Collagens - structure, function and biosynthesis.

The extracellular matrix represents a complex alloy of variable members of diverse protein families defining structural integrity and various physiological functions. The most abundant family is the collagens with more than 20 different collagen types identified so far. Collagens are centrally involved in the formation of fibrillar and microfibrillar networks of the extracellular matrix, basement membranes as well as other structures of the extracellular matrix. This review focuses on the distribution and function of various collagen types in different tissues. It introduces their basic structural subunits and points out major steps in the biosynthesis and supramolecular processing of fibrillar collagens as prototypical members of this protein family. A final outlook indicates the importance of different collagen types not only for the understanding of collagen-related diseases, but also as a basis for the therapeutical use of members of this protein family discussed in other chapters of this issue

Calculation of mechanical and thermal influences during coiling of hot strip

Coiled steel strip is the final product from flat hot rolling processes. With increasing demand for higher quality of hot rolled strips, especially the evolution of strip flatness during and after coiling becomes a crucial aspect. The main impacts on the flatness properties of hot rolled strips result from residual stresses and “eigen-strains” induced by the last hot rolling passes, by strip cooling at the run-out table, and finally, by the mechanical and thermal conditions during and after the coiling process itself. In this paper, a mathematical model is presented, which takes into account the mechanical and thermal effects on hot rolled strip during and after the coiling process. To improve the prediction quality of the underlying process, a customized self-developed 3D finite-element model has been developed and programmed in C++, leading to a software prototype, which is highly superior to commercial FEM-packages with respect to calculation time and storage capacities. The model is based on a dynamic implicit total Lagrangian formulation. All relevant devices directly interacting with the strip, such as pinch rolls, coiler rolls and mandrel are incorporated in the calculation model. Well known and established methods in the solid-shell theory, like the EAS- and ANS-method, were applied to prevent the occurrence of locking phenomena resulting from low order interpolation functions. Selected benchmark tests were performed to evaluate the accuracy of these novel solid-shell elements in comparison to the results attained by the FEM- package ABAQUS©. The results obtained so far agree very satisfactorily. A further important topic is the contact and friction algorithm, where Coulomb’s friction law is applied. The accurate and reliable determination of the contact between strip and interacting devices as well as the aspect of self-contact was treated by applying a sophisticated two dimensional contact search algorithm, leading to a significantly reduced calculation time. The highly non-linear time-dependent system of equations is integrated by utilizing the (implicit) Newmark time-integration scheme. The developed calculation model serves as an effective tool to predict the interesting stress-distributions and local plastic deformations inside the strip, which induce residual stresses and strip unflatness (latent or even manifest waviness). Furthermore, this tool p ovides the basis for further improvements and investigations on hot rolling production lines

Biofabrication using recombinant spider silk proteins as a biomaterial

Biofabrication for applications in regenerative medicine is a rapidly expanding field. Remarkable about this approach compared to traditional approaches is its feasibility for larger scale production at high quality and reproducibility. However, there is a lack of process-compatible materials for biofabrication due to the need for mild, aqueous processing conditions. More specifically, the solvents used must have neutral pH, and salts in proper osmolality, temperatures used cannot be too high or low, and so forth. The recombinant spider-silk protein eADF4(C16) (engineered Araneus diadematus fibroin 4) is biocompatible, biodegradable and hypoallergenic and can be provided in large quantities with consistent material qualities. In order to overcome limitations in terms of cell adhesion and proliferation e.g. the integrin recognition sequence RGD was genetically introduced. eADF4(C16) and its variants can be fabricated into various types of scaffold. Morphologies produced from recombinant spider silk proteins include films, foams, fibers, particles, microcapsules and hydrogels. However, with the exception of thermally-gelled hydrogels, the established processes are not cytocompatible due to extreme physical (e.g. high voltages, high salt concentration) and/or chemical (e.g. toxic solvents) conditions. Thereby, current research with these recombinant proteins focuses on utilizing thermally-gelled hydrogel as bioinks to be used in biofabrication and optimizing current processing protocols for other morphologies to be cell-friendly

Plantar Erythrodysesthesia Caused by Antiretroviral Treatment: A Case Report and Review of the Literature

Palmoplantar erythrodysesthesia is an uncommon localised cutaneous reaction to certain chemotherapeutic agents and characterized by painful palmoplantar erythema and dysesthesia. To the best of our knowledge, we report the first case of plantar erythrodysesthesia in a 40-year-old male patient receiving an antiretroviral combination therapy for HIV

