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Obesity appears to be a major contributing factor for many health problems. Effective treatments for reducing weight gain, other than caloric restriction and exercise, are limited. The consumption of sugars is a major factor in the development of obesity in part by stimulating the transcription factor, carbohydrate response element binding protein (ChREBP), a process that is driven by

Cancer pain is a significant issue in terminally ill cancer patients (TICPs). The fentanyl patch (FP) is used extensively for treating cancer pain, but FP requirements vary between patients. We aimed to identify determinants of FP requirements in TICPs and propose effective pain relief using a FP. In a retrospective chart review, we investigated cancer patients admitted to our hospital from April 2012 to July 2015 and used FP until death. The time course of FP use in TICPs until death was examined. The primary endpoint was the final dose of FP use (FDFP). In total, 79 patients were included the analysis. FDFP was inversely correlated with age (R= -0.262

The carbohydrate response element‐binding protein (ChREBP), a glucose‐responsive transcription factor that plays a critical role in the glucose‐mediated induction of genes involved in hepatic glycolysis and lipogenesis, exists as two isoforms: ChREBPα and ChREBPβ. However, the mechanism responsible for regulating the expression of both ChREBPα and β, as well as the mechanism that determines which specific isoform is more responsive to different stimuli, remains unclear. To address this issue, we compared the effects of several stimuli, including oxidative stress, on the mRNA and protein expression levels of ChREBPα and β in the hepatocyte cell line, HepG2. We found that H2O2 stimulation suppressed the expression of both mRNA and protein in HepG2 cells, but the mRNA expression level of ChREBPβ was, The carbohydrate response element binding protein (ChREBP) is a glucose‐responsive transcription factor that strongly regulates glycolysis and lipogenesis. In this study, we showed that oxidative stress, including STS and TPA treatment, suppressed the expression of both ChREBPα and β through activation of ERK signaling in HepG2 cells.

Post-exposure prophylaxis (PEP) for healthcare workers is one of the effective strategies for preventing nosocomial outbreaks of influenza. However, PEP adherence in healthcare workers is rarely analysed, and no strategies have been established to improve adherence to PEP for healthcare workers. We aimed to retrospectively analyse adherence to PEP and the factors associated with non-adherence in healthcare workers. A survey of 221 healthcare workers who were eligible for PEP at Tokushima University Hospital in the 2016/2017 season was conducted. Once-daily oseltamivir (75 mg for 10 d) was used as the PEP regimen. Of the 221 healthcare workers, 175 received PEP and were surveyed for adherence using a questionnaire. Of the 130 healthcare workers who responded to the questionnaire, 121 (93.1%) had been vaccinated. In this survey, 82 healthcare workers (63.1%) did not fully complete PEP. Multiple logistic regression analysis revealed that physicians (odds ratio: 4.62, 95% confidence interval [CI]: 2.08-10.25) and non-vaccination (odds ratio: 9.60, 95% CI: 1.12-82.25) were the factors for non-adherence to PEP. Of the 47 healthcare workers who responded to the item regarding reasons for non-adherence, 36 (76.6%) reported forgetting to take oseltamivir or discontinuing it due to a misguided self-decision that continuation of PEP was unnecessary, and 5 (10.6%) reported discontinuing treatment due to adverse effects. In conclusion, healthcare workers, particularly physicians, had low PEP adherence owing to forgetting or stopping to take oseltamivir due to a misguided self-decision. To obtain the maximum preventive effect of PEP, medication education should be provided to endorse PEP compliance.

