Effects of inbreeding and genetic modification on Aedes aegypti larval competition and adult energy reserves

<p>Abstract</p> <p>Background</p> <p>Genetic modification of mosquitoes offers a promising strategy for the prevention and control of mosquito-borne diseases. For such a strategy to be effective, it is critically important that engineered strains are competitive enough to serve their intended function in population replacement or reduction of wild mosquitoes in nature. Thus far, fitness evaluations of genetically modified strains have not addressed the effects of competition among the aquatic stages and its consequences for adult fitness. We therefore tested the competitive success of combinations of wild, inbred and transgenic (created in the inbred background) immature stages of the dengue vector <it>Aedes aegypti </it>in the presence of optimal and sub-optimal larval diets.</p> <p>Results</p> <p>The wild strain of <it>Ae. aegypti </it>demonstrated greater performance (based on a composite index of survival, development rate and size) than the inbred strain, which in turn demonstrated greater performance than the genetically modified strain. Moreover, increasing competition through lowering the amount of diet available per larva affected fitness disproportionately: transgenic larvae had a reduced index of performance (95-119%) compared to inbred (50-88%) and wild type larvae (38-54%). In terms of teneral energy reserves (glycogen, lipid and sugar), adult wild type mosquitoes had more reserves directly available for flight, dispersal and basic metabolic functions than transgenic and inbred mosquitoes.</p> <p>Conclusions</p> <p>Our study provides a detailed assessment of inter- and intra-strain competition across aquatic stages of wild type, inbred, and transgenic mosquitoes and the impact of these conditions on adult energy reserves. Although it is not clear what competitive level is adequate for success of transgenic strains in nature, strong gene drive mechanisms are likely to be necessary in order to overcome competitive disadvantages in the larval stage that carryover to affect adult fitness.</p

Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells.

The Notch ligand, Dll4, is essential for angiogenesis during embryonic vascular development and is involved in tumour angiogenesis. Several recent publications demonstrated that blockade of Dll4 signalling inhibits tumour growth, suggesting that it may constitute a good candidate for anti-cancer therapy. In order to understand the role of Dll4 at the cellular level, we performed an analysis of Dll4-regulated genes in HUVECs. The genes identified included several angiogenic signalling pathways, such as VEGF, FGF and HGF. In particular we identified downregulation (VEGFR2, placenta growth factor PlGF) of VEGF pathway components resulting in the overall effect of limiting the response of HUVEC to VEGF. However extensive upregulation of VEGFR1 was observed allowing continued response to its ligand PlGF but the soluble form of the VEGFR1, sVEGFR1 was also upregulated. PlGF enhanced tubulogenesis of HUVEC suggesting that downregulation of PlGF and upregulation of VEGFR1 including sVEGFR1 are important mechanisms by which Dll4 attenuates PlGF and VEGF signalling. Dll4-stimulated HUVECs had impaired ERK activation in response to VEGF and HGF indicating that Dll4 signalling negatively regulates these pathways. Dll4 expression reduced vessel sprout length in a 3D tubulogenesis assay confirming that Dll4 signalling inhibits angiogenesis. Altogether, our data suggest that Dll4 expression acts as a switch from the proliferative phase of angiogenesis to the maturation and stabilisation phase by blocking endothelial cell proliferation and allowing induction of a more mature, differentiated phenotype. The regulation of sVEGFR1 provides a novel mechanism for Dll4 signalling to regulate cells at distance, not just in adjacent cells

Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination.

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process

APOBEC3B-mediated Corruption of the Tumor Cell Immunopeptidome Induces Heteroclitic Neoepitopes for Cancer Immunotherapy

APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation of neoepitopes, which prime anti-tumor T cells. Here, we show that overexpression of APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity to immune checkpoint blockade in a murine model of melanoma. However, in the vaccine setting, APOBEC3B-mediated mutations reproducibly generate heteroclitic neoepitopes in vaccine cells which activate de novo T cell responses. These cross react against parental, unmodified tumors and lead to a high rate of cures in both subcutaneous and intra-cranial tumor models. Heteroclitic Epitope Activated Therapy (HEAT) dispenses with the need to identify patient specific neoepitopes and tumor reactive T cells ex vivo. Thus, actively driving a high mutational load in tumor cell vaccines increases their immunogenicity to drive anti-tumor therapy in combination with immune checkpoint blockade

