (DFC) is a major concern in combine harvesting of soybeans (Glycine max (L.)), especially in northern Japan, which has a short harvesting period. The combine harvest maturity, which was defined as the day at which the moisture content of the stem reached 30%, was analyzed using 7 soybean varieties for 3 yr in Hokkaido. There were significant differences in DFC among varieties (12 to 31 d) and among the 3 yr (16 to 25 d). DFC was closely associated with dry matter partitioning to stem (DMPS) at full maturity, that is, high DMPS increased DFC. The relationship between DMPS and DFC was examined by pod removal experiments conducted for 2 yr. In the soybean plants with high DMPS pod removal increased the stem desiccation period and DFC. These results indicated that DMPS at full maturity is an informative indicator for predicting the harvest maturity in the combine harvesting system.

In retroviral vector-mediated gene transfer, transduction efficiency can be hampered by inhibitory molecules derived from the culture fluid of virus producer cell lines. To remove these inhibitory molecules to enable better gene transduction, we had previously developed a transduction method using a fibronectin fragment-coated vessel (i.e., the RetroNectin-bound virus transduction method). In the present study, we developed a method that combined RetroNectin-bound virus transduction with low-temperature shaking and applied this method in manufacturing autologous retroviral-engineered T cells for adoptive transfer gene therapy in a large-scale closed system. Retroviral vector was preloaded into a RetroNectin-coated bag and incubated at 4°C for 16 h on a reciprocating shaker at 50 rounds per minute. After the supernatant was removed, activated T cells were added to the bag. The bag transduction method has the advantage of increasing transduction efficiency, as simply flipping over the bag during gene transduction facilitates more efficient utilization of the retroviral vector adsorbed on the top and bottom surfaces of the bag. Finally, we performed validation runs of endoribonuclease MazF-modified CD4(+) T cell manufacturing for HIV-1 gene therapy and T cell receptor-modified T cell manufacturing for MAGE-A4 antigen-expressing cancer gene therapy and achieved over 200-fold (≥ 10(10)) and 100-fold (≥ 5 × 10(9)) expansion, respectively. In conclusion, we demonstrated that the large-scale closed transduction system is highly efficient for retroviral vector-based T cell manufacturing for adoptive transfer gene therapy, and this technology is expected to be amenable to automation and improve current clinical gene therapy protocols.

The objective of this study is to verify if only the use of robotic force feedback enables indirect and dynamic manipulations which are difficult for human beings to perform. Human beings usually control the trajectory of an object using visual feedback; force/tactile information are secondarily employed because they are further qualitative in comparison with visual information. However, it is supposed that robots have the potential to perform such the tasks without visual information because force/tactile information can be also used quantitatively in the control system. This paper especially focuses on an indirect manipulation of a sphere on a flat plate realized by employing only force information. In this paper, we propose a very simple method to estimate the position of the sphere on the plate which is put on a multi-fingered robot and try to control the trajectory by changing the fingertip heights based on the error between the desired and estimated positions. We also analyze the stability of the proposed control system with an approximate Lyapunov's stability criterion. Finally, this paper shows very attractive robotic demonstrations based on the proposed method.

The objective of this study is to verify if only the use of robotic force feedback enables indirect and dynamic manipulations which are difficult for human beings to perform. Human beings usually control the trajectory of an object using visual feedback; force/tactile information are secondarily employed because they are further qualitative in comparison with visual information. However, it is supposed that robots have the potential to perform such the tasks without visual information because force/tactile information can be also used quantitatively in the control system. This paper especially focuses on an indirect manipulation of a sphere on a flat plate realized by employing only force information. In this paper, we propose a very simple method to estimate the position of the sphere on the plate which is put on a multi-fingered robot and try to control the trajectory by changing the fingertip heights based on the error between the desired and estimated positions. We also analyze the stability of the proposed control system with an approximate Lyapunov's stability criterion. Finally, this paper shows very attractive robotic demonstrations based on the proposed method.

The objective of this study is to verify if only the use of robotic force feedback enables indirect and dynamic manipulations which are difficult for human beings to perform. Human beings usually control the trajectory of an object using visual feedback; force/tactile information are secondarily employed because they are further qualitative in comparison with visual information. However, it is supposed that robots have the potential to perform such the tasks without visual information because force/tactile information can be also used quantitatively in the control system. This paper especially focuses on an indirect manipulation of a sphere on a flat plate realized by employing only force information. In this paper, we propose a very simple method to estimate the position of the sphere on the plate which is put on a multi-fingered robot and try to control the trajectory by changing the fingertip heights based on the error between the desired and estimated positions. We also analyze the stability of the proposed control system with an approximate Lyapunov's stability criterion. Finally, this paper shows very attractive robotic demonstrations based on the proposed method.

