The beneficial effects of Cyclooxygenases (COX) inhibitors on human health have been known for thousands of years. Nevertheless, COXs, particularly COX-1, have been linked to a plethora of human ...diseases such as cancer, heart failure, neurological and neurodegenerative diseases only recently. COXs catalyze the first step in the biosynthesis of prostaglandins (PGs) and are among the most important mediators of inflammation. All published structural work on COX-1 deals with the ovine isoenzyme, which is easier to produce in milligram-quantities than the human enzyme and crystallizes readily. Here, we report the long-sought structure of the human cyclooxygenase-1 (hCOX-1) that we refined to an R/R
of 20.82/26.37, at 3.36 Å resolution. hCOX-1 structure provides a detailed picture of the enzyme active site and the residues crucial for inhibitor/substrate binding and catalytic activity. We compared hCOX-1 crystal structure with the ovine COX-1 and human COX-2 structures by using metrics based on Cartesian coordinates, backbone dihedral angles, and solvent accessibility coupled with multivariate methods. Differences and similarities among structures are discussed, with emphasis on the motifs responsible for the diversification of the various enzymes (primary structure, stability, catalytic activity, and specificity). The structure of hCOX-1 represents an essential step towards the development of new and more selective COX-1 inhibitors of enhanced therapeutic potential.
SIR2011, the successor of SIR2004, is the latest program of the SIR suite. It can solve ab initio crystal structures of small‐ and medium‐size molecules, as well as protein structures, using X‐ray or ...electron diffraction data. With respect to the predecessor the program has several new abilities: e.g. a new phasing method (VLD) has been implemented, it is able to exploit prior knowledge of the molecular geometry via simulated annealing techniques, it can use molecular replacement methods for solving proteins, it includes new tools like free lunch and new approaches for electron diffraction data, and it visualizes three‐dimensional electron density maps. The graphical interface has been further improved and allows the straightforward use of the program even in difficult cases.
The term social jetlag is used to describe the discrepancy between biological time, determined by our internal body clock, and social times, mainly dictated by social obligations such as school or ...work. In industrialized countries, two-thirds of the studying/working population experiences social jetlag, often for several years. Described for the first time in 2006, a considerable effort has been put into understanding the effects of social jetlag on human physiopathology, yet our understanding of this phenomenon is still very limited. Due to its high prevalence, social jetlag is becoming a primary concern for public health. This review summarizes current knowledge regarding social jetlag, social jetlag associated behavior (e.g., unhealthy eating patterns) and related risks for human health.
The approach based on atomic pair distribution function (PDF) has revolutionized structural investigations by X-ray/electron diffraction of nano or quasi-amorphous materials, opening up the ...possibility of exploring short-range order. However, the ab initio crystal structural solution by the PDF is far from being achieved due to the difficulty in determining the crystallographic properties of the unit cell. A method for estimating the crystal cell parameters directly from a PDF profile is presented, which is composed of two steps: first, the type of crystal cell is inferred using machine-learning approaches applied to the PDF profile; second, the crystal cell parameters are extracted by means of multivariate analysis combined with vector superposition techniques. The procedure has been validated on a large number of PDF profiles calculated from known crystal structures and on a small number of measured PDF profiles. The lattice determination step has been benchmarked by a comprehensive exploration of different classifiers and different input data. The highest performance is obtained using the k -nearest neighbours classifier applied to whole PDF profiles. Descriptors calculated from the PDF profiles by recurrence quantitative analysis produce results that can be interpreted in terms of PDF properties, and the significance of each descriptor in determining the prediction is evaluated. The cell parameter extraction step depends on the cell metric rather than its type. Monometric, dimetric and trimetric cells have top-1 estimates that are correct 40, 20 and 5% of the time, respectively. Promising results were obtained when analysing real nanocrystals, where unit cells close to the true ones are found within the top-1 ranked solution in the case of monometric cells and within the top-6 ranked solutions in the case of dimetric cells, even in the presence of a crystalline impurity with a weight fraction up to 40%.
SIR2004 is the evolution of the SIR2002 program Burla, Camalli, Carrozzini, Cascarano, Giacovazzo, Polidori & Spagna (2003). J. Appl. Cryst.36, 1103. It is devoted to the solution of crystal ...structures by direct and Patterson methods. Several new features implemented in SIR2004 make this program efficient: it is able to solve ab initio both small/medium‐size structures as well as macromolecules (up to 2000 atoms in the asymmetric unit). In favourable circumstances, the program is also able to solve protein structures with data resolution up to 1.4–1.5 Å, and to provide interpretable electron density maps. A powerful user‐friendly graphical interface is provided.
