Mitochondria of Malaria Parasites as a Drug Target

Mitochondria are organelle, which is found in most eukaryotic cells, and play an important roll in production of many biosynthetic intermediates as well as energy transduction. Recently, it has been reported that mitochondria contribute to cellular stress responses such as apoptosis and autophagy. These functions of mitochondria are known to be essential for survival and maintenance of homeostasis. The mitochondria of malaria parasites are quite different from those of their vertebrate hosts. Because these differences markedly contribute to drug selectivity, we have focused on the Plasmodium mitochondrion to develop antimalarial drugs. Here we summarize recent advances in our knowledge of the mitochondria of malaria parasites and discuss future prospective antimalarial drugs targeting the parasite mitochondrion

Usefulness and Problems of Endoscopic Ultrasonography in Prediction of the Depth of Tumor Invasion in Early Gastric Cancer

The objectives of this study were to evaluate the accuracy of endoscopic ultrasonography (EUS) in local and regional staging of early gastric cancer, to analyze the factors influencing the accuracy of EUS, and to reveal the usefulness and problems of EUS in pre-treatment staging of gastric cancer. We examined 105 lesions in 104 patients with histologically confirmed gastric cancer and retrospectively evaluated them with EUS. The diagnostic accuracy, sensitivity, and specificity of EUS were determined by comparing the pre-treatment EUS with the postoperative histopathological findings. The overall diagnostic accuracy of EUS for the depth of cancer invasion was 86%. The overall sensitivity and specificity were 60% and 96%, respectively. The accuracy significantly declined in lesions located in the upper-third of the stomach (70%). Type 0-I lesions tended to be over-staged (12&), and the upper-third lesions tended to be under-staged (23%). The accuracy significantly declined in differentiated adenocarcinoma with massive submucosal invasion (56.5%). EUS is useful for evaluating the depth of gastric cancer invasion which determines the feasibility of endoscopic treatment. However, it is noteworthy that the diagnostic accuracy of the invasion depth diminished for lesions in the upper third of the stomach

An endeavor for a multidisciplinary case study : discussion on immigration and adaptation from the perspective of Human Sciences : Part 1

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Ectopic sebaceous glands in the esophagus that became evident over a three-year span

A 43-year-old Japanese woman was diagnosed with ectopic sebaceous glands in the esophagus by esophagogastroduodenoscopy and biopsy. At the age of 46, typical ectopic sebaceous glands were recognized in the upper esophagus, whereas yellowish white granules were faintly observed in the lower esophagus. Esophagogastroduodenoscopy examinations were repeated when she was 47 and again at 50 years old, and the lesions in the lower esophagus had become more evident over the ensuing 3 years. Esophageal ectopic sebaceous glands are relatively infrequent, and there have been few case reports describing the progression of the endoscopic features. We also report the clinical and endoscopic features of the five similar cases with pathologically proven ectopic sebaceous glands in the esophagus

Malaria Parasites Hijack Host Receptors From Exosomes to Capture Lipoproteins

Malaria parasites cannot multiply in host erythrocytes without cholesterol because they lack complete sterol biosynthesis systems. This suggests parasitized red blood cells (pRBCs) need to capture host sterols, but its mechanism remains unknown. Here we identified a novel high-density lipoprotein (HDL)-delivery pathway operating in blood-stage Plasmodium. In parasitized mouse plasma, exosomes positive for scavenger receptor CD36 and platelet-specific CD41 increased. These CDs were detected in pRBCs and internal parasites. A low molecular antagonist for scavenger receptors, BLT-1, blocked HDL uptake to pRBCs and suppressed Plasmodium growth in vitro. Furthermore, platelet-derived exosomes were internalized in pRBCs. Thus, we presume CD36 is delivered to malaria parasites from platelets by exosomes, which enables parasites to steal HDL for cholesterol supply. Cholesterol needs to cross three membranes (RBC, parasitophorous vacuole and parasite’s plasma membranes) to reach parasite, but our findings can explain the first step of sterol uptake by intracellular parasites

Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response

Background & aimsGenetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine.MethodsWe performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies.ResultsHLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84–87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses.ConclusionHLA-DRβ1 position 26 and HLA-DPβ1 positions 84–87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination

Ectopic Pancreas in the Stomach Successfully Resected by Endoscopic Submucosal Dissection

