Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated (...) region contain multiple transcription factor binding sites, such as AP-1, CREB and MEF2. A 91 bp fragment is the shortest region with significant reporter gene activity and constitutes the minimal promoter element for BACE1. The BACE1 promoter contains six unique functional domains and three structural domains of increasing sequence complexity as the "ATG" start codon is approached. Notably, the BACE1 gene promoter contains basal regulatory elements, inducible features and sites for regulation by various important transcription factors. Herein, we also discuss and speculate how the interaction of these transcription factors with the BACE1 promoter can modulate synaptic plasticity, neuronal apoptosis and oxidative stress, which are pertinent to the pathogenesis and progression of AD. (shrink)

Objectives: To quantify the use of do-not-resuscitate orders in a tertiary-care children’s hospital and to characterise the circumstances in which such orders are written.Design: Retrospective study conducted in a 500-bed children’s hospital in Taiwan.Patients: The course of 101 patients who died between January 2002 and December 2005 was reviewed. The following data were collected: age at death, gender, disease and its status, place of death and survival. There were 59 males and 42 females with a median age of 103 months (...) . 50 children had leukaemias, and 51 had malignancies other than leukaemia. The t test and the χ2 test were applied as appropriate.Results: The study found that 44% of patient deaths occurred in the paediatric oncology ward; 29% of patient deaths occurred in the intensive care unit; and 28% of patients died in their home or at another hospital. Other findings included the following: 46 of 101 patients died after attempted cardiopulmonary resuscitation and 55 died with a DNR order in effect. The mean age at death was 9.8 years in both groups with or without DNR orders.Conclusions: From the study of patient deaths in this tertiary-care children’s hospital, it was concluded that an explicit DNR order is now the rule rather than the exception, with more DNR orders being written for patients who have been ill longer, who have solid tumours, who are not in remission and who are in the ward. (shrink)

Background Biobank participants often do not understand much of the information they are provided as part of the informed consent process, despite numerous attempts at simplifying consent forms and improving their readability. We report the first assessment of biobank enrollees’ comprehension under an "integrated consent” process, where patients were asked to enroll in a research biobank as part of their normal healthcare experience. A number of healthcare systems have implemented similar integrated consent processes for biobanking, but it is unknown how (...) much patients understand after enrolling under these conditions. Methods: We recruited patients who enrolled in a biobank while in a healthcare setting when receiving ordinary care. We assessed knowledge of consent materials using 11 true/false questions drawn from a well-known biobank knowledge test. After reviewing the results from 114 participants, we revised the consent form and repeated the knowledge assessment with 144 different participants. Results: Participants scored poorly on the knowledge test in both rounds, with no significant differences in overall scores or individual items between the rounds. In Phase 1, participants answered 53% of the questions correctly, 25% incorrectly, and 22% “I don’t know.” In Phase 2, participants answered 53% of questions correctly, 24% incorrectly, and 23% “I don’t know.” Participants scored particularly poorly on questions about data sharing and accessing medical records. Conclusions: Enrollees under an integrated consent model had significant misunderstandings that persisted despite an attempt to improve information specifically about those topics in a consent form. These results raise challenges for current approaches that attribute misunderstanding to overly complex consent forms. They also suggest that the pressures of the clinic may compound other problems with patient understanding of biobank consent. As health systems increasingly blend research and care, they may need to rethink their approach to educating patients about participation in a biobank. (shrink)

Medium- and high-spin states of Pr-134 were populated using the Cd-116(Na-23, 5n) reaction and studied with the GAMMASPHERE spectrometer. Several new bands have been found in this nucleus, one of them being linked to the previously observed chiral-candidate twin-band structure. The ground state of Pr-134 could be determined through establishing a level structure that connects the two previously known long-lived isomeric states. Unambiguous spin-parity assignments for the excited states could be performed based on the known 2(-) spin-parity of the ground (...) state combined with the present experimental data. Intrinsic single-particle configurations have been assigned to the newly observed bands on the basis of the measured B(M1)/B(E2) ratios, alignments, band-crossing frequencies, bandhead spins, the observed single-particle configurations in the neighboring nuclei, and taking into account the predictions of total Routhian surface and tilted-axis cranking calculations. (shrink)

Deep brain stimulation — a novel surgical procedure — is emerging as a treatment of last resort for people diagnosed with neuropsychiatric disorders such as severe obsessive-compulsive disorder. The US Food and Drug Administration granted a so-called humanitarian device exemption to allow patients to access this intervention, thereby removing the requirement for a clinical trial of the appropriate size and statistical power. Bypassing the rigors of such trials puts patients at risk, limits opportunities for scientific discovery, and gives device manufacturers (...) unique marketing opportunities. We argue that Congress and federal regulators should revisit the humanitarian device exemption to ensure that it is not used to sidestep careful research that can offer valuable data with appropriate patient safeguards. (shrink)