Background Although rehabilitation is recommended for terminal cancer patients, the specific components and methods of such programs are poorly documented. No studies to date have examined the effectiveness of rehabilitation for terminal cancer patients. This study aims to evaluate the efficacy of a new intervention for rehabilitation therapists, using the Op-reha Guide (Guide to Optimal and Patient-Centred Rehabilitation Practice for Patients in Palliative Care Units [PCUs]) in rehabilitation practice. This guide consists of recommended actions and attitudes for rehabilitation therapists and aims to optimise therapists’ actions according to the patient’s needs and condition. It shares goals with terminal cancer patients to maintain their activities of daily living (ADL). Methods This study uses a multicentre, prospective, randomised controlled trial (RCT) design with two parallel groups in PCUs where specialised rehabilitation will be routinely performed for terminal cancer patients by rehabilitation therapists. Participants will be randomised (1:1) to intervention (the Op-reha Guide) and control groups (usual rehabilitation). We will then conduct an observational study in PCUs that do not perform specialised rehabilitation for terminal cancer patients; this will be considered the usual care group, and the efficacy of usual rehabilitation will be quantitatively evaluated. Inclusion criteria are hospitalisation in PCU, European Cooperative Oncology Group Performance Status of 2 or 3, and clinical estimation of life expectancy of 3 weeks or more. Patients with severe symptom burden will be excluded. We hypothesise that the Op-reha Guide will be more effective in maintaining the ADL of terminal cancer patients hospitalised in PCUs than usual rehabilitation. The primary endpoint is defined as the change in (total) modified Barthel Index from baseline to Day 22. Quality of life will be a secondary endpoint. In total, 135 patients will be recruited from 16 Japanese sites between July 2019 and December 2021. Discussion This will be the first trial to evaluate the efficacy of specialised rehabilitation for terminal cancer patients hospitalised in PCUs, and will contribute to the evidence on the efficacy of implementing rehabilitation for terminal cancer patients. Trial registration UMIN-CTR, UMIN000037298 R000042525 (date of registration 7 July 2019).

Immune checkpoint inhibitor‐induced diabetes mellitus is a rare immune‐related adverse event. This report illustrates clinical data and insulin secretory ability before and after the onset of immune checkpoint inhibitor‐induced diabetes.

Caffeine intake is associated with a reduced risk developing non-alcoholic fatty liver disease (NAFLD), but the underlying molecular mechanisms remain to be fully elucidated. We report here that caffeine markedly improved high fat diet-induced NAFLD in mice resulting in a 10-fold increase in circulating IL-6 levels, leading to STAT3 activation in the liver. Interestingly, the expression of IL-6 mRNA was not increased in the liver, but increased substantially in the muscles of caffeine-treated mice. Caffeine was found to stimulate IL-6 production in cultured myotubes but not in hepatocytes, adipocytes, or macrophages. The inhibition of p38/MAPK abrogated caffeine-induced IL-6 production in muscle cells. Caffeine failed to improve NAFLD in IL-6 and hepatocyte-specific STAT3 knockout mice, indicating that the IL-6/STAT3 pathway is vital for the hepatoprotective effects of caffeine in NAFLD. The possibility that IL-6/STAT3-mediated hepatic autophagosome induction and hepatocytic oxygen consumption are involved in the anti-NAFLD effects of caffeine cannot be excluded, based on the findings presented here. Our results reveal that caffeine ameliorates NAFLD via crosstalk between muscle IL-6 production and liver STAT3 activation.

Viet Nam is currently one of the most dynamic economies increasing greenhouse gas (GHG) emissions. The country faces multiple challenges such as meeting energy demand, changing the energy mix as well as responding to climate change. In order to address how policies can contribute to creating synergies between climate change and the sustainable development goals (SDGs), this chapter focuses on SDG7 (affordable and clean energy). More concretely, key questions are how Viet Nam plans to achieve transition to green growth by scaling up renewable energy and where major barriers lie. Based on the recent progress in this policy area, it considers prospects for closer cooperation on sustainable development, climate change and renewable energy between the EU and Viet Nam.

The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that increases the transcription of multiple genes. ChREBP is highly localized in the liver, where it upregulates the expression of genes that code for glycolytic and lipogenic enzymes, resulting in the conversion of excess carbohydrate into storage fat. ChREBP knockout (KO) mice display an anti-obese phenotype. However, at this time, role of ChREBP in adipose tissue remains unclear. Therefore, the energy metabolism and morphology of mitochondrial brown adipose tissue (BAT) in ChREBP KO mice was examined. We found increased expression levels of electron transport system proteins including the mitochondrial uncoupling protein (UCP1), and mitochondrial structural alterations such as dysplasia of the cristae and the presence of small mitochondria in BAT of ChREBP KO mice. Mass spectrometry analyses revealed that fatty acid synthase was absent in the BAT of ChREBP KO mice, which probably led to a reduction in fatty acids and cardiolipin, a regulator of various mitochondrial events. Our study clarified the new role of ChREBP in adipose tissue and its involvement in mitochondrial function. A clearer understanding of ChREBP in mitochondria could pave the way for improvements in obesity management.

