Fano schemes of lines on singular cubic hypersurfaces and their Picard schemes

To every cubic hypersurface $X$ we associate the parameter space of lines contained in $X$; this is called the Fano scheme of lines on $X$ and denoted $F(X)$. If X admits an isolated singular point of ADE-type, we prove that $F(X)$ admits hypersurface singularities of the same type transversally along the regular part of its singular locus. As was shown by H. Clemens and P. Griffiths, the Albanese variety $\operatorname{Alb}(F(X))$ of the Fano scheme of lines $F(X)$ on a smooth cubic threefold $X$ is isomorphic to the intermediate Jacobian $IJ(X)$ of $X$. G. van der Geer and A. Kouvidakis generalised this result to nodal cubic threefolds, replacing the Albanese variety $\operatorname{Alb}(F(X))$ by the Picard scheme $\operatorname{Pic}^0(F(X))$. We study more generally degenerations of the Picard scheme $\operatorname{Pic}^0(F(X))$ when the smooth cubic threefold $X$ degenerates to a cubic threefold with unique singular point of type $A_k$ and prove that these degenerations define points in Mumford’s partial compactification $\mathcal{A}_5'$ of the moduli space $\mathcal{A}_5$ of principally polarised Abelian varieties of genus five

Updating Probabilistic Knowledge on Condition/Event Nets using Bayesian Networks

The paper extends Bayesian networks (BNs) by a mechanism for dynamic changes to the probability distributions represented by BNs. One application scenario is the process of knowledge acquisition of an observer interacting with a system. In particular, the paper considers condition/event nets where the observer\u27s knowledge about the current marking is a probability distribution over markings. The observer can interact with the net to deduce information about the marking by requesting certain transitions to fire and observing their success or failure. Aiming for an efficient implementation of dynamic changes to probability distributions of BNs, we consider a modular form of networks that form the arrows of a free PROP with a commutative comonoid structure, also known as term graphs. The algebraic structure of such PROPs supplies us with a compositional semantics that functorially maps BNs to their underlying probability distribution and, in particular, it provides a convenient means to describe structural updates of networks

Timing the tides: Genetic control of diurnal and lunar emergence times is correlated in the marine midge Clunio marinus

Background The intertidal zone of seacoasts, being affected by the superimposed tidal, diurnal and lunar cycles, is temporally the most complex environment on earth. Many marine organisms exhibit lunar rhythms in reproductive behaviour and some show experimental evidence of endogenous control by a circalunar clock, the molecular and genetic basis of which is unexplored. We examined the genetic control of lunar and diurnal rhythmicity in the marine midge Clunio marinus (Chironomidae, Diptera), a species for which the correct timing of adult emergence is critical in natural populations. Results We crossed two strains of Clunio marinus that differ in the timing of the diurnal and lunar rhythms of emergence. The phenotype distribution of the segregating backcross progeny indicates polygenic control of the lunar emergence rhythm. Diurnal timing of emergence is also under genetic control, and is influenced by two unlinked genes with major effects. Furthermore, the lunar and diurnal timing of emergence is correlated in the backcross generation. We show that both the lunar emergence time and its correlation to the diurnal emergence time are adaptive for the species in its natural environment. Conclusions The correlation implies that the unlinked genes affecting lunar timing and the two unlinked genes affecting diurnal timing could be the same, providing an unexpectedly close interaction of the two clocks. Alternatively, the genes could be genetically linked in a two-by-two fashion, suggesting that evolution has shaped the genetic architecture to stabilize adaptive combinations of lunar and diurnal emergence times by tightening linkage. Our results, the first on genetic control of lunar rhythms, offer a new perspective to explore their molecular clockwork

