In this book, Allen Wood investigates Kant's conception of ethical theory, using it to develop a viable approach to the rights and moral duties of human beings. By remaining closer to Kant's own view ...of the aims of ethics, Wood's understanding of Kantian ethics differs from the received 'constructivist' interpretation, especially on such matters as the ground and function of ethical principles, the nature of ethical reasoning and autonomy as the ground of ethics. Wood does not hesitate to criticize and modify Kant's conclusions when they seem inconsistent with his basic principles or fail to make the best use of the resources Kantian principles make available. Of special interest are the book's treatment of such topics as freedom of the will, the state's role in securing economic justice, sexual morality, the justification of punishment, and the prohibition on lying.
Engineered purification tags can facilitate very efficient purification of recombinant proteins, resulting in high yields and purities in a few standard steps. Over the years, many different ...purification tags have been developed, including short peptides, epitopes, folded protein domains, non-chromatographic tags and more recently, compound multifunctional tags with optimized capabilities. Although classic proteases are still primarily used to remove the tags from target proteins, new self-cleaving methods are gaining traction as a highly convenient alternative. In this review, we discuss some of these emerging trends, and examine their potential impacts and remaining challenges in recombinant protein research.
We present optical light curves, redshifts, and classifications for spectroscopically confirmed Type Ia supernovae (SNe Ia) discovered by the Pan-STARRS1 (PS1) Medium Deep Survey. We detail ...improvements to the PS1 SN photometry, astrometry, and calibration that reduce the systematic uncertainties in the PS1 SN Ia distances. We combine the subset of PS1 SNe Ia (0.03 < z < 0.68) with useful distance estimates of SNe Ia from the Sloan Digital Sky Survey (SDSS), SNLS, and various low-z and Hubble Space Telescope samples to form the largest combined sample of SNe Ia, consisting of a total of SNe Ia in the range of 0.01 < z < 2.3, which we call the "Pantheon Sample." When combining Planck 2015 cosmic microwave background (CMB) measurements with the Pantheon SN sample, we find and for the wCDM model. When the SN and CMB constraints are combined with constraints from BAO and local H0 measurements, the analysis yields the most precise measurement of dark energy to date: and for the CDM model. Tension with a cosmological constant previously seen in an analysis of PS1 and low-z SNe has diminished after an increase of 2× in the statistics of the PS1 sample, improved calibration and photometry, and stricter light-curve quality cuts. We find that the systematic uncertainties in our measurements of dark energy are almost as large as the statistical uncertainties, primarily due to limitations of modeling the low-redshift sample. This must be addressed for future progress in using SNe Ia to measure dark energy.
Many current metrics of drought are derived solely from analyses of climate variables such as precipitation and temperature. Drought is clearly a consequence of climate anomalies, as well as of human ...water use practices, but many impacts to society are more directly related to hydrologic conditions resulting from these two factors. Modern hydrology models can provide a valuable counterpart to existing climate‐based drought indices by simulating hydrologic variables such as land surface runoff. We contrast the behavior of a standardized runoff index (SRI) with that of the well‐known standardized precipitation index (SPI) during drought events in a snowmelt region. Although the SRI and SPI are similar when based on long accumulation periods, the SRI incorporates hydrologic processes that determine seasonal lags in the influence of climate on streamflow. As a result, on monthly to seasonal time scales, the SRI is a useful complement to the SPI for depicting hydrologic aspects of drought.
When students answer an in-class conceptual question individually using clickers, discuss it with their neighbors, and then revote on the same question, the percentage of correct answers typically ...increases. This outcome could result from gains in understanding during discussion, or simply from peer influence of knowledgeable students on their neighbors. To distinguish between these alternatives in an undergraduate genetics course, we followed the above exercise with a second, similar (isomorphic) question on the same concept that students answered individually. Our results indicate that peer discussion enhances understanding, even when none of the students in a discussion group originally knows the correct answer.
The 12th St Gallen International Breast Cancer Conference (2011) Expert Panel adopted a new approach to the classification of patients for therapeutic purposes based on the recognition of intrinsic ...biological subtypes within the breast cancer spectrum. For practical purposes, these subtypes may be approximated using clinicopathological rather than gene expression array criteria. In general, systemic therapy recommendations follow the subtype classification. Thus, ‘Luminal A’ disease generally requires only endocrine therapy, which also forms part of the treatment of the ‘Luminal B’ subtype. Chemotherapy is considered indicated for most patients with ‘Luminal B', ‘Human Epidermal growth factor Receptor 2 (HER2) positive’, and ‘Triple negative (ductal)’ disease, with the addition of trastuzumab in ‘HER2 positive’ disease. Progress was also noted in defining better tolerated local therapies in selected cases without loss of efficacy, such as accelerated radiation therapy and the omission of axillary dissection under defined circumstances. Broad treatment recommendations are presented, recognizing that detailed treatment decisions need to consider disease extent, host factors, patient preferences, and social and economic constraints.
