23 research outputs found
EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription
Caveolae are small invaginated pits that function as dynamic mechanosensors to buffer tension variations at the plasma membrane. Here we show that under mechanical stress, the EHD2 ATPase is rapidly released from caveolae, SUMOylated, and translocated to the nucleus, where it regulates the transcription of several genes including those coding for caveolae constituents. We also found that EHD2 is required to maintain the caveolae reservoir at the plasma membrane during the variations of membrane tension induced by mechanical stress. Metal-replica electron microscopy of breast cancer cells lacking EHD2 revealed a complete absence of caveolae and a lack of gene regulation under mechanical stress. Expressing EHD2 was sufficient to restore both functions in these cells. Our findings therefore define EHD2 as a central player in mechanotransduction connecting the disassembly of the caveolae reservoir with the regulation of gene transcription under mechanical stress
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Interaction between a cationic surfactant-like peptide and lipid vesicles and its relationship to antimicrobial activity
We investigate the properties of an antimicrobial
surfactant-like peptide (Ala)6(Arg), A6R, containing a
cationic headgroup. The interaction of this peptide with
zwitterionic (DPPC) lipid vesicles is investigated using a range of microscopic, X-ray scattering, spectroscopic, and calorimetric methods. The β-sheet structure adopted by A6R is disrupted in the presence of DPPC. A strong effect on the
small-angle X-ray scattering profile is observed: the Bragg
peaks from the DPPC bilayers in the vesicle walls are
eliminated in the presence of A6R and only bilayer form factor peaks are observed. All of these observations point to the interaction of A6R with DPPC bilayers. These studies provide insight into interactions between a model cationic peptide and vesicles, relevant to understanding the action of antimicrobial peptides on lipid membranes. Notably, peptide A6R exhibits antimicrobial activity without membrane lysis
Amyloidogenic Peptides at Hydrophobic-Hydrophilic Interfaces: Coordination Affinities and the Chelate Effect Dictate the Competitive Binding of Cu2+ and Zn2+
Influence of the hydrophobic interface and transition metal ions on the conformation of amyloidogenic model peptides
Triggers for beta-sheet formation at the hydrophobic-hydrophilic interface: high concentra-tion, in-plane orientational order, and metal ion complexation
Amyloid formation plays a causative role in neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. Soluble peptides form β-sheets that subsequently rearrange into fibrils and deposit as amyloid plaques. Many parameters trigger and influence the onset of the β-sheet formation. Early stages are recently discussed to be cell-toxic. Aiming at understanding various triggers such as interactions with hydrophobic-hydrophilic interfaces and metal ion complexation and their interplay, we investigated a set of model peptides at the air-water interface. We are using a general approach to a variety of diseases such as Alzheimer's disease, Parkinson's disease, and type II diabetes that are connected to amyloid formation. Surface sensitive techniques combined with film balance measurements have been used to assess the conformation of the peptides and their orientation at the air-water interface (IR reflection-absorption spectroscopy). Additionally, the structures of the peptide layers were characterized by grazing incidence X-ray diffraction and X-ray reflectivity. The peptides adsorb to the air-water interface and immediately adopt an α-helical conformation. This helical intermediate transforms into β-sheets upon further triggering. The factors that result in β-sheet formation are dependent on the peptide sequence. In general, the interface has the strongest effect on peptide conformation compared to high concentrations or metal ions. Metal ions are able to prevent aggregation in bulk but not at the interface. At the interface, metal ion complexation has only minor effects on the peptide secondary structure, influencing the in-plane structure that is formed in two dimensions. At the air-water interface, increased concentrations or a parallel arrangement of the α-helical intermediates are the most effective triggers. This study reveals the role of various triggers for β-sheet formation and their complex interplay. Our main finding is that the hydrophobic-hydrophilic interface largely governs the conformation of peptides. Therefore, the present study implies that special care is needed when interpreting data that may be affected by different amounts or types of interfaces during experimentation
Antimicrobial activity and interactions of cationic peptides derived from Galleria mellonella cecropin D-like peptide with model membranes
Solvent-Dependent Structural Dynamics in the Ultrafast Photodissociation Reaction of Triiodide Observed with Time-Resolved X-ray Solution Scattering
Resolving the structural dynamics of bond breaking, bond formation, and solvation is required for a deeper understanding of solutionphase chemical reactions. In this work, we investigate the photodissociation of triiodide in four solvents using femtosecond time-resolved X-ray solution scattering following 400 nm photoexcitation. Structural analysis of the scattering data resolves the solvent-dependent structural evolution during the bond cleavage, internal rearrangements, solvent-cage escape, and bond reformation in real time. The nature and structure of the reaction intermediates during the recombination are determined, elucidating the full mechanism of photodissociation and recombination on ultrafast time scales. We resolve the structure of the precursor state for recombination as a geminate pair. Further, we determine the size of the solvent cages from the refined structures of the radical pair. The observed structural dynamics present a comprehensive picture of the solvent influence on structure and dynamics of dissociation reactions
Global health education in medical schools (GHEMS): a national, collaborative study of medical curricula
Background: Global health is the study, research, and practice of medicine focused on improving health and achieving health equity for all persons worldwide. International and national bodies stipulate that global health be integrated into medical school curricula. However, there is a global paucity of data evaluating the state of global health teaching in medical schools. This study aimed to evaluate the extent of global health teaching activities at United Kingdom (UK) medical schools. Methods: A national, cross-sectional study assessing all timetabled teachings sessions within UK medical courses for global health content during the academic year 2018/19. Global health content was evaluated against a comprehensive list of global health learning outcomes for medical students. Results: Data from 39 medical courses representing 86% (30/36) of eligible medical schools was collected. Typically, medical courses reported timetabled teaching covering over three-quarters of all global health learning outcomes. However, a wide degree of variation existed among granular global health learning objectives covered within the different medical courses. On average, each learning outcome had a 79% [95% CI: 73, 83%] probability of being included in course curricula. There were a number of learning outcomes that had a lower probability, such as ‘access to surgeons with the necessary skills and equipment in different countries’ (36%) [95% CI: 21, 53%], ‘future impact of climate change on health and healthcare systems’ (67%) [95% CI: 50, 81%], and ‘role of the WHO’ (54%) [95% CI: 28, 60%]. Conclusions: This study served as the first national assessment of global health education and curricula within UK medical schools. Through a formalised assessment of teaching events produced by medical schools around the country, we were able to capture a national picture of global health education, including the strengths of global health prioritisation in the UK, as well as areas for improvement. Overall, it appears broad-level global health themes are widely discussed; however, the granularities of key, emerging areas of concern are omitted by curricula. In particular, gaps persist relating to international healthcare systems, multilateral global health agencies such as the WHO, global surgery, climate change and more