Proteins are major targets for radicals and two-electron oxidants in biological systems due to their abundance and high rate constants for reaction. With highly reactive radicals damage occurs at ...multiple side-chain and backbone sites. Less reactive species show greater selectivity with regard to the residues targeted and their spatial location. Modification can result in increased side-chain hydrophilicity, side-chain and backbone fragmentation, aggregation via covalent cross-linking or hydrophobic interactions, protein unfolding and altered conformation, altered interactions with biological partners and modified turnover. In the presence of O2, high yields of peroxyl radicals and peroxides (protein peroxidation) are formed; the latter account for up to 70% of the initial oxidant flux. Protein peroxides can oxidize both proteins and other targets. One-electron reduction results in additional radicals and chain reactions with alcohols and carbonyls as major products; the latter are commonly used markers of protein damage. Direct oxidation of cysteine (and less commonly) methionine residues is a major reaction; this is typically faster than with H2O2, and results in altered protein activity and function. Unlike H2O2, which is rapidly removed by protective enzymes, protein peroxides are only slowly removed, and catabolism is a major fate. Although turnover of modified proteins by proteasomal and lysosomal enzymes, and other proteases (e.g. mitochondrial Lon), can be efficient, protein hydroperoxides inhibit these pathways and this may contribute to the accumulation of modified proteins in cells. Available evidence supports an association between protein oxidation and multiple human pathologies, but whether this link is causal remains to be established.
Magnesium, the lightest structural metal, is difficult to form at room temperature due to an insufficient number of deformation modes imposed by its hexagonal structure and a strong texture developed ...during thermomechanical processes. Although appropriate alloying additions can weaken the texture, formability improvement is limited because alloying additions do not fundamentally alter deformation modes. Here we show that magnesium can become super-formable at room temperature without alloying. Despite possessing a strong texture, magnesium can be cold rolled to a strain at least eight times that possible in conventional processing. The resultant cold-rolled sheet can be further formed without cracking due to grain size reduction to the order of one micron and inter-granular mechanisms becoming dominant, rather than the usual slip and twinning. These findings provide a pathway for developing highly formable products from magnesium and other hexagonal metals that are traditionally difficult to form at room temperature.Replacing steel or aluminium vehicle parts with magnesium would result in reduced emissions, but shaping magnesium without cracking remains challenging. Here, the authors successfully extrude and roll textured magnesium into ductile foil at low temperatures by activating intra-granular mechanisms.
Exposure of biological molecules to oxidants is inevitable and therefore commonplace. Oxidative stress in cells arises from both external agents and endogenous processes that generate reactive ...species, either purposely (e.g. during pathogen killing or enzymatic reactions) or accidentally (e.g. exposure to radiation, pollutants, drugs, or chemicals). As proteins are highly abundant and react rapidly with many oxidants, they are highly susceptible to, and major targets of, oxidative damage. This can result in changes to protein structure, function, and turnover and to loss or (occasional) gain of activity. Accumulation of oxidatively-modified proteins, due to either increased generation or decreased removal, has been associated with both aging and multiple diseases. Different oxidants generate a broad, and sometimes characteristic, spectrum of post-translational modifications. The kinetics (rates) of damage formation also vary dramatically. There is a pressing need for reliable and robust methods that can detect, identify, and quantify the products formed on amino acids, peptides, and proteins, especially in complex systems. This review summarizes several advances in our understanding of this complex chemistry and highlights methods that are available to detect oxidative modifications—at the amino acid, peptide, or protein level—and their nature, quantity, and position within a peptide sequence. Although considerable progress has been made in the development and application of new techniques, it is clear that further development is required to fully assess the relative importance of protein oxidation and to determine whether an oxidation is a cause, or merely a consequence, of injurious processes.
The end-Triassic extinction is one of the Phanerozoic's largest mass extinctions. This extinction is typically attributed to climate change associated with degassing of basalt flows from the central ...Atlantic magmatic province (CAMP). However, recent work suggests that the earliest known CAMP basalts occur above the extinction horizon and that climatic and biotic changes began before the earliest known CAMP eruptions. Here we present new high-precision U-Pb ages from CAMP mafic intrusive units, showing that magmatic activity was occurring ∼100 Kyr ago before the earliest known eruptions. We correlate the early magmatic activity with the onset of changes to the climatic and biotic records. We also report ages from sills in an organic rich sedimentary basin in Brazil that intrude synchronously with the extinction suggesting that degassing of these organics contributed to the climate change which drove the extinction. Our results indicate that the intrusive record from large igneous provinces may be more important for linking to mass extinctions than the eruptive record.
We have used data from the Next Generation Virgo Survey to investigate the dwarf galaxy population of the Virgo cluster. We mask and smooth the data, and then use the object detection algorithm ...SExtractor to make our initial dwarf galaxy selection. All candidates are then visually inspected to remove artefacts and duplicates. We derive parameters to best select low surface brightness galaxies using central surface brightness values of
$22.5 \le \mu ^{g}_{0} \le 26.0$
μg and exponential scale lengths of 3.0 ≤ h ≤ 10.0 arcsec to identify 443 cluster dwarf galaxies – 303 of which are new detections, with a surface density that decreases with radius from the cluster centre. We also apply our selection algorithm to ‘background’, non-cluster, fields and find zero detections. In combination, this leads us to believe that we have isolated a cluster dwarf galaxy population. The range of objects we detect is limited because smaller scale sized galaxies are confused with the background, while larger galaxies are split into numerous smaller objects by the detection algorithm. Combining our data with that from other surveys, we find a faint-end slope to the luminosity function of −1.35 ± 0.03, which is not significantly different to what has previously been found, but is a little steeper than the slope for field galaxies. There is no evidence for a faint-end slope steep enough to correspond with galaxy formation models, unless those models invoke either strong feedback processes or use warm dark matter.
