Anatomy, biology, physiology and basic pathology of the nail organ

The nail is the largest skin appendage. It grows continuously through life in a non-cyclical manner; its growth is not hormone-dependent. The nail of the middle finger of the dominant hand grows fastest with approximately 0.1 mm/day, whereas the big toe nail grows only 0.03-0.05 mm/d. The nails' size and shape vary characteristically from finger to finger and from toe to toe, for which the size and shape of the bone of the terminal phalanx is responsible. The nail apparatus consists of both epithelial and connective tissue components. The matrix epithelium is responsible for the production of the nail plate whereas the nail bed epithelium mediates firm attachment. The hyponychium is a specialized structure sealing the subungual space and allowing the nail plate to physiologically detach from the nail bed. The proximal nail fold covers most of the matrix. Its free end forms the cuticle which seals the nail pocket or cul-de-sac. The dermis of the matrix and nail bed is specialized with a morphogenetic potency. The proximal and lateral nail folds form a frame on three sides giving the nail stability and allowing it to grow out. The nail protects the distal phalanx, is an extremely versatile tool for defense and dexterity and increases the sensitivity of the tip of the finger. Nail apparatus, finger tip, tendons and ligaments of the distal interphalangeal joint form a functional unit and cannot be seen independently. The nail organ has only a certain number of reaction patterns that differ in many respects from hairy and palmoplantar skin.

The Chemical Space of Flavours

The flavour of foods is determined by the interaction of taste molecules with receptors in the mouth, and fragrances or aroma with receptors in the upper part of the nose. Here, we discuss the properties of taste and fragrance molecules, from the public databases Superscent, Flavornet, SuperSweet and BitterDB, taken collectively as flavours, in the perspective of the chemical space. We survey simple descriptor profiles in comparison with the public collections ChEMBL (bioactive small molecules), ZINC (commercial drug-like molecules) and GDB-13 (all possible organic molecules up to 13 atoms of C, N, O, S, Cl). A global analysis of the chemical space of flavours is also presented based on molecular quantum numbers (MQN) and SMILES fingerprints (SMIfp). While taste molecules span a very broad property range, fragrances occupy a narrow area of the chemical space consisting of generally very small and relatively nonpolar molecules distinct of standard drug molecules. Proximity searching in the chemical space is exemplified as a simple method to facilitate the search for new fragrances.

Composition Space Analysis in the Development of Copper Molybdate Hybrids Decorated by a Bifunctional Pyrazolyl/1,2,4-Triazole Ligand

A bitopic ligand, 4-(3,5-dimethylpyrazol-4-yl)-1,2,4-triazole (Hpz-tr) (1), containing two different heterocyclic moieties was employed for the design of copper(II)–molybdate solids under hydrothermal conditions. In the multicomponent CuII/Hpz-tr/MoVI system, a diverse set of coordination hybrids, [Cu(Hpz-tr)2SO4]·3H2O (2), [Cu(Hpz-tr)Mo3O10] (3), [Cu4(OH)4(Hpz-tr)4Mo8O26]·6H2O (4), [Cu(Hpz-tr)2Mo4O13] (5), and [Mo2O6(Hpz-tr)]·H2O (6), was prepared and characterized. A systematic investigation of these systems in the form of a ternary crystallization diagram approach was utilized to show the influence of the molar ratios of starting reagents, the metal (CuII and MoVI) sources, the temperature, etc., on the reaction products outcome. Complexes 2–4 dominate throughout a wide crystallization range of the composition triangle, while the other two compounds 5 and 6 crystallize as minor phases in a narrow concentration range. In the crystal structures of 2–6, the organic ligand behaves as a short [N–N]-triazole linker between metal centers Cu···Cu in 2–4, Cu···Mo in 5, and Mo···Mo in 6, while the pyrazolyl function remains uncoordinated. This is the reason for the exceptional formation of low-dimensional coordination motifs: 1D for 2, 4, and 6 and 2D for 3 and 5. In all cases, the pyrazolyl group is involved in H bonding (H-donor/H-acceptor) and is responsible for π–π stacking, thus connecting the chain and layer structures in more complicated H-bonding architectures. These compounds possess moderate thermal stability up to 250–300 °C. The magnetic measurements were performed for 2–4, revealing in all three cases antiferromagnetic exchange interactions between neighboring CuII centers and long-range order with a net moment below Tc of 13 K for compound 4.

