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Mutations in histone H3.3‐encoding genes causing mutant histone tails are associated with specific cancers such as pediatric glioblastomas (H3.3‐G34R/V) and giant cell tumor of the bone (H3.3‐G34W). The mechanisms by which these mutations promote malignancy are not completely understood. Here we show that cells expressing H3.3‐G34W exhibit DNA double‐strand breaks (DSBs) repair defects and increased cellular sensitivity to ionizing radiation (IR). Mechanistically, H3.3‐G34W can be deposited to damaged chromatin, but in contrast to wild‐type H3.3, does not interact with non‐homologous end‐joining (NHEJ) key effectors KU70/80 and XRCC4 leading to NHEJ deficiency. Together with defective cell cycle checkpoints reported previously, this DNA repair deficiency in H3.3‐G34W cells led to accumulation of micronuclei and cytosolic DNA following IR, which subsequently led to activation of the cyclic GMP‐AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immune‐stimulatory cytokines. These findings suggest a potential for radiotherapy for tumors expressing H3.3‐G34W, which can be further improved by combination with STING agonists to induce immune‐mediated therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Electron attachment to CF3Cl clusters has been studied mass spectrometrically in a beam experiment. In addition to the fragments known from dissociative attachment to the isolated compound (F-, Cl-, etc.), a veriety of larger complexes such as M-n, Mn·Cl-, Mn·F-, n≥1 (M=CF3Cl) could be observed. The resonance profiles of the ion yield curves suggest that the initial step of electron capture proceeds via the formation of a temporary CF3Cl- ion within the target aggregate followed by different decomposition reactions. Among the various products, the parent radical anion (CF3Cl-) is generated in its relaxed configuration not accessible in electron capture by the isolated molecule. A time-of-flight (TOF) analysis of the Cl- products reveals two decay channels, one associated with high excess translational energy and a second releasing the Cl- ion with only thermal energy. [ABSTRACT FROM AUTHOR]

Dissociative electron attachment by methanol, different deuterated methanols, and allylalcohol is studied including an analysis of the translational excess energy release of the ionic fragments. Although the energetic threshold for negative ion formation (OH-, O-) is near 2 eV, these ions are generated in methanol only within a prominent resonance at 10.5 eV. OH- and OD- formation is characterized by hydrogen scrambling in the temporary parent ion while the formation of CH3O- (and the deuterated analog) proceeds directly (no hydrogen scrambling). Only O- is generated with considerable translational excess energy (1.0±0.2 eV). In contrast to methanol, allylalcohol captures electrons at 1.7 eV to form OH- and the enolate anion (M–H)-. This resonance is interpreted as a Π radical anion comparable to that known in ethylene. [ABSTRACT FROM AUTHOR]

Inhibitors of DNA methyltransferases (DNMTis) or histone deacetylases (HDACis) are epigenetic drugs which are investigated since decades. Several have been approved and are applied in the treatment of hematopoietic and lymphatic malignancies, although their mode of action has not been fully understood. Two recent findings improved mechanistic insights: i) activation of human endogenous retroviral elements (HERVs) with concomitant synthesis of double-stranded RNAs (dsRNAs), and ii) massive activation of promoters from long terminal repeats (LTRs) which originated from past HERV invasions. These dsRNAs activate an antiviral response pathway followed by apoptosis. LTR promoter activation leads to synthesis of non-annotated transcripts potentially encoding novel or cryptic proteins. Here, we discuss the current knowledge of the molecular effects exerted by epigenetic drugs with a focus on DNMTis and HDACis. We highlight the role in LTR activation and provide novel data from both in vitro and in vivo epigenetic drug treatment. [ABSTRACT FROM AUTHOR]