Team-based learning (TBL) is an active learning method used in many educational institutions. However, there are few examples of its use in basic medicine, such as biochemistry in medical schools. This study used TBL to teach glucose metabolism to first-year medical students. The process was in four phases: preclass preparation, readiness assurance tests, advanced questions, and a TBL test, with peer evaluation and a questionnaire. There were positive correlations between the TBL test, peer evaluation, and individual readiness test performance. Tests were taken immediately after learning and 2 weeks later, and scores decreased significantly less with TBL than traditional lectures (-2.3% vs. -17.5%). This suggests that TBL was more effective than traditional lectures in supporting knowledge retention. We used a Moodle system to facilitate communication between students and teachers, and this was evaluated positively by both groups. It was particularly useful for managing TBL. These findings suggest that TBL could be used to improve student performance in biochemistry.

IntroductionManagement of neuropathic cancer pain (NCP) refractory to regular opioids remains an important challenge. The efficacy of pregabalin for NCP except chemotherapy-induced peripheral neuropathy (CIPN) has already been confirmed in two randomised controlled trials (RCTs) compared with placebo. Duloxetine offers the potential of analgesia in opioid refractory NCP. However, there are no RCT of duloxetine for the management of opioid-refractory NCP as a first line treatment. Both classes of drugs have the potential to reduce NCP, but there has been no head-to-head comparison for the efficacy and safety, especially given differing side effect profiles.Methods and analysisAn international, multicentre, double-blind, dose increment, parallel-arm, RCT is planned. Inclusion criteria include: adults with cancer experiencing NCP refractory to opioids; Brief Pain Inventory (BPI)-item 3 (worst pain) of ≥4; Neuropathic Pain on the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale of ≥12 despite of an adequate trial of regular opioid medication (≥60 mg/day oral morphine equivalent dose). Patients with CIPN are excluded.The study will recruit from palliative care teams (both inpatients and outpatients) in Japan and Australia. Participants will be randomised (1:1 allocation ratio) to duloxetine or pregabalin arm. Dose escalation is until day 14 and from day 14 to 21 is a dose de-escalation period to avoid withdrawal effects. The primary endpoint is defined as the mean difference in BPI item 3 for worst pain intensity over the previous 24 hours at day 14 between groups. A sample size of 160 patients will be enrolled between February 2020 and March 2023.Ethics and disseminationEthics approval was obtained at Osaka City University Hospital Certified Review Board and South Western Sydney Local Health District Human Research Ethics Committee. The results of this study will be submitted for publication in international journals and the key findings presented at international conferences.Trial registration numbersjRCTs051190097, ACTRN12620000656932.

We identified a waterborne pseudo-outbreak of Mycobacterium chimaera in our stem cell transplantation center, which likely resulted from biofilm on the aerators of the handwashing machines in each patient’s room. Regular replacement of faucet parts can prevent biofilm formation and pseudo-outbreaks of M. chimaera through aerators.

Background Japan has an aging population and an increasing number of patients who reside in long-term care and mental health facilities. Both pneumococcal pneumonia and influenza B infection outbreaks have been observed in these populations, although no reports have described concurrent outbreaks of pneumococcal pneumonia and influenza B infection in these facilities. Case presentation Six patients and two staffs were initially diagnosed with influenza B infection at a mental health facility on March 14, 2015. By March 21, influenza B infection was diagnosed in 26 patients and 10 staff; all individuals received anti-influenza drugs. On March 19, two patients were diagnosed with pneumococcal pneumonia, and seven patients had developed pneumococcal pneumonia by March 24. Six of these seven patients also had influenza B infection. All individuals who developed pneumococcal pneumonia were hospitalized and treated using ampicillin/sulbactam at our hospital, and their symptoms subsequently subsided. Among the seven pneumococcal strains that were frozen and stored, two strains were type 3 and five strains were type 11A/E. Pulsed-field gel electrophoresis testing revealed that each of the serum types were from the same clone. Conclusion It appears that an outbreak of influenza B infection was followed by the spread of multi-clone pneumococcal pneumonia among elderly patients at a mental health facility. Therefore, it may be prudent to use vaccinations to prevent the spread of pneumococcal pneumonia among elderly patients and this diagnosis should be actively considered during outbreaks of influenza infection at elder care facilities.

