Quantitative patterns in drone wars

Attacks by drones (i.e., unmanned combat air vehicles) continue to generate heated political and ethical debates. Here we examine the quantitative nature of drone attacks, focusing on how their intensity and frequency compare with that of other forms of human conflict. Instead of the power-law distribution found recently for insurgent and terrorist attacks, the severity of attacks is more akin to lognormal and exponential distributions, suggesting that the dynamics underlying drone attacks lie beyond these other forms of human conflict. We find that the pattern in the timing of attacks is consistent with one side having almost complete control, an important if expected result. We show that these novel features can be reproduced and understood using a generative mathematical model in which resource allocation to the dominant side is regulated through a feedback loop.Comment: 5 pages, 3 figure

Genetic control of photoreceptor terminal differentiation in Drosophila melanogaster

Why do photoreceptors differentiate in the eye? Though simple, biologically this is an important question, and it may prove complex to answer. To present a bigger picture: animals have evolved a diversity of highly specialised sensory organs, which they use to obtain information from their environment and thus survive. These organs contain different types of receptor neurons. For example, there are chemoreceptors in the labellum and in the antennae of insects, or mechanoreceptors in the inner ear of vertebrates... and each of these types of receptor neurons specifically possesses the molecular machinery to detect and transduce stimuli from one particular sensory modality. In the case of the eye, it contains photoreceptor neurons, which are specialised in light detection. Neither photoreceptors nor most of the components of the phototransduction cascade appear commonly outside the eye. Therefore, what are mechanisms that ensure that photoreceptors differentiate correctly in the eye, and not in other body parts? To start answering this question, first it might be useful to understand the early-acting process of eye field specification. This depends on a group of transcription factors that are collectively called the ‘retinal determination network’ (RDN), and work in combination with each other to confer eye identity to the developing, multipotent tissue. RDN genes are both necessary and sufficient for eye formation in different animal species, from Drosophila to vertebrates, and they tend to act through an evolutionarily conserved sequence of transcriptional events. First in this sequence, following the Drosophila nomenclature, the transcription factor Eyeless activates the expression of sine oculis and eyes absent. Then, Sine oculis and Eyes absent form a heterodimer and direct eye formation. Despite the importance of the RDN, until recently, little was known about its targets, or about the molecular mechanisms by which it coordinates eye development. In particular, how does it instruct photoreceptor differentiation? Our work suggests that a key step in this process is coordinated by the zinc finger transcription factor glass, which is a direct target of Sine oculis. While previous literature has shown that the Glass protein is primarily expressed in photoreceptors, its role in these cells was not known because it was believed that glass mutant photoreceptor precursors died during metamorphosis. Contrary to former studies, we demonstrate that glass mutant photoreceptor precursors survive and are present in the adult retina, but fail to mature as functional photoreceptors. Importantly, we have found that Glass is required for the expression of virtually all the proteins that are involved in the phototransduction cascade, and thus glass mutant flies are blind. Consistent with this, ectopic expression of Glass is able to induce some phototransduction components in the brain. Another step in the formation of photoreceptors is regulated by the homeodomain transcription factor Hazy, which is a direct target of Glass. While we show that both Glass and Hazy act synergistically to induce the expression of phototransduction proteins, we have also found that Glass can initiate the expression of most of the components of the phototransduction machinery in a Hazy-independent manner, and that hazy mutant flies only fail to detect white light after they are older than five days. Glass seems to be both required and sufficient for the expression of Hazy, and inducing Hazy in the retina partly rescues the glass mutant phenotype. Taken together, our results show a transcriptional link between the RDN and the expression of the proteins that adult Drosophila