A Real-time Impedance-Based Screening Assay for Drug-Induced Vascular Leakage

Vascular leakage is a serious side effect of therapies based on monoclonal antibodies or cytokines which may lead to life-threatening situations. With the steady increase of new drug development programs for large molecules, there is an urgent need for reliable tools to assess this potential liability of new medicines in a rapid and cost-effective manner. Using human umbilical vein endothelial cells (HUVECs) as a model for endothelium, we established an impedance-based assay measuring the integrity of the endothelial cell monolayer in real time. We could demonstrate that the HUVEC monolayer in our system was a relevant model as cells expressed major junctional proteins known to be responsible for maintaining tightness as well as receptors targeted by molecules known to induce vascular leakage in vivo. We assessed the time-dependent loss of barrier function using impedance and confirmed that signals obtained corresponded well to those from standard transwell assays. We assayed a series of reference molecules which led to the expected change of barrier integrity. A nonspecific cytotoxic effect could be excluded by using human fibroblasts as a nonresponder cell line. Finally, we could show reversibility of vascular permeability induced by histamine, IL-1β, or TNF-α by coincubation with established antagonists, further demonstrating relevance of this new model. Taken together, our results suggest that impedance in combination with HUVECs as a specific model can be applied to assess clinically relevant vascular leakage on an in vitro leve

Functional analysis and transcriptional output of the Göttingen minipig genome

In the past decade the Göttingen minipig has gained increasing recognition as animal model in pharmaceutical and safety research because it recapitulates many aspects of human physiology and metabolism. Genome-based comparison of drug targets together with quantitative tissue expression analysis allows rational prediction of pharmacology and cross-reactivity of human drugs in animal models thereby improving drug attrition which is an important challenge in the process of drug development.; Here we present a new chromosome level based version of the Göttingen minipig genome together with a comparative transcriptional analysis of tissues with pharmaceutical relevance as basis for translational research. We relied on mapping and assembly of WGS (whole-genome-shotgun sequencing) derived reads to the reference genome of the Duroc pig and predict 19,228 human orthologous protein-coding genes. Genome-based prediction of the sequence of human drug targets enables the prediction of drug cross-reactivity based on conservation of binding sites. We further support the finding that the genome of Sus scrofa contains about ten-times less pseudogenized genes compared to other vertebrates. Among the functional human orthologs of these minipig pseudogenes we found HEPN1, a putative tumor suppressor gene. The genomes of Sus scrofa, the Tibetan boar, the African Bushpig, and the Warthog show sequence conservation of all inactivating HEPN1 mutations suggesting disruption before the evolutionary split of these pig species. We identify 133 Sus scrofa specific, conserved long non-coding RNAs (lncRNAs) in the minipig genome and show that these transcripts are highly conserved in the African pigs and the Tibetan boar suggesting functional significance. Using a new minipig specific microarray we show high conservation of gene expression signatures in 13 tissues with biomedical relevance between humans and adult minipigs. We underline this relationship for minipig and human liver where we could demonstrate similar expression levels for most phase I drug-metabolizing enzymes. Higher expression levels and metabolic activities were found for FMO1, AKR/CRs and for phase II drug metabolizing enzymes in minipig as compared to human. The variability of gene expression in equivalent human and minipig tissues is considerably higher in minipig organs, which is important for study design in case a human target belongs to this variable category in the minipig. The first analysis of gene expression in multiple tissues during development from young to adult shows that the majority of transcriptional programs are concluded four weeks after birth. This finding is in line with the advanced state of human postnatal organ development at comparative age categories and further supports the minipig as model for pediatric drug safety studies.; Genome based assessment of sequence conservation combined with gene expression data in several tissues improves the translational value of the minipig for human drug development. The genome and gene expression data presented here are important resources for researchers using the minipig as model for biomedical research or commercial breeding. Potential impact of our data for comparative genomics, translational research, and experimental medicine are discussed

Innovative organotypic in vitro models for safety assessment: aligning with regulatory requirements and understanding models of the heart, skin, and liver as paradigms

