No abstract

Presenilin (PS) is essential for the ␥-cleavage required for the generation of the C terminus of amyloid ␤-protein (A␤). However, the mechanism underlying PS-mediated ␥-cleavage remains unclear. We have identified Herp cDNA by our newly developed screening method for the isolation of cDNAs that increase the degree of ␥-cleavage. Herp was originally identified as a homocysteine-responsive protein, and its expression is up-regulated by endoplasmic reticulum stress. Herp is an endoplasmic reticulum-localized membrane protein that has a ubiquitin-like domain. Here, we report that a high expression of Herp in cells increases the level of A␤ generation, although not in PS-deficient cells. We found that Herp interacts with both PS1 and PS2. Thus, Herp regulates PS-mediated A␤ generation, possibly through its binding to PS. Immunohistochemical analysis of a normal human brain section with an anti-Herp antibody revealed the exclusive staining of neurons and vascular smooth muscle cells. Moreover, the antibody strongly stained activated microglia in senile plaques in the brain of patients with Alzheimer disease. Taken together, Herp could be involved in A␤ accumulation, including the formation of senile plaques and vascular A␤ deposits.

N-3DP significantly increased the erythrocyte membrane n-3/n-6 ratio in IBD patients, and this ratio was significantly higher in the remission group, suggesting that n-3DP alters the fatty acid composition of the cell membrane and influences clinical activity in IBD patients.

Herp is an endoplasmic reticulum (ER)-stress-inducible membrane protein, which has a ubiquitin-like domain (ULD). However, its biological function is as yet unknown. Previously, we reported that a high expression level of Herp in cells increases the generation of amyloid L L-protein (AL L) and that Herp interacts with presenilin (PS). Here, we addressed the role of the ULD of Herp in AL L generation and intracellular Herp stability. We found that the ULD is not essential for the enhancement of AL L generation by Herp expression and the interaction of Herp with PS, but is involved in the rapid degradation of Herp, most likely via the ubiquitin/proteasome pathway. Thus, the ULD of Herp most likely plays a role in the regulation of the intracellular level of Herp under ER stress.

Anguillid eels are found globally in fresh, transitional and saline waters and have played an important role in human life for centuries. The population status of several species is now of significant concern. The threats to populations include direct exploitation at different life stages, blockages to migratory routes by dams and other structures, changes in river basin management that impact habitat carrying capacity and suitability, pollution, climate change, diseases and parasites. While much has been done to understand eel biology and ecology, a major challenge is to identify the key research and management questions so that effective and targeted studies can be designed to inform conservation, management and policy. We gathered 30 experts in the field of eel biology and management to review the current state of knowledge for anguillid eel species and to identify the main topics for research. The identified research topics fell into three themes: (a) Lifecycle and Biology; (b) Impacts and (c) Management. Although tropical anguillid eels are by far the least well understood, significant knowledge gaps exist for all species. Considerable progress has been made in the last 20 years, but the status of many species remains of great concern, particularly for northern temperate species. Without improved engagement and coordination at the regional, national and international level, the situation is unlikely to improve. Further, adaptive management mechanisms to respond to developments in science, policy and our knowledge of potential threats are required to ensure the future of these important and enigmatic species.

Familial Alzheimer disease-causing mutations in the presenilins increase production of longer pathogenic amyloid ␤-peptides (A␤ 42/43 ) by altering ␥-secretase activity. The mechanism underlying this effect remains unknown, although it has been proposed that heteromeric macromolecular complexes containing presenilins mediate ␥-secretase cleavage of the amyloid ␤-precursor protein. Using a random mutagenesis screen of presenilin-1 (PS1) for PS1 endoproteolysis-impairing mutations, we identified five unique mutants, including R278I-PS1 and L435H-PS1, that exclusively generated a high level of A␤ 43 , but did not support physiological PS1 endoproteolysis or A␤ 40 generation. These mutants did not measurably alter the molecular size or subcellular localization of PS1 complexes. Pharmacological studies indicated that the up-regulation of activity for A␤ 43 generation by these mutations was not further enhanced by the difluoroketone inhibitor DFK167 and was refractory to inhibition by sulindac sulfide. These results suggest that PS1 mutations can lead to a wide spectrum of changes in the activity and specificity of ␥-secretase and that the effects of PS1 mutations and ␥-secretase inhibitors on the specificity are mediated through a common mechanism.

BackgroundJapanese people have become increasingly interested in the expression and enhancement of their individual autonomy in medical decisions made regarding medical treatment at and toward the end of life. However, while many Western countries have implemented legislation that deals with patient autonomy in the case of terminal illness, no such legislation exists in Japan. The rationale for this research is based on the need to investigate patient's preferences regarding treatment at the end of life in order to re-evaluate advance directives policy and practice.MethodsWe conducted a cross-sectional survey with 418 members of the general middle-aged and senior adults (aged between 40 and 65) in Tokyo, Japan. Respondents were asked about their attitudes toward advance directives, and preferences toward treatment options.ResultsOver 60% of respondents agreed that it is better to express their wishes regarding advance directives (treatment preferences in writing, appointment of proxy for care decision making, appointment of legal administrator of property, stating preferences regarding disposal of one's property and funeral arrangements) but less than 10% of them had already done so. About 60% of respondents in this study preferred to indicate treatment preferences in broad rather than concrete terms. Over 80% would like to decide treatment preferences in consultation with others (22.2% with their proxy, 11.0% with the doctor, and 47.8% with both their proxy and the doctor).ConclusionThis study revealed that many Japanese people indicate an interest in undertaking advance directives. This study found that there is a range of preferences regarding how advance directives are undertaken, thus it is important to recognize that any processes put into place should allow flexibility in order to best respect patients' wishes and autonomy.

We present the clinical outcome of five patients who had reconstruction of large osseous defects in the iliosacral region after excision of aggressive bone tumors using pedicled-or free-vascularized iliac bone grafts. Surgical margin, incidence of recurrence and metastasis, patient survival, time to bone union, and postoperative function were evaluated. Limb-salvage surgery resulted in wide excisions in two patients with giant-cell tumors of bone and chordoma, respectively, a marginal excision in one patient with a schwannoma, and intralesional excisions to preserve nerve roots in two patients with giant-cell tumors. There was no recurrence at final followup in any of the patients. Bone union required an average of 5.4 months. The postoperative functional results were excellent in all patients except for the patient with a chordoma. In one of the patients with a giant-cell tumor, the screws and rod were removed partially because of skin necrosis in the instrumentation area. This technique is considered a good alternative for reconstruction of a large osseous defect in the pelvis because graft harvest is relatively simple and rapid, especially if a pedicled iliac bone transfer is performed.