Site-directed mutations in the C-terminal extension of human aB-Crystalline affect chaperone function and block amyloid fibril formation

Copyright: 2007 Treweek et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background. Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob disease are associated with inappropriate protein deposition and ordered amyloid fibril assembly. Molecular chaperones, including aB-crystallin, play a role in the prevention of protein deposition. Methodology/Principal Findings. A series of site-directed mutants of the human molecular chaperone, aBcrystallin, were constructed which focused on the flexible C-terminal extension of the protein. We investigated the structural role of this region as well as its role in the chaperone function of aB-crystallin under different types of protein aggregation, i.e. disordered amorphous aggregation and ordered amyloid fibril assembly. It was found that mutation of lysine and glutamic acid residues in the C-terminal extension of aB-crystallin resulted in proteins that had improved chaperone activity against amyloid fibril forming target proteins compared to the wild-type protein. Conclusions/Significance. Together, our results highlight the important role of the C-terminal region of aB-crystallin in regulating its secondary, tertiary and quaternary structure and conferring thermostability to the protein. The capacity to genetically modify aB-crystallin for improved ability to block amyloid fibril formation provides a platform for the future use of such engineered molecules in treatment of diseases caused by amyloid fibril formation

Primitive sarcoma of the breast: New insight on the proper surgical management

Background: Primitive sarcoma of the breast is a rare and challenging disease at high risk of recurrence and with poor prognosis. There are controversies in the diagnosis and management of such solid tumor due to its rarity and heterogeneity. This sarcoma is poorly responsive to both chemotherapy and radiotherapy, thus, surgery is the first and most important therapeutic approach. However, given the rarity of this type tumor it has not be possible to standardize unique guidelines for the proper surgical strategy to adopt. Here, we performed a retrospective study of new 10 cases of primitive sarcoma of the breast that underwent either mastectomy or a more conservative quadrantectomy, in the attempt to better standardize correct surgical indications. Methods: Ten new cases of primitive sarcoma of the breast were registered between 2002 and 2012 and constituted the study group. They underwent either mastectomy or quadrantectomy and the clinical, prognostic and survival characteristics after surgery were analysed. Results: Within the group of patients treated with mastectomy, two had metastasis and died because of that. Among the five patients treated with quadrantectomy four are alive and free of disease after 3 to 5 years follow-up, while the patient with sarcoma arising in pregnancy, although is still alive, developed lung metastases four years after surgery. Conclusions: The first and most important therapeutic approach to primary sarcomas of the breast is surgical which has the purpose to achieve radical tumor excision to prevent local recurrence and skip metastases. However, given the rarity of the condition and the consequent small number of cases in this, like in similar studies, it is not possible to draw any definitive conclusions and further studies with larger numbers are necessary. However it would appear that performing a larger procedure such as mastectomy rather than performing a more limited one such as a quadrantectomy, has no advantage in terms of overall prognosis. Keywords: Primitive breast sarcoma, Surgery, Mastectomy, Quadrantectomy, Skip metastase

Design and Evaluation Challenges of Conversational Agents in Health Care and Well-being: Selective Review Study.

BACKGROUND: Health care and well-being are 2 main interconnected application areas of conversational agents (CAs). There is a significant increase in research, development, and commercial implementations in this area. In parallel to the increasing interest, new challenges in designing and evaluating CAs have emerged. OBJECTIVE: This study aims to identify key design, development, and evaluation challenges of CAs in health care and well-being research. The focus is on the very recent projects with their emerging challenges. METHODS: A review study was conducted with 17 invited studies, most of which were presented at the ACM (Association for Computing Machinery) CHI 2020 conference workshop on CAs for health and well-being. Eligibility criteria required the studies to involve a CA applied to a health or well-being project (ongoing or recently finished). The participating studies were asked to report on their projects' design and evaluation challenges. We used thematic analysis to review the studies. RESULTS: The findings include a range of topics from primary care to caring for older adults to health coaching. We identified 4 major themes: (1) Domain Information and Integration, (2) User-System Interaction and Partnership, (3) Evaluation, and (4) Conversational Competence. CONCLUSIONS: CAs proved their worth during the pandemic as health screening tools, and are expected to stay to further support various health care domains, especially personal health care. Growth in investment in CAs also shows the value as a personal assistant. Our study shows that while some challenges are shared with other CA application areas, safety and privacy remain the major challenges in the health care and well-being domains. An increased level of collaboration across different institutions and entities may be a promising direction to address some of the major challenges that otherwise would be too complex to be addressed by the projects with their limited scope and budget