Molecular Basis of Mechanosensitivity

Mechanosensation is arguably the least understood of all senses. For most physiological processes, the first response to membrane stress is thought to be the opening or closing of mechanosensitive channels1, but the clonal nature of the first mechanotransducers is still largely unknown. The objective of my research was to identify molecules involved in mechanosensory transduction by both studying known channels as well as performing screens to identify previously uncharacterized channels. Shortly before my research began, Daniel Schmidt from the MacKinnon Lab showed that certain voltage gated potassium channels, not previously associated with mechanosensation, are in fact remarkably sensitive to membrane tension in isolated membrane patches2. I therefore began investigating the possibility of voltage gated potassium channels being mechanosensitive in physiological contexts. Results using hypo-osmotic swelling provided additional support that Paddle Chimaera and Kv2.1 are indeed mechanosensitive in cellular contexts3. Given the close structural similarity between voltage gated potassium channels and other ion channel families, I extended these studies to include sodium and calcium selective voltage gated ion channels using patch inflation, swelling, poking, and stretching. However the sodium selective voltage gated channel, Nav1.7, and calcium selective voltage gated channels, Cav1.2 and Cav1.3, were not found to display major mechanosensitive properties. In a complimentary approach, I performed a screen of 10 different cell lines using the poking assay to identify novel molecules involved in mechanical transduction. My results identified multiple undescribed slow-inactivating mechanosensitive currents in cell lines from a variety of sources including numerous cancer cell lines, human stem cells and mouse stem cells. Further work using transcriptome analysis, bioinformatic techniques, and electrophysiological recordings identified that the pore forming subunit responsible for the slowinactivating mechanosensitive conductances in mouse embryonic stem cells is Piezo1, a mechanosensitive channel canonically known for displaying fastinactivating kinetics. With very few modulators known to date45, the mechanism by which Piezo1 could produce slow inactivating currents was not known. To address possible novel sources of modulation of Piezo1 currents, I performed transcriptome analyses that identified 2 potential candidates including one novel protein subsequently confirmed to modify the behavior of Piezo1 in vitro. This protein, Plp2, is a small transmembrane protein of undescribed function that amplifies the magnitude and slows down the kinetics of Piezo1 in heterologous expression. The other protein, Cd63, is also a transmembrane protein that only amplifies the magnitude of Piezo1 currents, with no modification of its kinetics, in heterologous expression. Given the remarkably large set of functions that have been attributed to Piezo channels6,7,8,9 in the very few years since its discovery, and how little we still know of its functional mechanisms, the identification of novel modulators provides a crucial next step in elucidating the molecular basis of mechanosensation

Refractory Hand Ulceration: A Case of Chronic Ulceration and Sporotrichoid Spread in a Fish Tank Hobbyist following Mycobacterium marinum Infection

We report the case of a 35-year-old man with a chronic ulceration of the hand in whom an infection with Mycobacterium marinum was diagnosed. Clarithromycin and doxycycline were prescribed, resulting in a slow resolution of the ulceration. M. marinum is a nontuberculous mycobacterium that causes skin lesions such as nodules, ulcerations, and sporotrichoid spread, but may also be responsible for osteoarticular lesions. In this case report, we discuss the clinical characteristics of this condition, as well as its diagnostic methods and treatments

Prevalence and determinants of AK in Euromelanoma screenees

Actinic keratosis (AK) is the most common skin lesion with malignant potential, and one of the main reasons for consulting a dermatologist. Found predominantly on sun-exposed body sites in fairskinned, older and male subjects, AK is among the strongest predictors of skin cancer, and a precursor of SCC. However, estimates of prevalence and study of determinants of AK are relatively scarce and generally based on small, hospital-based series. Clinical suspicion of AK is a reliable predictor of diagnosis. The presence of AK is documented by dermatologists during the Euromelanoma screening examinations so that the Euromelanoma database probably constitutes the largest series of AK cases worldwide. This study aimed at (1) describing the prevalence and risk pattern of AK among Euromelanoma screenees during the 2009-2013 time period, and (2) identifying determinants of AK by means of multivariate analysis. In particular, the contribution of host characteristics, sun exposure and sunrelated behaviour to the risk of AK was explored. Results will be discussed in the light of this large, self-selected, Pan-European series

Taller vertical de procesos constructivos 02

Trabajos presentados por los alumnos en los diferentes talleres de la FAU entre los años 2003 y 2005. Selección de ejercicios de los niveles 1 a 3 de la cátedra Savari-Del Marmol-García, sobre los temas: centro de difusión ecológica en el Bosque de La Plata, Museo del Bosque de La Plata, prototipo de parador de ómnibus.Facultad de Arquitectura y Urbanism

<i>In vivo</i> assessment of optical properties of basal cell carcinoma and differentiation of BCC subtypes by high-definition optical coherence tomography

High-definition optical coherence tomography (HD-OCT) features of basal cell carcinoma (BCC) have recently been defined. We assessed in vivo optical properties (IV-OP) of BCC, by HD-OCT. Moreover their critical values for BCC subtype differentiation were determined. The technique of semi-log plot whereby an exponential function becomes linear has been implemented on HD-OCT signals. The relative attenuation factor (µ(raf)) at different skin layers could be assessed.(.) IV-OP of superficial BCC with high diagnostic accuracy (DA) and high negative predictive values (NPV) were (i) decreased µ(raf) in lower part of epidermis and (ii) increased epidermal thickness (E-T). IV-OP of nodular BCC with good to high DA and NPV were (i) less negative µ(raf) in papillary dermis compared to normal adjacent skin and (ii) significantly decreased E-T and papillary dermal thickness (PD-T). In infiltrative BCC (i) high µ(raf) in reticular dermis compared to normal adjacent skin and (ii) presence of peaks and falls in reticular dermis had good DA and high NPV. HD-OCT seems to enable the combination of in vivo morphological analysis of cellular and 3-D micro-architectural structures with IV-OP analysis of BCC. This permits BCC sub-differentiation with higher accuracy than in vivo HD-OCT analysis of morphology alone