Acute coronary syndromes (ACS) are a global cause of mortality and morbidity that affect millions of lives worldwide. Following atherosclerotic plaque rupture, platelet activation and aggregation are ...the two major elements that initiate thrombus formation inside a coronary artery, which can obstruct blood flow and cause myocardial ischemia; ergo, antiplatelet therapy forms a major part of the treatment strategy for ACS. Patients with ACS routinely receive dual antiplatelet therapy (DAPT), which consists of aspirin and a platelet P2Y
12
inhibitor to both treat and prevent atherothrombosis. Use of platelet glycoprotein (GP) IIb/IIIa inhibitors is now limited due to the risk of severe bleeding and thrombocytopenia. Thus, administration of GPIIb/IIIa inhibitors is generally restricted to bail out thrombotic events associated with PCI. Furthermore, current antiplatelet medications mainly rely on thromboxane A
2
and P2Y
12
inhibition, which have broad-acting effects on platelets and are known to cause bleeding, which especially limits the long-term use of these agents. In addition, not all ACS patients treated with current antiplatelet treatments are protected from recurrence of arterial thrombosis, since many platelet mechanisms and activation pathways remain uninhibited by current antiplatelet therapy. Pharmacological antagonism of novel targets involved in platelet function could shape future antiplatelet therapies that could ultimately lead to more effective or safer therapeutic approaches. In this article, we focus on inhibitors of promising targets that have not yet been introduced into clinical practice, including inhibitors of GPVI, protease-activated receptor (PAR)-4, GPIb, 5-hydroxytryptamine receptor subtype 2A (5-HT
2A
), protein disulfide isomerase, P-selectin and phosphoinositide 3-kinase β.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Polar bears (Ursus maritimus) are among those species most susceptible to the rapidly changing arctic climate, and their survival is of global concern. Despite this, little is known about polar bear ...species history. Future conservation strategies would significantly benefit from an understanding of basic evolutionary information, such as the timing and conditions of their initial divergence from brown bears (U. arctos) or their response to previous environmental change.
We used a spatially explicit phylogeographic model to estimate the dynamics of 242 brown bear and polar bear matrilines sampled throughout the last 120,000 years and across their present and past geographic ranges. Our results show that the present distribution of these matrilines was shaped by a combination of regional stability and rapid, long-distance dispersal from ice-age refugia. In addition, hybridization between polar bears and brown bears may have occurred multiple times throughout the Late Pleistocene.
The reconstructed matrilineal history of brown and polar bears has two striking features. First, it is punctuated by dramatic and discrete climate-driven dispersal events. Second, opportunistic mating between these two species as their ranges overlapped has left a strong genetic imprint. In particular, a likely genetic exchange with extinct Irish brown bears forms the origin of the modern polar bear matriline. This suggests that interspecific hybridization not only may be more common than previously considered but may be a mechanism by which species deal with marginal habitats during periods of environmental deterioration.
► Polar bears and brown bears have been hybridizing throughout the last 100,000 years ► The current polar bear matriline descends from brown bears that lived near Ireland ► This matriline most likely originated prior to or during the last ice age ► The dynamics of bear matrilines have been driven by largely by climate change
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We sequenced Early Neolithic genomes from the Zagros region of Iran (eastern Fertile Crescent), where some of the earliest evidence for farming is found, and identify a previously uncharacterized ...population that is neither ancestral to the first European farmers nor has contributed substantially to the ancestry of modern Europeans. These people are estimated to have separated from Early Neolithic farmers in Anatolia some 46,000 to 77,000 years ago and show affinities to modern-day Pakistani and Afghan populations, but particularly to Iranian Zoroastrians. We conclude that multiple, genetically differentiated hunter-gatherer populations adopted farming in southwestern Asia, that components of pre-Neolithic population structure were preserved as farming spread into neighboring regions, and that the Zagros region was the cradle of eastward expansion.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Debate on the ancestry of Europeans centers on the interplay between Mesolithic foragers and Neolithic farmers. Foragers are generally believed to have disappeared shortly after the arrival of ...agriculture. To investigate the relation between foragers and farmers, we examined Mesolithic and Neolithic samples from the Blätterhöhle site. Mesolithic mitochondrial DNA sequences were typical of European foragers, whereas the Neolithic sample included additional lineages that are associated with early farmers. However, isotope analyses separate the Neolithic sample into two groups: one with an agriculturalist diet and one with a forager and freshwater fish diet, the latter carrying mitochondrial DNA sequences typical of Mesolithic hunter-gatherers. This indicates that the descendants of Mesolithic people maintained a foraging lifestyle in Central Europe for more than 2000 years after the arrival of farming societies.