Background Clinical research coordinators play a pivotal role in phase I cancer clinical trials. Purpose We clarified the care coordination and practice for patients provided by clinical research coordinators in phase I cancer clinical trials in Japan and elucidated clinical research coordinators' perspective on patients' expectations and understanding of these trials. Method Fifteen clinical research coordinators participated in semi-structured interviews regarding clinical practices; perceptions of patients' expectations; and the challenges that occur before, during, and after phase I cancer clinical trials. Discussion Qualitative content analysis showed that most clinical research coordinators observed that patients have high expectations from the trials. Most listened to patients to confirm patients' understanding and reflected on responses to maintain hope, but to avoid excessive expectations; clinical research coordinators considered avoiding unplanned endings; and they aimed to establish good relationships between patients, medical staff, and among the professional team. Conclusions Clinical research coordinators were insightful about the needs of patients and took a meticulous approach to the phase I cancer clinical trial process, allowing time to connect with patients and to coordinate the inter-professional research team. Additionally, education in advanced oncology care was valuable for comforting participants in cancer clinical trials.

Background Liver cancer is the fifth cause of cancer-related deaths in Japan. The BioBank Japan (BBJ) project included 200,000 patients with 47 diseases and samples; their clinical information can be used for further studies. Methods Patients diagnosed with liver cancer (n = 1733; 1316 men, 417 women) were included. Histology, patient characteristics, clinical characteristics, and causes of death were collected. Cumulative and relative survival rates for liver cancer were calculated. Results Of the 1354 patients with available liver cancer histology, 91.9% had hepatocellular carcinoma (HCC). Compared with the National Health and Nutrition Examination Survey, greater proportions of the male patients in this cohort were daily alcohol consumers (26%), and a greater proportion of the men was overweight/obesity (22%). Although Japan is the only Asian country with a predominance of hepatitis C virus (HCV)-related HCC, the prevalence of HCV infection (44%) was lower than that in a previous study. The 3-, 5-, and 10-year cumulative survival rates were 57%, 47%, and 25% in men, respectively, and 49%, 41%, and 27% in women, respectively. Conclusions The present results provide an overview of the patients with liver cancer in the BBJ project. We are planning further analyses combined with various high-throughput ‘omics’ technologies., Highlights • Liver cancer is the second leading cause of death worldwide. • We aimed to provide an overview of patients with liver cancer. • Based on liver cancer histology, 91.9% had hepatocellular carcinoma. • The 10-year relative survival rates were 34% in men and 38% in women. • Future studies will help develop preventive programs for liver cancer.

Background This article presents the main findings from a meta-analysis of how climate change mitigation policy evaluations have been undertaken in the European Union (EU) and six of its Member States: Austria, Czech Republic, France, Germany, Greece and the United Kingdom. It aims to provide insights into how policy evaluations are carried out and how those practices might be improved. As a first step, this article reviews the literature on the theory and practice of policy evaluations to guide our methodology and further analysis. Results Our sample of 236 policy evaluations in the EU and six Member States covers the period 2010–2016. Compared with the results of a similar meta-analysis carried out covering the period 1998–2007, formal evaluations commissioned by government bodies have been on the rise in 2010–2016. Most evaluations focus on effectiveness and goal achievement and usually forgo a deeper level of reflexivity and/or public participation in the evaluation process. The analysis also reveals the dominance of the energy sector in the sampled evaluations. The article finds that the low number of any policy evaluations in the agriculture, waste or land-use sectors is an area for further investigation. Conclusions The exercise of identifying, coding and categorising these evaluations for 7 years helps to provide insights into the potential use of ex-post evaluations in support of future EU legislative proposals and accompanying impact assessments. Having a good understanding on how a certain policy performed particularly according to evaluation criteria might form the basis for more ambitious climate change mitigation policies in the future. Our analysis further shows that it is crucial and urgent to allocate sufficient resources to the coverage of relatively under-represented sectors, such as land use, land-use change and forestry, and waste.

We identified a waterborne pseudo-outbreak of Mycobacterium chimaera in our stem cell transplantation center, which likely resulted from biofilm on the aerators of the handwashing machines in each patient's room. Regular replacement of faucet parts can prevent biofilm formation and pseudo-outbreaks of M. chimaera through aerators.