Polarization due to rotational distortion in the bright star Regulus

This is the full published article (retrieved from the 6 months post-publication posting on arXiv) including the Methods and Supplementary Information sections: 33 pages, 10 figures, 8 tablesPolarization in stars was first predicted by Chandrasekhar [1] who calculated a substantial linear polarization at the stellar limb for a pure electron-scattering atmosphere. This polarization will average to zero when integrated over a spherical star but could be detected if the symmetry is broken, for example by the eclipse of a binary companion. Nearly 50 years ago, Harrington and Collins [2] modeled another way of breaking the symmetry and producing net polarization - the distortion of a rapidly rotating hot star. Here we report the first detection of this effect. Observations of the linear polarization of Regulus, with two different high-precision polarimeters, range from +42 parts-per-million (ppm) at a wavelength of 741 nm to -22 ppm at 395 nm. The reversal from red to blue is a distinctive feature of rotation-induced polarization. Using a new set of models for the polarization of rapidly rotating stars we find that Regulus is rotating at 96.5(+0.6/-0.8)% of its critical angular velocity for breakup, and has an inclination greater than 76.5 degrees. The rotation axis of the star is at a position angle of 79.5+/-0.7 degrees. The conclusions are independent of, but in good agreement with, the results of previously published interferometric observations of Regulus [3]. The accurate measurement of rotation in early-type stars is important for understanding their stellar environments [4], and course of their evolution [5].Peer reviewedFinal Accepted Versio

Synchronisation of egg hatching of brown hairstreak (Thecla betulae) and budburst of blackthorn (Prunus spinosa) in a warmer future

Synchronisation of the phenology of insect herbivores and their larval food plant is essential for the herbivores’ fitness. The monophagous brown hairstreak (Thecla betulae) lays its eggs during summer, hibernates as an egg, and hatches in April or May in the Netherlands. Its main larval food plant blackthorn (Prunus spinosa) flowers in early spring, just before the leaves appear. As soon as the Blackthorn opens its buds, and this varies with spring temperatures, food becomes available for the brown hairstreak. However, the suitability of the leaves as food for the young caterpillars is expected to decrease rapidly. Therefore, the timing of egg hatch is an important factor for larval growth. This study evaluates food availability for brown hairstreak at different temperatures. Egg hatch and budburst were monitored from 2004 to 2008 at different sites in the Netherlands. Results showed ample food availability at all monitored temperatures and sites but the degree of synchrony varied strongly with spring temperatures. To further study the effect of temperature on synchronisation, an experiment using normal temperatures of a reference year (T) and temperatures of T + 5°C was carried out in climate chambers. At T + 5°C, both budburst and egg hatch took place about 20 days earlier and thus, on average, elevated temperature did not affect synchrony. However, the total period of budburst was 11 days longer, whereas the period of egg hatching was 3 days shorter. The implications for larval growth by the brown hairstreak under a warmer climate are considered.

自家受精魚マングローブキリフィッシュ（Kryptolebias marmoratus）の生殖腺の形態

We conducted anatomical and histological observations of the gonads in the self-fertilizing mangrove killifish, Kryptolebias marmoratus to investigate the self-fertilizing mechanism of this species. The gonad has a bilobed structure. The elongated gonadal lumen (GL) along the dorsal surface of the gonad connects to the common genital sinus. The elongate testicular region is closely attached to the GL. Among the ovulated eggs in the GL, those in the anterior part of the GL have micropyles but no perivitelline space (are not yet fertilized), whereas those in the posterior part of the GL are fertilized. In our histological analysis, we found free sperm in the posterior area of the GL. We conclude that ovulated eggs may be self-fertilized in the posterior GL.マングローブキリフィッシュ（Kryptolebias marmoratus）の生殖腺の解剖学および組織学的な観察を行い，本種の自家受精機構を考察した。生殖腺は二葉に分かれ，生殖管は生殖腺背面を通り泌尿生殖口へ達した。精巣組織は生殖管に隣接していた。生殖管内に排卵された卵のうち，生殖管前方の卵には囲卵腔がなく卵門を有しており未受精であったが，生殖管後方の卵は受精していた。組織学的観察から，生殖管後方で排精の起こっていることが明らかとなった。排卵後に卵が生殖管を通る段階で自家受精が起こると考えられた

Screening and early psychological intervention for depression in schools: systematic review and meta-analysis.

Abstract Depression in children and adolescents is considerably undertreated, and the school may be a good setting for identifying and treating depression. We conducted a meta-analysis of studies in which students were screened for depression, and those with depressive symptoms were treated with a psychological intervention. Only randomised controlled trials were included. Eight studies met the inclusion criteria. Five studies focused on younger children (7–14 years) and three studies were aimed at adolescents (12–19 years). In total 5803 students were screened, of whom 7.2% were included in the intervention studies (95% CI: 7.1–7.3). The ‘numbers-needed-to-screen’ was 31 (95% CI: 27–32), which means that 31 students had to be screened in order to generate one successfully treated case of depression. The effects of the psychological treatments at posttest were compared to control conditions in the 8 studies comprising 12 contrast groups, with a total of 413 students. The mean effect size was 0.55 (95% CI: 0.35– 0.76). There were not enough studies to examine whether specific psychotherapies were superior to other psychotherapies. Although the number of studies is small and their quality is limited, screening and early intervention at schools may be an effective strategy to reduce the burden of disease from depression in children and adolescents. More research on the (negative) effects of these interventions is needed