Nonlinearity arising from noncooperative transcription factor binding enhances negative feedback and promotes genetic oscillations

We study the effects of multiple binding sites in the promoter of a genetic oscillator. We evaluate the regulatory function of a promoter with multiple binding sites in the absence of cooperative binding, and consider different hypotheses for how the number of bound repressors affects transcription rate. Effective Hill exponents of the resulting regulatory functions reveal an increase in the nonlinearity of the feedback with the number of binding sites. We identify optimal configurations that maximize the nonlinearity of the feedback. We use a generic model of a biochemical oscillator to show that this increased nonlinearity is reflected in enhanced oscillations, with larger amplitudes over wider oscillatory ranges. Although the study is motivated by genetic oscillations in the zebrafish segmentation clock, our findings may reveal a general principle for gene regulation.Comment: 11 pages, 8 figure

COVID-19, Carceri e “Giustizia taglia e incolla”

Amidst the current pandemic, the cut-and-paste justice (the exportation of the American prison system around the world) is stronger than ever: the virus is ravaging prison populations because prisons are — and always have been — a health disaster. As a result, some countries have released a lot of people, while others have not released a single person, not to mention the suspension of prison visits and the sudden urgency for technology, which is something not all prisons were prepared for, with the obvious consequence that some people are simply denied any kind of connection to the outside world. The Writing on the Wall, an art installation made from writings by people in prison around the world, is a reminder that those people behind the wall still exist.Amidst the current pandemic, the cut-and-paste justice (the exportation of the American prison system around the world) is stronger than ever: the virus is ravaging prison populations because prisons are — and always have been — a health disaster. As a result, some countries have released a lot of people, while others have not released a single person, not to mention the suspension of prison visits and the sudden urgency for technology, which is something not all prisons were prepared for, with the obvious consequence that some people are simply denied any kind of connection to the outside world. The Writing on the Wall, an art installation made from writings by people in prison around the world, is a reminder that those people behind the wall still exist

Faf1 is expressed during neurodevelopment and is involved in Apaf1-dependent caspase-3 activation in proneural cell

Fas-associated factor 1 (Faf1) has been described as a Fas-binding pro-apoptotic protein and as a component of the death-inducing signaling complex (DISC) in Fas-mediated apoptosis. Faf1 is able to potentiate Fas-induced apoptosis in several cell lines, although its specific functions are still not clear. Here we show that Faf1 is highly expressed in several areas of the developing telencephalon. Its expression pattern appears to be dynamic at different embryonic stages and to be progressively confined within limited territories. To decipher the specific role of Faf1 in developing brain, we used cDNA over-expression and mRNA down-regulation experiments to modulate Faf1 expression in telencephalic neural precursor cells, and we showed that in neural cell death Faf1 acts as a Fas-independent apoptotic enhancer. Moreover, we found that Faf1 protein level is down-regulated during apoptosis in a caspase- and Apaf1-dependent manner

Potenziale und Ressourcen erkennen und entwickeln: Zugänge und Modelle

Hanni Bütler stellt in ihrem Aufsatz das Zürcher Ressourcenmodell ZRM, ein Verfahren zum Selbstmanagement, das auf aktuellsten neurowissenschaftlichen Erkenntnissen zum menschlichen Handeln beruht, vor. Wie diese differenzierte psychologische Methode, deren Ausgangspunkt und Kernelement die Arbeit mit Bildern darstellt, in der Laufbahnberatung eingesetzt werden kann, wird von der Autorin anschaulich und nachvollziehbar beschrieben. Da die Beratung von geflüchteten Menschen in jüngster Zeit an Bedeutung gewonnen hat, ist auch das Thema Trauma stärker ins Bewusstsein gerückt. Doris Deixler gibt in ihrem Artikel einen Überblick über das aktuelle Wissen über das Wesen von Traumata und über deren Folgen. Aus ihrer Praxis als Traumaberaterin zeigt sie, auf welche Weise sich Traumafolgen in Beratungssituationen auswirken können - und wie BeraterInnen darauf reagieren können. Georg Gittler und Test 4 U GmbH stellen ein neuartiges, in jahrelanger Forschung entwickeltes Online-Instrument vor, das eine Orientierungshilfe für die Studienwahl bietet: Das "Studien-Navi" vergleicht persönliche Interessensprofile mit denen bereits Studierender und rangreiht mögliche Alternativen nach dem Grad ihrer Passung. Das Instrument ist auf wissenschaftlicher Basis entwickelt und umfangreich empirisch abgesichert. Es hat in der wissenschaftlichen Community große Beachtung gefunden und wird im Rahmen des vom österreichischen Wissenschaftsministerium gemeinsam mit dem Bildungsministerium ins Leben gerufenen Programm "18plus - Berufs- und Studienchecker" für angehende MaturantInnen im Zusammenhang mit individueller Beratung angeboten. Martin Busch und Laura Soroldoni berichten über eine weitere innovative Entwicklung im Zusammenhang mit dem Programm "18plus": Auf Basis von Forschungen zur Berufswahl unter den gegenwärtigen gesellschaftlichen Bedingungen hat Mark Savickas ein von den in der Berufsberatung üblichen Interessenstests abweichendes Instrumentarium entwickelt, das Auskunft über den Stand des Orientierungsprozesses und die damit zusammenhängenden Einstellungen und Verfasstheiten der Ratsuchenden gibt. Dieses Instrumentarium wurde mit Genehmigung des Autors ins Deutsche übersetzt und um spezifische Empfehlungen an die Ratsuchenden für die weitere Gestaltung des Orientierungsprozesses erweitert