Background The aim of the present study was to evaluate spleen volume (SV) and the factors influencing it after adult-to-adult living donor liver transplantation (A2LDLT) using a left lobe. Methods Pretransplant computed tomography (CT) and post-transplant CT 2 years after A2LDLT were examined by volumetric analysis in 24 patients. We divided the recipients into the following 2 groups according to the post-transplant SV: >500 mL (Group A) and ≤500 mL (Group B). The factors affecting the change in post-transplant SV were compared between the 2 groups. Results The mean pretransplant SV decreased significantly after A2LDLT. Platelet counts after living donor liver transplantation increased significantly relative to the pretransplant values. Post-transplant SV was >500 mL in 9 patients (Group A) and ≤500 mL in 15 (Group B). Pretransplant SV, platelet count, anhepatic time, operative time, intraoperative blood loss, post-transplant portal vein pressure >20 mm Hg, and post-transplant portal vein flow >250 mL/min/100 g graft weight showed significant differences between the 2 groups. Actual graft volume (GV) and GV/standard liver volume ratio showed no intergroup differences. Multivariate analysis showed that the only significant factor related to a post-transplant SV of >500 mL was the pretransplant SV. Post-transplant platelet counts were significantly increased from the pretransplant values in both Group A and Group B. Conclusions Pretransplant SV is the only significant factor predicting a SV of >500 mL after A2LDLT. However, even in patients with a SV of >500 mL, the platelet count increased significantly from the pretransplant value.

University lectures are mainly passive in nature, and there are few subjects in which students need to learn and function independently. Tutorial education and related activities at universities that specialize in medical and pharmaceutical training have been actively carried out, and lectures in conjunction with practical skills are gradually being developed, although progress has been slow in this area. In past years, our biochemistry practice classes have been evaluated in reports dealing with experiments and written examinations, as is done in other universities. However, using this methodology, we are not able to evaluate the extent to which students master biochemical experimental skills. To address this, we introduced a basic skill test to our biochemical curriculum for the first time. Our exams contributed to a deeper understanding of student skills and could be good tools for evaluating the degree of understanding of the students. The students understood the contents of the training well and felt interested in research in the field of basic medicine. Thus, we conclude that introducing practical testing to biochemical practice was effective for medical students in the field of biochemistry. © 2019 International Union of Biochemistry and Molecular Biology, 47(3):279-287, 2019.

Under certain conditions, amyloid-like fibrils can develop into three-dimensional networks and form hydrogels by a self-assembly process. When Cu/Zn superoxide dismutase (SOD1), an anti-oxidative enzyme, undergoes misfolding, fibrillar aggregates are formed, which are a hallmark of a certain form of familial amyotrophic lateral sclerosis (ALS). However, the issue of whether SOD1 fibrils can be assembled into hydrogels remains to be tested. Here, we show that the SOD1 polypeptides undergo hydrogelation accompanied by the formation of thioflavin T-positive fibrils at pH 3.0 and 4.0, but not at pH 5.0 where precipitates are formed. The results of viscoelastic analyses indicate that the properties of SOD1 hydrogels (2%) were similar to and slightly more fragile than a 0.25% agarose gel. In addition, monitoring by a quartz crystal microbalance with admittance analysis showed that the denaturing of immobilized SOD1 on a sensor under the hydrogelation conditions at pH 3.0 and 4.0 resulted in an increase in the effective acoustic thickness from ~3.3 nm (a folded rigid form) to ~50 and ~100 nm (an extended water-rich state), respectively. In contrast, when SOD1 was denatured under the same conditions at pH 5.0, a compact water-poor state with an effective acoustic thickness of ~10 nm was formed. The addition of physiological concentrations of NaCl to the pH 4.0 sample induced a further extension of the SOD1 with larger amounts of water molecules (with an effective acoustic thickness of ~200 nm) but suppressed hydrogel formation. These results suggest that different denatured intermediate states of the protein before self-assembly play a major role in determining the characteristics of the resulting aggregates and that a conformational change to a suitable level of extended water-rich intermediate state before and/or during intermolecular assembling is required for fibrillation and hydrogelation in the case of globular proteins.

