L-BSE prions after propagation in a non-human primate model

Classical- (C-) and atypical L-type bovine spongiform encephalopathy (BSE) prions cause different pathological phenotypes in cattle brains, and the disease-associated forms of each prion protein (PrPSc) has a dissimilar biochemical signature. Bovine C-BSE prions are the causative agent of variant Creutzfeldt-Jakob disease. To date, human infection with L-BSE prions has not been reported, but they can be transmitted experimentally from cows to cynomolgus monkeys (Macaca fascicularis), a non-human primate model. When transmitted to monkeys, C- and L-BSE prions induce different pathological phenotypes in the brain. However, when isolated from infected brains, the two prion proteins (PrPSc) have similar biochemical signatures (i.e., electrophoretic mobility, glycoforms, and resistance to proteinase K). Such similarities suggest the possibility that L-BSE prions alter their virulence to that of C-BSE prions during propagation in monkeys. To clarify this possibility, we conducted bioassays using inbred mice. C-BSE prions with or without propagation in monkeys were pathogenic to mice, and exhibited comparable incubation periods in secondary passage in mice. By contrast, L-BSE prions, either with or without propagation in monkeys, did not cause the disease in mice, indicating that the pathogenicity of L-BSE prions does not converge towards a C-BSE prion type in this primate model. These results suggest that, although C- and L-BSE prions propagated in cynomolgus monkeys exhibit similar biochemical PrPSc signatures and consist of the monkey amino acid sequence, the two prions maintain strain-specific conformations of PrPSc in which they encipher and retain unique pathogenic traits

Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

Purpose The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods We studied 282 patients with hormone receptor–positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen

RELATIONSHIP BETWEEN PROGRESSION OF AORTIC STENOSIS AND INFLAMMATORY CHANGE IN AORTIC VALVE IN HEMODIALYSIS PATIENTS

The entire manuscript is available for download as a single PDF file. Higher-resolution images are unavailable. For assistance, please contact [email protected]. Fieldwork Team: Philippe Beaujard (Director of Research, French National Centre for Scientific Research). Technical Team: Dr. Vika Zafrin (Digital Scholarship Librarian, BU Libraries), Eleni Castro (OpenBU and Electronic Theses & Dissertations Librarian, BU Libraries), Dr. Fallou Ngom (Director of the African Studies Center), Dr. Peter Quella (Assistant Director, African Studies Center), Mustapha Hashim Kurfi (PhD Candidate, Department of Political Science), and Zachary Gersten (Research Assistant, African Studies Center). This collection of Malagasy Ajami materials is copied as part of the African Studies Center’s African Ajami Library. This project is partly funded by the BU African Studies Center. We thank Dr. Tim Longman, past Director of the African Studies Center, and the entire African Studies team for their support. For Inquiries: Please contact Professor Fallou Ngom ([email protected]).The material is the second part of the sixth of eleven texts (the fourth text and the second and third parts of the eleventh were not digitized) owned by Iaban’i Totôry, a diviner-healer (called ombiasy in Malagasy). Iaban’i Totôry belonged to the Anakara Clan and lived in a village called Vatomasina in the Antemoro region (in the valley of the Matatàña River). He was known to be the grandson of a famous religious chief in his village, and was close with the French colonial administration in his region, with whom he also shared the material. The original author of the material is unknown. The material was photographed between 1983 and 1990. The pages were made out of a local plant called harandrànto in Malagasy, likely of the genus Afzelia. The material was bound in zebu skin and sinew. While the exact content of material is unknown, it is believed to contain guidance for charms, divination, and healing through prayers, geomancy, and astrology