The increased availability of user‐friendly and accessible computational tools for biomolecular modeling would expand the reach and application of biomolecular engineering and design. For protein ...modeling, one key challenge is to reduce the complexities of 3D protein folds to sets of parametric equations that nonetheless capture the salient features of these structures accurately. At present, this is possible for a subset of proteins, namely, repeat proteins. The α‐helical coiled coil provides one such example, which represents ≈ 3–5% of all known protein‐encoding regions of DNA. Coiled coils are bundles of α helices that can be described by a small set of structural parameters. Here we describe how this parametric description can be implemented in an easy‐to‐use web application, called CCBuilder 2.0, for modeling and optimizing both α‐helical coiled coils and polyproline‐based collagen triple helices. This has many applications from providing models to aid molecular replacement for X‐ray crystallography, in silico model building and engineering of natural and designed protein assemblies, and through to the creation of completely de novo “dark matter” protein structures. CCBuilder 2.0 is available as a web‐based application, the code for which is open‐source and can be downloaded freely. http://coiledcoils.chm.bris.ac.uk/ccbuilder2.
Lay Summary
We have created CCBuilder 2.0, an easy to use web‐based application that can model structures for a whole class of proteins, the α‐helical coiled coil, which is estimated to account for 3–5% of all proteins in nature. CCBuilder 2.0 will be of use to a large number of protein scientists engaged in fundamental studies, such as protein structure determination, through to more‐applied research including designing and engineering novel proteins that have potential applications in biotechnology.
Here, we use single-molecule techniques to study the aggregation of α-synuclein, the protein whose misfolding and deposition is associated with Parkinson's disease. We identify a conformational ...change from the initially formed oligomers to stable, more compact proteinase-K-resistant oligomers as the key step that leads ultimately to fibril formation. The oligomers formed as a result of the structural conversion generate much higher levels of oxidative stress in rat primary neurons than do the oligomers formed initially, showing that they are more damaging to cells. The structural conversion is remarkably slow, indicating a high kinetic barrier for the conversion and suggesting that there is a significant period of time for the cellular protective machinery to operate and potentially for therapeutic intervention, prior to the onset of cellular damage. In the absence of added soluble protein, the assembly process is reversed and fibrils disaggregate to form stable oligomers, hence acting as a source of cytotoxic species.
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► A variety of oligomers form during αS amyloid fibril assembly and disaggregation ► A slow process converts early oligomers to stable, proteinase-K-resistant forms ► Oligomers arising from the conversion reaction are more toxic than the early species ► Mature amyloid fibrils can either sequester or release potentially cytotoxic oligomers
Single-molecule fluorescence reveals that the cytotoxic species of α-synuclein associated with Parkinson's disease forms via the slow structural conversion of disordered, nontoxic oligomers into a stable form that is toxic to primary neurons and that precedes fibril formation.
The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, ...farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein-protein interactions and signal transduction. Numerous essential intracellular proteins undergo prenylation, including most members of the small GTPase superfamily as well as heterotrimeric G proteins and nuclear lamins, and are involved in regulating a plethora of cellular processes and functions. Dysregulation of isoprenoids and protein prenylation is implicated in various disorders, including cardiovascular and cerebrovascular diseases, cancers, bone diseases, infectious diseases, progeria, and neurodegenerative diseases including Alzheimer's disease (AD). Therefore, isoprenoids and/or prenyltransferases have emerged as attractive targets for developing therapeutic agents. Here, we provide a general overview of isoprenoid synthesis, the process of protein prenylation and the complexity of prenylated proteins, and pharmacological agents that regulate isoprenoids and protein prenylation. Recent findings that connect isoprenoids/protein prenylation with AD are summarized and potential applications of new prenylomic technologies for uncovering the role of prenylated proteins in the pathogenesis of AD are discussed.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The discovery of inteins in the early 1990s opened the door to a wide variety of new technologies. Early engineered inteins from various sources allowed the development of self-cleaving affinity tags ...and new methods for joining protein segments through expressed protein ligation. Some applications were developed around native and engineered split inteins, which allow protein segments expressed separately to be spliced together in vitro. More recently, these early applications have been expanded and optimized through the discovery of highly efficient trans-splicing and trans-cleaving inteins. These new inteins have enabled a wide variety of applications in metabolic engineering, protein labeling, biomaterials construction, protein cyclization, and protein purification.
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