photoreceptors need to sense light, placing Glass at a key position in this developmental process. Finally, we compare the expression pattern of Glass in Drosophila and in the annelid Platynereis, and discuss the possibility that Glass plays an evolutionarily conserved role across different phyla.Warum bilden sich Fotorezeptoren gerade im Auge aus? Obwohl diese Frage einfach erscheint, ist sie aus biologischer Sicht doch sehr bedeutend und bedarf eventuell einer komplexen Antwort. Allgemein lässt sich sagen, dass Tiere eine Vielfalt von hoch spezialisierten Sinnesorganen entwickelt haben, durch die sie Informationen aus ihrer Umwelt aufnehmen und auf diese Weise ihr Überleben sichern. Diese Organe enthalten verschiedene Arten von Rezeptorneuronen. Zum Beispiel gibt es Chemorezeptoren im Labellum und in den Antennen der Insekten, oder Mechanorezeptoren im Innenohr von Wirbeltieren... und jedes dieser Rezeptorneuronen besitzt eine spezifische molekulare Maschinerie, um Reize einer bestimmten Sinnesmodalität wahrzunehmen und umzuwandeln. Beim Auge sind es Fotorezeptorneuronen, die auf die Wahrnehmung von Lichtreizen spezialisiert sind. Weder die Fotorezeptoren noch die meisten der Komponenten der Fototransduktionskaskade kommen außerhalb des Auges vor. Welche Mechanismen sind demzufolge ausschlaggebend, damit sich Fotorezeptoren im Auge und nicht in anderen Körperteilen entwickeln? Um diese Frage zu beantworten, ist es zunächst wichtig die frühen Mechanismen der Augenspezifizierung zu verstehen. Diese erfolgt unter Einfluss einer Gruppe von Transkriptionsfaktoren, die als „Retinales Determinations Netzwerk“ (RDN) bezeichnet werden. Diese Transkriptionsfaktoren interagieren, um aus dem sich entwickelnden multipotenten Gewebe ein Sehorgan zu bilden. RDN-Gene sind für die Augenentwicklung verschiedener Tierarten, von Drosophila bis zu Wirbeltieren, sowohl notwendig als auch ausreichend. Sie agieren durch eine evolutionär konservierte Sequenz transkriptioneller Mechanismen. An erster Stelle dieser Sequenz, nach der Drosophila Nomenklatur, aktiviert der Transkriptionsfaktor Eyeless die Expression von sine oculis und eyes absent. Anschließend bilden Sine Oculis und Eyes absent ein Heterodimer und induzieren die Entwicklung des Auges. Trotz der Bedeutung des RDNs war bis vor Kurzem nur sehr wenig über seinen Zweck oder die molekularen Mechanismen durch die es die Augenentwicklung koordiniert, bekannt. Vor allem stellt sich die Frage, wie es die Differenzierung der Fotorezeptoren reguliert? Unsere Arbeit legt nahe, dass ein wesentlicher Schritt in diesem Prozess durch den Zinkfinger-Transkriptionsfaktor glass koordiniert wird. Dabei handelt es sich um ein direktes Zielgen von Sine oculis. Obwohl in früheren wissenschaftlichen Arbeiten belegt wurde, dass das Glass-Protein in erster Linie in Fotorezeptoren exprimiert wird, war seine Rolle in diesen Zellen nicht bekannt, da angenommen wurde, dass Fotorezeptoren von glass Mutanten während der Metamorphose absterben. Im Gegensatz zu früheren Studien belegen wir das Überleben der Fotorezeptor-Vorläuferzellen von glass Mutanten und ihre Präsenz in der Retina adulter Fliegen, wobei sie jedoch nicht zu funktionsfähigen Fotorezeptoren heranreifen. Insbesondere konnten wir zeigen, dass Glass für die Expression fast aller Proteine, die in der Fototransduktionskaskade involviert sind, erforderlich ist. Daher sind glass Mutanten blind. In Übereinstimmung mit diesen Erkenntnissen bewirkt die ektopische Expression von Glass die Induktion einiger Komponenten der Fototransduktion im Gehirn. Ein weiterer Schritt in der Bildung von Fotorezeptoren wird reguliert durch den Homeodomänen-Transkriptionsfaktor Hazy, der ein direktes Ziel von Glass ist. Wir zeigen zum einen die synergetische Wirkung von Glass und Hazy bei der Expression von Fototransduktionsproteinen, zum anderen belegen wir, dass Glass die meisten Komponenten der Fototransduktionsmaschinerie unabhängig von Hazy induzieren kann, und dass hazy Mutanten ab dem Alter von fünf Tagen weißes Licht nicht mehr wahrnehmen können. Glass scheint notwendig und ausreichend für die Expression von Hazy zu sein und die Induktion von Hazy in der Retina rettet teilweise den Phänotyp von glass Mutanten. Insgesamt beweisen unsere Ergebnisse einen transkriptionellen Zusammenhang zwischen dem RDN und der Expression von Proteinen, die in Fotorezeptoren von adulten Drosophila Fliegen notwendig sind um Licht wahrzunehmen. Bei diesem Entwicklungsprozess hat Glass eine Schlüsselposition. Schließlich vergleichen wir die Expressionsmuster von Glass in Drosophila und im Anneliden Platynereis und diskutieren die Möglichkeit, dass Glass eine evolutionär konservierte Rolle über verschiedene Phyla hinweg spielt

