Structure and stability of the lamin A tail domain and HGPS mutant

Hutchinson–Gilford progeria syndrome (HGPS) is a premature aging syndrome caused by the expression and accumulation of a mutant form of lamin A, Δ50 lamin A. As a component of the cell’s nucleoskeleton, lamin A plays an important role in the mechanical stabilization of the nuclear envelope and in other nuclear functions. It is largely unknown how the characteristic 50 amino acid deletion affects the conformation of the mostly intrinsically disordered tail domain of lamin A. Here we perform replica exchange molecular dynamics simulations of the tail domain and determine an ensemble of semi-stable structures. Based on these structures we show that the ZMPSTE 24 cleavage site on the precursor form of the lamin A tail domain orients itself in such a way as to facilitate cleavage during the maturation process. We confirm our simulated structures by comparing the thermodynamic properties of the ensemble structures to in vitro stability measurements. Using this combination of experimental and computational techniques, we compare the size, heterogeneity of size, thermodynamic stability of the Ig-fold, as well as the mechanisms of force-induced denaturation. Our data shows that the Δ50 lamin A tail domain is more compact and displays less heterogeneity than the mature lamin A tail domain. Altogether these results suggest that the altered structure and stability of the tail domain can explain changed protein–protein and protein–DNA interactions and may represent an etiology of the disease. Also, this study provides the first molecular structure(s) of the lamin A tail domain, which is confirmed by thermodynamic tests in experiment.United States. Air Force Office of Scientific ResearchUnited States. Dept. of Defense. Presidential Early Career Award for Scientists and Engineer

Dynamical Response of Nanomechanical Oscillators in Immiscible Viscous Fluid for in vitro Biomolecular Recognition

Dynamical response of nanomechanical cantilever structures immersed in a viscous fluid is important to in vitro single-molecule force spectroscopy, biomolecular recognition of disease-specific proteins, and the detection of microscopic dynamics of proteins. Here we study the stochastic response of biofunctionalized nanomechanical cantilevers beam in a viscous fluid. Using the fluctuation-dissipation theorem we derive an exact expression for the spectral density of the displacement and a linear approximation for the resonance frequency shift. We find that in a viscous solution the frequency shift of the nanoscale cantilever is determined by surface stress generated by biomolecular interaction with negligible contributions from mass loading.Comment: 4 pages, 2 figures, RevTex4. See http://nano.bu.edu/ for related paper

Koncepcja zdrowia i jego ochrony w świetle literatury przedmiotu = Health concept and its protections in the light of subject literature

Kozłowska Ewelina, Marzec Agnieszka, Kalinowski Paweł, Bojakowska Urszula. Koncepcja zdrowia i jego ochrony w świetle literatury przedmiotu = Health concept and its protections in the light of subject literature. Journal of Education, Health and Sport. 2016;6(9):575-585. eISSN 2391-8306. DOI 1http://dx.doi.org/10.5281/zenodo.155048http://ojs.ukw.edu.pl/index.php/johs/article/view/3883    The journal has had 7 points in Ministry of Science and Higher Education parametric evaluation. Part B item 755 (23.12.2015).755 Journal of Education, Health and Sport eISSN 2391-8306 7© The Author (s) 2016;This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, PolandOpen Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium,provided the original author(s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License(http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited.This is an open access article licensed under the terms of the Creative Commons Attribution Non Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted, non commercialuse, distribution and reproduction in any medium, provided the work is properly cited.The authors declare that there is no conflict of interests regarding the publication of this paper.Received: 05.08.2016. Revised 25.08.2016. Accepted: 21.09.2016.   Koncepcja zdrowia i jego ochronyw świetle literatury przedmiotu Health concept and its protections in the light of subject literature Ewelina Kozłowska1, Agnieszka Marzec2, Paweł Kalinowski1, Urszula Bojakowska1 1Samodzielna Pracownia Epidemiologii, Uniwersytet Medyczny w Lublinie 2Zakład Dietetyki Klinicznej, Uniwersytet Medyczny w Lublinie    Streszczenie Na przestrzeni lat powstawały liczne koncepcje zdrowia i jego ochrony. Ulegają one ewolucji przede wszystkim w konsekwencji rozwoju nauki i rozszerzania podejść do  otaczającej rzeczywistości. Celem pracy jest przedstawienie ewolucji pojęcia zdrowia oraz teorii uwarunkowań stanu zdrowia formułowanych na przestrzeni wieków. Wielość definicji ukazuje ewolucję jako proces kształtujący rozumienie zdrowia, a co za tym idzie działań podejmowanych na rzecz jego ochrony. Przyjęta koncepcja i specyfika zidentyfikowanych grup czynników wpływa na cele i przyjmowane strategie umacniania potencjału zdrowotnego ludności. W pracy szczegółowo omówiono biomedyczny, psychosocjomedyczny i socjologiczny paradygmat zdrowia. Przybliżono również koncepcję stylu życia jako efektywnej drogi w zapobieganiu występowania chorób, ich rozwoju i powikłań. Słowa kluczowe: koncepcja zdrowia, paradygmat zdrowia, determinanty zdrowia, styl życia. AbstractOver the years numerous concepts of health and its protection arose. They undergo evolution above all in consequence of science development and extending approaches of surrounding reality.An aim of the work is to present the evolution of health concept and theory of health determinants formulated over the centuries. The multitude of definition shows evolution as a process that shapes understanding the health, and consequently activities undertaken for the benefit of its protection. Adopted concept and specificity of identified groups of factors affects the objectives and adopted strategies to strengthen the health potential of population.The work in detail discusses biomedical, psychosociomedical and sociological paradigm of the health. Lifestyle concept as an effective way to prevent the occurrence of diseases, their development and complications were also described. Keywords: health concept, paradigm of the health, health determinants, lifestyle

