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The reduction of genetic diversity due to genetic hitchhiking is widely used to find past selective sweeps from sequencing data, but very little is known about how spatial structure affects hitchhiking. We use mathematical modeling and simulations to find the unfolded site frequency spectrum left by hitchhiking in the genomic region of a sweep in a population occupying a 1D range. For such populations, sweeps spread as Fisher waves, rather than logistically. We find that this leaves a characteristic 3-part site frequency spectrum at loci very close to the swept locus. Very low frequencies are dominated by recent mutations that occurred after the sweep and are unaffected by hitchhiking. At moderately low frequencies, there is a transition zone primarily composed of alleles that briefly "surfed" on the wave of the sweep before falling out of the wavefront, leaving a spectrum close to that expected in well-mixed populations. However, for moderate-to-high frequencies, there is a distinctive scaling regime of the site frequency spectrum produced by alleles that drifted to fixation in the wavefront and then were carried throughout the population. For loci slightly farther away from the swept locus on the genome, recombination is much more effective at restoring diversity in 1D populations than it is in well-mixed ones. We find that these signatures of space can be strong even in apparently well-mixed populations with negligible spatial genetic differentiation, suggesting that spatial structure may frequently distort the signatures of hitchhiking in natural populations. [ABSTRACT FROM AUTHOR]

Allele substitution effects at quantitative trait loci (QTL) are part of the basis of quantitative genetics theory and applications such as association analysis and genomic prediction. In the presence of nonadditive functional gene action, substitution effects are not constant across populations. We develop an original approach to model the difference in substitution effects across populations as a first order Taylor series expansion from a "focal" population. This expansion involves the difference in allele frequencies and second-order statistical effects (additive by additive and dominance). The change in allele frequencies is a function of relationships (or genetic distances) across populations. As a result, it is possible to estimate the correlation of substitution effects across two populations using three elements: magnitudes of additive, dominance, and additive by additive variances; relationships (Nei's minimum distances or Fst indexes); and assumed heterozygosities. Similarly, the theory applies as well to distinct generations in a population, in which case the distance across generations is a function of increase of inbreeding. Simulation results confirmed our derivations. Slight biases were observed, depending on the nonadditive mechanism and the reference allele. Our derivations are useful to understand and forecast the possibility of prediction across populations and the similarity of GWAS effects. [ABSTRACT FROM AUTHOR]

"Interference" is a major force governing the patterning of meiotic crossovers. A leading model describing how interference influences crossover patterning is the beam-film model, a mechanical model based on the accumulation and redistribution of crossover-promoting "stress" along the chromosome axis. We use the beam-film model in conjunction with a large Arabidopsis reciprocal backcross data set to gain "mechanistic" insights into the differences between male and female meiosis, and crossover patterning. Beam-film modeling suggests that the underlying mechanics of crossover patterning and interference are identical in the two sexes, with the large difference in recombination rates and distributions able to be entirely explained by the shorter chromosome axes in females. The modeling supports previous indications that fewer crossovers occur via the class II pathway in female meiosis and that this could be explained by reduced DNA double-strand breaks in female meiosis, paralleling the observed reduction in synaptonemal complex length between the two sexes. We also demonstrate that changes in the strength of suppression of neighboring class I crossovers can have opposite effects on "effective" interference depending on the distance between two genetic intervals. [ABSTRACT FROM AUTHOR]