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs)

The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis

Post-transcriptional mechanisms have the potential to influence complex changes in gene expression, yet their role in cell fate transitions remains largely unexplored. Here, we show that suppression of the RNA helicase DDX6 endows human and mouse primed embryonic stem cells (ESCs) with a differentiation-resistant, “hyper-pluripotent” state, which readily reprograms to a naive state resembling the preimplantation embryo. We further demonstrate that DDX6 plays a key role in adult progenitors where it controls the balance between self-renewal and differentiation in a context-dependent manner. Mechanistically, DDX6 mediates the translational suppression of target mRNAs in P-bodies. Upon loss of DDX6 activity, P-bodies dissolve and release mRNAs encoding fate-instructive transcription and chromatin factors that re-enter the ribosome pool. Increased translation of these targets impacts cell fate by rewiring the enhancer, heterochromatin, and DNA methylation landscapes of undifferentiated cell types. Collectively, our data establish a link between P-body homeostasis, chromatin organization, and stem cell potency

The strong thirteen spheres problem

The thirteen spheres problem is asking if 13 equal size nonoverlapping spheres in three dimensions can touch another sphere of the same size. This problem was the subject of the famous discussion between Isaac Newton and David Gregory in 1694. The problem was solved by Schutte and van der Waerden only in 1953. A natural extension of this problem is the strong thirteen spheres problem (or the Tammes problem for 13 points) which asks to find an arrangement and the maximum radius of 13 equal size nonoverlapping spheres touching the unit sphere. In the paper we give a solution of this long-standing open problem in geometry. Our computer-assisted proof is based on a enumeration of the so-called irreducible graphs.Comment: Modified lemma 2, 16 pages, 12 figures. Uploaded program packag

Illuminating spindle convex bodies and minimizing the volume of spherical sets of constant width

A subset of the d-dimensional Euclidean space having nonempty interior is called a spindle convex body if it is the intersection of (finitely or infinitely many) congruent d-dimensional closed balls. The spindle convex body is called a "fat" one, if it contains the centers of its generating balls. The core part of this paper is an extension of Schramm's theorem and its proof on illuminating convex bodies of constant width to the family of "fat" spindle convex bodies.Comment: 17 page

Calculation of some determinants using the s-shifted factorial

Several determinants with gamma functions as elements are evaluated. This kind of determinants are encountered in the computation of the probability density of the determinant of random matrices. The s-shifted factorial is defined as a generalization for non-negative integers of the power function, the rising factorial (or Pochammer's symbol) and the falling factorial. It is a special case of polynomial sequence of the binomial type studied in combinatorics theory. In terms of the gamma function, an extension is defined for negative integers and even complex values. Properties, mainly composition laws and binomial formulae, are given. They are used to evaluate families of generalized Vandermonde determinants with s-shifted factorials as elements, instead of power functions.Comment: 25 pages; added section 5 for some examples of application

volumetric characterisation and correlation to established classification systems

Objective and sensitive assessment of cartilage repair outcomes lacks suitable methods. This study investigated the feasibility of 3D ultrasound biomicroscopy (UBM) to quantify cartilage repair outcomes volumetrically and their correlation with established classification systems. 32 sheep underwent bilateral treatment of a focal cartilage defect. One or two years post- operatively the repair outcomes were assessed and scored macroscopically (Outerbridge, ICRS-CRA), by magnetic resonance imaging (MRI, MOCART), and histopathology (O'Driscoll, ICRS-I and ICRS-II). The UBM data were acquired after MRI and used to reconstruct the shape of the initial cartilage layer, enabling the estimation of the initial cartilage thickness and defect volume as well as volumetric parameters for defect filling, repair tissue, bone loss and bone overgrowth. The quantification of the repair outcomes revealed high variations in the initial thickness of the cartilage layer, indicating the need for cartilage thickness estimation before creating a defect. Furthermore, highly significant correlations were found for the defect filling estimated from UBM to the established classification systems. 3D visualisation of the repair regions showed highly variable morphology within single samples. This raises the question as to whether macroscopic, MRI and histopathological scoring provide sufficient reliability. The biases of the individual methods will be discussed within this context. UBM was shown to be a feasible tool to evaluate cartilage repair outcomes, whereby the most important objective parameter is the defect filling. Translation of UBM into arthroscopic or transcutaneous ultrasound examinations would allow non-destructive and objective follow-up of individual patients and better comparison between the results of clinical trials