Superficial Depressed Type (IIc) Early Cancer of the Colon : Report of Two Cases

Two cases of superficial depressed type (IIc) early cancer of the colon are reported. Case 1 was a 65-year-old male and case 2 a 69-year old male. The lesion was located in the descending colon in both cases, and was removed by strip biopsy endoscopically in the former and surgically in the latter. The size of the lesion after resection was 6 mm in case 1 and 5 mm in case 2. Histopathologically, both cases were well differentiated adenocarcinoma without adenomatous components, and carcinoma developed de novo by submucosal (sm) invasion. As to the immunohistochemical staining of the cancer tissue by tumor associated antigen, case 1 showed a strong expression of carcinoembrionic antigen (CEA) and partial expression of sialyl Lewisx, and case 2 showed expressions of both CEA and sialyl Lewisx . The nuclear DNA content by flow cytometry was aneuploid only in case 1. Thus, although the two cases were morphologically the same IIc type cancer, the process of carcinogenesis and secondary phenomena varied

Identification and structural analysis of C-terminally truncated collapsin response mediator protein-2 in a murine model of prion diseases

<p>Abstract</p> <p>Background</p> <p>Prion diseases are fatal neurodegenerative disorders that accompany an accumulation of the disease-associated form(s) of prion protein (PrP^Sc) in the central nervous system. The neuropathological changes in the brain begin with focal deposits of PrP^Sc, followed by pathomorphological abnormalities of axon terminal degeneration, synaptic loss, atrophy of dendritic trees, and eventual neuronal cell death in the lesions. However, the underlying molecular basis for these neuropathogenic abnormalities is not fully understood.</p> <p>Results</p> <p>In a proteomic analysis of soluble proteins in the brains of mice challenged intracerebrally with scrapie prion (Obihiro I strain), we found that the amount of the full-length form of collapsin response mediator protein-2 (CRMP-2; 61 kDa) decreased in the late stages of the disease, while the amount of its truncated form (56 kDa) increased to comparable levels observed for the full-length form. Detailed analysis by liquid chromatography-electrospray ionization-tandem mass spectrometry showed that the 56-kDa form (named CRMP-2-ΔC) lacked the sequence from serine⁵¹⁸to the C-terminus, including the C-terminal phosphorylation sites important for the regulation of axonal growth and axon-dendrite specification in developing neurons. The invariable size of the mRNA transcript in Northern blot analysis suggested that the truncation was due to post-translational proteolysis. By overexpression of CRMP-2-ΔC in primary cultured neurons, we observed the augmentation of the development of neurite branch tips to the same levels as for CRMP-2^T514A/T555A, a non-phosphorylated mimic of the full-length protein. This suggests that the increased level of CRMP-2-ΔC in the brain modulates the integrity of neurons, and may be involved in the pathogenesis of the neuronal abnormalities observed in the late stages of the disease.</p> <p>Conclusions</p> <p>We identified the presence of CRMP-2-ΔC in the brain of a murine model of prion disease. Of note, C-terminal truncations of CRMP-2 have been recently observed in models for neurodegenerative disorders such as ischemia, traumatic brain injury, and Wallerian degeneration. While the structural identity of CRMP-2-ΔC in those models remains unknown, the present study should provide clues to the molecular pathology of degenerating neurons in prion diseases in connection with other neurodegenerative disorders.</p

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Formation of Fe- and Mg-Rich Smectite under Hyperalkaline Conditions at Narra in Palawan, the Philippines

The formation of Fe- and Mg-rich smectite and zeolite under alkaline conditions, as secondary minerals after the alkaline alteration of bentonite in repositories for radioactive waste, is of major concern. It is crucial for safety assessments to know whether smectite is formed as a secondary mineral after the alkaline alteration of bentonite. In the present paper, Fe- and Mg-rich smectite, which interacted with the hyperalkaline groundwater at Narra in Palawan, Philippines, was used. Mineralogical and geochemical investigation was conducted to understand the formation process of the smectite and the factors determining the formation of secondary mineral species. The results suggest that a certain amount of smectite may be generated under hyperalkaline conditions, by alteration from amorphous or poorly crystalline components such as M-S-H and F-S-H. Therefore, the controlling factor determining whether smectite or zeolite will be generated as secondary minerals after alkaline alteration of bentonite could be whether nuclei of M-S-H and/or F-S-H are formed. Whether such formation takes place may be determined by the presence of dissolved Mg2+ and Fe2+ in the environment. The formation process of smectite under alkaline conditions, suggested by the results here, is analogous to the generally accepted model of smectite formation as it may have occurred on early Mars