Recent findings for a young (31.5 ± 0.7 Ma) age of high-pressure metamorphism at ∼90 km depths in the Eclogite Zone of the Tauern Window, Eastern Alps, prompt the question about the timing of the structural development of the Tauern Window and its relation to high-pressure metamorphism. We show that all major structures in the Tauern Window, resulting from strong N-S lithospheric shortening and simultaneous minor E-W extension, began developing coevally with high-pressure metamorphism in the Eclogite Zone. Large-scale strike-slip shear zones started to form at ∼32-30 Ma and facilitated the spatial accommodation of simultaneous shortening and extension. At least some of the strike-slip and extensional shear zones operated into the Middle Miocene, either continuously or intermittently, with pronounced activity at ∼21-15 Ma. The considerable exhumation of the Eclogite Zone from ∼90 km depths into the middle crust, and the tectonic development of its framework occurred within only 1-2 Ma after eclogitization. This is evidenced by almost identical ages for eclogite facies metamorphism and for the development of the major structures that bound the Eclogite Zone under blueschist- and greenschist facies metamorphic conditions. We discuss a tectonic model in which considerable transpressional shortening and thickening took place in the present central-southern part of the Tauern Window. We propose that the Tauern Window nucleated here and that most of the regional deformation at ∼32-30 Ma is today found at the periphery of the window and in the adjacent Austroalpine units. Afterward, transpression continued, the window grew to the E, W, and N, and deformation progressed to those parts of the window. Ductile deformation in the present-day surface level ceased at ∼15 Ma. [ABSTRACT FROM AUTHOR]

We identified a transcription factor of the onecut class in the sea urchin Strongylocentrotus purpuratus that represents an ortholog of the mammalian gene HNF6, the founding member of the onecut class of proteins. The isolated sea urchin gene, named SpOnecut, encodes a protein of 483 amino acids with one cut domain and a homeodomain. Phylogenetic analysis clearly places the sea urchin gene into this family, most closely related to the ascidian onecut gene HNF-6. Nevertheless, phylogenetic analysis reveals a difficult phylogeny indicating that certain members of the family evolve more rapidly than others and also that the cut domain and homeodomain evolve at a different pace. In fly, worm, ascidian, and teleost fish, the onecut genes isolated so far are exclusively expressed in cells of the central nervous system (CNS), whereas in mammals the two copies of the gene have acquired additional functions in liver and pancreas development. In the sea urchin embryo, expression is first detected in the emerging ciliary band at the late blastula stage. During the gastrula stage, expression is limited to the ciliary band. In the early pluteus stage, SpOnecut is expressed at the apical organ and the elongating arms but continues most prominently in the ciliary band. This is the first gene known that exclusively marks the ciliary band and therein the apical organ in a pluteus larva, whereas chordate orthologs execute essential functions in dorsal CNS development. The significance of this finding for the hypothesis that the ciliary bands and apical organs of the hypothetical “dipleurula”-like chordate ancestor and the chordate/vertebrate CNS are of common origin is discussed. [ABSTRACT FROM AUTHOR]

Petrological and isotopic (Rb-Sr, Sm-Nd and U-Pb) investigations of garnet bearing pegmatites and trondhjemites in the northernmost Lindås Nappe, Bergen Arcs, Norway are reported. The formation of these pegmatites (sample sites Håjerringa and Ervik) is dated to around 425 Ma by means of Rb/Sr and Sm/Nd mineral isochrons. U-Pb dating of zircons from a trondhjemitic dyke (sample site Fonnes quay) yields a lower intercept age of 418 ± 9 Ma. Based on field observations, negative εNd values and a comparatively high initial 87sr/86sr for the Håkjerringa pegmatite, we suggest a crustal-anatectic source for the pegmatite-forming melts. The ages are interpreted to represent the time of crystallization of the granitic melts at mid-crustal levels (8-10 kbar, 650 to 700 °C). The partial melts formed due to the addition of a fluid phase that lowered the solidus of the rocks during a major phase of Scandian deformation in the Lindås Nappe. Fluid mediated edogitization (17 kbar, 700 °C) took place in the western part (Holsnøy), contemporaneously with the formation of the granitoid dykes. This either means very rapid exhumation from depths corresponding to 17 kbars to 10 kbars. Or, and more likely, that the Lindås Nappe represents a part of a former crustal section where the bottom parts (Holsnøy) and the shallower north-eastern parts (Lindås-Austrheim) experienced hydration at the same time. [ABSTRACT FROM AUTHOR]

Abstract: The oral–aboral (OA) axis in the sea urchin is specified by the TGFβ family members Nodal and BMP2/4. Nodal promotes oral specification, whereas BMP2/4, despite being expressed in the oral territory, is required for aboral specification. This study explores the role of Chordin (Chd) during sea urchin embryogenesis. Chd is a secreted BMP inhibitor that plays an important role in axial and neural specification and patterning in Drosophila and vertebrate embryos. In Lytechinus variegatus embryos, Chd and BMP2/4 are functionally antagonistic. Both are expressed in overlapping domains in the oral territory prior to and during gastrulation. Perturbation shows that, surprisingly, Chd is not involved in OA axis specification. Instead, Chd is required both for normal patterning of the ciliary band at the OA boundary and for development of synaptotagmin B-positive (synB) neurons in a manner that is reciprocal with BMP2/4. Chd expression and synB-positive neural development are both downstream from p38 MAPK and Nodal, but not Goosecoid. These data are summarized in a model for synB neural development. [Copyright &y& Elsevier]

