Genetic polymorphisms, platelet activation and plasma homocysteine concentrations in atherothrombotic stroke

Atherothrombotic stroke arises following rupture of an atheromatous plaque, and occlusion occurs directly due to thrombosis in small arteries, or indirectly by embolisation if a large vessel plaque ruptures. Three risk factors that are claimed to influence these process were investigated. The influence of platelet activation and genetic polymorphisms of platelet membrane glycoproteins on the risk of thrombotic stroke was assessed. Following plaque rupture, platelets have a pivotal role in arterial thrombus formation, and platelet membrane glycoproteins (GP) IIIa (the fibrinogen receptor) and Ib (which binds von Willebrand factor) are crucial in this process. The lb allele of the HPA 1a/1b GPIIIa polymorphism and the 2b allele of the HPA 2a/2b GPIb polymorphism are claimed to be risk factors for stroke and myocardial infarction (MI), but reports are conflicting and consistent functional evidence of enhanced thrombogenicity is lacking. Increased factor VII activity (VIIc) has been claimed to be a risk factor for MI and stroke, but the data are conflicting. VIIc is dependent on both environmental and genetic influences, and recently two polymorphisms of the factor VII gene associated with lower VIIc have been claimed to be protective against MI. A raised plasma homocysteine concentration has been proposed as a cause for atherosclerosis. However the role of homocysteine in stroke aetiology remains controversial, since prospective studies have reported a weaker association than those conducted retrospectively. Furthermore there are few reports of plasma homocysteine concentrations both before and after the event. The following studies were conducted to address these issues: An investigation of the effect of HPA la/lb genotype on platelet fibrinogen binding by whole blood flow cytometry in healthy subjects. The effect of the lb allele on platelet fibrinogen binding was investigated in healthy subjects by whole blood flow cytometry. 35 platelet or plasma donors (34 HPA 1a/1b and one HPA 1b/1b) possessing the lb allele were compared with 35 donors homozygous for the la allele. There was no allele dependent difference in the percentage of platelets binding fibrinogen at baseline (p=0.14, Mann Whitney U test) or following stimulation with ADP (p=0.72, Student's t-test). An paradoxical increase in the density of fibrinogen binding sites was observed in la platelets after ADP stimulation (p=0.05, Mann Whitney U test), 1b platelets tended to exhibit greater activation as assessed by the percentage of platelets expressing P-Selectin, but this did not reach statistical significance (p=0.08, Mann-Whitney U test). These data do not identify a functional mechanism by which the 1b allele might mediate an increased risk of arterial thrombosis. (Abstract shortened by ProQuest.)

Mitochondrial-nuclear epistasis affects fitness within species but does not contribute to fixed incompatibilities between species of \u3ci\u3eDrosophila\u3c/i\u3e

Efficient mitochondrial function requires physical interactions between the proteins encoded by the mitochondrial and nuclear genomes. Co-evolution between these genomes may result in the accumulation of incompatibilities between divergent lineages. We test whether mitochondrialnuclear incompatibilities have accumulated within the Drosophila melanogaster species subgroup by combining divergent mitochondrial and nuclear lineages and quantifying the effects on relative fitness. Precise placement of nine mtDNAs from D. melanogaster, D. simulans and D. mauritiana into two D. melanogaster nuclear genetic backgrounds reveals significant mitochondrial-nuclear epistasis affecting fitness in females. Combining the mitochondrial genomes with three different D. melanogaster X chromosomes reveals significant epistasis for male fitness between X-linked and mitochondrial variation. However, we find no evidence that the more than 500 fixed differences between the mitochondrial genomes of D. melanogaster and the D. simulans species complex are incompatible with the D. melanogaster nuclear genome. Rather, the interactions of largest effect occur between mitochondrial and nuclear polymorphisms that segregate within species of the D. melanogaster species subgroup. We propose that a low mitochondrial substitution rate, resulting from a low mutation rate and/or efficient purifying selection, precludes the accumulation of mitochondrial-nuclear incompatibilities among these Drosophila species

On Physical Anthropological Aspects of the Mesolithic-Neolithic Transition in the Iberian Peninsula

https://www.journals.uchicago.edu/doi/abs/10.1086/20467

The Aveline's Hole 9 Cranium: A Partial Solution to a Long Standing Enigma

Aveline's Hole is both one of the best-known sites with early human skeletal material in Britain and one of the most problematic in its history. First discovered and explored at the close of the 18th century, it yielded an estimated burial count of at least fifty individuals. Twentieth century work suggested a Late Upper Palaeolithic date for the material, in a context that might be called Creswellian. A recent dating programme places the human remains into the early Holocene and confirms the site as a Mesolithic cemetery in all senses of that word. Though a number of partial studies of the material have been published, no full description was attempted or published prior to the destruction of much of the collection in 1940. Recently one of us published a full study of the site history and a description and analysis of the surviving material. However, that study did note the small number of intact but undated crania that have been attributed to the site at various times. This study looks at one of these, denoted as AH9 and never previously described, in the aftermath of direct radiocarbon dating. Both direct dating and indirect analyses indicate that it is highly unlikely that this skull was part of the Mesolithic assemblage from this site."The work of CM was made possible by grants from the Canada Council and the Social Sciences and Humanities Research Council of Canada. The dating of the specimen was funded by a grant through NERC’s ORADS programme."https://www.ubss.org.uk/resources/proceedings/vol25/UBSS_Proc_25_3_275-294.pd

Population preference values for treatment outcomes in chronic lymphocytic leukaemia: a cross-sectional utility study