BACKGROUND Intractable ascites is one of the causes of graft loss after adult-to-adult living donor liver transplantation (LDLT) using a small graft. Identification of factors associated with increasing posttransplant ascites has important implications for prevention and treatment. METHODS All 59 consecutive adult patients who underwent left lobe LDLT without portal inflow modulation between October 2002 and February 2016 were prospectively enrolled. Factors associated with the average daily amount of ascites for 2 weeks after LDLT were assessed. RESULTS The median daily amount of ascites during the 2 weeks was 1052 mL (range, 52-3480 mL). Although 16 of the 59 patients developed intractable ascites, exceeding 1500 mL daily (massive ascites group), the remaining 43 patients produced less than 1500 mL of ascites daily (nonmassive ascites group). The presence of pretransplant ascites (P = 0.001), albumin (P = 0.011), albumin/globulin ratio (P = 0.026), cold ischemia time (P = 0.004), operation time (P = 0.022), and pretransplant portal vein pressure (PVP) (P = 0.047) differed significantly between the 2 groups. Neither posttransplant PVP nor portal vein flow differed between the 2 groups. The variables associated with intractable ascites that remained significant after logistic regression analysis were pretransplant PVP (P = 0.047) and cold ischemia time (P = 0.049). After appropriate fluid resuscitation for intractable ascites, 58 (98%) of the 59 recipients were discharged from hospital after removal of the indwelling drains. CONCLUSIONS It is important to shorten the scold ischemia time to reduce massive ascites after LDLT. Pretransplant portal hypertension is more closely associated with ascites production than posttransplant hemodynamic status.

Micronutrient deficiencies such as vitamin A, iron, zinc, and selenium have been known to occur as a consequence of pancreaticoduodenectomy (PD), but vitamin B6 deficiency has not been previously reported. We report two post-PD patients who developed anemias attributed to vitamin B6 deficiency. Oral supplementations of vitamin B6 significantly improved anemias in both cases. Micronutrients including vitamin B6 should be monitored in post-PD patients, and supplementations should be carried out when necessary.

Aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) is a pathological signature of amyotrophic lateral sclerosis (ALS). Although accumulating evidence suggests the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy, it remains unclear how native TDP-43 is converted to pathogenic forms. To elucidate the role of homeostasis of RRM1 structure in ALS pathogenesis, conformations of RRM1 under high pressure were monitored by NMR. We first found that RRM1 was prone to aggregation and had three regions showing stable chemical shifts during misfolding. Moreover, mass spectrometric analysis of aggregated RRM1 revealed that one of the regions was located on protease-resistant β-strands containing two cysteines (Cys-173 and Cys-175), indicating that this region served as a core assembly interface in RRM1 aggregation. Although a fraction of RRM1 aggregates comprised disulfide-bonded oligomers, the substitution of cysteine(s) to serine(s) (C/S) resulted in unexpected acceleration of amyloid fibrils of RRM1 and disulfide-independent aggregate formation of full-length TDP-43. Notably, TDP-43 aggregates with RRM1-C/S required the C terminus, and replicated cytopathologies of ALS, including mislocalization, impaired RNA splicing, ubiquitination, phosphorylation, and motor neuron toxicity. Furthermore, RRM1-C/S accentuated inclusions of familial ALS-linked TDP-43 mutants in the C terminus. The relevance of RRM1-C/S-induced TDP-43 aggregates in ALS pathogenesis was verified by immunolabeling of inclusions of ALS patients and cultured cells overexpressing the RRM1-C/S TDP-43 with antibody targeting misfolding-relevant regions. Our results indicate that cysteines in RRM1 crucially govern the conformation of TDP-43, and aberrant self-assembly of RRM1 at amyloidogenic regions contributes to pathogenic conversion of TDP-43 in ALS. Background: The role of RRM1 in the pathogenesis of TDP-43 proteinopathy is unclear. Results: RRM1 was aggregate-prone, mediated by a self-assembly at newly identified amyloidogenic β-strands containing cysteines; cysteine substitution(s) replicated diverse cytopathologies of TDP-43 in ALS. Conclusion: RRM1 misfolding may underlie TDP-43 proteinopathy. Significance: This study proposes a novel mechanism and a new in vitro model for TDP-43 proteinopathy.