With aging, there is a decline in cardiac function accompanying increasing risk of arrhythmias. These effects are likely to be mechanistically associated with age-associated changes in calcium regulation within cardiac myocytes. Previous studies suggest that lifelong exercise can potentially reduce age-associated changes in the heart. Although exercise itself is associated with changes in cardiac function, little is known about the interactions of aging and exercise with respect to myocyte calcium regulation. To investigate this, adult (12 months) and old (24 months) C57/Bl6 mice were trained using moderate-intensity treadmill running. In response to 10 weeks' training, comparable cardiac hypertrophic responses were observed, although aging independently associated with additional cardiac hypertrophy. Old animals also showed increased L- and T-type calcium channels, the sodium-calcium exchange, sarcoendoplasmic reticulum calcium ATPase, and collagen (by 50%, 92%, 66%, 88%, and 113% respectively). Short-term exercise training increased D-type and T-type calcium channels in old animals only, whereas an increase in sodium-calcium exchange was seen only in adult animals. Long-term (12 months) training generally opposed the effects of aging. Significant hypertrophy remained in long-term trained old animals, but levels of sarcoendoplasmic reticulum calcium ATPase, sodium-calcium exchange, and collagen were not significantly different from those found in the adult trained animals. [ABSTRACT FROM AUTHOR]

Background: The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.Methods: To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.Results: While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.Conclusions: This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling. [ABSTRACT FROM AUTHOR]

Enterococcus faecium is a common cause of nosocomial infections, of which infective endocarditis is associated with substantial mortality. In this study, we used a microarray-based transposon mapping (M-TraM) approach to evaluate a rat endocarditis model and identified a gene, originally annotated as "fruA" and renamed "bepA," putatively encoding a carbohydrate phosphotransferase system (PTS) permease (biofilm and endocarditis-associated permease A [BepA]), as important in infective endocarditis. This gene is highly enriched in E. faecium clinical isolates and absent in commensal isolates that are not associated with infection. Confirmation of the phenotype was established in a competition experiment of wild-type and a markerless bepA mutant in a rat endocarditis model. In addition, deletion of bepA impaired biofilm formation in vitro in the presence of 100% human serum and metabolism of β-methyl-D-glucoside. β-glucoside metabolism has been linked to the metabolism of glycosaminoglycans that are exposed on injured heart valves, where bacteria attach and form vegetations. Therefore, we propose that the PTS permease BepA is directly implicated in E. faecium pathogenesis. [ABSTRACT FROM AUTHOR]

Objectives: Although miltefosine and paromomycin were only recently introduced to treat visceral leishmaniasis, increasing numbers of miltefosine treatment failures and occasional primary resistance to both drugs have been reported. Understanding alterations in parasite behaviour linked to drug resistance is essential to assess the propensity for emergence and spread of resistant strains, particularly since a positive effect on fitness has been reported for antimony-resistant parasites. This laboratory study compared the fitness of a drug-susceptible parent WT clinical Leishmania infantum isolate (MHOM/FR/96/LEM3323) and derived miltefosine and paromomycin drug-resistant lines that were experimentally selected at the intracellular amastigote level.Methods: Parasite fitness of WT, paromomycin-resistant and miltefosine-resistant strains, in vitro and in vivo parasite growth, metacyclogenesis, infectivity and macrophage stress responses were comparatively evaluated.Results: No significant differences in promastigote fitness were noted between the WT and paromomycin-resistant strain, while clear benefits could be demonstrated for paromomycin-resistant amastigotes in terms of enhanced in vitro and in vivo growth potential and intracellular stress response. The miltefosine-resistant phenotype showed incomplete promastigote metacyclogenesis, decreased intracellular growth and weakened stress response, revealing a reduced fitness compared with WT parent parasites.Conclusions: The rapid selection and fitness advantages of paromomycin-resistant amastigotes endorse the current use of paromomycin in combination therapy. Although a reduced fitness of miltefosine-resistant strains may explain the difficulty of miltefosine resistance selection in vitro, the growing number of miltefosine treatment failures in the field still requires further exploratory research. [ABSTRACT FROM AUTHOR]

Information regarding several papers discussed at a symposium on the functions and adaptations of the human brain and its relation with age is presented. Topics include the receptor biology of the brain, the impact of environmental factors into the brain, and the secular changes of the brain in aging. The symposium featured several international nutrition experts including Tom Kirkwood, Marshal Folstein, and Richard Wurtman.