The development of improved, innovative models for the detection of toxicity of drugs, chemicals, or chemicals in cosmetics is crucial to efficiently bring new products safely to market in a cost-effective and timely manner. In addition, improvement in models to detect toxicity may reduce the incidence of unexpected post-marketing toxicity and reduce or eliminate the need for animal testing. The safety of novel products of the pharmaceutical, chemical, or cosmetics industry must be assured; therefore, toxicological properties need to be assessed. Accepted methods for gathering the information required by law for approval of substances are often animal methods. To reduce, refine, and replace animal testing, innovative organotypic in vitro models have emerged. Such models appear at different levels of complexity ranging from simpler, self-organized three-dimensional (3D) cell cultures up to more advanced scaffold-based co-cultures consisting of multiple cell types. This review provides an overview of recent developments in the field of toxicity testing with in vitro models for three major organ types: heart, skin, and liver. This review also examines regulatory aspects of such models in Europe and the UK, and summarizes best practices to facilitate the acceptance and appropriate use of advanced in vitro models

Beyond using composite measures to analyze the effect of unmet supportive care needs on caregivers’ anxiety and depression

This is the peer reviewed version of the following article: Lambert, S., Hulbert-Williams, N., Belize, E., Ciampi, A. & Girgis, A. (2018). Beyond using composite measures to analyse the effect of unmet supportive care needs on caregiver's anxiety and depression? Psycho-Oncology, 27(6), 1572-1579. http://doi.org/10.1002/pon.4696, which has been published in final form at https://doi.org/10.1002/pon.4696. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Objective: Caregiver research has relied on composite measures (e.g., count) of unmet supportive care needs to determine relationships with anxiety and depression. Such composite measures assume that all unmet needs have a similar impact on outcomes. The purpose of this study is to identify individual unmet needs most associated with caregivers’ anxiety and depression. Methods: 219 Caregivers completed the 44-item Supportive Care Needs Survey and the Hospital Anxiety and Depression scale [minimal clinically important difference (MCID)=1.5] at 6-8 months, 1, 2, 3.5, and 5 years following the patients' cancer diagnosis. The list of needs was reduced using Partial Least Square regression and those with a Variance Importance in Projection > 1 were analyzed using Bayesian Model Averaging. Results: Across time, eight items remained in the top 10 based on prevalence and were labelled “core”. Three additional ones were labelled “frequent”, as they remained in the top 10 from 1- year onwards. Bayesian Model Averaging identified a maximum of four significant unmet needs per time point – all leading to a difference greater than the MCID. For depression, none of the core unmet needs were significant, rather significance was noted for frequent needs and needs that were not prevalent. For anxiety, 3/8 core and 3/3 frequent unmet needs were significant. Conclusions: Prevalent Those unmet needs that are most prevalent are not necessarily the most significant ones, and findings provide an evidence-based framework to guide the development of caregiver interventions. A broader contribution is proposing a different approach to identify significant unmet needs

The neutron and its role in cosmology and particle physics

Experiments with cold and ultracold neutrons have reached a level of precision such that problems far beyond the scale of the present Standard Model of particle physics become accessible to experimental investigation. Due to the close links between particle physics and cosmology, these studies also permit a deep look into the very first instances of our universe. First addressed in this article, both in theory and experiment, is the problem of baryogenesis ... The question how baryogenesis could have happened is open to experimental tests, and it turns out that this problem can be curbed by the very stringent limits on an electric dipole moment of the neutron, a quantity that also has deep implications for particle physics. Then we discuss the recent spectacular observation of neutron quantization in the earth's gravitational field and of resonance transitions between such gravitational energy states. These measurements, together with new evaluations of neutron scattering data, set new constraints on deviations from Newton's gravitational law at the picometer scale. Such deviations are predicted in modern theories with extra-dimensions that propose unification of the Planck scale with the scale of the Standard Model ... Another main topic is the weak-interaction parameters in various fields of physics and astrophysics that must all be derived from measured neutron decay data. Up to now, about 10 different neutron decay observables have been measured, much more than needed in the electroweak Standard Model. This allows various precise tests for new physics beyond the Standard Model, competing with or surpassing similar tests at high-energy. The review ends with a discussion of neutron and nuclear data required in the synthesis of the elements during the "first three minutes" and later on in stellar nucleosynthesis.Comment: 91 pages, 30 figures, accepted by Reviews of Modern Physic