Purpose:  To utilize 4 D flow MRI to acquire normal values of "conventional 2 D flow MRI parameters" in healthy volunteers in order to replace multiple single 2 D flow measurements with a single 4 D flow acquisition., Materials and Methods:  A kt-GRAPPA accelerated 4 D flow sequence was used. Flow volumes were assessed by forward (FFV), backward (BFV), and net flow volumes (NFV) [ml/heartbeat] and flow velocities by axial (VAX) and absolute velocity (VABS) [m/s] in 116 volunteers (58 females, 43 ± 13 years). The aortic regurgitant fraction (RF) was calculated., Results:  The sex-neutral mean FFV, BFV, NFV, and RF in the ascending aorta were 93.5 ± 14.8, 3.6 ± 2.8, 89.9 ± 0.6 ml/heartbeat, and 3.9 ± 2.9 %, respectively. Significantly higher values were seen in males regarding FFV, BFV, NFV and RF, but there was no sex dependency regarding VAX and VABS. The mean maximum VAX was lower (1.01 ± 0.31 m/s) than VABS (1.23 ± 0.35 m/s). We were able to determine normal ranges for all intended parameters., Conclusion:  This study provides quantitative 4 D flow-derived thoracic aortic normal values of 2 D flow parameters in healthy volunteers. FFV, BFV, NFV, and VAX did not differ significantly from single 2 D flow acquisitions and could therefore replace time-consuming multiple single 2 D flow acquisitions. VABS should not be used interchangeably., Key Points:   · 4 D flow MRI can be used to replace 2 D flow MRI measurements.. · The parameter absolute velocities can be assessed by 4 D flow MRI.. · There are sex-dependent differences regarding forward, backward, net aortic blood flow and the aortic valve regurgitant fraction.., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Interdisciplinary, patient-specific cooperation between orthodontics and speech therapy plays an important role in the therapy of myofunctional dysfunctions. The following orthodontic-logopedic screening procedure is intended to objectify the diagnosis of such dysfunctions and the progress of therapy. A diagnostic questionnaire was prepared based on existing diagnostic questionnaires for myofunctional dysfunction. It contains 32 questions, with a clinical weighting of 0 to 50 points in total. This results in a point score. The lower the score is, the lower the need for therapy is. The study included 108 patients between the ages of 6 and 50 years. After screening, the patient population was divided into Group 0 (score < 15; no speech therapy need; n = 36) and Group 1 (score ≥ 15; a speech therapy need; n = 72). Group 1 was additionally randomized into Subgroups A (with speech therapy; n = 36) and B (without speech therapy; n = 36). After a treatment interval of 6 months, all patients in Group 1 were examined again with the help of the screening procedure. Statistical analysis (SPSS) and significance testing (Mann-Whitney U test) were performed. At baseline, there was no significant difference between patients in Subgroups A and B ( p = 0.157). Subgroup A had a median score of 25, and Subgroup B had a median score of 30. However, after the treatment interval, a significant improvement ( p = 0.001) for Subgroup A with a median score of 11 (mean score difference = 14.67) over Subgroup B with a median score 23 (mean score difference of 7.08) was observed. The developed screening procedure was shown to be equally applicable to all patients and treatment providers. With the help of the scores in point form, the need for speech therapy and the progress of such therapy can be objectified.

Molecular medicine is undergoing fundamental changes driving the whole area towards a revolution in modern medicine. The breakthrough was generated the fast-developing technologies in molecular biology since the first draft sequence of the human genome was published. The technological advances enabled the analysis of biological samples from cells and organs to whole organisms in a depth that was not possible before. These technologies are increasingly implemented in the medical and health care system to study diseases and refine diagnostics. As a consequence, the understanding of diseases and the health status of an individual patient is now based on an enormous amount of data that can only be interpreted in the context of the body as a whole. Systems biology as a new field in the life sciences develops new approaches for data integration and interpretation. Systems medicine as a specialized aspect of systems biology combines in an interdisciplinary approach all expertise necessary to decipher the human body in all its complexity. This created new challenges in the area of information and communication technologies to provide the infrastructure and technology needed to cope with the data flood that will accompany the next generation of medicine. The new initiative 'IT Future of Medicine' aims at driving this development even further and integrates not only molecular data (especially genomic information), but also anatomical, physiological, environmental, and lifestyle data in a predictive model approach-the 'virtual patient'-that will allow the clinician or the general practitioner to predict and anticipate the optimal treatment for the individual patient. The application of the virtual patient model will allow truly personalized medicine.