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Plant parasitic nematodes, including root knot nematode Meloidogyne species, cause extensive damage to agriculture and horticultural crops. As Vitis vinifera cultivars are susceptible to root knot ...nematode parasitism, rootstocks resistant to these soil pests provide a sustainable approach to maintain grapevine production. Currently, most of the commercially available root knot nematode resistant rootstocks are highly vigorous and take up excess potassium, which reduces wine quality. As a result, there is a pressing need to breed new root knot nematode resistant rootstocks, which have no impact on wine quality. To develop molecular markers that predict root knot nematode resistance for marker assisted breeding, a genetic approach was employed to identify a root knot nematode resistance locus in grapevine. To this end, a Meloidogyne javanica resistant Vitis cinerea accession was crossed to a susceptible Vitis vinifera cultivar Riesling and results from screening the F1 individuals support a model that root knot nematode resistance, is conferred by a single dominant allele, referred as MELOIDOGYNE JAVANICA RESISTANCE1 (MJR1). Further, MJR1 resistance appears to be mediated by a hypersensitive response that occurs in the root apical meristem. Single nucleotide polymorphisms (SNPs) were identified using genotyping-by-sequencing and results from association and genetic mapping identified the MJR1 locus, which is located on chromosome 18 in the Vitis cinerea accession. Validation of the SNPs linked to the MJR1 locus using a Sequenom MassARRAY platform found that only 50% could be validated. The validated SNPs that flank and co-segregate with the MJR1 locus can be used for marker-assisted selection for Meloidogyne javanica resistance in grapevine.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four ...children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group
. One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region
. However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Periodontal disease is highly prevalent, with 90% of the world population affected by either periodontitis or its preceding condition, gingivitis. These conditions are caused by bacterial ...biofilms on teeth, which stimulate a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The present research sought to demonstrate development of a multiple drug delivery system for stepwise treatment of different stages of periodontal disease. More specifically, multilayered films were fabricated from an association polymer comprising cellulose acetate phthalate and Pluronic F-127 to achieve sequential release of drugs. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. Different erosion times and adjustable sequential release profiles were achieved by modifying the number of layers or by inclusion of a slower-eroding polymer layer. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. The multilayered CAPP delivery system offers a versatile approach for releasing different drugs based on the pathogenesis of periodontitis and other conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The genetic history of Europeans Pinhasi, Ron; Thomas, Mark G; Hofreiter, Michael ...
Trends in genetics,
10/2012, Volume:
28, Issue:
10
Journal Article
Peer reviewed
The evolutionary history of modern humans is characterized by numerous migrations driven by environmental change, population pressures, and cultural innovations. In Europe, the events most widely ...considered to have had a major impact on patterns of genetic diversity are the initial colonization of the continent by anatomically modern humans (AMH), the last glacial maximum, and the Neolithic transition. For some decades it was assumed that the geographical structuring of genetic diversity within Europe was mainly the result of gene flow during and soon after the Neolithic transition, but recent advances in next-generation sequencing (NGS) technologies, computer simulation modeling, and ancient DNA (aDNA) analyses are challenging this simplistic view. Here we review the current knowledge on the evolutionary history of humans in Europe based on archaeological and genetic data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
C-type lectin-like receptor 2 (CLEC-2) is highly expressed on platelets and a subpopulation of myeloid cells, and is critical in lymphatic development. CLEC-2 has been shown to support ...thrombus formation at sites of inflammation, but to have a minor/negligible role in hemostasis. This identifies CLEC-2 as a promising therapeutic target in thromboinflammatory disorders, without hemostatic detriment. We utilized a GPIbα-Cre recombinase mouse for more restricted deletion of platelet-CLEC-2 than the previously used PF4-Cre mouse. clec1b
fl/fl
GPIbα-Cre
+
mice are born at a Mendelian ratio, with a mild reduction in platelet count, and present with reduced thrombus size post-FeCl
3
-induced thrombosis, compared to littermates. Antibody-mediated depletion of platelet count in C57BL/6 mice, to match clec1b
fl/fl
GPIbα-Cre
+
mice, revealed that the reduced thrombus size post-FeCl
3
-injury was due to the loss of CLEC-2, and not mild thrombocytopenia. Similarly, clec1b
fl/fl
GPIbα-Cre
+
mouse blood replenished with CLEC-2-deficient platelets
ex vivo
to match littermates had reduced aggregate formation when perfused over collagen at arterial flow rates. In contrast, platelet-rich thrombi formed following perfusion of human blood under flow conditions over collagen types I or III, atherosclerotic plaque, or inflammatory endothelial cells were unaltered in the presence of CLEC-2-blocking antibody, AYP1, or recombinant CLEC-2-Fc. The reduction in platelet aggregation observed in clec1b
fl/fl
GPIbα-Cre
+
mice during arterial thrombosis is mediated by the loss of CLEC-2 on mouse platelets. In contrast, CLEC-2 does not support thrombus generation on collagen, atherosclerotic plaque, or inflamed endothelial cells in human at arterial shear.
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