Increased Rate of Arterial Stiffening with Obesity in Adolescents: A Five-Year Follow-Up Study

Background

We prospectively and longitudinally determined the effects of childhood obesity on arterial stiffening and vascular wall changes. Changes in arterial stiffness measured as pulse wave velocity (PWV) and vascular morphology of the radial (RA) and dorsal pedal arteries (DPA) were examined in obese adolescents compared to lean subjects in a 5-year follow-up study.

Methodology/Principal Findings

A total of 28 obese subjects and 14 lean controls participated in both baseline (14 years old) and follow-up studies. PWV was measured by tonometer (SphygmoCor®) and recorded at RA and carotid artery, respectively. Intima thickness (IT), intima-media thickness (IMT) and RA and DPA diameters were measured using high-resolution ultrasound (Vevo 770™). Over the course of 5 years, PWV increased by 25% in the obese subjects as compared to 3% in the controls (p = 0.01). Diastolic blood pressure (DBP) increased by 23% in the obese subjects as opposed to 6% in controls (p = 0.009). BMI increased similarly in both groups, as did the IT and IMT. The change in PWV was strongly associated to the baseline BMI z -score (r = 0.51, p<0.001), as was the change in DBP (r = 0.50, p = 0.001).

Conclusions/Significance

During the transition from early to late adolescence, there was a general increase in arterial stiffness, which was aggravated by childhood obesity. The increase in arterial stiffness and DBP after 5 years was closely correlated to the baseline BMI z -score, indicating that childhood obesity has an adverse impact on vascular adaptation.     

Innate preference hierarchies coupled with adult experience,rather than larval imprinting or transgenerational acclimation,determine host plant use in Pieris rapae

The evolution of host range drives diversification in phytophagous insects, and understanding the female oviposition choices is pivotal for understanding host specialization. One controversial mechanism for female host choice is Hopkins’ host selection principle, where females are predicted to increase their preference for the host species they were feeding upon as larvae. A recent hypothesis posits that such larval imprinting is especially adaptive in combination with anticipatory transgenerational acclimation, so that females both allocate and adapt their offspring to their future host. We study the butterfly Pieris rapae, for which previous evidence suggests that females prefer to oviposit on host individuals of similar nitrogen content as the plant they were feeding upon as larvae, and where the offspring show higher performance on the mother's host type. We test the hypothesis that larval experience and anticipatory transgenerational effects influence female host plant acceptance (no‐choice) and preference (choice) of two host plant species (Barbarea vulgaris and Berteroa incana) of varying nitrogen content. We then test the offspring performance on these hosts. We found no evidence of larval imprinting affecting female decision‐making during oviposition, but that an adult female experience of egg laying in no‐choice trials on the less‐preferred host Be. incana slightly increased the P. rapae propensity to oviposit on Be. incana in subsequent choice trials. We found no transgenerational effects on female host acceptance or preference, but negative transgenerational effects on larval performance, because the offspring of P. rapae females that had developed on Be. incana as larvae grew slower on both hosts, and especially on Be. incana. Our results suggest that among host species, preferences are guided by hard‐wired preference hierarchies linked to species‐specific host traits and less affected by larval experience or transgenerational effects, which may be more important for females evaluating different host individuals of the same species.     

Sexually Antagonistic Zygotic Drive: A New Form of Genetic Conflict between the Sex Chromosomes