Copper/zinc superoxide dismutase (SOD1), a primary anti-oxidative enzyme, protects cells against oxidative stress. We report herein on a comparison of behavioral and neurobiological changes between SOD1 knockout (KO) and wild-type mice, in an attempt to assess the role of SOD1 in brain functions. SOD1 KO mice exhibited impaired motivational behavior in both shuttle-box learning and three-chamber social interaction tests. High levels of dopamine transporter protein and an acceleration of serotonin turnover were also detected in the cerebrums of the SOD1 KO mice. These findings suggest that SOD1 deficiency disturbs monoaminergic neurotransmission leading to a decrease in motivational behavior.

NMR active nuclei, 1H, 13C and 15N, are usually used for determination of protein structure. However, solution 17O-NMR application to proteins is extremely limited although oxygen is an essential element in biomolecules. Proteins are oxidized through cysteine residues by two types of oxidation. One is reversible oxidation such as disulphide bonding (Cys-S-S-Cys) and the other is irreversible oxidation to cysteine sulfinic acid (Cys-SO 2H) and cysteine sulfonic acid (Cys-SO 3H). Copper,Zinc-superoxide dismutase (SOD1) is a key enzyme in the protection of cells from the superoxide anion radical. The SH group at Cys 111 residue in human SOD1 is selectively oxidized to -SO 2H and -SO 3H with atmospheric oxygen, and this oxidized human SOD1 is also suggested to play an important role in the pathophysiology of various neurodegenerative diseases, probably mainly via protein aggregation. Therefore, information on the structural and the dynamics of the oxidized cysteine residue would be crucial for the understanding of protein aggregation mechanism. Although the -SO 3H group on proteins cannot be directly detected by conventional NMR techniques, we successfully performed the site-specific 17O-labeling of Cys 111 in SOD1 using \(^{17}\textit {O}_{2}\) gas and the 17O-NMR analysis for the first time. We observed clear 17O signal derived from a protein molecule and show that 17O-NMR is a sensitive probe for studying the structure and dynamics of the 17O-labeled protein molecule. This novel and unique strategy can have great impact on many research fields in biology and chemistry.

Background: Emergency admissions and emergency department visits (EAs/EDVs) have been used as quality indicators of home care in terminally ill cancer patients. We established a cancer transitional care (CTC) program to monitor and manage terminally ill cancer patients receiving care at home. The purpose of this study was to evaluate the effectiveness of CTC by the frequency of EAs/EDVs. Methods: In a retrospective chart review, we identified 133 patients with cancer admitted to our department, of whom 56 met study eligibility criteria. The CTC consisted of at least 1 or more following components: (1) a 24-hour hotline for general physicians or home care nurses to reach hospital-based physicians, (2) periodic phone calls from an expert hospital-based oncology nurse to home care medical staff, and (3) reports sent to our department from home care medical staff. The primary outcome variable was the frequency of EAs/EDVs. Results: There were 32 EAs/EDVs and 69 planned admissions during the observation period. In the last 30 days of life, 16 patients (28.6%) had 1 EA/EDV and none had multiple EAs/EDVs. Compared with previous studies, our study found a similar or lower frequency of EAs/EDVs. Conclusion: Our findings suggest that the implementation of CTC reduces the number of EAs/EDVs by replacing them with planned admissions. Further prospective studies to evaluate CTC are warranted.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic diseases, and results in the development of fibrosis. Oxidative stress is thought to be one of the underlying causes of NAFLD. Copper/zinc superoxide dismutase (SOD1) is a primary antioxidative enzyme that scavenges superoxide anion radicals. Although SOD1 knockout (KO) mice have been reported to develop fatty livers, it is not known whether this lack of SOD1 leads to the development of fibrosis. Since the accumulation of collagen typically precedes liver fibrosis, we assessed the balance between the synthesis and degradation of collagen in liver tissue from SOD1 KO mice. We found a higher accumulation of collagen in the livers of SOD1 KO mice compared to wild type mice. The level of expression of HSP47, a chaperone of collagen, and a tissue inhibitor (TIMP1) of matrix metalloproteinases (a collagen degradating enzyme) was also increased in SOD1 KO mice livers. These results indicate that collagen synthesis is increased but that its degradation is inhibited in SOD1 KO mice livers. Moreover, SOD1 KO mice liver sections were extensively modified by advanced glycation end products (AGEs), which suggest that collagen in SOD1 KO mice liver might be also modified with AGEs and then would be more resistant to the action of collagen degrading enzymes. These findings clearly show that oxidative stress plays an important role in the progression of liver fibrosis.