Translational genetic modelling of 3D craniofacial dysmorphology: elaborating the facial phenotype of neurodevelopmental disorders through the prism of schizophrenia

Purpose of Review: In the context of human developmental conditions, we review the conceptualisation of schizophrenia as a neurodevelopmental disorder, the status of craniofacial dysmorphology as a clinically accessible index of brain dysmorphogenesis, the ability of genetically modified mouse models of craniofacial dysmorphology to inform on the underlying dysmorphogenic process and how geometric morphometric techniques in mutant mice can extend quantitative analysis. Recent Findings: Mutant mice with disruption of neuregulin-1, a gene associated meta-analytically with risk for schizophrenia, constitute proof-of-concept studies of murine facial dysmorphology in a manner analogous to clinical studies in schizophrenia. Geometric morphometric techniques informed on the topography of facial dysmorphology and identified asymmetry therein. Summary: Targeted disruption in mice of genes involved in individual components of developmental processes and analysis of resultant facial dysmorphology using geometric morphometrics can inform on mechanisms of dysmorphogenesis at levels of incisiveness not possible in human subjects

Narrowband spectroscopy by all-optical correlation of broadband pulses

High peak power ultrafast lasers are widely used in nonlinear spectroscopy but often limit its spectral resolution because of the broad frequency bandwidth of ultrashort laser pulses. Improving the resolution by achieving spectrally narrow excitation of, or emission from, the resonant medium by means of multi-photon interferences has been the focus of many recent developments in ultrafast spectroscopy. We demonstrate an alternative approach, in which high resolution is exercised by detecting narrow spectral correlations between broadband excitation and emission optical fields. All-optical correlation analysis, easily incorporated into the traditional spectroscopic setup, enables direct, robust and simultaneous detection of multiple narrow resonances with a single femtosecond pulse.Comment: 5 pages, 4 figures, submitted to PR

Biological Characteristics of Colon Cancer Cells in In Vitro Models and its Use for Individualization of Therapy

Zhoubné nádory patří celosvětově na druhé místo mezi příčinami úmrtí hned po kardiovaskulárních onemocněních. Trend se ale zvláště v rozvinutých zemích (dle Světové zdravotnické organizace, WHO - World Health Organization) vyrovnává, v některých oblastech se dokonce diagnóza zhoubného novotvaru dostala již na místo první.(Ferlay 2012) Protože se rakovina stala ve dvacátém století závažným celosvětovým socioekonomickým problémem, patří její výzkum ve spolupráci s Mezinárodní agenturou k výzkumu rakoviny (IARC - International Agency for Research on Cancer) k prioritám WHO. (Mendis 2014) Incidence stále roste, a to jak relativně, tak absolutně, což je dáno, mimo jiné, celkovým stárnutím populace a zvyšováním průměrného věku obyvatel. Protože se k hlavním prognostickým faktorům výskytu nádorových onemocnění řadí věk, mají tak lidé větší šanci se nádorového onemocnění "dožít". Zlepšily se i možnosti diagnostiky, a tak je mnoho nádorů odhaleno již v časných stádiích, což zpětně zlepšuje možnosti a úspěšnost léčby. K tomu přispívá i zavedení některých screeningových vyšetření do běžné zdravotní praxe (např. mamografie, prostatický specifický antigen, test okultního krvácení nebo koloskopie) a s tím spojená osvěta v běžné populaci. (Dušek et al. 2005; Mendis 2014) V neposlední řadě se za posledních 15 až...Malignant tumours are the second most common cause of death worldwide right behind the cardiovascular diseases. This tendency is by the opinion of the World Health Organisation increasing especially in well developed countries. (Ferlay 2012) Because cancer has become in 20th century serious social and economic problem, research on it is for WHO and IARC (International Agency for Research on Cancer) the top priority. (Mendis 2014) Relative and absolute incidence is also rising. The reason, besides others, is aging of population. Because age is one of the main prognostic factors for cancer, people are more likely to "survive" till the onset of it. However, diagnostic options are improved and many tumours are detected in early stage which in turn boosts the ability and effectiveness of treatment. Screening programmes are introduced into routine medical practice (e.g. mammography, prostate-specific antigene, occult blood testing or colonoscopy) inducing awareness in the general population. (Dušek et al. 2005; Mendis 2014) Last but not least, the treatment itself has developed considerably over the last 15 to 20 years, with the focus on patient "tailor-made" therapy. It includes new mini-invasive or robot-assisted surgical techniques, new radiation techniques (IG-IMRT - Image-Guided Intensity-Modulated...Ústav lékařské biologie a genetikyDepartment of Medical Biology and GeneticsLékařská fakulta v Hradci KrálovéFaculty of Medicine in Hradec Králov

