Absence Of A2 Research Articles

Coarse-grained modeling of annexin A2-induced microdomain formation on a vesicle

Annexin A2 (A2)-induced microdomain formation is a key step in biological processes such as Ca2+-mediated exocytosis in neuroendocrine cells. In this work, a total of 15 coarse-grained molecular dynamics simulations were performed on vesicle models having a diameter of approximately 250 Å for 15 μs each using the Martini2 force field. Five simulations were performed in the presence of 10 A2, 5 in the presence of A2 but absence of PIP2, and 5 simulations in the absence of A2 but presence of PIP2. Consistent results were generated among the simulations. A2-induced PIP2 microdomain formation was observed and shown to occur in three phases: A2-vesicle association, localized A2-induced PIP2 clustering, and A2 aggregation driving PIP2 microdomain formation. The relationship between A2 aggregation and PIP2 microdomain formation was quantitatively described using a novel method which calculated the variance among protein and lipid positions via the Fréchet mean. A large reduction in PIP2 variance was observed in the presence of A2 but not in its absence. This reduction in PIP2 variance was proportional to the reduction observed in A2 variance and demonstrates that the observed PIP2 microdomain formation is dependent upon A2 aggregation. The three-phase model of A2-induced microdomain formation generated in this work will serve as a valuable guide for further experimental studies and the development of novel A2 inhibitors. No microdomain formation was observed in the absence of A2 and minimal A2-membrane interaction was observed in the absence of PIP2.

Insights into the synergistic mechanism of target resistance: A case study of N. lugens RDL-GABA receptors and fipronil

It is known that a single mutation exerts moderate resistance to pesticide, while double mutations (DM) cause severe resistance problem through synergistic effect, and even result in failure application of pesticides. However, little is known about how double mutations would synergistically cause much high resistance level. In this work, computational studies were performed on the interaction of fipronil with N. lugens RDL-GABA receptors, to see how single and double mutations changed receptor structure properties and then conferred distinct resistance levels. The A2′S mutation displayed relative weak influence on receptor structure properties. The R0′Q mutation, which has not been detected in the absence of A2′S, however could deeply alter the electrostatic potential around the inner pore region and significantly narrow the bottom region around -2′Pro. For the DM system, the synergistic effect of two mutations lead to similar pore diameters to the WT system, except for the slightly reduced middle part. Docking study and binding free energy calculation revealed that fipronil displayed binding potencies in the order of WT > A2′S > R0′Q > DM systems, coinciding well with the reported fipronil sensitivity trends and resistance levels.

New Evidence of Ancient Mitochondrial DNA of the Southern Andes (Calchaquí Valleys, Northwest Argentina, 3,600–1,900 Years before Present)

Genetic studies on pre-Hispanic populations of the Southern Andes have been increasing steadily in the last decade. Nevertheless, ancient DNA characterization of Formative Period archaeological human remains is particularly scant, especially for Northwest Argentina. To expand current information on genetic characterization of the first agricultural communities of the southern Calchaquí Valleys, we present and discuss the first mitochondrial ancient DNA information obtained on samples dated to ca. 3,600-1,900 years before present from the Cajón Valley, Catamarca Province. Reproducible mtDNA hypervariable region 1 (HVR-1) sequences were obtained in seven individuals. Mitochondrial HVR-1 haplotypes were assigned to three of the four founding haplogroups, D1 (57.1%), C1 (28.5%), and B2 (14.2%), with absence of A2. Our results show that the Cajón Valley sample, with predominance of D1 and C1, differs from that commonly observed in ancient and modern Andean populations, which usually show a high prevalence of haplogroup B2. The fact that the Cajón Valley and Pampa Grande (Salta Province, Argentina) share a prevalence of haplogroup D1 could provide additional evidence to support possible genetic affinities between the valleys and the eastern sub-Andean region during the Formative Period in Northwest Argentina, expanding the archaeological evidence of contact between both populations. Future complete mitogenomic analysis will provide substantial information to formulate new hypotheses about the origins and phylogenetic relationships between the individuals of the Cajón Valley and other groups from the Andes, Gran Chaco, and the Amazon.

