Mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia

Resultados de investigaciónIn addition to its structural role in skeletogenesis, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders and one attributed mechanism results from the deleterious effects of mutated proteins on ECM structure. Yet, the consequences of abnormal ECM on cellular communication remains less well understood. Herein, we describe an unclassified form of bent bone dysplasia caused by recessively inherited mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin- mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered b1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling, tying focal adhesion molecules to key skeletal signaling molecules. This newly described mechanism reveals that a LAMA5-b1 Integrin-PYK2-FYN focal adhesion complex regulatesskeletogenesis and, when dysregulated, produces a distinct skeletal disorder.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Free Energy Approach to the Formation of an Icosahedral Structure during the Freezing of Gold Nanoclusters

The freezing of metal nanoclusters such as gold, silver, and copper exhibits a novel structural evolution. The formation of the icosahedral (Ih) structure is dominant despite its energetic metastability. This important phenomenon, hitherto not understood, is studied by calculating free energies of gold nanoclusters. The structural transition barriers have been determined by using the umbrella sampling technique combined with molecular dynamics simulations. Our calculations show that the formation of Ih gold nanoclusters is attributed to the lower free energy barrier from the liquid to the Ih phases compared to the barrier from the liquid to the face-centered-cubic crystal phases

Blind source separation aided characterization of the γ′ strengthening phase in an advanced nickel-based superalloy by spectroscopic 4D electron microscopy

The γ’ strengthening phase in an advanced nickel-based superalloy, ATI 718Plus, was characterized using a blind source separation applied to a four dimensional X-ray microanalysis dataset obtained by scanning transmission electron microscopy. Selected patterns in the X-ray spectra identified by independent component analysis were found to be spatially and chemically representative of the matrix (γ) and precipitate phases (γ’) present in the superalloy, enabling their size, shape and distribution to be determined. The three dimensional chemical reconstruction of the microstructure may provide insight into the role of the various alloying elements in the evolution of the microstructure at the nano-scale.The research leading to these results has received funding from the European Union Seventh Framework Programme under Grant Agreement 312483 - ESTEEM2 (Integrated Infrastructure Initiative-I3), as well as from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC grant agreement 291522 - 3DIMAGE. D.R. acknowledges support from the Royal Society’s Newton International Fellowship scheme. RKL acknowledges a Junior Research Fellowship at Clare College. RK acknowledges financial support from Rolls-Royce, EPSRC and the BMWi under EP/H022309/1, EP/H500375/1 and grant number 20T0813. F.d.l.P. and C.D. acknowledge 26 funding from the ERC under grant no. 259619 PHOTO EM. Special thanks to Giorgio Divitini and Lech Staniewicz for preparation of the FIB needle specimen and to Stephen A Croxall for SEM/FIB imaging.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.actamat.2016.01.04

Phase contrast electron microscopy: development of thin-film phase plates and biological applications

Phase contrast transmission electron microscopy (TEM) based on thin-film phase plates has been developed and applied to biological systems. Currently, development is focused on two techniques that employ two different types of phase plates. The first technique uses a Zernike phase plate, which is made of a uniform amorphous carbon film that completely covers the aperture of an objective lens and can retard the phase of electron waves by π/2, except at the centre where a tiny hole is drilled. The other technique uses a Hilbert phase plate, which is made of an amorphous carbon film that is twice as thick as the Zernike phase plate, covers only half of the aperture and retards the electron wave phase by π. By combining the power of efficient phase contrast detection with the accurate preservation achieved by a cryotechnique such as vitrification, macromolecular complexes and supermolecular structures inside intact bacterial or eukaryotic cells may be visualized without staining. Phase contrast cryo-TEM has the potential to bridge the gap between cellular and molecular biology in terms of high-resolution visualization. Examples using proteins, viruses, cyanobacteria and somatic cells are provided

On the crystallography and composition of topologically close-packed phases in ATI 718Plus®

ATI 718Plus® is a nickel-based superalloy developed to replace Inconel 718 in aero engines for static and rotating applications. Here, the long-term stability of the alloy was studied and it was found that topologically close-packed (TCP) phases can form at the γ-η interface or, less frequently, at grain boundaries. Conventional and scanning transmission electron microscopy techniques were applied to elucidate the crystal structure and composition of these TCP precipitates. The precipitates were found to be tetragonal sigma phase and hexagonal C14 Laves phase, both being enriched in Cr, Co, Fe and Mo though sigma has a higher Cr and lower Nb content. The precipitates were observed to be heavily faulted along multiple planes. In addition, the disorientations between the TCP phases and neighbouring η/γ were determined using scanning precession electron diffraction and evaluated in axis-angle space. This work therefore provides a series of compositional and crystallographic insights that may be used to guide future alloy design.The authors acknowledge Rolls-Royce plc, the EPSRC and the BMWi under grants EP/H022309/1, EP/H500375/1 and 20T0813. P.A.M acknowledges financial support from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement 291522-3DIMAGE, the Seventh Framework Programme of the European Commission: ESTEEM2, contract number 312483. DNJ acknowledges financial support from the University of Cambridge through the Cambridge Home & EU Scholarship scheme and the EPSRC Cambridge NanoDTC EP/L015978/1

Nosology of genetic skeletal disorders: 2023 revision.

The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine

Emotion dysregulation mediates the relationship between nightmares and psychotic experiences: Results from a student population

Sleep-disruption is commonly associated with psychotic experiences. Whilst sparse, the literature to date highlights nightmares and related distress as prominent risk factors for psychosis in students. We aimed to further explore the relationship between specific nightmare symptoms and psychotic experiences in university students whilst examining the mediating role of emotion dysregulation. A sample (N=1273) of student respondents from UK universities completed measures of psychotic experiences, nightmare disorder symptomology, and emotion dysregulation. Psychotic experiences were significantly more prevalent in students reporting nightmares (n=757) relative to those who did not (n=516). Hierarchical linear regression analysis showed that psychotic experiences were significantly associated (Adjusted R2 = 32.4%) with perceived nightmare intensity, consequences and resulting awakenings, and with emotion regulation difficulties. Furthermore, multiple mediation analysis showed that the association between psychotic experiences and nightmare factors was mediated by emotion regulation difficulties. Adaptive regulation of dream content during rapid eye-movement sleep has previously been demonstrated to attenuate surges in affective arousal by controlling the intensity and variability of emotional content. Difficulties in emotion regulation may partially explain the experience of more intense and disruptive nightmares amongst individuals with psychotic experiences. Emotion regulation may represent an important control mechanism that safeguards dream content and sleep quality