A 32-year-old Japanese man presented with a gastric submucosal tumor. Esophagogastroduodenoscopy showed a sessile submucosal tumor measuring approximately 10 mm in diameter on the greater curvature of the gastric antrum. Endoscopic ultrasonography examination revealed a solid tumor with a diameter of 11.8 mm, which was located in the deep mucosal and submucosal layers. The internal echogenicity was homogenous and hypoechoic. Biopsy examinations were performed twice but were not diagnostic since only the intact mucosal layer was obtained. The patient was subsequently diagnosed with ectopic pancreas in the stomach by endoscopic submucosal dissection (ESD). This case underscores the usefulness of the ESD technique for the pathological diagnosis of gastric submucosal tumors

Truncated SRSF3 regulates IL-8 production

Serine/arginine-rich splicing factor 3 (SRSF3) is a member of the SR protein family and plays wide-ranging roles in gene expression. The human SRSF3 gene generates two alternative splice transcripts, a major mRNA isoform (SRSF3-FL) encoding functional full-length protein and a premature termination codon (PTC)-containing isoform (SRSF3-PTC). The latter is degraded through nonsense-mediated mRNA decay (NMD). Treatment of a human colon cancer cell line (HCT116) with 100 μM sodium arsenite increased SRSF3-PTC mRNA levels without changing SRSF3-FL mRNA levels. A chemiluminescence-based NMD reporter assay system demonstrated that arsenite treatment inhibited NMD activity and increased SRSF3-PTC mRNA levels in the cytoplasm, facilitating translation of a truncated SRSF3 protein (SRSF3-TR) from SRSF3-PTC mRNA. SRSF3-TR lacked two-thirds of Arg/Ser-rich (RS) domain whose phosphorylation state is known to be crucial for subcellular distribution. SRSF3-FL was localized in the nucleus, while overexpressed SRSF3-TR was diffusely distributed in the cytoplasm and the nucleus. A part of SRSF3-TR was also associated with stress granules in the cytoplasm. Interestingly, treatment of HCT116 cells with a small interference RNA specifically targeting SRSF3-PTC mRNA significantly attenuated arsenite-stimulated induction of c-JUN protein, its binding activity to the AP-1 binding site (-126 to 120 bp) in the interleukin (IL)-8 gene promoter, and AP-1 promoter activity, resulting in significant reduction of arsenite-stimulated IL-8 production. Our results suggest that SRSF3-TR may function as a positive regulator of oxidative stress-initiated inflammatory responses in colon cancer cells

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study

[Background] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. [Methods] A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. [Results] In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01–1.07; IL-8, HR = 1.04, 95% CI 1.01–1.08; MIP-1α, HR = 1.19, 95% CI 1.00–1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02–1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01–1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. [Conclusions] CTACK is a novel prognostic biomarker of IPF

The ASCT/SCS cycle fuels mitochondrial ATP and acetate production in Trypanosoma brucei

Acetate:succinate CoA transferase (ASCT) is a mitochondrial enzyme that catalyzes the production of acetate and succinyl-CoA, which is coupled to ATP production with succinyl-CoA synthetase (SCS) in a process called the ASCT/SCS cycle. This cycle has been studied in Trypanosoma brucei (T. brucei), a pathogen of African sleeping sickness, and is involved in (i) ATP and (ii) acetate production and proceeds independent of oxygen and an electrochemical gradient. Interestingly, knockout of ASCT in procyclic form (PCF) of T. brucei cause oligomycin A-hypersensitivity phenotype indicating that ASCT/SCS cycle complements the deficiency of ATP synthase activity. In bloodstream form (BSF) of T. brucei, ATP synthase works in reverse to maintain the electrochemical gradient by hydrolyzing ATP. However, no information has been available on the source of ATP, although ASCT/ SCS cycle could be a potential candidate. Regarding mitochondrial acetate production, which is essential for fatty acid biosynthesis and growth of T. brucei, ASCT or acetyl-CoA hydrolase (ACH) are known to be its source. Despite the importance of this cycle, direct evidence of its function is lacking, and there are no comprehensive biochemical or structural biology studies reported so far. Here, we show that in vitro-reconstituted ASCT/SCS cycle is highly specific towards acetyl-CoA and has a higher k cat than that of yeast and bacterial ATP synthases. Our results provide the first biochemical basis for (i) rescue of ATP synthase-deficient phenotype by ASCT/SCS cycle in PCF and (ii) a potential source of ATP for the reverse reaction of ATP synthase in BSF.Voies métaboliques glycosomales non glycolytiques: nouvelles fonctions pour le développement et la virulence des trypanosomesAlliance française contre les maladies parasitaire