Drosophila Lethal Giant Larvae Neoplastic Mutant as a Genetic Tool for Cancer Modeling

Drosophila lethal giant larvae (lgl) is a tumour suppressor gene whose function in establishing apical-basal cell polarity as well as in exerting proliferation control in epithelial tissues is conserved between flies and mammals. Individuals bearing lgl null mutations show a gradual loss of tissue architecture and an extended larval life in which cell proliferation never ceases and no differentiation occurs, resulting in prepupal lethality. When tissues from those individuals are transplanted into adult normal recipients, a subset of cells, possibly the cancer stem units, are again able to proliferate and give rise to metastases which migrate to distant sites killing the host. This phenotype closely resembles that of mammalian epithelial cancers, in which loss of cell polarity is one of the hallmarks of a malignant, metastatic behaviour associated with poor prognosis. Lgl protein shares with its human counterpart Human giant larvae-1 (Hugl-1) significant stretches of sequence similarity that we demonstrated to translate into a complete functional conservation, pointing out a role in cell proliferation control and tumorigenesis also for the human homologue. The functional conservation and the power of fly genetics, that allows the researcher to manipulate the fly genome at a level of precision that exceeds that of any other multicellular genetic system, make this Drosophila mutant a very suitable model in which to investigate the mechanisms underlying epithelial tumour formation, progression and metastatisation. In this review, we will summarise the results obtained in these later years using this model for the study of cancer biology. Moreover, we will discuss how recent advances in developmental genetics techniques have succeeded in enhancing the similarities between fly and human tumorigenesis, giving Drosophila a pivotal role in the study of such a complex genetic disease

Estimating Influenza Vaccine Efficacy From Challenge and Community-based Study Data

In this paper, the authors provide estimates of 4 measures of vaccine efficacy for live, attenuated and inactivated influenza vaccine based on secondary analysis of 5 experimental influenza challenge studies in seronegative adults and community-based vaccine trials. The 4 vaccine efficacy measures are for susceptibility (VES), symptomatic illness given infection (VEP), infection and illness (VESP), and infectiousness (VEI). The authors also propose a combined (VEC) measure of the reduction in transmission in the entire population based on all of the above efficacy measures. Live influenza vaccine and inactivated vaccine provided similar protection against laboratory-confirmed infection (for live vaccine: VES  = 41%, 95% confidence interval (CI): 15, 66; for inactivated vaccine: VES  = 43%, 95% CI: 8, 79). Live vaccine had a higher efficacy for illness given infection (VEP  = 67%, 95% CI: 24, 100) than inactivated vaccine (VEP  = 29%, 95% CI: −19, 76), although the difference was not statistically significant. VESP for the live vaccine was higher than for the inactivated vaccine. VEI estimates were particularly low for these influenza vaccines. VESP and VEC can remain high for both vaccines, even when VEI is relatively low, as long as the other 2 measures of vaccine efficacy are relatively high

Hierarchical black hole triples in young star clusters: impact of Kozai-Lidov resonance on mergers

Mergers of compact-object binaries are one of the most powerful sources of gravitational waves (GWs) in the frequency range of second-generation ground-based GW detectors (advanced LIGO and Virgo). Dynamical simulations of young dense star clusters (SCs) indicate that ~27 per cent of all double compact-object binaries are members of hierarchical triple systems (HTs). In this paper, we consider 570 HTs composed of three compact objects (black holes or neutron stars) that formed dynamically in N-body simulations of young dense SCs. We simulate them for a Hubble time with a new code based on the Mikkola's algorithmic regularization scheme, including the 2.5 post-Newtonian term. We find that ~88 per cent of the simulated systems develop Kozai-Lidov (KL) oscillations. KL resonance triggers the merger of the inner binary in three systems (corresponding to 0.5 per cent of the simulated HTs), by increasing the eccentricity of the inner binary. Accounting for KL oscillations leads to an increase of the total expected merger rate by 4850 per cent. All binaries that merge because of KL oscillations were formed by dynamical exchanges (i.e. none is a primordial binary) and have chirp mass >20 M 99. This result might be crucial to interpret the formation channel of the first recently detected GW events

Effect of metallicity on the gravitational-wave signal from the cosmological population of compact binary coalescences

Recent studies on stellar evolution have shown that the properties of compact objects strongly depend on the metallicity of the environment in which they were formed. Using some very simple assumptions on the metallicity of the stellar populations, we explore how this property affects the unresolved gravitational-wave background from extragalactic compact binaries. We obtained a suit of models using population synthesis code, estimated the gravitational-wave background they produce, and discuss its detectability with second- (advanced LIGO, advanced Virgo) and third- (Einstein Telescope) generation detectors. Our results show that the background is dominated by binary black holes for all considered models in the frequency range of terrestrial detectors, and that it could be detected in most cases by advanced LIGO/Virgo, and with Einstein Telescope with a very high signal-to-noise ratio. The observed peak in a gravitational wave spectrum depends on the metallicity of the stellar population.Comment: 9 pages, 5 figures, accepted to A&

Coenzyme Q10 modulates sulfide metabolism and links the mitochondrial respiratory chain to pathways associated to one carbon metabolism