Background: Gene Regulatory Networks (GRNs) control the differentiation, specification and function of cells at the genomic level. The levels of interactions within large GRNs are of enormous depth and complexity. Details about many GRNs are emerging, but in most cases it is unknown to what extent they control a given process, i.e. the grade of completeness is uncertain. This uncertainty stems from limited experimental data, which is the main bottleneck for creating detailed dynamical models of cellular processes. Parameter estimation for each node is often infeasible for very large GRNs. We propose a method, based on random parameter estimations through Monte-Carlo simulations to measure completeness grades of GRNs., Results: We developed a heuristic to assess the completeness of large GRNs, using ODE simulations under different conditions and randomly sampled parameter sets to detect parameter-invariant effects of perturbations. To test this heuristic, we constructed the first ODE model of the whole sea urchin endomesoderm GRN, one of the best studied large GRNs. We find that nearly 48% of the parameter-invariant effects correspond with experimental data, which is 65% of the expected optimal agreement obtained from a submodel for which kinetic parameters were estimated and used for simulations. Randomized versions of the model reproduce only 23.5% of the experimental data., Conclusion: The method described in this paper enables an evaluation of network topologies of GRNs without requiring any parameter values. The benefit of this method is exemplified in the first mathematical analysis of the complete Endomesoderm Network Model. The predictions we provide deliver candidate nodes in the network that are likely to be erroneous or miss unknown connections, which may need additional experiments to improve the network topology. This mathematical model can serve as a scaffold for detailed and more realistic models. We propose that our method can be used to assess a completeness grade of any GRN. This could be especially useful for GRNs involved in human diseases, where often the amount of connectivity is unknown and/or many genes/interactions are missing.

Modeling of specification events during development poses new challenges to biochemical modeling. These include data limitations and a notorious absence of homeostasis in developing systems. The sea urchin is one of the best studied model organisms concerning development and a network, the Endomesoderm Network, has been proposed that is presumed to control endoderm and mesoderm specification in the embryo of Strongy-locentrotus purpuratus. We have constructed a dynamic model of a subnetwork of the Endomesoderm Network. In constructing the model, we had to resolve the following issues: choice of appropriate subsystem, assignment of embryonic data to cellular model, choice of appropriate kinetics. Although the resulting model is capable of reproducing fractions of the experimental data, it falls short of reproducing specification of cell types. These findings can facilitate the refinement of the Endomesoderm Network.

Background: The genome of the sea urchin Strongylocentrotus purpuratus has recently been sequenced because it is a major model system for the study of gene regulatory networks. Embryonic expression patterns for most genes are unknown, however., Results: Using large-scale screens on arrays carrying 50% to 70% of all genes, we identified novel territory-specific markers. Our strategy was based on computational selection of genes that are differentially expressed in lithium-treated embryos, which form excess endomesoderm, and in zinc-treated embryos, in which endomesoderm specification is blocked. Whole-mount in situ hybridization (WISH) analysis of 700 genes indicates that the apical organ region is eliminated in lithium-treated embryos. Conversely, apical and specifically neural markers are expressed more broadly in zinc-treated embryos, whereas endomesoderm signaling is severely reduced. Strikingly, the number of serotonergic neurons is amplified by at least tenfold in zinc-treated embryos. WISH analysis further indicates that there is crosstalk between the Wnt (wingless int), Notch, and fibroblast growth factor signaling pathways in secondary mesoderm cell specification and differentiation, similar to signaling cascades that function during development of presomitic mesoderm in mouse embryogenesis. We provide differential expression data for more than 4,000 genes and WISH patterns of more than 250 genes, and more than 2,400 annotated WISH images., Conclusion: Our work provides tissue-specific expression patterns for a large fraction of the sea urchin genes that have not yet been included in existing regulatory networks and await functional integration. Furthermore, we noted neuron-inducing activity of zinc on embryonic development; this is the first observation of such activity in any organism.