High-spin states have been studied in Pr-135(59), populated through the Cd-116(Na-23,4n) reaction at 115 MeV, using the Gammasphere gamma-ray spectrometer. The negative-parity yrast band has been significantly extended to spin similar to 45 (h) over bar and excitation energy 21.5 MeV, showing evidence for several rotational alignments. The positive-parity yrast band of Ce-135(58), populated through the p4n channel of this reaction, was also populated to spin similar to 38 (h) over bar and excitation energy 18 MeV. Cranking calculations indicate that (...) these nuclei are soft with respect to the triaxiality parameter gamma and that several competing nuclear shapes occur at high spin. (shrink)

BackgroundIn the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies.MethodsBetween 2013 and 2019, 8252 participants (...) (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported.ResultsSevere structural abnormalities occurred in 8.3% (95% confidence interval 7.7–8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy.ConclusionThe management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/nct02220582. (shrink)

This volume explores how Catholicism began and continues to open its doors to the wider world and to other confessions in embracing ecumenism, thanks to the vision and legacy of the Second Vatican Council. It explores such themes as the twentieth century context preceding the council; parallels between Vatican II and previous councils; its distinctively pastoral character; the legacy of the council in relation to issues such as church-world dynamics, as well as to ethics, social justice, economic activity. Several chapters (...) discuss the role of women in the church before, during, and since the council. Others discern inculturation in relation to Vatican II. The book also contains a wide and original range of ecumenical considerations of the council, including by and in relation to Free Church, Reformed, Orthodox, and Anglican perspectives. Finally, it considers the Council’s ongoing promise and remaining challenges with regard to ecumenical issues, including a groundbreaking essay on the future of ecumenical dialogue by Cardinal Walter Kasper. (shrink)

Context. The identification of the sources that reionized the Universe and their specific contribution to this process are key missing pieces of our knowledge of the early Universe. Faint star-forming galaxies may be the main contributors to the ionizing photon budget during the epoch of reionization, but their escaping photons cannot be detected directly due to inter-galactic medium opacity. Hence, it is essential to characterize the properties of faint galaxies with significant Lyman continuum photon leakage up to z 4 to (...) define indirect indicators allowing analogues to be found at the highest redshift. Aims. Long gamma-ray bursts explode typically in star-forming regions of faint, star-forming galaxies. Through LGRB afterglow spectroscopy it is possible to detect directly LyC photons. Our aim is to use LGRBs as tools to study LyC leakage from faint, star-forming galaxies at high redshift. Methods. Here we present the observations of LyC emission in the afterglow spectra of GRB 191004B at z = 3:5055, together with those of the other two previously known LyC-emitting LGRB, to determine their LyC escape fraction and compare their properties. Results. From the afterglow spectrum of GRB 191004B we determine a neutral hydrogen column density at the LGRB redshift of og =17:2 0:15, and negligible extinction. The only metal absorption lines detected are C iv and Si iv. In contrast to GRB 050908 and GRB 060607A, the host galaxy of GRB 191004B displays significant Ly emission. From its Ly emission and the non-detection of Balmer emission lines we constrain its star-formation rate to 1 SFR 4:7 M yr. 1. We fit the Ly emission with a shell model and find parameters values consistent with the observed ones. The absolute LyC escape fractions we find for GRB 191004B, GRB 050908 and GRB 060607A are of 0:35+0:10.0:11, 0:08+0:05.0:04 and :20+0:05.0:05, respectively. We compare the LyC escape fraction of LGRBs to the values of other LyC emitters found from the literature, showing that LGRB afterglows can be powerful tools to study LyC escape for faint high-redshift star-forming galaxies. Indeed we could push LyC leakage studies to much higher absolute magnitudes. The host galaxies of the three LGRB presented here have all M1600 >.19:5 mag, with the GRB 060607A host at M1600 >.16 mag. LGRB hosts may therefore be particularly suitable for exploring the ionizing escape fraction in galaxies that are too faint or distant for conventional techniques. Furthermore the time investment is very small compared to galaxy studies. (shrink)

© 2016 Regents of the University of California.The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,062 new measurements from 721 papers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as supersymmetric particles, heavy bosons, axions, dark photons, etc. All the particle properties and search limits are listed in Summary Tables. We also give numerous (...) tables, figures, formulae, and reviews of topics such as Higgs Boson Physics, Supersymmetry, Grand Unified Theories, Neutrino Mixing, Dark Energy, Dark Matter, Cosmology, Particle Detectors, Colliders, Probability and Statistics. Among the 117 reviews are many that are new or heavily revised, including those on Pentaquarks and Inflation. The complete Review is published online in a journal and on the website of the Particle Data Group. The printed PDG Book contains the Summary Tables and all review articles but no longer includes the detailed tables from the Particle Listings. A Booklet with the Summary Tables and abbreviated versions of some of the review articles is also available. (shrink)

