Molecular Basis of Enhanced Activity in Factor VIIa-Trypsin Variants Conveys Insights into Tissue Factor-mediated Allosteric Regulation of Factor VIIa Activity

The complex of coagulation factor VIIa (FVIIa), a trypsin-like serine protease, and membrane-bound tissue factor (TF) initiates blood coagulation upon vascular injury. Binding of TF to FVIIa promotes allosteric conformational changes in the FVIIa protease domain and improves its catalytic properties. Extensive studies have revealed two putative pathways for this allosteric communication. Here we provide further details of this allosteric communication by investigating FVIIa loop swap variants containing the 170 loop of trypsin that display TF-independent enhanced activity. Using x-ray crystallography, we show that the introduced 170 loop from trypsin directly interacts with the FVIIa active site, stabilizing segment 215–217 and activation loop 3, leading to enhanced activity. Molecular dynamics simulations and novel fluorescence quenching studies support that segment 215–217 conformation is pivotal to the enhanced activity of the FVIIa variants. We speculate that the allosteric regulation of FVIIa activity by TF binding follows a similar path in conjunction with protease domain N terminus insertion, suggesting a more complete molecular basis of TF-mediated allosteric enhancement of FVIIa activity

Two possible source regions for Central Greenland last glacial dust

Dust in Greenland ice cores is used to reconstruct the activity of dust-emitting regions and atmospheric circulation. However, the source of dust material to Greenland over the last glacial period is the subject of considerable uncertainty. Here we use new clay mineral and <10 µm Sr–Nd isotopic data from a range of Northern Hemisphere loess deposits in possible source regions alongside existing isotopic data to show that these methods cannot discriminate between two competing hypothetical origins for Greenland dust: an East Asian and/or central European source. In contrast, Hf isotopes (<10 µm fraction) of loess samples show considerable differences between the potential source regions. We attribute this to a first-order clay mineralogy dependence of Hf isotopic signatures in the finest silt/clay fractions, due to absence of zircons. As zircons would also be absent in Greenland dust, this provides a new way to discriminate between hypotheses for Greenland dust sources

Tendon collagen synthesis declines with immobilization in elderly humans:no effect of anti-inflammatory medication

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used as pain killers during periods of unloading caused by traumatic occurrences or diseases. However, it is unknown how tendon protein turnover and mechanical properties respond to unloading and subsequent reloading in elderly humans, and whether NSAID treatment would affect the tendon adaptations during such periods. Thus we studied human patellar tendon protein synthesis and mechanical properties during immobilization and subsequent rehabilitating resistance training and the influence of NSAIDs upon these parameters. Nineteen men (range 60–80 yr) were randomly assigned to NSAIDs (ibuprofen 1,200 mg/day; Ibu) or placebo (Plc). One lower limb was immobilized in a cast for 2 wk and retrained for 6 wk. Tendon collagen protein synthesis, mechanical properties, size, expression of genes related to collagen turnover and remodeling, and signal intensity (from magnetic resonance imaging) were investigated. Tendon collagen synthesis decreased ( P &lt; 0.001), whereas tendon mechanical properties and size were generally unchanged with immobilization, and NSAIDs did not influence this. Matrix metalloproteinase-2 mRNA tended to increase ( P &lt; 0.1) after immobilization in both groups, whereas scleraxis mRNA decreased with inactivity in the Plc group only ( P &lt; 0.05). In elderly human tendons, collagen protein synthesis decreased after 2 wk of immobilization, whereas tendon stiffness and modulus were only marginally reduced, and NSAIDs had no influence upon this. This indicates an importance of mechanical loading for maintenance of tendon collagen turnover. However, reduced collagen production induced by short-term unloading may only marginally affect tendon mechanical properties in elderly individuals.NEW &amp; NOTEWORTHY In elderly humans, 2 wk of inactivity reduces tendon collagen protein synthesis, while tendon stiffness and modulus are only marginally reduced, and NSAID treatment does not affect this. This indicates that mechanical loading is important for maintenance of tendon collagen turnover and that changes in collagen turnover induced by short-term immobilization may only have minor impact on the internal structures that are essential for mechanical properties in elderly tendons.</jats:p

Typing Late Prehistoric Cows and Bulls—Osteology and Genetics of Cattle at the Eketorp Ringfort on the Öland Island in Sweden

Human management of livestock and the presence of different breeds have been discussed in archaeozoology and animal breeding. Traditionally osteometrics has been the main tool in addressing these questions. We combine osteometrics with molecular sex identifications of 104 of 340 morphometrically analysed bones in order to investigate the use of cattle at the Eketorp ringfort on the Öland island in Sweden. The fort is dated to 300–1220/50 A.D., revealing three different building phases. In order to investigate specific patterns and shifts through time in the use of cattle the genetic data is evaluated in relation to osteometric patterns and occurrence of pathologies on cattle metapodia. Males were genotyped for a Y-chromosomal SNP in UTY19 that separates the two major haplogroups, Y1 and Y2, in taurine cattle. A subset of the samples were also genotyped for one SNP involved in coat coloration (MC1R), one SNP putatively involved in resistance to cattle plague (TLR4), and one SNP in intron 5 of the IGF-1 gene that has been associated to size and reproduction

