Immune genes undergo more adaptive evolution than non-immune system genes in Daphnia pulex

<p>Abstract</p> <p>Background</p> <p>Understanding which parts of the genome have been most influenced by adaptive evolution remains an unsolved puzzle. Some evidence suggests that selection has the greatest impact on regions of the genome that interact with other evolving genomes, including loci that are involved in host-parasite co-evolutionary processes. In this study, we used a population genetic approach to test this hypothesis by comparing DNA sequences of 30 putative immune system genes in the crustacean <it>Daphnia pulex</it> with 24 non-immune system genes.</p> <p>Results</p> <p>In support of the hypothesis, results from a multilocus extension of the McDonald-Kreitman (MK) test indicate that immune system genes as a class have experienced more adaptive evolution than non-immune system genes. However, not all immune system genes show evidence of adaptive evolution. Additionally, we apply single locus MK tests and calculate population genetic parameters at all loci in order to characterize the mode of selection (directional versus balancing) in the genes that show the greatest deviation from neutral evolution.</p> <p>Conclusions</p> <p>Our data are consistent with the hypothesis that immune system genes undergo more adaptive evolution than non-immune system genes, possibly as a result of host-parasite arms races. The results of these analyses highlight several candidate loci undergoing adaptive evolution that could be targeted in future studies.</p

Relative persistence of AAV serotype 1 vector genomes in dystrophic muscle

The purpose of this study was to assess the behavior of pseudotyped recombinant adeno-associated virus type 1 (rAAV2/1) vector genomes in dystrophic skeletal muscle. A comparison was made between a therapeutic vector and a reporter vector by injecting the hindlimb in a mouse model of Limb Girdle Muscular Dystrophy Type 2D (LGMD-2D) prior to disease onset. We hypothesized that the therapeutic vector would establish long-term persistence through prevention of myofiber turnover. In contrast, the reporter vector genome copy number would diminish over time due to disease-associated muscle degradation

Equine or porcine synovial fluid as a novel ex vivo model for the study of bacterial free-floating biofilms that form in human joint infections

Bacterial invasion of synovial joints, as in infectious or septic arthritis, can be difficult to treat in both veterinary and human clinical practice. Biofilms, in the form of free-floating clumps or aggregates, are involved with the pathogenesis of infectious arthritis and periprosthetic joint infection (PJI). Infection of a joint containing an orthopedic implant can additionally complicate these infections due to the presence of adherent biofilms. Because of these biofilm phenotypes, bacteria within these infected joints show increased antimicrobial tolerance even at high antibiotic concentrations. To date, animal models of PJI or infectious arthritis have been limited to small animals such as rodents or rabbits. Small animal models, however, yield limited quantities of synovial fluid making them impractical for in vitro research. Herein, we describe the use of ex vivo equine and porcine models for the study of synovial fluid induced biofilm aggregate formation and antimicrobial tolerance. We observed Staphylococcus aureus and other bacterial pathogens adapt the same biofilm aggregate phenotype with significant antimicrobial tolerance in both equine and porcine synovial fluid, analogous to human synovial fluid. We also demonstrate that enzymatic dispersal of synovial fluid aggregates restores the activity of antimicrobials. Future studies investigating the interaction of bacterial cell surface proteins with host synovial fluid proteins can be readily carried out in equine or porcine ex vivo models to identify novel drug targets for treatment of prevention of these difficult to treat infectious diseases

Are cryptocurrencies a safe haven for equity markets? An international perspective from the COVID-19 pandemic

The COVID-19 pandemic provided the first widespread bear market conditions since the inception of cryptocurrencies. We test the widely mooted safe haven properties of Bitcoin, Ethereum and Tether from the perspective of international equity index investors. Bitcoin and Ethereum are not a safe haven for the majority of international equity markets examined, in fact increasing portfolio downside risk. Only investors in the Chinese CSI 300 index realized modest downside risk benefits, but only from small relative allocations to Bitcoin or Ethereum. As Tether successfully maintained its peg to the US dollar during the COVID-19 turmoil, it acted as a safe haven investment for all of the international indices examined. We caveat the latter findings with a warning that this dollar peg has not always been maintained, impairing the earlier downside risk hedging properties of Tether