PDB-Explorer: a web-based interactive map of the protein data bank in shape space

Background The RCSB Protein Data Bank (PDB) provides public access to experimentally determined 3D-structures of biological macromolecules (proteins, peptides and nucleic acids). While various tools are available to explore the PDB, options to access the global structural diversity of the entire PDB and to perceive relationships between PDB structures remain very limited. Methods A 136-dimensional atom pair 3D-fingerprint for proteins (3DP) counting categorized atom pairs at increasing through-space distances was designed to represent the molecular shape of PDB-entries. Nearest neighbor searches examples were reported exemplifying the ability of 3DP-similarity to identify closely related biomolecules from small peptides to enzyme and large multiprotein complexes such as virus particles. The principle component analysis was used to obtain the visualization of PDB in 3DP-space. Results The 3DP property space groups proteins and protein assemblies according to their 3D-shape similarity, yet shows exquisite ability to distinguish between closely related structures. An interactive website called PDB-Explorer is presented featuring a color-coded interactive map of PDB in 3DP-space. Each pixel of the map contains one or more PDB-entries which are directly visualized as ribbon diagrams when the pixel is selected. The PDB-Explorer website allows performing 3DP-nearest neighbor searches of any PDB-entry or of any structure uploaded as protein-type PDB file. All functionalities on the website are implemented in JavaScript in a platform-independent manner and draw data from a server that is updated daily with the latest PDB additions, ensuring complete and up-to-date coverage. The essentially instantaneous 3DP-similarity search with the PDB-Explorer provides results comparable to those of much slower 3D-alignment algorithms, and automatically clusters proteins from the same superfamilies in tight groups. Conclusion A chemical space classification of PDB based on molecular shape was obtained using a new atom-pair 3D-fingerprint for proteins and implemented in a web-based database exploration tool comprising an interactive color-coded map of the PDB chemical space and a nearest neighbor search tool. The PDB-Explorer website is freely available at www.​cheminfo.​org/​pdbexplorer and represents an unprecedented opportunity to interactively visualize and explore the structural diversity of the PDB.

The Chemical Space Project

One of the simplest questions that can be asked about molecular diversity is how many organic molecules are possible in total? To answer this question, my research group has computationally enumerated all possible organic molecules up to a certain size to gain an unbiased insight into the entire chemical space. Our latest database, GDB-17, contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens, by far the largest small molecule database reported to date. Molecules allowed by valency rules but unstable or nonsynthesizable due to strained topologies or reactive functional groups were not considered, which reduced the enumeration by at least 10 orders of magnitude and was essential to arrive at a manageable database size. Despite these restrictions, GDB-17 is highly relevant with respect to known molecules. Beyond enumeration, understanding and exploiting GDBs (generated databases) led us to develop methods for virtual screening and visualization of very large databases in the form of a “periodic system of molecules” comprising six different fingerprint spaces, with web-browsers for nearest neighbor searches, and the MQN- and SMIfp-Mapplet application for exploring color-coded principal component maps of GDB and other large databases. Proof-of-concept applications of GDB for drug discovery were realized by combining virtual screening with chemical synthesis and activity testing for neurotransmitter receptor and transporter ligands. One surprising lesson from using GDB for drug analog searches is the incredible depth of chemical space, that is, the fact that millions of very close analogs of any molecule can be readily identified by nearest-neighbor searches in the MQN-space of the various GDBs. The chemical space project has opened an unprecedented door on chemical diversity. Ongoing and yet unmet challenges concern enumerating molecules beyond 17 atoms and synthesizing GDB molecules with innovative scaffolds and pharmacophores.

Granular layer in the periplasmic space of gram-positive bacteria and fine structures of Enterococcus gallinarum and Streptococcus gordonii septa revealed by cryo-electron microscopy of vitreous sections.

