Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target

The Coenzyme A (CoA), as a cofactor involved in >100 metabolic reactions, is essential to the basic biochemistry of life. Here, we investigated the CoA biosynthetic pathway of Entamoeba histolytica (E. histolytica), an enteric protozoan parasite responsible for human amebiasis. We identified four key enzymes involved in the CoA pathway: pantothenate kinase (PanK, EC 2.7.1.33), bifunctional phosphopantothenate-cysteine ligase/decarboxylase (PPCS-PPCDC), phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK). Cytosolic enzyme PanK, was selected for further biochemical, genetic, and phylogenetic characterization. Since E. histolytica PanK (EhPanK) is physiologically important and sufficiently divergent from its human orthologs, this enzyme represents an attractive target for the development of novel anti-amebic chemotherapies. Epigenetic gene silencing of PanK resulted in a significant reduction of PanK activity, intracellular CoA concentrations, and growth retardation in vitro, reinforcing the importance of this gene in E. histolytica. Furthermore, we screened the Kitasato Natural Products Library for inhibitors of recombinant EhPanK, and identified 14 such compounds. One compound demonstrated moderate inhibition of PanK activity and cell growth at a low concentration, as well as differential toxicity towards E. histolytica and human cells

English Poetry Criteria and Dataset for Evaluating Large Language Models Used for Analyzing the Influence of Poetry

application/pdfdepartmental bulletin pape

Between close and distant reading : How can we incorporate digital humanities methodology into traditional literary studies?

application/pdfThe purpose of this article is to examine how close reading incorporates computational methods in digital humanities and distant reading. The article reviews the critical history of close and distant reading, studies of distant reading in digital humanities and digital humanities studies in English Romanticism, the practice of close reading, and the pitfalls of distant reading. The article proposes five research procedural stages to link close and distant reading; 1.a starting point based on literary works or literary problem 2.construction of a model to solve the literary problem 3.analyses of a small amount of text using computational methods and a small interpretation 4.engagement in dialogue with texts and incorporation of distant reading and 5. a return to the literary problem and its original texts and a large interpretation from a larger point of view.departmental bulletin pape

Verrucous carcinoma of the esophagus with complete response after chemoradiotherapy

Background : Verrucous carcinoma of the esophagus (VCE) is a rare tumor that is difficult to diagnose. In most cases, biopsies show nonspecific inflammatory and hyperkeratotic changes and do not show malignant findings. Most VCEs are slowly growing, locally advanced tumors with few metastases. Treatments for VCE are the same as for normal esophageal cancer, involving combined chemotherapy, surgical resection, and radiation therapy. However, it has been reported that VCE has a poor response to radiation or chemoradiotherapy (CRT). A case of VCE with complete response (CR) after CRT is presented. Case presentation : A 70-year-old man was found to have white, irregular esophageal mucosa 4 years earlier. He had been followed up as an outpatient as having candidal esophagitis. However, his tumor grew gradually, and biopsy was performed by endoscopic mucosal resection (EMR). He was finally diagnosed with VCE. He had no metastases to distant organs, but some lymph node metastases were suspected. The tumor invaded his left bronchus. The esophagostomy and gastrostomy were constructed as emergent procedures. The patient then underwent definitive CRT. 4 weeks after the end of CRT, two-stage esophagectomy was performed. First, he underwent esophagectomy with thoracic lymph node dissection. A latissimus dorsi flap was patched to the bronchus after primary suture of the hole. 6 weeks later, reconstruction of the gastric tube was performed through the antethoracic route. The pathological findings showed CR to CRT, with no proliferative cancer cells in the specimen. The patient has had no recurrence for three and half years after the resection. Conclusions : We presented a locally advanced VCE that achieved CR to CRT. In cases that have some difficulty for local resection, CRT might be an appropriate treatment for VCE

Nonperturbative studies of fuzzy spheres in a matrix model with the Chern-Simons term

Fuzzy spheres appear as classical solutions in a matrix model obtained via dimensional reduction of 3-dimensional Yang-Mills theory with the Chern-Simons term. Well-defined perturbative expansion around these solutions can be formulated even for finite matrix size, and in the case of $k$ coincident fuzzy spheres it gives rise to a regularized U($k$) gauge theory on a noncommutative geometry. Here we study the matrix model nonperturbatively by Monte Carlo simulation. The system undergoes a first order phase transition as we change the coefficient ($\alpha$) of the Chern-Simons term. In the small $\alpha$ phase, the large $N$ properties of the system are qualitatively the same as in the pure Yang-Mills model ($\alpha =0$), whereas in the large $\alpha$ phase a single fuzzy sphere emerges dynamically. Various `multi fuzzy spheres' are observed as meta-stable states, and we argue in particular that the $k$ coincident fuzzy spheres cannot be realized as the true vacuum in this model even in the large $N$ limit. We also perform one-loop calculations of various observables for arbitrary $k$ including $k=1$. Comparison with our Monte Carlo data suggests that higher order corrections are suppressed in the large $N$ limit.Comment: Latex 37 pages, 13 figures, discussion on instabilities refined, references added, typo corrected, the final version to appear in JHE