A global map of surface heat flow is presented on a 2° × 2° equal area grid. It is based on a global heat flow data set of over 38,000 measurements. The map consists of three components. First, in ...regions of young ocean crust (<67.7 Ma) the model estimate uses a half‐space conduction model based on the age of the oceanic crust, since it is well known that raw data measurements are frequently influenced by significant hydrothermal circulation. Second, in other regions of data coverage the estimate is based on data measurements. At the map resolution, these two categories (young ocean, data covered) cover 65% of Earth's surface. Third, for all other regions the estimate is based on the assumption that there is a correlation between heat flow and geology. This assumption is assessed and the correlation is found to provide a minor improvement over assuming that heat flow would be represented by the global average. The map is made available digitally.
Key Points
A global map is presented for Surface Heat Flow on a 2 degree equal area grid
Map uses data‐set of 38000+ heat flow measurements, ocean crust age and geology
Complete global map is provided in digital files
Repairing trauma to the central nervous system by replacement of glial support cells is an increasingly attractive therapeutic strategy. We have focused on the less-studied replacement of astrocytes, ...the major support cell in the central nervous system, by generating astrocytes from embryonic human glial precursor cells using two different astrocyte differentiation inducing factors. The resulting astrocytes differed in expression of multiple proteins thought to either promote or inhibit central nervous system homeostasis and regeneration. When transplanted into acute transection injuries of the adult rat spinal cord, astrocytes generated by exposing human glial precursor cells to bone morphogenetic protein promoted significant recovery of volitional foot placement, axonal growth and notably robust increases in neuronal survival in multiple spinal cord laminae. In marked contrast, human glial precursor cells and astrocytes generated from these cells by exposure to ciliary neurotrophic factor both failed to promote significant behavioral recovery or similarly robust neuronal survival and support of axon growth at sites of injury. Our studies thus demonstrate functional differences between human astrocyte populations and suggest that pre-differentiation of precursor cells into a specific astrocyte subtype is required to optimize astrocyte replacement therapies. To our knowledge, this study is the first to show functional differences in ability to promote repair of the injured adult central nervous system between two distinct subtypes of human astrocytes derived from a common fetal glial precursor population. These findings are consistent with our previous studies of transplanting specific subtypes of rodent glial precursor derived astrocytes into sites of spinal cord injury, and indicate a remarkable conservation from rat to human of functional differences between astrocyte subtypes. In addition, our studies provide a specific population of human astrocytes that appears to be particularly suitable for further development towards clinical application in treating the traumatically injured or diseased human central nervous system.
Summary 415 million people live with diabetes worldwide, and an estimated 193 million people have undiagnosed diabetes. Type 2 diabetes accounts for more than 90% of patients with diabetes and leads ...to microvascular and macrovascular complications that cause profound psychological and physical distress to both patients and carers and put a huge burden on health-care systems. Despite increasing knowledge regarding risk factors for type 2 diabetes and evidence for successful prevention programmes, the incidence and prevalence of the disease continues to rise globally. Early detection through screening programmes and the availability of safe and effective therapies reduces morbidity and mortality by preventing or delaying complications. Increased understanding of specific diabetes phenotypes and genotypes might result in more specific and tailored management of patients with type 2 diabetes, as has been shown in patients with maturity onset diabetes of the young. In this Seminar, we describe recent developments in the diagnosis and management of type 2 diabetes, existing controversies, and future directions of care.
Bioimpedance analysis (BIA) derives two main pieces of information—total tissue fluid content, which when referring to the whole patient is equivalent to the total body water (TBW), and cell mass, ...which in the limbs mainly reflects muscle. The relationship between these measures, expressed in different ways, is abnormal in dialysis patients due to muscle wasting combined with tissue overhydration. In both dialysis modalities this is associated with aging, comorbidity, and inflammation, and there is a conflict between achieving euvolemia to improve blood pressure control and prevent left ventricular hypertrophy on one hand, but risking episodes of hypovolemia and loss of residual renal function on the other. In peritoneal dialysis, the situation is exacerbated by hypoalbuminemia, whereas in hemodialysis BIA is unable to distinguish between the plasma volume and tissue edema components of interdialytic weight gain. In longitudinal studies BIA can identify changes in hydration following a defined intervention, and spontaneous loss in TBW consequent on muscle wasting not appreciated clinically, resulting in a failure to sufficiently reduce the dry weight. Cardiac biomarkers provide additional information but it is not clear whether this reflects fluid status or underlying structural organ damage. Intervention studies are now needed that show how this information is best used to improve patient outcomes, including meaningful end points such as hospitalization and survival.
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