Sisters and brothers are completely unrelated with respect to the sex chromosomes they inherit from their heterogametic parent. This has the potential to result in a previously unappreciated form of genetic conflict between the sex chromosomes, called sexually antagonistic zygotic drive (SA-ZD). SA-ZD can arise whenever brothers and sisters compete over limited resources or there is brother–sister mating coupled with inbreeding depression. Although theory predicts that SA-ZD should be common and influence important evolutionary processes, there is little empirical evidence for its existence. Here we discuss the current understanding of SA-ZD, why it would be expected to elude empirical detection when present, and how it relates to other forms of genetic conflict.When a diploid individual reproduces sexually, the two alleles at heterozygous loci are necessarily in competition because reproduction by one allele must be at the expense of the other. Such competition is an inescapable component of the organismal level of evolution that was originally advanced by Darwin and later integrated with the field of genetics during the modern synthesis of the early 20th century (Huxley 1942). If the competition is mediated by Mendelian segregation followed by (1) differences in the Darwinian fitness (i.e., survival and fecundity) that each allele produces in offspring, (2) random sampling (genetic drift), and/or (3) differences in the alleles’ mutation or migration rates, then no genetic conflict exists and only canonical evolution at the organismal level occurs. But alleles can also compete outside the context of organismal evolution via diverse mechanisms of selection at the level of the gene that are collectively called genomic conflict (or selfish, ultraselfish, and parasitic DNA). These mechanisms can be divided into three general classes (Burt and Trivers 2006): (1) gonotaxis (in which the selfish elements bias Mendelian segregation by moving away from dead-end polar bodies and into the functional egg during oogenesis, i.e., meiotic or centromeric drive), (2) interference (in which the selfish element kills or debilitates noncarrier gametes or offspring, i.e., segregation distortion and zygotic drive), and (3) overreplication (in which the selfish element increases its copy number in the genome, e.g., biased gene conversion, transposable elements, and homing endonucleases). De novo mutations can also gain a transmission advantage by increasing the rate of stem cell division in the germ line (germline drive) (e.g., Yoon et al. 2013). All of these genomic conflict mechanisms have been described in detail in Burt and Trivers (2006).Genomic conflict frequently leads to reduced fitness at the organismal level. Meiotic drive can harm the organism as a whole because the attributes that provide a segregation advantage in oogenesis (e.g., the structure of the centromere and neighboring heterochromatin) can be maladaptive during spermatogenesis and contribute to male sterility (see, for review, Elde et al. 2011). Segregation distorters and zygotic drivers can substantially reduce a carrier male’s fitness because they kill up to half of his sperm (leading to reduced fertility) and offspring, respectively. Sex-linked, meiotic drivers in WZ females (like birds) and segregation distorters and zygotic drivers in XY males (like insects and mammals) cause biased sex ratios that reduce fitness with respect to Fisherian sex ratio selection and can also reduce population growth and potentially drive species to extinction. Biased gene conversion and germline drive (Yoon et al. 2013) reduce organismal fitness when harmful mutations accumulate to elevated levels (i.e., beyond the conventional values predicted by mutation-selection balance) because they have a molecular drive advantage over an allele that is more beneficial at the organismal level. Transposable elements insert at new places in the genome where they can disrupt gene function and thereby reduce their carrier’s fitness.Zygotic drive is an unusual form of genetic conflict because it directly reduces Darwinian fitness by killing or debilitating offspring. It is favored by gene-level selection when there is competition among siblings for limiting resources. By killing or weakening noncarrier competitor siblings, the gene(s) coding for zygotic drive gain a selective advantage because their survival is increased at the expense of siblings carrying alleles that are not identical by descent—despite any fitness loss to the parents, siblings, or other parts of the genome.Zygotic drive of the autosomes has been observed in a wide diversity of model organisms (e.g., worms, beetles, and mice) (reviewed in Burt and Trivers 2006) in which it can be efficiently detected because of the availability of numerous genetic markers. In general, an autosomal zygotic driver must have both a driver allele at one locus and a protective allele at a responder locus. In worms (Caenorhabditis elegans), a molecular mechanism leading to zygotic drive was recently discovered. Here a zygotic driver is coded by a pair of tightly linked genes, in which an allele at one gene (peel-1) produces a toxin, the driver locus, which is packaged in the sperm and transmitted to the zygote, whereas an allele at another gene (zeel-1) produces an antidote (the protective allele, which is expressed very early in development) that rescues only those embryos that inherit zeel-1 (and usually also the tightly linked driver, peel-1) (Seidel et al. 2011). Zygotic drive on the autosomes is expected to be difficult to evolve—and therefore to be relatively rare in genomes—because it requires an improbable phenotype (i.e., a functionally coupled driver gene product and a responder gene sequence or product) and genotype (i.e., very close linkage between the loci coding for the driver and responder).     

Idealized Computational Models for Auditory Receptive Fields

We present a theory by which idealized models of auditory receptive fields can be derived in a principled axiomatic manner, from a set of structural properties to (i) enable invariance of receptive field responses under natural sound transformations and (ii) ensure internal consistency between spectro-temporal receptive fields at different temporal and spectral scales. For defining a time-frequency transformation of a purely temporal sound signal, it is shown that the framework allows for a new way of deriving the Gabor and Gammatone filters as well as a novel family of generalized Gammatone filters, with additional degrees of freedom to obtain different trade-offs between the spectral selectivity and the temporal delay of time-causal temporal window functions. When applied to the definition of a second-layer of receptive fields from a spectrogram, it is shown that the framework leads to two canonical families of spectro-temporal receptive fields, in terms of spectro-temporal derivatives of either spectro-temporal Gaussian kernels for non-causal time or a cascade of time-causal first-order integrators over the temporal domain and a Gaussian filter over the logspectral domain. For each filter family, the spectro-temporal receptive fields can be either separable over the time-frequency domain or be adapted to local glissando transformations that represent variations in logarithmic frequencies over time. Within each domain of either non-causal or time-causal time, these receptive field families are derived by uniqueness from the assumptions. It is demonstrated how the presented framework allows for computation of basic auditory features for audio processing and that it leads to predictions about auditory receptive fields with good qualitative similarity to biological receptive fields measured in the inferior colliculus (ICC) and primary auditory cortex (A1) of mammals.     

Sex-specific Trans-regulatory Variation on the Drosophila melanogaster X Chromosome

The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change.     

Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: A case report

ABSTRACT: BACKGROUND: The autosomal dominant spinocerebellar ataxias (SCAs) confine a group of rare and heterogeneous disorders, which present with progressive ataxia and numerous other features e.g. peripheral neuropathy, macular degeneration and cognitive impairment, and a subset of these disorders is caused by CAG-repeat expansions in their respective genes. The diagnosing of the SCAs is often difficult due to the phenotypic overlap among several of the subtypes and with other neurodegenerative disorders e.g. Huntington's disease, CASE PRESENTATION: We report a family in which the proband had rapidly progressing cognitive decline and only subtle cerebellar symptoms from age 42. Sequencing of the TATA-box binding protein gene revealed a modest elongation of the CAG/CAA-repeat of only two repeats above the non-pathogenic threshold of 41, confirming a diagnosis of SCA17. Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset. Thus, this case presented with an unusual phenotype. CONCLUSIONS: The current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.