Endothelial Cell Annexin A2 Regulates Polyubiquitination and Degradation of Its Binding Partner S100A10/p11

The annexin A2 (A2) heterotetramer, consisting of two copies of A2 and two copies of S100A10/p11, promotes fibrinolytic activity on the surface of vascular endothelial cells by assembling plasminogen and tissue plasminogen activator (tPA) and accelerating the generation of plasmin. In humans, overexpression of A2 by acute promyelocytic leukemia cells is associated with excessive fibrinolysis and hemorrhage, whereas anti-A2 autoantibodies appear to accentuate the risk of thrombosis in patients with anti-phospholipid syndrome. Complete deficiency of A2 in mice leads to a lack of tPA cofactor activity, accumulation of intravascular fibrin, and failure to clear arterial thrombi. Within the endothelial cell, p11 is required for Src kinase-mediated tyrosine phosphorylation of A2, which signals translocation of both proteins to the cell surface. Here we show that p11 is expressed at very low levels in the absence of A2 both in vitro and in vivo. We demonstrate further that unpartnered p11 becomes polyubiquitinated and degraded via a proteasome-dependent mechanism. A2 stabilizes intracellular p11 through direct binding, thus masking an autonomous p11 polyubiquitination signal that triggers proteasomal degradation. This interaction requires both the p11-binding N-terminal domain of A2 and the C-terminal domain of p11. This mechanism prevents accumulation of free p11 in the endothelial cell and suggests that regulation of tPA-dependent cell surface fibrinolytic activity is precisely tuned to the intracellular level of p11.

Blood groups, serum proteins, and red cell enzymes in the Nganasans (Tavghi)-reindeer hunters from Taimir Peninsula.

The Nganasans are made up of two recently tribal populations. These, the Avam and Vadey, were established in the seventeenth century from small reindeer hunting bands, themselves apparently descended from the Yukaghir. Data on 13 blood systems have been described for the first time in the Vadey Nganasans, and the results compared with those previously reported for the two Avam subgroups. As a whole, the Nganasans are characterized by low frequency of B blood group, high frequencies of Ns, cDE, Fy(a), Hp(2), absence of A2, P(c), K, and apparently an absence of cde alleles or haplotypes. Measurement of intrapopulation heterogeneity reveals significant divergence among the two Avam subdivisions (chi 2/16=57.59; P less than 0.001), as well as between the total Avam and Vadey (chi 2/17=79.31; P less than 0.001). Founder principle, and local genetic drift, are believed to account for the greater difference between the Avam and Vadey subgroups than that observed between the two Avam populations. The Nganasans of the Taimir Peninsula appear to be the last group of reindeer hunters remaining in Northern Siberia. For ages they have lived in relative isolation, and therefore are the least touched genetically, either by surrounding herding groups originating in Southern Siberia, or by recent Caucasian admixture.

A Population Genetic Study of the Kota in the Nilgiri Hills, South India

A population genetic study among the Kota of the Nilgiri Hills, South India, involved tests for abnormal haemoglobins, 5 red cell antigen systems, 4 serum protein and 13 red cell enzymes systems. Twelve systems are invariant in the Kota. The most distinctive characteristics are extremely low frequency of the A1 gene and complete absence of A2 in the ABO system, r(cde) in the Rh system, LDH cal-1 among the enzyme systems as well as absence of abnormal haemoglobins. A comparison of gene frequencies in those systems, which show variation, suggests that the Kota are more similar to the Toda than to any other tribal or caste population of the area. Genetic distance as well principal component analysis also reveals that the Toda and Kota are close to each other, in agreement with tradition.

Blood Groups, Serum Genetic Factors and Hemoglobins in Western Solomon Islanders

A sample of 186 Western Solomon Islanders characterizes this population by an absence of A2, high N, S associated only with N, an Le(a−b−) frequency as high as Maoris, high Rh1, and an absence of Dia, Jsa and Lua.The high frequency of absent haptoglobins is probably related to the high malaria rate in the area. The absence of abnormal hemoglobins is noted in relation to the same disease.