Calcium Causes a Conformational Change in Lamin A Tail Domain that Promotes Farnesyl-Mediated Membrane Association

AbstractLamin proteins contribute to nuclear structure and function, primarily at the inner nuclear membrane. The posttranslational processing pathway of lamin A includes farnesylation of the C-terminus, likely to increase membrane association, and subsequent proteolytic cleavage of the C-terminus. Hutchinson Gilford progeria syndrome is a premature aging disorder wherein a mutant version of lamin A, Δ50 lamin A, retains its farnesylation. We report here that membrane association of farnesylated Δ50 lamin A tail domains requires calcium. Experimental evidence and molecular dynamics simulations collectively suggest that the farnesyl group is sequestered within a hydrophobic region in the tail domain in the absence of calcium. Calcium binds to the tail domain with an affinity KD ≈ 250 μM where it alters the structure of the Ig-fold and increases the solvent accessibility of the C-terminus. In 2 mM CaCl2, the affinity of the farnesylated protein to a synthetic membrane is KD ≈ 2 μM, as measured with surface plasmon resonance, but showed a combination of aggregation and binding. Membrane binding in the absence of calcium could not be detected. We suggest that a conformational change induced in Δ50 lamin A with divalent cations plays a regulatory role in the posttranslational processing of lamin A, which may be important in disease pathogenesis

Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson–Gilford progeria syndrome

Hutchinson–Gilford progeria syndrome is a premature aging disorder associated with the expression of ∆50 lamin A (∆50LA), a mutant form of the nuclear structural protein lamin A (LA). ∆50LA is missing 50 amino acids from the tail domain and retains a C-terminal farnesyl group that is cleaved from the wild-type LA. Many of the cellular pathologies of HGPS are thought to be a consequence of protein–membrane association mediated by the retained farnesyl group. To better characterize the protein–membrane interface, we quantified binding of purified recombinant ∆50LA tail domain (∆50LA-TD) to tethered bilayer membranes composed of phosphatidylserine and phosphocholine using surface plasmon resonance. Farnesylated ∆50LA-TD binds to the membrane interface only in the presence of Ca[superscript 2 +] or Mg[superscript 2 +] at physiological ionic strength. At extremely low ionic strength, both the farnesylated and non-farnesylated forms of ∆50LA-TD bind to the membrane surface in amounts that exceed those expected for a densely packed protein monolayer. Interestingly, the wild-type LA-TD with no farnesylation also associates with membranes at low ionic strength but forms only a single layer. We suggest that electrostatic interactions are mediated by charge clusters with a net positive charge that we calculate on the surface of the LA-TDs. These studies suggest that the accumulation of ∆50LA at the inner nuclear membrane observed in cells is due to a combination of aggregation and membrane association rather than simple membrane binding; electrostatics plays an important role in mediating this association.National Institute of General Medical Sciences (U.S.) (1R01-GM101647)United States. Office of Naval Research. Presidential Early Career Award for Scientists and Engineers (N000141010562)National Institutes of Health (U.S.) (U01 EB014976

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a common disease in Western society and ranges from steatosis to steatohepatitis to end-stage liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanisms that are involved in the progression of steatosis to more severe liver damage in patients are not fully understood. A deeper investigation of NAFLD pathogenesis is possible due to the many different animal models developed recently. In this review, we present a comparative overview of the most common dietary NAFLD rodent models with respect to their metabolic phenotype and morphological manifestation. Moreover, we describe similarities and controversies concerning the effect of NAFLD-inducing diets on mitochondria as well as mitochondria-derived oxidative stress in the progression of NAFLD

Short- and long-term outcomes of continuous-flow left ventricular assist device therapy in 79 patients with end-stage heart failure