The objectives of this study were to develop a high-density chromosome bin map of homoeologous group 7 in hexaploid wheat, to identify gene distribution in these chromosomes, and to perform comparative studies of wheat with rice and barley. We mapped 2148 loci from 919 EST clones onto group 7 chromosomes of wheat. In the majority of cases the numbers of loci were significantly lower in the centromeric regions and tended to increase in the distal regions. The level of duplicated loci (...) in this group was 24% with most of these loci being localized toward the distal regions. One hundred nineteen EST probes that hybridized to three fragments and mapped to the three group 7 chromosomes were designated landmark probes and were used to construct a consensus homoeologous group 7 map. An additional 49 probes that mapped to 7AS, 7DS, and the ancestral translocated segment involving 7BS also were designated landmarks. Landmark probe orders and comparative maps of wheat, rice, and barley were produced on the basis of corresponding rice BAC/PAC and genetic markers that mapped on chromosomes 6 and 8 of rice. Identification of landmark ESTs and development of consensus maps may provide a framework of conserved coding regions predating the evolution of wheat genomes. (shrink)

We present a one per cent measurement of the cosmic distance scale from the detections of the baryon acoustic oscillations in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey, which is part of the Sloan Digital Sky Survey III. Our results come from the Data Release 11 sample, containing nearly one million galaxies and covering approximately 8500 square degrees and the redshift range 0.2 < z < 0.7. We also compare these results with those from the publicly released (...) DR9 and DR10 samples. Assuming a concordance Λ cold dark matter cosmological model, the DR11 sample covers a volume of 13 Gpc3 and is the largest region of the Universe ever surveyed at this density. We measure the correlation function and power spectrum, including density-field reconstruction of the BAO feature. The acoustic features are detected at a significance of over 7σ in both the correlation function and power spectrum. Fitting for the position of the acoustic features measures the distance relative to the sound horizon at the drag epoch, rd, which has a value of rd,fid = 149.28 Mpc in our fiducial cosmology. We find DV = at z = 0.32 and DV = at z = 0.57. At 1.0 per cent, this latter measure is the most precise distance constraint ever obtained from a galaxy survey. Separating the clustering along and transverse to the line of sight yields measurements at z = 0.57 of DA = and H =. Our measurements of the distance scale are in good agreement with previous BAO measurements and with the predictions from cosmic microwave background data for a spatially flat CDM model with a cosmological constant. © 2014 The Author Published by Oxford University Press on behalf of the Royal Astronomical Society. (shrink)

This anthology of the very latest research on truth features the work of recognized luminaries in the field, put together following a rigorous refereeing process. Along with an introduction outlining the central issues in the field, it provides a unique and unrivaled view of contemporary work on the nature of truth, with papers selected from key conferences in 2011 such as Truth Be Told (Amsterdam), Truth at Work (Paris), Paradoxes of Truth and Denotation (Barcelona) and Axiomatic Theories of Truth (Oxford).

© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the frequency (...) of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (shrink)

Why do we persist in the relentless pursuit of artificial nourishment and other treatments to maintain a permanently unconscious existence? In facing the future, if not the present world-wide reality of a huge number of persistent vegetative state (PVS) patients, will they be treated because of our ethical commitment to their humanity, or because of an ethical paralysis in the face of biotechnical progress? The PVS patient is cut off from the normal patterns of human connection and communication, with a (...) life unlike other forms of human existence. Why the struggle to justify ending a life which, it is said, has suffered an irreversible loss of the content of consciousness? Elsewhere, the authors have addressed the ethical controversies and confusion engendered by ambiguous terminology, misuse of medical facts and the differing interpretations of what constitutes 'effective' treatment: in particular, the issue of whether in fact artificial nutrition and hydration is a medical treatment, or simply part of the obligatory care owed to all patients, permanently unconscious or not. In this paper, we intend to argue that recent analyses of medical futility, its meaning and ethical implications, despite an absence of public consensus, permit some tentative re-evaluation of our ethical obligations to the PVS patient. (shrink)

The power of technology to transform religions, science, and political institutions has often been presented as nothing short of revolutionary. Does technology have a similarly transformative influence on societies’ morality? Scholars have not rigorously investigated the role of technology in moral revolutions, even though existing research on technomoral change suggests that this role may be considerable. In this paper, we explore what the role of technology in moral revolutions, understood as processes of radical group-level moral change, amounts to. We do (...) so by investigating four historical episodes of radical moral change in which technology plays a noteworthy role. Our case-studies illustrate the plurality of mechanisms involved in technomoral revolutions, but also suggest general patterns of technomoral change, such as technology’s capacity to stabilize and destabilize moral systems, and to make morally salient phenomena visible or invisible. We find several leads to expand and refine conceptual tools for analysing moral change, specifically by crystallizing the notions of ‘technomoral niche construction’ and ‘moral payoff mechanisms’. Coming to terms with the role of technology in radical moral change, we argue, enriches our understanding of moral revolutions, and alerts us to the depths of which technology can change our societies in wanted and unwanted ways. (shrink)