The transcription factor Glass links eye field specification with photoreceptor differentiation in Drosophila

Eye development requires an evolutionarily conserved group of transcription factors, termed the retinal determination network (RDN). However, little is known about the molecular mechanism by which the RDN instructs cells to differentiate into photoreceptors. We show that photoreceptor cell identity in Drosophila is critically regulated by the transcription factor Glass, which is primarily expressed in photoreceptors and whose role in this process was previously unknown. Glass is both required and sufficient for the expression of phototransduction proteins. Our results demonstrate that the RDN member Sine oculis directly activates glass expression, and that Glass activates the expression of the transcription factors Hazy and Otd. We identified hazy as a direct target of Glass. Induced expression of Hazy in the retina partially rescues the glass mutant phenotype. Together, our results provide a transcriptional link between eye field specification and photoreceptor differentiation in Drosophila, placing Glass at a central position in this developmental process

Successive requirement of Glass and Hazy for photoreceptor specification and maintenance in Drosophila

Development of the insect compound eye requires a highly controlled interplay between transcription factors. However, the genetic mechanisms that link early eye field specification to photoreceptor terminal differentiation and fate maintenance remain largely unknown. Here, we decipher the function of 2 transcription factors, Glass and Hazy, which play a central role during photoreceptor development. The regulatory interactions between Glass and Hazy suggest that they function together in a coherent feed-forward loop in all types of Drosophila photoreceptors. While the glass mutant eye lacks the expression of virtually all photoreceptor genes, young hazy mutants correctly express most phototransduction genes. Interestingly, the expression of these genes is drastically reduced in old hazy mutants. This age-dependent loss of the phototransduction cascade correlates with a loss of phototaxis in old hazy mutant flies. We conclude that Glass can either directly or indirectly initiate the expression of most phototransduction proteins in a Hazy-independent manner, and that Hazy is mainly required for the maintenance of functional photoreceptors in adult flies

Glass confers rhabdomeric photoreceptor identity in Drosophila, but not across all metazoans

Across metazoans, visual systems employ different types of photoreceptor neurons (PRs) to detect light. These include rhabdomeric PRs, which exist in distantly related phyla and possess an evolutionarily conserved phototransduction cascade. While the development of rhabdomeric PRs has been thoroughly studied in the fruit fly Drosophila melanogaster, we still know very little about how they form in other species. To investigate this question, we tested whether the transcription factor Glass, which is crucial for instructing rhabdomeric PR formation in Drosophila, may play a similar role in other metazoans. Glass homologues exist throughout the animal kingdom, indicating that this protein evolved prior to the metazoan radiation. Interestingly, our work indicates that glass is not expressed in rhabdomeric photoreceptors in the planarian Schmidtea mediterranea nor in the annelid Platynereis dumerilii. Combined with a comparative analysis of the Glass DNA-binding domain, our data suggest that the fate of rhabdomeric PRs is controlled by Glass-dependent and Glass-independent mechanisms in different animal clades

Serial electron microscopic reconstruction of the drosophila larval eye: Photoreceptors with a rudimentary rhabdomere of microvillar-like processes