This work was supported by grants from Ministerio de Ciencia e Innovacion, Spain, and the ERDF (RTI2018-093503-B-100); the Muscular Dystrophy Association (MDA-602322); the University of Granada (grant reference 'UNETE', UCE-PP2017-06) (L.C.L.) and the National Institute of Health (NIH, United States) P01 HD080642-01 (C.M.Q.). A.H.-G. and P.G.-G. are `FPU fellows' from the Ministerio de Universidades, Spain. E.B.-C. was supported by the Junta de Andalucia. U.B.A. was supported by the Erasmus+ Program.Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine β-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.Spanish GovernmentEuropean Union (EU) RTI2018-093503-B-100Muscular Dystrophy Association MDA-602322University of Granada UCE-PP2017-06United States Department of Health & Human Services National Institutes of Health (NIH) - USA P01 HD080642-01Junta de AndaluciaErasmus+ Progra

On the role of ethylene, auxin and a GOLVEN-like peptide hormone in the regulation of peach ripening

Background: In melting flesh peaches, auxin is necessary for system-2 ethylene synthesis and a cross-talk between ethylene and auxin occurs during the ripening process. To elucidate this interaction at the transition from maturation to ripening and the accompanying switch from system-1 to system-2 ethylene biosynthesis, fruits of melting flesh and stony hard genotypes, the latter unable to produce system-2 ethylene because of insufficient amount of auxin at ripening, were treated with auxin, ethylene and with 1-methylcyclopropene (1-MCP), known to block ethylene receptors. The effects of the treatments on the different genotypes were monitored by hormone quantifications and transcription profiling. Results: In melting flesh fruit, 1-MCP responses differed according to the ripening stage. Unexpectedly, 1-MCP induced genes also up-regulated by ripening, ethylene and auxin, as CTG134, similar to GOLVEN (GLV) peptides, and repressed genes also down-regulated by ripening, ethylene and auxin, as CTG85, a calcineurin B-like protein. The nature and transcriptional response of CTG134 led to discover a rise in free auxin in 1-MCP treated fruit. This increase was supported by the induced transcription of CTG475, an IAA-amino acid hydrolase. A melting flesh and a stony hard genotype, differing for their ability to synthetize auxin and ethylene amounts at ripening, were used to study the fine temporal regulation and auxin responsiveness of genes involved in the process. Transcriptional waves showed a tight interdependence between auxin and ethylene actions with the former possibly enhanced by the GLV CTG134. The expression of genes involved in the regulation of ripening, among which are several transcription factors, was similar in the two genotypes or could be rescued by auxin application in the stony hard. Only GLV CTG134 expression could not be rescued by exogenous auxin. Conclusions: 1-MCP treatment of peach fruit is ineffective in delaying ripening because it stimulates an increase in free auxin. As a consequence, a burst in ethylene production speeding up ripening occurs. Based on a network of gene transcriptional regulations, a model in which appropriate level of CTG134 peptide hormone might be necessary to allow the correct balance between auxin and ethylene for peach ripening to occur is proposed

Transcriptomic signatures across human tissues identify functional rare genetic variation

© 2020 American Association for the Advancement of Science. All rights reserved. INTRODUCTION: The human genome contains tens of thousands of rare (minor allele frequency 800 genomes matched with transcriptomes across 49 tissues, we were able to study RVs that underlie extreme changes in the transcriptome. To capture the diversity of these extreme changes, we developed and integrated approaches to identify expression, allele-specific expression, and alternative splicing outliers, and characterized the RV landscape underlying each outlier signal. We demonstrate that personal genome interpretation and RV discovery is enhanced by using these signals. This approach provides a new means to integrate a richer set of functional RVs into models of genetic burden, improve disease gene identification, and enable the delivery of precision genomics

Notch inhibits Yorkie activity in Drosophila wing discs.

During development, tissues and organs must coordinate growth and patterning so they reach the right size and shape. During larval stages, a dramatic increase in size and cell number of Drosophila wing imaginal discs is controlled by the action of several signaling pathways. Complex cross-talk between these pathways also pattern these discs to specify different regions with different fates and growth potentials. We show that the Notch signaling pathway is both required and sufficient to inhibit the activity of Yorkie (Yki), the Salvador/Warts/Hippo (SWH) pathway terminal transcription activator, but only in the central regions of the wing disc, where the TEAD factor and Yki partner Scalloped (Sd) is expressed. We show that this cross-talk between the Notch and SWH pathways is mediated, at least in part, by the Notch target and Sd partner Vestigial (Vg). We propose that, by altering the ratios between Yki, Sd and Vg, Notch pathway activation restricts the effects of Yki mediated transcription, therefore contributing to define a zone of low proliferation in the central wing discs

Mechanisms and mechanics of cell competition in epithelia

When fast-growing cells are confronted with slow-growing cells in a mosaic tissue, the slow-growing cells are often progressively eliminated by apoptosis through a process known as cell competition. The underlying signalling pathways remain unknown, but recent findings have shown that cell crowding within an epithelium leads to the eviction of cells from the epithelial sheet. This suggests that mechanical forces could contribute to cell elimination during cell competition