Introduction An increasing number of patients with end‑stage heart failure, along with a shortage of heart donors, necessitates the use of mechanical circulatory support. Objecti ves This single‑center retrospective study evaluated short- and long‑term outcomes of continuous‑flow left ventricular assist device (CF‑LVAD) therapy in patients with end‑stage heart failure. Patient s and methods We collected and assessed data of 79 patients (77 men, 2 women; mean age, 50.3 years; mean INTERMACS profile, 3.1) implanted with a CF‑LVAD between 2009 and 2017 (HeartMate 3 in 19 patients [24%]; HeartMate 2 in 9 [11.4%]; and HeartWare in 51 [64.6%]). Result s The mean time on CF‑LVAD support was 604 days (range, 1–1758 days). There were 2 device exchanges due to pump thrombosis and 1 explantation due to heart regeneration; 9 patients (11.4%) underwent heart transplant. Stroke (nondisabling, 48%) occurred in 27.8% of patients (ischemic in 9 patients; hemorrhagic, in 14; both types, in 1) despite the standardized anticoagulation regimen. Major gastrointestinal bleeding and pump thrombosis were reported in 13 patients (16.5%), while 18 patients (22.8%) developed driveline infections (recurrent in 15 patients [19%]). Hemorrhagic stroke and bacteremia had a negative impact on survival. Hemorrhagic stroke was the main cause of death. Survival probability was 0.9 at 1 month and 0.81, 0.71, 0.61, and 0.53 at 1, 2, 3, and 4 years, respectively. Conclusions Although CF‑LVAD support is associated with substantial adverse events, they do not significantly affect mortality (except hemorrhagic stroke and bacteremia). Novel devices seem to overcome these limitations, but larger studies are needed to support these findings

Kultura bezpieczeństwa obywateli a funkconowanie systemu zarządzania kryzysowego w wymiarze lokalnym. Wyniki badań empirycznych

On the basis of results of empirical research conducted in 2013, the authors present the level of security culture of representatives of administration, services of crisis management and so called common citizens in a few poviat cities and three voivodeship cities in Poland. Moreover, there are presented data concerning the quality of functioning of the crisis management system in the places where research took place, as well as the mutual dependencies between security culture of entities functioning within the crisis management system and the quality of such “a system” on the local level. The conclusion contains findings and propositions concerning the development of security culture and the increase of the quality of functioning of the crisis management system in the local dimensionNa podstawie wyników badań empirycznych przeprowadzonych w 2013 roku zaprezentowano poziom kultury bezpieczeństwa przedstawicieli administracji, służb zarządzania kryzysowego i tzw. zwykłych obywateli w kilku miastach powiatowych i w trzech miastach wojewódzkich w Polsce. Przedstawiono także dane dotyczące jakości funkcjonowania Systemu Zarządzania Kryzysowego w objętych badaniami miejscowościach, oraz wzajemne zależności między kulturą bezpieczeństwa podmiotów funkcjonujących w ramach SZK a jakością funkcjonowania tego „systemu” na szczeblu lokalnym. Zakończenie zawiera wnioski i propozycje dotyczące doskonalenia kultury bezpieczeństwa i podnoszenia jakości funkcjonowania SZK w wymiarze lokalny

Mechanical circulatory support restores eligibility for heart transplant in patients with significant pulmonary hypertension

Background: An increasing number of patients with end‑stage heart failure implies a wider use of left ventricular assist devices (LVADs). Irreversible pulmonary hypertension (PH) is a predictor of unfavorable prognosis and a contraindication to orthotopic heart transplant (OHT). Aims: The aim of this study was to evaluate the effect of continuous‑flow LVAD (CF‑LVAD) support on pulmonary pressure and pulmonary vascular resistance (PVR) as well as the impact of pre‑LVAD hemodynamic parameters on survival during LVAD support. Methods: Data collected from 106 patients who underwent CF‑LVAD implantation in the years 2009 to 2018 (men, 95.3%; mean [SD] age, 51.8 [12] years; mean [SD] INTERMACS profile, 2.9 [1.6]; mean [SD] LVAD support time, 661 [520] days; follow‑up until May 2019) were retrospectively analyzed. Results: Right heart catheterization was performed before LVAD implantation in 94 patients (88.7%), after implantation—in 31 (29.2%), and before and after implantation—in 28 (26.4%). We observed mean pulmonary artery pressure (mPAP) > 25 mm Hg in 65 patients (61.3%) and PVR > 2.5 Wood units in 33 patients (31.1%) before LVAD implantation. A significant improvement after CF‑LVAD implantation was noted in mPAP, pulmonary capillary wedge pressure, transpulmonary gradient, PVR, cardiac output (P < 0.001 for all parameters), and cardiac index (P = 0.003). All patients with initially irreversible PH became eligible for OHT during LVAD support. Survival during LVAD support did not depend on initial mPAP and PVR. Conclusions: In patients with end‑stage heart failure, CF‑LVAD support leads to a significant reduction of pre‑ and postcapillary PH. Survival on CF‑LVAD support is independent of elevated mPAP and PVR before implantation, which suggests that LVADs decrease the risk associated with PH