MiR-107 and MiR-185 Can Induce Cell Cycle Arrest in Human Non Small Cell Lung Cancer Cell Lines

Background: MicroRNAs (miRNAs) are short single stranded noncoding RNAs that suppress gene expression through either translational repression or degradation of target mRNAs. The annealing between messenger RNAs and 5' seed region of miRNAs is believed to be essential for the specific suppression of target gene expression. One miRNA can have several hundred different targets in a cell. Rapidly accumulating evidence suggests that many miRNAs are involved in cell cycle regulation and consequentially play critical roles in carcinogenesis. Methodology/Principal Findings: Introduction of synthetic miR-107 or miR-185 suppressed growth of the human non-small cell lung cancer cell lines. Flow cytometry analysis revealed these miRNAs induce a G1 cell cycle arrest in H1299 cells and the suppression of cell cycle progression is stronger than that by Let-7 miRNA. By the gene expression analyses with oligonucleotide microarrays, we find hundreds of genes are affected by transfection of these miRNAs. Using miRNA-target prediction analyses and the array data, we listed up a set of likely targets of miR-107 and miR-185 for G1 cell cycle arrest and validate a subset of them using real-time RT-PCR and immunoblotting for CDK6. Conclusions/Significance: We identified new cell cycle regulating miRNAs, miR-107 and miR-185, localized in frequently altered chromosomal regions in human lung cancers. Especially for miR-107, a large number of down-regulated genes are annotated with the gene ontology term 'cell cycle'. Our results suggest that these miRNAs may contribute to regulate cell cycle in human malignant tumors.Full Tex

Clearance and Safety of the Radiocontrast Medium Iopamidol in Peritoneal Dialysis Patients

Although the characteristics and safety of radiocontrast media in peritoneal dialysis (PD) patients are not yet well defined, their use in PD patients is considered generally safe. In this study, we evaluated clearance and adverse events of iopamidol in PD patients. We measured the iopamidol concentration in the plasma, dialysate, and urine of 11 patients. Iopamidol clearance from patient plasma was delayed with a half-life of 33.3 h, and the elimination ratio was 83.6% for 96 h. We retrospectively investigated adverse events occurring in a total of 50 stable PD patients who underwent a total of 64 angiographic computed tomography (CT) scans. In 64 angiographic CT scans, two cases of adverse events were observed. Our results suggest that iopamidol can be eliminated by regular PD and careful observation for adverse events are necessary for the safe use of radiocontrast media

Accurate Detection of Tumor Infiltration by 11C-Methionine Positron Emission Tomography in a Patient with Central Nervous System Intravascular Lymphoma: A Case Report

Intravascular lymphoma (IVL) is a rare and clinically devastating subtype of extranodal diffuse large B-cell lymphoma with a distinct presentation. Diagnostic difficulty derives from marked variability in clinical presentations and nonspecific laboratory and radiological findings, especially when central nervous system (CNS) symptoms are the only manifestation. Establishing the diagnosis premortem thus remains a major challenge. We describe a 70-year-old male with CNS IVL. He presented with acute onset of neurocognitive impairments. Diffusion-weighted magnetic resonance imaging (MRI) showed multiple high-intensity areas suggesting occlusive cerebrovascular disease due to emboli, but extensive investigations detected no embolic sources. Intracranial neoplasm was included in a differential diagnosis based on elevated serum lactate dehydrogenase and interleukin 2 receptor levels. Gadolinium-enhanced MRI or 18-fluorodeoxyglucose positron emission tomography (PET) failed to demonstrate specific findings leading to a definite diagnosis, while 11C-methionine PET (MET-PET) distinctively demonstrated an area of focally increased MET uptake in the frontal cortex, suggesting the extent of tumor infiltration. Stereotactic biopsy was conducted under MET-PET imaging guidance and immunohistological examinations confirmed the proliferation and aggregation of CD20-positive lymphoma cells within the lumina of small blood vessels. The findings of the present case first suggest that MET-PET may provide important information on the diagnosis of CNS IVL and on the selection of the optimal site for brain biopsy. Further investigation is necessary to clarify whether positive findings on MET-PET are truly specific and pathognomonic for CNS IVL