High-resolution structural information on optimally preserved bacterial cells can be obtained with cryo-electron microscopy of vitreous sections. With the help of this technique, the existence of a periplasmic space between the plasma membrane and the thick peptidoglycan layer of the gram-positive bacteria Bacillus subtilis and Staphylococcus aureus was recently shown. This raises questions about the mode of polymerization of peptidoglycan. In the present study, we report the structure of the cell envelope of three gram-positive bacteria (B. subtilis, Streptococcus gordonii, and Enterococcus gallinarum). In the three cases, a previously undescribed granular layer adjacent to the plasma membrane is found in the periplasmic space. In order to better understand how nascent peptidoglycan is incorporated into the mature peptidoglycan, we investigated cellular regions known to represent the sites of cell wall production. Each of these sites possesses a specific structure. We propose a hypothetic model of peptidoglycan polymerization that accommodates these differences: peptidoglycan precursors could be exported from the cytoplasm to the periplasmic space, where they could diffuse until they would interact with the interface between the granular layer and the thick peptidoglycan layer. They could then polymerize with mature peptidoglycan. We report cytoplasmic structures at the E. gallinarum septum that could be interpreted as cytoskeletal elements driving cell division (FtsZ ring). Although immunoelectron microscopy and fluorescence microscopy studies have demonstrated the septal and cytoplasmic localization of FtsZ, direct visualization of in situ FtsZ filaments has not been obtained in any electron microscopy study of fixed and dehydrated bacteria.

A versatile toolkit to produce sensitive FRET biosensors to visualize signaling in time and space

Genetically encoded, ratiometric biosensors based on fluorescence resonance energy transfer (FRET) are powerful tools to study the spatiotemporal dynamics of cell signaling. However, many biosensors lack sensitivity. We present a biosensor library that contains circularly permutated mutants for both the donor and acceptor fluorophores, which alter the orientation of the dipoles and thus better accommodate structural constraints imposed by different signaling molecules while maintaining FRET efficiency. Our strategy improved the brightness and dynamic range of preexisting RhoA and extracellular signal-regulated protein kinase (ERK) biosensors. Using the improved RhoA biosensor, we found micrometer-sized zones of RhoA activity at the tip of F-actin bundles in growth cone filopodia during neurite extension, whereas RhoA was globally activated throughout collapsing growth cones. RhoA was also activated in filopodia and protruding membranes at the leading edge of motile fibroblasts. Using the improved ERK biosensor, we simultaneously measured ERK activation dynamics in multiple cells using low-magnification microscopy and performed in vivo FRET imaging in zebrafish. Thus, we provide a construction toolkit consisting of a vector set, which enables facile generation of sensitive biosensors.

Tissue Crowding Induces Caspase-Dependent Competition for Space.

Regulation of tissue size requires fine tuning at the single-cell level of proliferation rate, cell volume, and cell death. Whereas the adjustment of proliferation and growth has been widely studied [1, 2, 3, 4 and 5], the contribution of cell death and its adjustment to tissue-scale parameters have been so far much less explored. Recently, it was shown that epithelial cells could be eliminated by live-cell delamination in response to an increase of cell density [6]. Cell delamination was supposed to occur independently of caspase activation and was suggested to be based on a gradual and spontaneous disappearance of junctions in the delaminating cells [6]. Studying the elimination of cells in the midline region of the Drosophila pupal notum, we found that, contrary to what was suggested before, Caspase 3 activation precedes and is required for cell delamination. Yet, using particle image velocimetry, genetics, and laser-induced perturbations, we confirmed [ 6] that local tissue crowding is necessary and sufficient to drive cell elimination and that cell elimination is independent of known fitness-dependent competition pathways [ 7, 8 and 9]. Accordingly, activation of the oncogene Ras in clones was sufficient to compress the neighboring tissue and eliminate cells up to several cell diameters away from the clones. Mechanical stress has been previously proposed to contribute to cell competition [ 10 and 11]. These results provide the first experimental evidences that crowding-induced death could be an alternative mode of super-competition, namely mechanical super-competition, independent of known fitness markers [ 7, 8 and 9], that could promote tumor growth.

Bioprocessing in space.

Mode of access: Internet.