The tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils

Mice carrying the Tight skin (Tsk) mutation harbor a genomic duplication within the fibrillin-1 (Fbn 1) gene that results in a larger than normal in-frame Fbn 1 transcript. In this study, the consequences of the Tsk mutation for fibrillin-containing microfibrils have been examined. Dermal fibroblasts from Tsk/+ mice synthesized and secreted both normal fibrillin (approximately 330 kD) and the mutant oversized Tsk fibrillin-1 (approximately 450 kD) in comparable amounts, and Tsk fibrillin-1 was stably incorporated into cell layers. Immunohistochemical and ultrastructural analyses of normal and Tsk/+ mouse skin highlighted differences in the gross organization and distribution of microfibrillar arrays. Rotary shadowing of high Mr preparations from Tsk/+ skin demonstrated the presence of abundant beaded microfibrils. Some of these had normal morphology and periodicity, but others were distinguished by diffuse interbeads, longer periodicity, and tendency to aggregate. The presence of a structurally abnormal population of microfibrils in Tsk/+ skin was unequivocally demonstrated after calcium chelation and in denaturating conditions. Scanning transmission electron microscopy highlighted the presence of more mass in Tsk/+ skin microfibrils than in normal mice skin microfibrils. These data indicate that Tsk fibrillin-1 polymerizes and becomes incorporated into a discrete population of beaded microfibrils with altered molecular organization

Biotribology of the ageing skin—why we should care

Ageing of populations has emerged as one of the most pressing societal, economic and healthcare challenges currently facing most nations across the globe. The ageing process itself results in degradation of physiological functions and biophysical properties of organs and tissues, and more particularly those of the skin. Moreover, in both developed and emerging economies, population ageing parallels concerning increases in lifestyle-associated conditions such as Type 2 diabetes, obesity and skin cancers. When considered together, these demographic trends call for even greater urgency to find clinical and engineering solutions for the numerous age-related deficits in skin function. From a tribological perspective, detrimental alterations of skin biophysical properties with age have fundamental consequences on how one interacts with the body's inner and outer environments. This stems from the fact that, besides being the largest organ of the human body, and also nearly covering its entirety, the skin is a multifunctional interface which mediates these interactions. The aim of this paper is to present a focused review to discuss some of the consequences of skin ageing from the viewpoint of biotribology, and their implications on health, well-being and human activities. Current and future research questions/challenges associated with biotribology of the ageing skin are outlined. They provide the background and motivation for identifying future lines of research that could be taken up by the biotribology and biophysics communities

The Effects of Ionising and Non-Ionising Electromagnetic Radiation on Extracellular Matrix Proteins

From MDPI via Jisc Publications RouterHistory: accepted 2021-10-30, pub-electronic 2021-11-05Publication status: PublishedFunder: Singapore Nuclear research and Safety Inititative; Grant(s): N/AExposure to sub-lethal doses of ionising and non-ionising electromagnetic radiation can impact human health and well-being as a consequence of, for example, the side effects of radiotherapy (therapeutic X-ray exposure) and accelerated skin ageing (chronic exposure to ultraviolet radiation: UVR). Whilst attention has focused primarily on the interaction of electromagnetic radiation with cells and cellular components, radiation-induced damage to long-lived extracellular matrix (ECM) proteins has the potential to profoundly affect tissue structure, composition and function. This review focuses on the current understanding of the biological effects of ionising and non-ionising radiation on the ECM of breast stroma and skin dermis, respectively. Although there is some experimental evidence for radiation-induced damage to ECM proteins, compared with the well-characterised impact of radiation exposure on cell biology, the structural, functional, and ultimately clinical consequences of ECM irradiation remain poorly defined

Peptide Location Fingerprinting Reveals Tissue Region-Specific Differences in Protein Structures in an Ageing Human Organ

From MDPI via Jisc Publications RouterHistory: accepted 2021-09-14, pub-electronic 2021-09-27Publication status: PublishedFunder: Manchester Institute for Collaborative Research on Ageing; Grant(s): n/aFunder: Walgreens Boots Alliance; Grant(s): n/aIn ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural differences in complex proteomes. PLF applied to published young and aged intervertebral disc (IVD) MS datasets (posterior, lateral and anterior regions of the annulus fibrosus) identified 268 proteins with age-associated structural differences. For several ECM assemblies (collagens I, II and V and aggrecan), these differences were markedly conserved between degeneration-prone (posterior and lateral) and -resistant (anterior) regions. Significant differences in peptide yields, observed within collagen I α2, collagen II α1 and collagen V α1, were located within their triple-helical regions and/or cleaved C-terminal propeptides, indicating potential accumulation of damage and impaired maintenance. Several proteins (collagen V α1, collagen II α1 and aggrecan) also exhibited tissue region (lateral)-specific differences in structure between aged and young samples, suggesting that some ageing mechanisms may act locally within tissues. This study not only reveals possible age-associated differences in ECM protein structures which are tissue-region specific, but also highlights the ability of PLF as a proteomic tool to aid in biomarker discovery

Cytological and transcript analyses reveal fat and lazy persister-like bacilli in tuberculous sputum

As nonreplicating tubercle bacilli are tolerant to the cidal action of antibiotics and resistant to multiple stresses, identification of this persister-like population of tubercle bacilli in sputum presents exciting and tractable new opportunities to investigate both responses to chemotherapy and the transmission of tuberculosis