Multivariate analysis (MA) is becoming a fundamental tool for processing in an efficient way the large amount of data collected in X-ray diffraction experiments. Multi-wedge data collections can ...increase the data quality in case of tiny protein crystals; in situ or operando setups allow investigating changes on powder samples occurring during repeated fast measurements; pump and probe experiments at X-ray free-electron laser (XFEL) sources supply structural characterization of fast photo-excitation processes. In all these cases, MA can facilitate the extraction of relevant information hidden in data, disclosing the possibility of automatic data processing even in absence of a priori structural knowledge. MA methods recently used in the field of X-ray diffraction are here reviewed and described, giving hints about theoretical background and possible applications. The use of MA in the framework of the modulated enhanced diffraction technique is described in detail.
IL MILIONE is a suite of computer programs devoted to protein crystal structure determination by X‐ray crystallography. It may be used in the following key activities. (a) Ab initio phasing, via ...Patterson or direct methods. The program may succeed even with structures with up to 6000 non‐H atoms in the asymmetric unit, provided that atomic resolution is available, and with data at quasi‐atomic resolution (1.4–1.5 Å). (b) Single or multiple isomorphous replacement, single‐ or multiple‐wavelength anomalous diffraction, and single or multiple isomorphous replacement with anomalous scattering techniques. In the first step the program finds the heavy‐atom/anomalous scatterer substructure, then automatically uses the above information to phase protein reflections. Phase extension and refinement are performed by electron density modification techniques. (c) Molecular replacement. The orientation and the location of the protein molecules are found via reciprocal space methods. Phase extension and refinement are performed by electron density modification techniques. All the programs integrated into IL MILIONE are controlled by means of a user‐friendly graphical user interface, which is used to input data and to monitor intermediate and final results by means of real‐time updated messages, diagrams and histograms.
Abstract
Colloidal chemistry grants access to a wealth of materials through simple and mild reactions. However, even few elements can combine in a variety of stoichiometries and structures, ...potentially resulting in impurities or even wrong products. Similar issues have been long addressed in organic chemistry by using reaction-directing groups, that are added to a substrate to promote a specific product and are later removed. Inspired by such approach, we demonstrate the use of CsPbCl
3
perovskite nanocrystals to drive the phase-selective synthesis of two yet unexplored lead sulfochlorides: Pb
3
S
2
Cl
2
and Pb
4
S
3
Cl
2
. When homogeneously nucleated in solution, lead sulfochlorides form Pb
3
S
2
Cl
2
nanocrystals. Conversely, the presence of CsPbCl
3
triggers the formation of Pb
4
S
3
Cl
2
/CsPbCl
3
epitaxial heterostructures. The phase selectivity is guaranteed by the continuity of the cationic subnetwork across the interface, a condition not met in a hypothetical Pb
3
S
2
Cl
2
/CsPbCl
3
heterostructure. The perovskite domain is then etched, delivering phase-pure Pb
4
S
3
Cl
2
nanocrystals that could not be synthesized directly.
The evolution from solvated precursors to hybrid halide perovskite films dictates most of the photophysical and optoelectronic properties of the final polycrystalline material. Specifically, the ...complex equilibria and the importantly different solubilities of lead iodide (PbI2) and methylammonium iodide (MAI) induce inhomogeneous crystal growth, often leading to a defect dense film showing non-optimal optoelectronic properties and intrinsic instability. Here, we explore a supramolecular approach based on the use of cyclodextrins (CDs) to modify the underlying solution chemistry. The peculiar phenomenon demonstrated is a tunable complexation between different CDs and MA+ cations concurrent to an out of cage PbI2 intercalation, representing the first report of a connection between the solvation equilibria of the two perovskite precursors. The optimal conditions in terms of CD cavity size and polarity translate to a neat enhancement of PbI2 solubility in the reaction media, leading to an equilibration of the availability of the precursors in solution. The macroscopic result of this is an improved nucleation process, leading to a perovskite material with higher crystallinity, better optical properties and improved moisture resistance. Remarkably, the use of CDs presents a great potential for a wide range of device-related applications, as well as for the development of tailored composite materials.
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