Numerical Modeling of Self-Propagating Polymerization Fronts: The Role of Kinetics on Front Stability

Frontal propagation of a highly exothermic polymerization reaction in a liquid is studied with the goal of developing a mathematical model of the process. As a model case we consider monomers such as methacrylic acid and n-butyl acrylate with peroxide initiators, although the model is not limited to these reactants and can be applied to any system with the similar basic polymerization mechanism. A three-step reaction mechanism, including initiation, propagation and termination steps, as well as a more simple one-step mechanism, were considered. For the one-step mechanism the loss of stability of propagating front was observed as a sequence of period doubling bifurcations of the front velocity. It was shown that the one-step model cannot account for less than 100% conversion and product inhomogeneities as a result of front instability, therefore the three-step mechanism was exploited. The phenomenon of superadiabatic combustion temperature was observed beyond the Hopf bifurcation point for both kinetic schemes and supported by the experimental measurements. One- and two-dimensional numerical simulations were performed to observe various planar and nonplanar periodic modes, and the results for different kinetic schemes were compared. It was found that stability of the frontal mode for a one-step reaction mechanism does not differ for 1-D and 2-D cases. For the three-step reaction mechanism 2-D solutions turned out to be more stable with respect to the appearance of nonplanar periodic modes than corresponding 1-D solutions. Higher Zeldovich numbers (i.e., higher effective activation energies or lower initial temperatures) are necessary for the existence of planar and nonplanar periodic modes in the 2-D reactor with walls than in the 1-D case

Quasi-Materials and the Making of Interior Atmospheres

In The Architecture of the Well-Tempered Environment, Reyner Banham presents a parable in which, having come across an amount of wood, a nomadic tribe must decide how to use it to keep warm overnight: build a structure or build a fire (and burn the wood as fuel). The first of these uses the materials directly to create an amenable interior condition using the tangible materiality of geometric construction. The second, however, generates heat from combustion, thereby creating an intangible, graduated, thermal interiority, which one can draw deeper into, by moving closer to the fire, or recede from, by moving away. Interior architecture has largely been concerned with achieving shelter and creating an interior atmosphere through the dependability and predictability of physical materials. Less often has interior architecture considered the interiority achieved through the temporal contingency of atmospheric quasi-materials (taking a cue from Tonino Griffero’s quasithings), phenomena such as light, sound, temperature, and humidity. While these often strike one as outside of the realm of designers, their effects profoundly colour our experiences of our environments: the smells of street food, the heat of the metro air exhaust, the veil of fog rolling in. A selection of student projects probing quasi-materials in interior architecture reveals their nature and potential for making interior environments. More akin to building a fire than fitting out a shell, these projects question existing tenets of interior architecture, while they enable types of interiority that are fluid, graduated and temporal

