Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity.

N-acetyltransferase 2 (NAT2), an important enzyme in clinical pharmacology, metabolizes antibiotics such as isoniazid and sulfamethoxazole, and catalyzes the transformation of aromatic and heterocyclic amines from the environment and diet into carcinogenic intermediates. Polymorphisms in NAT2 account for variability in the acetylator phenotype and the pharmacokinetics of metabolized drugs. Native Americans, settled in rural areas and large cities of Latin America, are under-represented in pharmacogenetics studies; therefore, we sequenced the coding region of NAT2 in 456 chromosomes from 13 populations from the Americas, and two from Siberia, detecting nine substitutions and 11 haplotypes. Variants *4 (37%), *5B (23%) and *7B (24%) showed high frequencies. Average frequencies of fast, intermediate and slow acetylators across Native Americans were 18, 56 and 25%, respectively. NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent

Schlieren Imaging and Flow Analysis on a Cone/Flare Model in the AFRL Mach 6 Ludwieg Tube Facility

High-speed Schlieren photography was utilized to visualize flow in the Air Force Research Laboratory Mach 6 Ludwieg tube facility. A 7° half-angle cone/flare model with variable nosetip radius and flare angle options was used in the study. Testing was performed at two driver tube pressures, generating freestream Reynolds numbers of 10.0x106 and 19.8x106 per meter. The variable-angle flare portion of the model provided a method for adjusting the intensity of the adverse pressure gradient at the cone/flare junction. As expected from existing literature, boundary layer separation along the cone frustum occurred further upstream as the magnitude of the adverse pressure gradient increased. Imaging of the four cone tip radii revealed a slightly positive angle of attack for the model. This conclusion was supported by asymmetrical heating contours observed in a prior infrared thermography study on the same model. Measurements of the bow shock angles downstream of the cone tip verified Mach 6 flow from the Ludwieg tube nozzle when analyzed using Taylor-Maccoll theory. Blunt cone tips generated laminar boundary layers along the cone frustum. These laminar boundary layers led to unstable behavior in the recirculation region at the cone/flare junction. Analysis of the instability revealed loosely cyclical behavior. Pressure data from the model surface would provide much greater insight into local boundary layer behavior. Future hypersonic vehicles will inevitably include numerous adverse pressure gradients. A full understanding of these regions is imperative to successful design and flight testing

Characteristics of transposable element exonization within human and mouse

Insertion of transposed elements within mammalian genes is thought to be an important contributor to mammalian evolution and speciation. Insertion of transposed elements into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization. Elucidation of the evolutionary constraints that have shaped fixation of transposed elements within human and mouse protein coding genes and subsequent exonization is important for understanding of how the exonization process has affected transcriptome and proteome complexities. Here we show that exonization of transposed elements is biased towards the beginning of the coding sequence in both human and mouse genes. Analysis of single nucleotide polymorphisms (SNPs) revealed that exonization of transposed elements can be population-specific, implying that exonizations may enhance divergence and lead to speciation. SNP density analysis revealed differences between Alu and other transposed elements. Finally, we identified cases of primate-specific Alu elements that depend on RNA editing for their exonization. These results shed light on TE fixation and the exonization process within human and mouse genes.Comment: 11 pages, 4 figure

Induction of humoral immune response to multiple recombinant Rhipicephalus appendiculatus antigens and their effect on tick feeding success and pathogen transmission

BACKGROUND: Rhipicephalus appendiculatus is the primary vector of Theileria parva, the etiological agent of East Coast fever (ECF), a devastating disease of cattle in sub-Saharan Africa. We hypothesized that a vaccine targeting tick proteins that are involved in attachment and feeding might affect feeding success and possibly reduce tick-borne transmission of T. parva. Here we report the evaluation of a multivalent vaccine cocktail of tick antigens for their ability to reduce R. appendiculatus feeding success and possibly reduce tick-transmission of T. parva in a natural host-tick-parasite challenge model. METHODS: Cattle were inoculated with a multivalent antigen cocktail containing recombinant tick protective antigen subolesin as well as two additional R. appendiculatus saliva antigens: the cement protein TRP64, and three different histamine binding proteins. The cocktail also contained the T. parva sporozoite antigen p67C. The effect of vaccination on the feeding success of nymphal and adult R. appendiculatus ticks was evaluated together with the effect on transmission of T. parva using a tick challenge model. RESULTS: To our knowledge, this is the first evaluation of the anti-tick effects of these antigens in the natural host-tick-parasite combination. In spite of evidence of strong immune responses to all of the antigens in the cocktail, vaccination with this combination of tick and parasite antigens did not appear to effect tick feeding success or reduce transmission of T. parva. CONCLUSION: The results of this study highlight the importance of early evaluation of anti-tick vaccine candidates in biologically relevant challenge systems using the natural tick-host-parasite combination