Photoreceptor cells (PRCs) across the animal kingdom are characterized by a stacking of apical membranes to accommodate the high abundance of photopigment. In arthropods and many other invertebrate phyla PRC membrane stacks adopt the shape of densely packed microvilli that form a structure called rhabdomere. PRCs and surrounding accessory cells, including pigment cells and lens-forming cells, are grouped in stereotyped units, the ommatidia. In larvae of holometabolan insects, eyes (called stemmata) are reduced in terms of number and composition of ommatidia. The stemma of Drosophila (Bolwig organ) is reduced to a bilateral cluster of subepidermal PRCs, lacking all other cell types. In the present paper we have analyzed the development and fine structure of the Drosophila larval PRCs. Shortly after their appearance in the embryonic head ectoderm, PRC precursors delaminate and lose expression of apical markers of epithelial cells, including Crumbs and several centrosome-associated proteins. In the early first instar larva, PRCs show an expanded, irregularly shaped apical surface that is folded into multiple horizontal microvillar-like processes (MLPs). Apical PRC membranes and MLPs are covered with a layer of extracellular matrix. MLPs are predominantly aligned along an axis that extends ventro-anteriorly to dorso-posteriorly, but vary in length, diameter, and spacing. Individual MLPs present a “beaded” shape, with thick segments (0.2–0.3 μm diameter) alternating with thin segments (>0.1 μm). We show that loss of the glycoprotein Chaoptin, which is absolutely essential for rhabdomere formation in the adult PRCs, does not lead to severe abnormalities in larval PRCs

The promise and perils of using big data in the study of corporate networks: problems, diagnostics and fixes

Network data on connections among corporate actors and entities – for instance through co-ownership ties or elite social networks – is increasingly available to researchers interested in probing many important questions related to the study of modern capitalism. We discuss the promise and perils of using Big Corporate Network Data (BCND) given the analytical challenges associated with the nature of the subject matter, variable data quality, and other problems associated with currently available data at this scale. We propose a standard process for how researchers can deal with BCND problems. While acknowledging that different research questions require different approaches to data quality, we offer a schematic platform that researchers can follow to make informed and intelligent decisions about BCND issues and address these issues through a specific work-flow procedure. Within each step in this procedure, we provide a set of best practices for how to identify, resolve, and minimize BCND problems that arise

Multilevel regulation of the glass locus during Drosophila eye development

Development of eye tissue is initiated by a conserved set of transcription factors termed retinal determination network (RDN). In the fruit fly Drosophila melanogaster, the zinc-finger transcription factor Glass acts directly downstream of the RDN to control identity of photoreceptor as well as non-photoreceptor cells. Tight control of spatial and temporal gene expression is a critical feature during development, cell-fate determination as well as maintenance of differentiated tissues. The molecular mechanisms that control expression of glass, however, remain largely unknown. We here identify complex regulatory mechanisms controlling expression of the glass locus. All information to recapitulate glass expression are contained in a compact 5.2 kb cis-acting genomic element by combining different cell-type specific and general enhancers with repressor elements. Moreover, the immature RNA of the locus contains an alternative small open reading frame (smORF) upstream of the actual glass translation start, resulting in a small peptide instead of the three possible Glass protein isoforms. CRISPR/Cas9-based mutagenesis shows that the smORF is not required for the formation of functioning photoreceptors, but is able to attenuate effects of glass misexpression. Furthermore, editing the genome to generate glass loci eliminating either one or two isoforms shows that only one of the three proteins is critical for formation of functioning photoreceptors, while removing the two other isoforms did not cause defects in developmental or photoreceptor function. Our results show that eye development and function is largely unaffected by targeted manipulations of critical features of the glass transcript, suggesting a strong selection pressure to allow the formation of a functioning eye

Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus

Objective To assess whether genetically determined Amerindian ancestry predicts increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus (SLE). Methods Single-nucleotide polymorphisms (SNPs) within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation between ancestry and the presence of risk alleles was analyzed using linear regression. Results A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4 , STAT4 , ITGAM , and IRF5 were associated with lupus in a Hispanic Mestizo cohort enriched for European and Amerindian ancestry. In addition, 2 SNPs within the major histocompatibility complex region, previously shown to be associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression, we predicted an average increase of 2.34 risk alleles when comparing an SLE patient with 100% Amerindian ancestry versus an SLE patient with 0% Amerindian ancestry ( P < 0.0001). SLE patients with 43% more Amerindian ancestry were predicted to carry 1 additional risk allele. Conclusion Our results demonstrate that Amerindian ancestry is associated with an increased number of risk alleles for SLE.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78480/1/27753_ftp.pd

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management