Degradation of Mutant Protein Aggregates within the Endoplasmic Reticulum of Vasopressin Neurons

Misfolded or unfolded proteins in the ER are said to be degraded only after translocation or isolation from the ER. Here, we describe a mechanism by which mutant proteins are degraded within the ER. Aggregates of mutant arginine vasopressin (AVP) precursor were confined to ER-associated compartments (ERACs) connected to the ER in AVP neurons of a mouse model of familial neurohypophysial diabetes insipidus. The ERACs were enclosed by membranes, an ER chaperone and marker protein of phagophores and autophagosomes were expressed around the aggregates, and lysosomes fused with the ERACs. Moreover, lysosome-related molecules were present within the ERACs, and aggregate degradation within the ERACs was dependent on autophagic-lysosomal activity. Thus, we demonstrate that protein aggregates can be degraded by autophagic-lysosomal machinery within specialized compartments of the ER

Resting energy expenditure depends on energy intake during weight loss in people with obesity: a retrospective cohort study

Abstract Objective: Resting energy expenditure (REE) decreases if there is reduced energy intake and body weight (BW). The decrease in REE could make it difficult for patients with obesity to maintain decreased BW. This study aimed to investigate the correlation among changes in REE, energy intake, and BW during the weight loss process in patients with obesity. Materials and methods: We conducted a retrospective cohort study of patients hospitalized for the treatment of obesity in Japan. Patients received fully controlled diet during hospitalization and performed exercises if able. REE was measured once a week using a hand-held indirect calorimetry. Energy intake was determined by actual dietary intake. Results: Of 44 inpatients with obesity, 17 were included in the analysis. Their BW decreased significantly after 1 week (−4.7 ± 2.0 kg, P < 0.001) and 2 weeks (−5.7 ± 2.2 kg, P < 0.001). The change in REE after 1 and 2 weeks was positively correlated with the energy intake/energy expenditure ratio (r = 0.66, P = 0.004 at 1 week, r = 0.71, P = 0.002 at 2 weeks). Using a regression equation (y = 0.5257x – 43.579), if the energy intake/energy expenditure ratio within the second week was 82.9%, the REE after 2 weeks was similar to the baseline level. There was no significant correlation between the change in REE and BW. Conclusions: Our data suggest that changes in REE depend on energy intake/energy expenditure ratio and that the decrease in REE can be minimized by matching energy intake to energy expenditure, even during the weight loss process

A quantitatively-modeled homozygosity mapping algorithm, qHomozygosityMapping, utilizing whole genome single nucleotide polymorphism genotyping data

Homozygosity mapping is a powerful procedure that is capable of detecting recessive disease-causing genes in a few patients from families with a history of inbreeding. We report here a homozygosity mapping algorithm for high-density single nucleotide polymorphism arrays that is able to (i) correct genotyping errors, (ii) search for autozygous segments genome-wide through regions with runs of homozygous SNPs, (iii) check the validity of the inbreeding history, and (iv) calculate the probability of the disease-causing gene being located in the regions identified. The genotyping error correction restored an average of 94.2% of the total length of all regions with run of homozygous SNPs, and 99.9% of the total length of them that were longer than 2 cM. At the end of the analysis, we would know the probability that regions identified contain a disease-causing gene, and we would be able to determine how much effort should be devoted to scrutinizing the regions. We confirmed the power of this algorithm using 6 patients with Siiyama-type α1-antitrypsin deficiency, a rare autosomal recessive disease in Japan. Our procedure will accelerate the identification of disease-causing genes using high-density SNP array data

Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody

Introduction: Although immune checkpoint inhibitors (ICIs) have been considered as promising agents for the treatment of advanced hepatocellular carcinoma (HCC), previous clinical trials revealed that the response to anti-programmed cell death protein 1 (anti-PD-1) monotherapy was as low as 20%. Identifying subgroups that respond well to ICIs is clinically important. Here, we studied the prognostic factors for anti-PD-1 antibody treatment based on the molecular and immunological features of HCC. Methods: Patients who were administered anti-PD1 antibody for advanced HCC at Kindai University Hospital were included. Clinicopathological backgrounds and antitumor responses were examined in 34 cases where tumor tissues before treatment were available. Transcriptome analysis was performed using 40 HCC samples obtained from surgical resection, and immune status was compared between 20 HCCs with activating mutations in β-catenin and those without the mutations using transcriptome-based immunogram. Results: Univariate analysis showed that the disease control rate was significantly better in patients with α-fetoprotein &#x3c; 400 ng/mL, negative for β-catenin/glutamate synthetase (GS) staining, high combined positive score (CPS) of programmed death-ligand 1 (PD-L1), and increased infiltration of CD8+ cells in tumor tissues. Among them, negative staining of β-catenin/GS, CPS of PD-L1 ≥ 1, and high degree of CD8+ tumor-infiltrating lymphocytes (TILs) were significantly associated with longer survival in both progression-free survival (PFS) and overall survival (OS). The combination of these factors well stratified the survival of the patients on anti-PD-1 antibody in both PFS and OS (p &#x3c; 0.0001 and p = 0.0048 for PFS and OS, respectively). In addition, the immunogram revealed that tumor-carrying mutations in β-catenin showed downregulation of immune-related genes, especially in those related to priming and activation by dendritic cells, interferon-γ response, inhibitory molecules, and regulatory T cells. Discussion/Conclusion: The combined score including Wnt/β-catenin activation, CPS of PD-L1, and degree of CD8+ TILs in HCC is informative for predicting the response to ICI in HCC cases. Constitutive activation of β-catenin can induce an immune cold phenotype with downregulation of immune-related genes, and immunohistochemistry-based evaluation is beneficial for identifying the subgroup that shows a good response to ICI

Homozygosity Mapping on Homozygosity Haplotype Analysis to Detect Recessive Disease-Causing Genes from a Small Number of Unrelated, Outbred Patients

Genes involved in disease that are not common are often difficult to identify; a method that pinpoints them from a small number of unrelated patients will be of great help. In order to establish such a method that detects recessive genes identical-by-descent, we modified homozygosity mapping (HM) so that it is constructed on the basis of homozygosity haplotype (HM on HH) analysis. An analysis using 6 unrelated patients with Siiyama-type α1-antitrypsin deficiency, a disease caused by a founder gene, the correct gene locus was pinpointed from data of any 2 patients (length: 1.2–21.8 centimorgans, median: 1.6 centimorgans). For a test population in which these 6 patients and 54 healthy subjects were scrambled, the approach accurately identified these 6 patients and pinpointed the locus to a 1.4-centimorgan fragment. Analyses using synthetic data revealed that the analysis works well for IBD fragment derived from a most recent common ancestor (MRCA) who existed less than 60 generations ago. The analysis is unsuitable for the genes with a frequency in general population more than 0.1. Thus, HM on HH analysis is a powerful technique, applicable to a small number of patients not known to be related, and will accelerate the identification of disease-causing genes for recessive conditions

Impact of Baseline ALBI Grade on the Outcomes of Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Study

Background: This study investigated the impact of baseline liver function according to the Child–Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child–Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child–Pugh score 5 and ALBI grade 1 (group 1), (2) Child–Pugh score 5 and ALBI grade 2 (group 2), (3) Child–Pugh score 6 (group 3), and (4) Child–Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p &lt; 0.05 and p &lt; 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level &lt;200 ng/mL as the significant predictors of a high objective response rate (p &lt; 0.05 and p &lt; 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p &lt; 0.01). Conclusions: Patients with Child–Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment

ナイチンゲール病棟の設計思想とプライバシー ―時代背景にみるプライバシーの捉え方－

【要旨】著者らは，看護学生を対象にナイチンゲールが考案したナイチンゲール病棟に関するイメージ調査を行った結果，患者のプライバシー確保に関して否定的な回答がみられた．そこでナイチンゲールがプライバシーをどのように捉えているかを，ナイチンゲール著作集で確認すると，看護師側のプライバシーについてのみ記述され，患者側のプライバシーを守ることについての記述はなかった．そこで，ナイチンゲール病棟が提唱された 1860 年代からの英国文学作品 6 作品を用い，羞恥心への認識と，質問紙により現代の看護学生が感じる羞恥心レベルについて調査し，ナイチンゲール病棟の設計 思想と現代におけるプライバシーの捉え方について検討した．文献検討では，その時代前後で，病院の患者の階級や求められる医療が変化し，プライバシーが必要になった．ナイチンゲール病棟を提唱した時期はちょうどその過渡期であり，プライバシーへの十分な配慮がなされていなかったことが示唆された．看護学生のアンケート調査では，患者が治療を受ける場合，特に身体の一部が露出されるときに羞恥心が あると答えていた．ナイチンゲール病棟については，看護者の目が行き届き安心感を与えるが，患者のプラ イバシーがないと捉えていた．Abstract: We administered a questionnaire survey of a hospital ward designed by Florence Nightingale called “Nightingale ward” to nursing students, and obtained negative responses regarding securing patient privacy. Given the results above, we reviewed Nightingale’s publications to learn her perspective on privacy. Our review showed that privacy was described only from the standpoint of nurses and there was no reference to patient privacy protection. In order to investigate privacy issues with the Nightingale ward, we reviewed six British literary works published during the 1860s, the period in which the Nightingale ward was proposed, to investigate how people at that time thought about embarrassment, and surveyed the extent of patients’ embarrassment that was perceived by the present-day nursing students. Literature review showed that the social classes of inpatients and required medical care changed around the period of time in which Nightingale lived, leading to increased significance of privacy protection. The time when the Nightingale ward was proposed was exactly in the transition stage, and privacy had not been given adequate attention. According to the survey results, the nursing students felt that patients were embarrassed during treatment, especially when parts of their body were exposed. Openness of the Nightingale ward may bring a sense of ease for patients but it also poses difficulty in securing their privacy. The results indicated that this issue may be a potential factor to make patients feel embarrassed, and the Nightingale ward was therefore considered to “lack privacy.

ラット フツウ フン ト ガンスイ フン チュウ ノ ビ セイブツ ソウ

3週齢のSD系雄性ラット12匹を食糞行動を許容した対照区と食糞行動阻止区に6匹ずつ配し,4週間の飼育期間中に,対照区からは普通糞を,食糞行動阻止区からは含水糞を採取し,それぞれの糞の微生物数を測定した。普通糞では含水糞に比べStaphylococciとVeillonellaeが多く,StreptococciとBacteroidaceaeが少ないことが明らかとなった。普通糞と含水糞で微生物叢が異なることは,含水糞に含まれるビタミン類の合成や消費に関わるものと考えられた。Hydrous feces were ingested by rats in coprophagous behavior. Twelve healthy male Sprague-Dawley strain rats (3 weeks old) were divided into a control group (coprophagy-allowed) of 6 rats and a coprophagy-prevented group of 6 rats. The usual feces from the control group and the hydrous feces from the coprophagy-prevented group were collected during 4 weeks of the experimental period. The viable number of microorganisms in the feces was estimated. The numbers of Staphylococci and Veillonellae, in the usual feces were higher than those of the hydrous feces. Furthermore, the numbers of Streptococci and Bacteroidaceae in the usual feces were lower than those of the hydrous feces. The differences of microflora between the usual feces and hydrous feces seemed to relate to the synthesis and consumption of vitamins in hydrous feces

多糖ゲルによる糖質加水分解酵素のアフィニティ-クロマトグラフィ-

Soluble starch, pectic acid and alginic acid were cross-linked by polyacrylamide. Several enzymes, including commercially available specimen and food material sources, were examined for their specificities to the polysaccharide gels. α-Amylase showed high affinity for the starch-gel in the presence of 3M ammonium sulfate and eluted with the buffer solution containing no ammonium sulfate. Pectinase and alginate-lyase bound to the pectin-gel and the alginate-gel, respectively. On the other hand, galactanase form the common bean (Phaseolus vulgaris L) bound to the starch-gel ; however, trehalase did not bound to this gel. Highly purified alginate-lyase was obtained by the current affinity chromatography method. Based on these results, relationship between the chemical structure of the polysaccharide-gels and the substrate specificity of the enzymes was discussed