Unexpected Role of CD8 T Cells in Accelerated Clearance of Salmonella enterica Serovar Typhimurium from H-2 Congenic mice

Salmonella infection can cause gastroenteritis in healthy individuals or a serious, systemic infection in immunocompromised patients and has a global impact. CD4 Th1 cells represent the main lymphocyte population that participates in bacterial clearance during both primary and secondary infections in mice of the H-2b haplotype. Previous studies have used congenic mice to examine the function of major histocompatibility complex (MHC) molecules in elimination of this pathogen from the host. In this study, we further characterized the ability of H-2b, H-2k, and H-2u molecules to influence adaptive immunity to Salmonella in MHC congenic mice. By depleting different cell populations during infection, we unexpectedly found that CD8 T cells, in addition to CD4 T cells, play a major role in accelerated clearance of bacteria from H-2k congenic hosts. Our data suggest that CD8 T cells accelerate clearance in some MHC congenic mouse strains and could therefore represent an unexpected contributor to the protective efficacy of Salmonella vaccines outside the typical studies in C57BL/6 mice

Reconstructing Native American Population History

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved1–5. One contentious issue is whether the settlement occurred via a single6–8 or multiple streams of migration from Siberia9–15. The pattern of dispersals within the Americas is also poorly understood. To address these questions at higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. We show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call “First American”. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan-speakers on both sides of the Panama Isthmus, who have ancestry from both North and South America

A Praziquantel Treatment Study of Immune and Transcriptome Profiles in Schistosoma haematobium-Infected Gabonese Schoolchildren.

BACKGROUND: Although Schistosoma haematobium infection has been reported to be associated with alterations in immune function, in particular immune hyporesponsiveness, there have been only few studies that have used the approach of removing infection by drug treatment to establish this and to understand the underlying molecular mechanisms. METHODS: Schistosoma haematobium-infected schoolchildren were studied before and after praziquantel treatment and compared with uninfected controls. Cellular responses were characterized by cytokine production and flow cytometry, and in a subset of children RNA sequencing (RNA-Seq) transcriptome profiling was performed. RESULTS: Removal of S haematobium infection resulted in increased schistosome-specific cytokine responses that were negatively associated with CD4+CD25+FOXP3+ T-cells and accompanied by increased frequency of effector memory T-cells. Innate responses to Toll like receptor (TLR) ligation decreased with treatment and showed positive association with CD4+CD25+FOXP3+ T-cells. At the transcriptome level, schistosome infection was associated with enrichment in cell adhesion, whereas parasite removal was associated with a more quiescent profile. Further analysis indicated that alteration in cellular energy metabolism was associated with S haematobium infection and that the early growth response genes 2 and 3 (EGR 2 and EGR3), transcription factors that negatively regulate T-cell activation, may play a role in adaptive immune hyporesponsiveness. CONCLUSIONS: Using a longitudinal study design, we found contrasting effects of schistosome infection on innate and adaptive immune responses. Whereas the innate immune system appears more activated, the adaptive immunity is in a hyporesponsive state reflected in alterations in CD4+CD25+FOXP3+ T-cells, cellular metabolism, and transcription factors involved in anergy

Long-term changes in drought indices in eastern and central Europe

This study analyses long-term changes in drought indices (Standardised Precipitation Index—SPI, Standardised Precipitation–Evapotranspiration Index—SPEI) at 1 and 3 months scales at 182 stations in 11 central and eastern European countries during 1949–2018. For comparative purposes, the necessary atmospheric evaporative demand (AED) to obtain SPEI was calculated using two methods, Hargreaves-Samani (SPEIH) and Penman-Monteith (SPEIP). The results show some relevant changes and tendencies in the drought indices. Statistically significant increase in SPI and SPEI during the cold season (November–March), reflecting precipitation increase, was found in the northern part of the study region, in Estonia, Latvia, Lithuania, northern Belarus and northern Poland. In the rest of study domain, a weak and mostly insignificant decrease prevailed in winter. Summer season (June–August) is characterized by changes in the opposite sign. An increase was observed in the north, while a clear decrease in SPEI, reflecting a drying trend, was typical for the southern regions: the Czech Republic, Slovakia, Hungary, Romania, Moldova and southern Poland. A general drying tendency revealed also in April, which was statistically significant over a wide area in the Czech Republic and Poland. Increasing trends in SPI and SPEI for September and October were detected in Romania, Moldova and Hungary. The use of SPEI instead of SPI generally enhances drying trends