It has been shown that molecular hydrogen (H(2)) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H(2)-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H(2) showed that H(2) as low as 0.08 ppm had almost the same effect as saturated H(2) water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H(2)-containing water, whereas production of superoxide (O(2)*(-)) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H(2) in drinking water can reduce oxidative stress in the brain. Thus, drinking H(2)-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration.

Purpose. In women who reported a weak urinary stream, the efficacy of treatment chosen according to the urodynamic findings on pressure-flow study was prospectively evaluated. Materials and Methods. Twelve female patients with maximum flow rates of 10 mL/sec or lower were analyzed in the present study. At baseline, all underwent pressure-flow study to determine the degree of bladder outlet obstruction (BOO) and status of detrusor contractility on Schäfer's diagram. Distigmine bromide, 10 mg/d, was given to the patients with detrusor underactivity (DUA) defined as weak/very weak contractility, whereas urethral dilatation was performed using a metal sound for those with BOO (linear passive urethral resistance relation 2–6). Treatment efficacy was evaluated using the International Prostate Symptom Score (IPSS), uroflowmetry, and measurement of postvoid residual urine volume. Some patients underwent pressure-flow study after treatment. Results. Urethral dilatation was performed for six patients with BOO, while distigmine bromide was given to the remaining six showing DUA without BOO. IPSS, QOL index, and the urinary flow rate were significantly improved in both groups after treatment. All four of the patients with BOO and one of the three with DUA but no BOO who underwent pressure-flow study after treatment showed decreased degrees of BOO and increased detrusor contractility, respectively. Conclusions. Both BOO and DUA cause a decreased urinary flow rate in women. In the short-term, urethral dilatation and distigmine bromide are efficacious for female patients with BOO and those with DUA, respectively.

Hydrogen peroxide (H2O2) and calcium ions (Ca2+) are functional regulators of skeletal muscle contraction and metabolism. Although H2O2 is one of the activators of the type-1 ryanodine receptor (RyR1) in the Ca2+ release channel, the interdependence between H2O2 and Ca2+ dynamics remains unclear. This study tested the following hypotheses using an in vivo model of mouse tibialis anterior (TA) skeletal muscle. 1) Under resting conditions, elevated cytosolic H2O2 concentration ([H2O2]cyto) leads to a concentration-dependent increase in cytosolic Ca2+ concentration ([Ca2+]cyto) through its effect on RyR1; and 2) in hypoxia (cardiac arrest) and muscle contractions (electrical stimulation), increased [H2O2]cyto induces Ca2+ accumulation. Cytosolic H2O2 (HyPer7) and Ca2+ (Fura-2) dynamics were resolved by TA bioimaging in young C57BL/6J male mice under four conditions: 1) elevated exogenous H2O2; 2) cardiac arrest; 3) twitch (1 Hz, 60 s) contractions; and 4) tetanic (30 s) contractions. Exogenous H2O2 (0.1-100 mM) induced a concentration-dependent increase in [H2O2]cyto (+55% at 0.1 mM; +280% at 100 mM) and an increase in [Ca2+]cyto (+3% at 1.0 mM; +8% at 10 mM). This increase in [Ca2+]cyto was inhibited by pharmacological inhibition of RyR1 by dantrolene. Cardiac arrest-induced hypoxia increased [H2O2]cyto (+33%) and [Ca2+]cyto (+20%) 50 min postcardiac arrest. Compared with the exogenous 1.0 mM H2O2 condition, [H2O2]cyto after tetanic muscle contractions rose less than one-tenth as much, whereas [Ca2+]cyto was 4.7-fold higher. In conclusion, substantial increases in [H2O2]cyto levels evoke only modest Ca2+ accumulation via their effect on the sarcoplasmic reticulum RyR1. On the other hand, contrary to hypoxia secondary to cardiac arrest, increases in [H2O2]cyto from muscle contractions are small, indicating that H2O2 generation is unlikely to be a primary factor driving the significant Ca2+ accumulation after, especially tetanic, muscle contractions. NEW & NOTEWORTHY We developed an in vivo mouse myocyte H2O2 imaging model during exogenous H2O2 loading, ischemic hypoxia induced by cardiac arrest, and muscle contractions. In this study, the interrelationship between cytosolic H2O2 levels and Ca2+ homeostasis during muscle contraction and hypoxic conditions was revealed. These results contribute to the elucidation of the mechanisms of muscle fatigue and exercise adaptation. [ABSTRACT FROM AUTHOR]

The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3- II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway. [ABSTRACT FROM AUTHOR]