The focus of this study was to analyze the content, distribution, and comparative genome relationships of 996 chromosome bin-mapped expressed sequence tags accounting for 2266 restriction fragments on the homoeologous group 3 chromosomes of hexaploid wheat. Of these loci, 634, 884, and 748 were mapped on chromosomes 3A, 3B, and 3D, respectively. The individual chromosome bin maps revealed bins with a high density of mapped ESTs in the distal region and bins of low density in the proximal region of the (...) chromosome arms, with the exception of 3DS and 3DL. These distributions were more localized on the higher-resolution group 3 consensus map with intermediate regions of high-mapped-EST density on both chromosome arms. Gene ontology classification of mapped ESTs was not significantly different for homoeologous group 3 chromosomes compared to the other groups. A combined analysis of the individual bin maps using 537 of the mapped ESTs revealed rearrangements between the group 3 chromosomes. Approximately 232 of the consensus mapped ESTs matched sequences on rice chromosome 1 and revealed large- and small-scale differences in gene order. Of the group 3 mapped EST unigenes ∼21 and 32% matched the Arabidopsis coding regions and proteins, respectively, but no chromosome-level gene order conservation was detected. (shrink)

Successful applications of a conceptually novel setup of Quantum Field Theory, that accounts for all subtheories of the Standard Model (QED, Electroweak Interaction and Higgs, Yang–Mills and QCD) and beyond (Helicity 2), call for a perspective view in a broader conceptual context. The setting is “autonomous” in the sense of being intrinsically quantum. Its principles are: Hilbert space, Poincaré symmetry and causality. Its free quantum fields are obtained from Wigner’s unitary representations of the Poincaré group, with only physical and observable (...) degrees of freedom. A “quantization” of an “underlying” classical theory is not needed. It allows renormalizable perturbation theory with interactions whose detailed structure, and in some cases even the particle content, is predicted by internal consistency. The results confirm and extend observable predictions for the interactions of the Standard Model without assuming a “principle” of gauge invariance. (shrink)

ABSTRACT Global biodiversity declines are increasingly recognized as profound ecological and social crises. In areas subject to colonialization, these declines have advanced in lockstep with settler colonialism and imposition of centralized resource management by settler states. Many have suggested that resurgent Indigenous-led governance systems could help arrest these trends while advancing effective and socially just approaches to environmental interactions that benefit people and places alike. However, how dominant management and conservation approaches might be decolonized (i.e., how their underlying colonial structure (...) might be addressed, transformed, and replaced) is not always clear. Here, we describe a ‘Decolonial Model of Environmental Management and Conservation’ as an alternative paradigm to dominant approaches of conservation and management. The tenets of the model describe characteristics that might be expected of decolonized management, contrasted with those of dominant state-led approaches such as those embedded in the North American Model of Wildlife Conservation. The model does not prescribe how Indigenous governments or communities ought to govern their own territories, but instead offers insights into how external management and conservation agencies and practitioners might support (or stop impeding) Indigenous-led governance. We illustrate the model with a conservation ‘bright spot’: grizzly bear stewardship in the area now referred to as the Great Bear Rainforest in British Columbia, Canada, with a focus on work led by or in collaboration with, and within the territories of, the Haíɫzaqv, Kitasoo/xai’xais, Nuxalk, and Wuikinuxv First Nations. While acknowledging the important context-specific variability among place-based management and conservation applications, we also discuss the model’s broader applicability. (shrink)

A total of 944 expressed sequence tags generated 2212 EST loci mapped to homoeologous group 1 chromosomes in hexaploid wheat. EST deletion maps and the consensus map of group 1 chromosomes were constructed to show EST distribution. EST loci were unevenly distributed among chromosomes 1A, 1B, and ID with 660, 826, and 726, respectively. The number of EST loci was greater on the long arms than on the short arms for all three chromosomes. The distribution of ESTs along chromosome arms (...) was nonrandom with EST clusters occurring in the distal regions of short arms and middle regions of long arms. Duplications of group 1 ESTs in other homoeologous groups occurred at a rate of 35.5%. Seventy-five percent of wheat chromosome 1 ESTs had significant matches with rice sequences, where large regions of conservation occurred between wheat consensus chromosome 1 and rice chromosome 5 and between the proximal portion of the long arm of wheat consensus chromosome 1 and rice chromosome 10. Only 9.5% of group 1 ESTs showed significant matches to Arabidopsis genome sequences. The results presented are useful for gene mapping and evolutionary and comparative genomics of grasses. (shrink)