Spatiotemporal oscillations of Notch1, Dll1 and NICD are coordinated across the mouse PSM

During somitogenesis, epithelial somites form from the pre-somitic mesoderm (PSM) in a periodic manner. This periodicity is regulated by a molecular oscillator, known as the ‘segmentation clock’, that is characterised by an oscillatory pattern of gene expression that sweeps the PSM in a caudal-rostral direction. Key components of the segmentation clock are intracellular components of the Notch, Wnt and FGF pathways, and it is widely accepted that intracellular negative-feedback loops regulate oscillatory gene expression. However, an open question in the field is how intracellular oscillations are coordinated, in the form of spatiotemporal waves of expression, across the PSM. In this study, we provide a potential mechanism for this process. We show at the mRNA level that the Notch1 receptor and Delta-like 1 (Dll1) ligand vary dynamically across the PSM of both chick and mouse. Remarkably, we also demonstrate similar dynamics at the protein level; hence, the pathway components that mediate intercellular coupling themselves exhibit oscillatory dynamics. Moreover, we quantify the dynamic expression patterns of Dll1 and Notch1, and show they are highly correlated with the expression patterns of two known clock components [Lfng mRNA and the activated form of the Notch receptor (cleaved Notch intracellular domain, NICD)]. Lastly, we show that Notch1 is a target of Notch signalling, whereas Dll1 is Wnt regulated. Regulation of Dll1 and Notch1 expression thus links the activity of Wnt and Notch, the two main signalling pathways driving the clock

A balance of positive and negative regulators determines the pace of the segmentation clock

Somitogenesis is regulated by a molecular oscillator that drives dynamic gene expression within the pre-somitic mesoderm. Previous mathematical models of the somitogenesis clock that invoke the mechanism of delayed negative feedback predict that its oscillation period depends on the sum of delays inherent to negative-feedback loops and inhibitor half-lives. We develop a mathematical model that explores the possibility that positive feedback also plays a role in determining the period of clock oscillations. The model predicts that increasing the half-life of the positive regulator, Notch intracellular domain (NICD), can lead to elevated NICD levels and an increase in the oscillation period. To test this hypothesis, we investigate a phenotype induced by various small molecule inhibitors in which the clock is slowed. We observe elevated levels and a prolonged half-life of NICD. Reducing NICD production rescues these effects. These data provide the first indication that tight control of the turnover of positive as well as negative regulators of the clock determines its periodicity. DOI: http://dx.doi.org/10.7554/eLife.05842.00

Bioaccumulation and Toxicity of Organic Chemicals in Terrestrial Invertebrates

Terrestrial invertebrates are key components in ecosystems, with crucial roles in soil structure, functioning, and ecosystem services. The present chapter covers how terrestrial invertebrates are impacted by organic chemicals, focusing on up-to-date information regarding bioavailability, exposure routes and general concepts on bioaccumulation, toxicity, and existing models. Terrestrial invertebrates are exposed to organic chemicals through different routes, which are dependent on both the organismal traits and nature of exposure, including chemical properties and media characteristics. Bioaccumulation and toxicity data for several groups of organic chemicals are presented and discussed, attempting to cover plant protection products (herbicides, insecticides, fungicides, and molluscicides), veterinary and human pharmaceuticals, polycyclic aromatic compounds, polychlorinated biphenyls, flame retardants, and personal care products. Chemical mixtures are also discussed bearing in mind that chemicals appear simultaneously in the environment. The biomagnification of organic chemicals is considered in light of the consumption of terrestrial invertebrates as novel feed and food sources. This chapter highlights how science has contributed with data from the last 5 years, providing evidence on bioavailability, bioaccumulation, and toxicity derived from exposure to organic chemicals, including insights into the main challenges and shortcomings to extrapolate results to real exposure scenarios