Mortality following Campylobacter infection: a registry-based linkage study

BACKGROUND: Campylobacteriosis is one of the most commonly identified causes of bacterial diarrheal disease and a common cause of gastroenteritis in travellers from developed nations. Despite the widespread occurrence, there is little information on Campylobacter mortality. METHODS: Mortality among a cohort of Campylobacter cases were compared with the general population 0–1, 1–3, 3–12 and more than 12 month after the onset of the illness. The cases were sub-grouped according to if they had been infected domestically or abroad. RESULTS: The standardized mortality ratio for cases infected domestically was 2.9 (95% CI: 1.9–4.0) within the first month following the illness. The risk then gradually diminished and approached 1.0 after one year or more have passed since the illness. This initial excess risk was not attributable to any particular age group (such as the oldest). In contrast, for those infected abroad, a lower standardized mortality ratio 0.3 (95% CI: 0.04–0.8) was shown for the first month after diagnosis compared to what would be expected in the general population. CONCLUSION: Infection with Campylobacter is associated with an increased short-term risk of death among those who were infected domestically. On the contrary, for those infected abroad a lower than expected risk of death was evident. We suggest that the explanation behind this is a "healthy traveler effect" among imported cases, and effects of a more frail than average population among domestic cases

Ice-core data used for the construction of the Greenland Ice-Core Chronology 2005 and 2021 (GICC05 and GICC21)

We here describe, document, and make available a wide range of data sets used for annual-layer identification in ice cores from DYE-3, GRIP, NGRIP, NEEM, and EGRIP. The data stem from detailed measurements performed both on the main deep cores and shallow cores over more than 40 years using many different setups developed by research groups in several countries and comprise both discrete measurements from cut ice samples and continuous-flow analysis data. The data series were used for counting annual layers 60 000 years back in time during the construction of the Greenland Ice-Core Chronology 2005 (GICC05) and/or the revised GICC21, which currently only reaches 3800 years back. Now that the underlying data are made available (listed in Table 1) we also release the individual annual-layer positions of the GICC05 timescale which are based on these data sets. We hope that the release of the data sets will stimulate further studies of the past climate taking advantage of these highly resolved data series covering a large part of the interior of the Greenland ice sheet

Azimuthal Anisotropy of Photon and Charged Particle Emission in Pb+Pb Collisions at 158 A GeV/c

The azimuthal distributions of photons and charged particles with respect to the event plane are investigated as a function of centrality in Pb + Pb collisions at 158 A GeV/c in the WA98 experiment at the CERN SPS. The anisotropy of the azimuthal distributions is characterized using a Fourier analysis. For both the photon and charged particle distributions the first two Fourier coefficients are observed to decrease with increasing centrality. The observed anisotropies of the photon distributions compare well with the expectations from the charged particle measurements for all centralities.Comment: 8 pages and 6 figures. The manuscript has undergone a major revision. The unwanted correlations were enhanced in the random subdivision method used in the earlier version. The present version uses the more established method of division into subevents separated in rapidity to minimise short range correlations. The observed results for charged particles are in agreement with results from the other experiments. The observed anisotropy in photons is explained using flow results of pions and the correlations arising due to the decay of the neutral pion

Apoptosis-Like Death in Bacteria Induced by HAMLET, a Human Milk Lipid-Protein Complex

Background: Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. Methodology/Principal Findings: We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Conclusions/Significance: Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells

Magnitude, frequency and climate forcing of global volcanism during the last glacial period as seen in Greenland and Antarctic ice cores (60–9 ka)

Large volcanic eruptions occurring in the last glacial period can be detected by their accompanying sulfuric acid deposition in continuous ice cores. Here we employ continuous sulfate and sulfur records from three Greenland and three Antarctic ice cores to estimate the emission strength, the frequency and the climatic forcing of large volcanic eruptions that occurred during the second half of the last glacial period and the early Holocene, 60–9 kyr before 2000 CE (b2k). Over most of the investigated interval the ice cores are synchronized, making it possible to distinguish large eruptions with a global sulfate distribution from eruptions detectable in one hemisphere only. Due to limited data resolution and large variability in the sulfate background signal, particularly in the Greenland glacial climate, we only list Greenland sulfate depositions larger than 20 kg km−2 and Antarctic sulfate depositions larger than 10 kg km−2. With those restrictions, we identify 1113 volcanic eruptions in Greenland and 737 eruptions in Antarctica within the 51 kyr period – for which the sulfate deposition of 85 eruptions is found at both poles (bipolar eruptions). Based on the ratio of Greenland and Antarctic sulfate deposition, we estimate the latitudinal band of the bipolar eruptions and assess their approximate climatic forcing based on established methods. A total of 25 of the identified bipolar eruptions are larger than any volcanic eruption occurring in the last 2500 years, and 69 eruptions are estimated to have larger sulfur emission strengths than the Tambora, Indonesia, eruption (1815 CE). Throughout the investigated period, the frequency of volcanic eruptions is rather constant and comparable to that of recent times. During the deglacial period (16–9 ka b2k), however, there is a notable increase in the frequency of volcanic events recorded in Greenland and an obvious increase in the fraction of very large eruptions. For Antarctica, the deglacial period cannot be distinguished from other periods. This confirms the suggestion that the isostatic unloading of the Northern Hemisphere (NH) ice sheets may be related to the enhanced NH volcanic activity. Our ice-core-based volcanic sulfate records provide the atmospheric sulfate burden and estimates of climate forcing for further research on climate impact and understanding the mechanism of the Earth system