Aspects of Axion Phenomenology in a slice of AdS_5

Motivated by multi-throat considerations, we study the phenomenological implications of a bulk axion in a slice of AdS_5 with a large extra dimension: k~0.01 eV, kR > 1. In particular, we compare axion physics with a warped geometry to axions in flat compactifications. As in flat compactification scenarios, we find that the mass of the axion can become independent from the underlying Peccei-Quinn scale. Surprisingly, we find that in warped extra dimensions the axion's invisibility, cosmological viability, and basic phenomenology remain essentially unaltered in comparison to axions in flat compactifications.Comment: 25 pages, 9 figure

Rapid, widespread transduction of the murine myocardium using self-complementary Adeno-associated virus

Adeno-associated virus (AAV) has shown great promise as a gene transfer vector. However, the incubation time needed to attain significant levels of gene expression is often too long for some clinical applications. Self-complementary AAV (scAAV) enters the cell as double stranded DNA, eliminating the step of second-strand synthesis, proven to be the rate-limiting step for gene expression of single-stranded AAV (ssAAV). The aim of this study was to compare the efficiency of these two types of AAV vectors in the murine myocardium. Four day old CD-1 mice were injected with either of the two AAV constructs, both expressing GFP and packaged into the AAV1 capsid. The animals were held for 4, 6, 11 or 21 days, after which they were euthanized and their hearts were excised. Serial sections of the myocardial tissue were used for real-time PCR quantification of AAV genome copies and for confocal microscopy. Although we observed similar numbers of AAV genomes at each of the different time points present in both the scAAV and the ssAAV infected hearts, microscopic analysis showed expression of GFP as early as 4 days in animals injected with the scAAV, while little or no expression was observed with the ssAAV constructs until day 11. AAV transduction of murine myocardium is therefore significantly enhanced using scAAV constructs

Comprehensive Investigation of the Caveolin 2 Gene: Resequencing and Association for Kidney Transplant Outcomes

Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study

Chasing Brane Inflation in String-Theory

We investigate the embedding of brane anti-brane inflation into a concrete type IIB string theory compactification with all moduli fixed. Specifically, we are considering a D3-brane, whose position represents the inflaton $\phi$, in a warped conifold throat in the presence of supersymmetrically embedded D7-branes and an anti D3-brane localized at the tip of the warped conifold cone. After presenting the moduli stabilization analysis for a general D7-brane embedding, we concentrate on two explicit models, the Ouyang and the Kuperstein embeddings. We analyze whether the forces, induced by moduli stabilization and acting on the D3-brane, might cancel by fine-tuning such as to leave us with the original Coulomb attraction of the anti D3-brane as the driving force for inflation. For a large class of D7-brane embeddings we obtain a negative result. Cancelations are possible only for very small intervals of $\phi$ around an inflection point but not globally. For the most part of its motion the inflaton then feels a steep, non slow-roll potential. We study the inflationary dynamics induced by this potential.Comment: 34 pages, 4 figures. Final version published in JCA

Axions In String Theory

In the context of string theory, axions appear to provide the most plausible solution of the strong CP problem. However, as has been known for a long time, in many string-based models, the axion coupling parameter F_a is several orders of magnitude higher than the standard cosmological bounds. We re-examine this problem in a variety of models, showing that F_a is close to the GUT scale or above in many models that have GUT-like phenomenology, as well as some that do not. On the other hand, in some models with Standard Model gauge fields supported on vanishing cycles, it is possible for F_a to be well below the GUT scale.Comment: 62 pages, v2; references, acknowledgements and minor corrections adde

F-Theory GUT Vacua on Compact Calabi-Yau Fourfolds

We present compact three-generation F-theory GUT models meeting in particular the constraints of D3-tadpole cancellation and D-term supersymmetry. To this end we explicitly construct elliptically fibered Calabi-Yau fourfolds as complete intersections in a toric ambient space. Toric methods enable us to control the singular geometry of the SU(5) GUT model. The GUT brane wraps a non-generic del Pezzo surface admitting GUT symmetry breaking via hypercharge flux. It is contractible to a curve and we demonstrate the existence of a consistent decoupling limit. We compute the Euler characteristic of the singular Calabi-Yau fourfold to show that our three-generation flux solutions obtained via the spectral cover construction are consistent with D3-tadpole cancellation.Comment: 22+12 pages; v2: minor clarifications on decoupling limi