Explore the vast range of titles available.

Pokémon trainers Pearl and Diamond have a lifelong dream to star in a Pokémon comedy act, but somehow end up as bodyguards to a pampered rich girl on a quest to reach the peak of Mount Coronet.

Optineurin defects in ALS About 10% of cases of the motor neuron disease amyotrophic lateral sclerosis (ALS) are familial, but the small number of mutations so far identified account for only around 20–30% of the those cases. A new study of individuals from ALS-carrying families has now identified three different and previously unknown mutations of OPTN , the gene encoding optineurin. OPTN was earlier reported to be the causative gene of rare familial glaucoma. Optineurin's ability to inhibit activation of the regulatory protein NF-κB is lost in the mutant forms, suggesting that NF-κB inhibitors might be useful in ALS treatment. Amyotrophic lateral sclerosis (ALS) is a disorder characterized by the degeneration of motor neurons. About 10% of cases are familial, but the mutations identified in these families account for only 20–30% of such cases. Here a new set of mutations in familial ALS is found — in the gene encoding optineurin. Given the effect of optineurin mutations on the NF-κB protein, it is suggested that inhibiting NF-κB might be useful in treating ALS. Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord 1 . Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 ( SOD1 ) 2 , ANG encoding angiogenin 3 , TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4 ) and fused in sarcoma/translated in liposarcoma ( FUS , also known as TLS ) 5 , 6 . However, these genetic defects occur in only about 20–30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin ( OPTN ), earlier reported to be a causative gene of primary open-angle glaucoma (POAG) 7 , in patients with ALS. We found three types of mutation of OPTN : a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-κB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-κB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.

\"X was a Pokémon Trainer child prodigy. But now he's depressed and hides in his room avoiding everyone-- including his best friend Y. An attack on their hometown of Vaniville Town by Legendary Pokémon Xerneas and Yveltal, led by Team Flare, forces X outside ... Now what?\"--Page 4 of cover.

In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria. In this phase 3, randomised, double-blind, parallel-group study, patients aged 20–75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1–4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686. Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was −5·01 (SE 0·64) in the edavarone group and −7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99–3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal. Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria. Mitsubishi Tanabe Pharma Corporation.

\"X was a Pokémon Trainer child prodigy. But now he's depressed and hides in his room avoiding everyone-- including his best friend Y. An attack on their hometown of Vaniville Town by Legendary Pokémon Xerneas and Yveltal, led by Team Flare, forces X outside ... Now what?\"--Page 4 of cover.

Silica particles and asbestos fibers, which are known as typical causatives of pneumoconiosis, induce lung fibrosis. Moreover, silicosis patients often complicate with autoimmune diseases, and asbestos-exposed patients suffer from malignant diseases such as pleural mesothelioma and lung cancer. We have been conducting experimental studies to investigate altered regulation of self-tolerance caused by silica exposure, including analyses using specimens such as plasma and immunocompetent cells obtained from silicosis patients, as a means of examining the supposition that silica exposure induces molecular and cellular biological alterations of immune cells. These approaches have resulted in the detection of several specific autoantibodies, alterations of CD95/Fas and its related molecules, and evidence of chronic activation of responder T cells and regulatory T cells following silica exposure. In this review, we present details of our investigations as an introduction to scientific approaches examining the immunological effects of environmental and occupational substances.

Despite doubting his relationship with his Pokemon, Black finds a last-minute chance to earn the final badge he needs to compete in the Pokemon League.

Although high-fat diet intake is known to cause obesity and diabetes, the effect of high-fat diet itself on cognitive function remains to be clarified. We have previously shown that apoptosis signal-regulating kinase 1 (ASK1) is responsible for cognitive impairment caused by chronic cerebral hypoperfusion. The present work, by using ASK1 deficient mice, was undertaken to explore the influence of chronic high-fat diet intake on cognitive function and the role of ASK1. Cognitive function in wild-type mice fed high-fat diet from 2 to 24 months of age was significantly impaired compared to those fed control diet, which was associated with the significant white matter lesions, reduction of hippocampal capillary density and decrement of hippocampal neuronal cell. However, ASK1 deficiency abolished the development of cognitive impairment and cerebral injury caused by high-fat diet. Our results provided the evidence that high-fat diet itself causes cognitive impairment and ASK1 participates in such cognitive impairment.

Two years have passed since Team Plasma was defeated and Trainer Black was sucked into the Light Stone along with Legendary Pokâemon Reshiram ... Now Team Plasma is back to their wicked ways, controlling other people's Pokâemon and even wild Pokâemon with technology. Luckily, a new young hero and Looker of the International Police are on their trail.

Silicosis patients (SIL) suffer from respiratory disorders and dysregulation of autoimmunity. Frequent complications such as rheumatoid arthritis, systemic sclerosis (SSc) and vasculitis are known in SIL. Furthermore, we reported previously that some SIL exhibited better respiratory conditions in association with a worse immunological status. In this study, the clinical roles of anti-CENP-B and Scl-70 autoantibodies in SIL were analyzed. The titer index (Log10) of anti-CENP-B autoantibody in SIL was higher than that of healthy volunteers (HV), and that of SSc was higher than those of HV and SIL. This titer index was positively correlated with an assumed immune status of 1 for HV, 2 for SIL, and 3 for SSc. Moreover, although factor analysis revealed that the titer index of the anti-CENP-B autoantibody formed the same factor with the anti-Scl-70 autoantibody, IgG value and age in SIL cases, another extracted factor indicated that the IgA value and anti-Scl-70 antibody were positively related, but anti-CENP-B showed an opposite pattern in the results of the factor analysis. These findings indicated that the titer index of anti-CENP-B autoantibody may be a biomarker for dysregulation in SIL cases. Future clinical follow-up of SIL may therefore require both respiratory and immunological assessment.