<p>Abstract</p> <p>Background</p> <p>Given that treatments for chronic lymphocytic leukaemia (CLL) are palliative rather than curative, evaluating the patient-perceived impacts of therapy is critical. To date, no utility (preference) studies from the general public or patient perspective have been conducted in CLL. The objective of this study was to measure preferences for health states associated with CLL treatment.</p> <p>Methods</p> <p>This was a cross-sectional study of 89 members of the general population in the UK (England and Scotland). Using standard gamble, each participant valued four health states describing response status, six describing treatment-related toxicities based on Common Toxicity Criteria, and two describing line of treatment. The health states incorporated standardized descriptions of treatment response (symptoms have "improved," "stabilized," or "gotten worse"), swollen glands, impact on daily activities, fatigue, appetite, and night sweats. Utility estimates ranged from 0.0, reflecting dead, to 1.0, reflecting full health.</p> <p>Results</p> <p>Complete response (CR) was the most preferred health state (mean utility, 0.91), followed by partial response (PR), 0.84; no change (NC), 0.78; and progressive disease (PD), 0.68. Among the toxicity states, grade I/II nausea and nausea/vomiting had the smallest utility decrements (both were -0.05), and grade III/IV pneumonia had the greatest decrement (-0.20). The utility decrements obtained for toxicity states can be subtracted from utilities for CR, PR, NC, and PD, as appropriate. The utilities for second- and third-line treatments, which are attempted when symptoms worsen, were 0.71 and 0.65, respectively. No significant differences in utilities were observed by age, sex, or knowledge/experience with leukaemia.</p> <p>Conclusions</p> <p>This study reports UK population utilities for a universal set of CLL health states that incorporate intended treatment response and unintended toxicities. These utilities can be applied in future cost-effectiveness analyses of CLL treatment.</p

An Incompatibility between a Mitochondrial tRNA and Its Nuclear-Encoded tRNA Synthetase Compromises Development and Fitness in \u3ci\u3eDrosophila\u3c/i\u3e

Mitochondrial transcription, translation, and respiration require interactions between genes encoded in two distinct genomes, generating the potential for mutations in nuclear and mitochondrial genomes to interact epistatically and cause incompatibilities that decrease fitness. Mitochondrial-nuclear epistasis for fitness has been documented within and between populations and species of diverse taxa, but rarely has the genetic or mechanistic basis of these mitochondrial–nuclear interactions been elucidated, limiting our understanding of which genes harbor variants causing mitochondrial–nuclear disruption and of the pathways and processes that are impacted by mitochondrial–nuclear coevolution. Here we identify an amino acid polymorphism in the Drosophila melanogaster nuclear-encoded mitochondrial tyrosyl–tRNA synthetase that interacts epistatically with a polymorphism in the D. simulans mitochondrial-encoded tRNATyr to significantly delay development, compromise bristle formation, and decrease fecundity. The incompatible genotype specifically decreases the activities of oxidative phosphorylation complexes I, III, and IV that contain mitochondrial-encoded subunits. Combined with the identity of the interacting alleles, this pattern indicates that mitochondrial protein translation is affected by this interaction. Our findings suggest that interactions between mitochondrial tRNAs and their nuclear-encoded tRNA synthetases may be targets of compensatory molecular evolution. Human mitochondrial diseases are often genetically complex and variable in penetrance, and the mitochondrial–nuclear interaction we document provides a plausible mechanism to explain this complexity

Rock mass loss on a nunatak in Western Dronning Maud Land, Antarctica

This paper presents the first rock mass loss data for uncut clasts from continental Antarctica. A rock mass loss experiment using doleritic rock samples was conducted over a seven-year period, between 2008 and 2014, at the Vesleskarvet nunataks, Western Dronning Maud Land. The data show that approximately 10% of clasts suffered a mass loss that is an order of magnitude greater than the remaining 90% of clasts. Thus, the observed rock mass loss is suggested to occur in a series of events that are impossible to predict in terms of frequency and/or magnitude. However, extrapolating from the data obtained during the seven-year period indicates that rates of mass loss are slow and of the order of 1% per 100 years. Direct erosion by wind (including abrasion) as well as mechanical and chemical weathering are suggested to be responsible for rock mass loss. Rock properties, the weathering environment, and a lack of available moisture may be contributing factors to the slow rate of rock decay. This paper suggests that in this area of Antarctica, the slow rate of rock mass loss increases the longevity of existing periglacial landforms such as patterned ground and blockfields, but inhibits development of new patterned ground through the slow production of fines.The Department of Environmental Affairs and the National Research Foundation are gratefully acknowledged for logistical and financial support. This work is published under the NRF/SANAP project : Landscape and climate interactions in a changing sub-Antarctic environment (Grant no 93075).http://instaar.colorado.edu/AAAR/index.phphb2016Geography, Geoinformatics and Meteorolog

Gene flow mediates the role of sex chromosome meiotic drive during complex speciation

During speciation, sex chromosomes often accumulate interspecific genetic incompatibilities faster than the rest of the genome. The drive theory posits that sex chromosomes are susceptible to recurrent bouts of meiotic drive and suppression, causing the evolutionary build- up of divergent cryptic sex-linked drive systems and, incidentally, genetic incompatibilities. To assess the role of drive during speciation, we combine high-resolution genetic mapping of X-linked hybrid male sterility with population genomics analyses of divergence and recent gene flow between the fruitfly species, Drosophila mauritiana and D. simulans. Our findings reveal a high density of genetic incompatibilities and a corresponding dearth of gene flow on the X chromosome. Surprisingly, we find that a known drive element recently migrated between species and, rather than contributing to interspecific divergence, caused a strong reduction in local sequence divergence, undermining the evolution of hybrid sterility. Gene flow can therefore mediate the effects of selfish genetic elements during speciation