Exoplanet Catalogues

One of the most exciting developments in the field of exoplanets has been the progression from 'stamp-collecting' to demography, from discovery to characterisation, from exoplanets to comparative exoplanetology. There is an exhilaration when a prediction is confirmed, a trend is observed, or a new population appears. This transition has been driven by the rise in the sheer number of known exoplanets, which has been rising exponentially for two decades (Mamajek 2016). However, the careful collection, scrutiny and organisation of these exoplanets is necessary for drawing robust, scientific conclusions that are sensitive to the biases and caveats that have gone into their discovery. The purpose of this chapter is to discuss and demonstrate important considerations to keep in mind when examining or constructing a catalogue of exoplanets. First, we introduce the value of exoplanetary catalogues. There are a handful of large, online databases that aggregate the available exoplanet literature and render it digestible and navigable - an ever more complex task with the growing number and diversity of exoplanet discoveries. We compare and contrast three of the most up-to-date general catalogues, including the data and tools that are available. We then describe exoplanet catalogues that were constructed to address specific science questions or exoplanet discovery space. Although we do not attempt to list or summarise all the published lists of exoplanets in the literature in this chapter, we explore the case study of the NASA Kepler mission planet catalogues in some detail. Finally, we lay out some of the best practices to adopt when constructing or utilising an exoplanet catalogue.Comment: 14 pages, 6 figures. Invited review chapter, to appear in "Handbook of Exoplanets", edited by H.J. Deeg and J.A. Belmonte, section editor N. Batalh

Factors Affecting the Adoption of Peer Instruction in Computing Courses

Peer Instruction (PI) as defined by Mazur, and variations on this pedagogic technique, have been in use in computing courses for about a decade. Despite dozens of educational research publications documenting positive learning effects, improved retention, student acceptance, and effectiveness for large classes; PI does not appear to be widely adopted for computing courses. This paper reports on a three-way investigation into this apparent contradiction. First, the authors reflect on their own adoption, practice, experience, and abandonment of the use of PI in computing courses. Second, we surveyed the literature regarding the use of PI in computing courses and present a summary of the research findings, variations, and extensions to PI used in computing courses. Third, a survey of computing instructors was conducted to gauge the attitude toward PI in computing courses. To add context, this report considers publications documenting usage of PI in STEM courses, and the adoption of other pedagogic techniques in computing. Particular effort was made to identify the reasons computing instructors don’t adopt PI. This report also includes advice to instructors considering adopting PI in computing courses

The most reactive amide as a transition-state mimic for cis-trans interconversion.

1-Azatricyclo[3.3.1.1(3,7)]decan-2-one (3), the parent compound of a rare class of 90°-twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed cis-trans rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making 3 by some way the most reactive known "amide".Financial assistance from Enamine Ltd. (www.enamine.net) is gratefully acknowledged. We also thank Dr. V. Stepanenko for valuable advice and encouragement which helped to find the nonstandard solutions to the synthetic problems, and Vitaliy Bilenko for drawing our attention to the instructive EI mass spectrum of compound 8.This is the final published version of the article, originally published in the Journal of the American Chemical Society, 2015, 137 (2), pp 926–93, DOI: 10.1021/ja511460

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer

Despite distant metastases being the critical factor affecting patients' survival, they remain poorly understood. Our study thus aimed to molecularly characterize colorectal cancer liver metastases (CRCLMs) and explore whether molecular profiles differ between Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. This characterization was performed by whole exome sequencing, whole transcriptome, whole methylome, and miRNAome. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. Among the differently methylated and expressed genes were those involved in cell adhesion, extracellular matrix organization and degradation, neuroactive ligand-receptor interaction. The top up-regulated microRNAs were hsa-miR-135b-3p and -5p, and the hsa-miR-200-family while the hsa-miR-548-family belonged to the top down-regulated. MmCRC patients evinced higher tumor mutational burden, a wider median of duplications and deletions, and a heterogeneous mutational signature than SmCRC. Regarding chronicity, a significant down-regulation of SMOC2 and PPP1R9A genes in SmCRC compared to MmCRC was observed. Two miRNAs were deregulated between SmCRC and MmCRC, hsa-miR-625-3p and has-miR-1269-3p. The combined data identified the IPO5 gene. Regardless of miRNA expression levels, the combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signaling pathways, and intracellular second messenger signaling. The intersection between our and validation sets confirmed the validity of our results. We have identified genes and pathways that may be considered as actionable targets in CRCLMs. Our data also provide a valuable resource for understanding molecular distinctions between SmCRC and MmCRC. They have the potential to enhance the diagnosis, prognostication, and management of CRCLMs by a molecularly targeted approach