RESUMEN
We studied the mechanical leaflet coupling of prototypic mammalian plasma membranes using neutron spin-echo spectroscopy. In particular, we examined a series of asymmetric phospholipid vesicles with phosphatidylcholine and sphingomyelin enriched in the outer leaflet and inner leaflets composed of phosphatidylethanolamine/phosphatidylserine mixtures. The bending rigidities of most asymmetric membranes were anomalously high, exceeding even those of symmetric membranes formed from their cognate leaflets. Only asymmetric vesicles with outer leaflets enriched in sphingolipid displayed bending rigidities in conformity with these symmetric controls. We performed complementary small-angle neutron and x-ray experiments on the same vesicles to examine possible links to structural coupling mechanisms, which would show up in corresponding changes in membrane thickness. In addition, we estimated differential stress between leaflets originating either from a mismatch of their lateral areas or spontaneous curvatures. However, no correlation with asymmetry-induced membrane stiffening was observed. To reconcile our findings, we speculate that an asymmetric distribution of charged or H-bond forming lipids may induce an intraleaflet coupling, which increases the weight of hard undulatory modes of membrane fluctuations and hence the overall membrane stiffness.
Asunto(s)
Fosfatidilcolinas , Fosfolípidos , Animales , Membrana Celular/química , Fosfolípidos/química , Membranas , Fosfatidilcolinas/química , Esfingomielinas , Membrana Dobles de Lípidos/química , MamíferosRESUMEN
AIMS: Cardiac rehabilitation (CR), a key component of secondary prevention in cardiac patients, contributes fundamentally to improved cardiovascular health outcomes. Health-related quality of life (HRQOL) represents a widely employed outcome measure in CR, yet, its predictive properties on exercise capacity change during CR are poorly understood. Aim of this study was to examine the association between baseline HRQOL and its subdomains on improvement of exercise capacity during CR. METHODS: Study participants were 13,717 inpatients of six Swiss CR clinics from 2012 to 2018. We measured HRQOL at admission to CR with the MacNew Heart (MNH) questionnaire and exercise capacity at admission and discharge using the six minutes walking test (6MWT). Following factorial analyses, we performed univariate and multivariate analyses to test the predictive properties of baseline global HRQOL and its domains for improvement in exercise capacity, adjusting for demographic and clinical characteristics. RESULTS: Mean improvement in 6MWT was 114 m (SD = 90), achieved after 17.4 days (SD = 5.5). Lower emotional HRQOL (b = 7.85, p = < .001, 95% CI [- 5.67, 10.03]) and higher physical HRQOL (b = - 5.23, p < .001, 95% CI [- 6.56, - 3.90]) were associated with less improvement in the 6MWT. Global MNH and social HRQOL showed no association with exercise capacity improvement. CONCLUSION: Patients entering CR with low emotional and high physical HRQOL are at risk for a lower gain in exercise capacity during CR. Global MNH alone does not provide a reliable assessment of HRQOL; thus a focus on specific domains of HRQOL is needed.
Asunto(s)
Rehabilitación Cardiaca , Calidad de Vida , Humanos , Calidad de Vida/psicología , Terapia por Ejercicio , Emociones , CaminataRESUMEN
Forensic psychiatric populations commonly contain a subset of persons with schizophrenia spectrum disorders (SSD) who have committed sex offenses. A comprehensive delineation of the features that distinguish persons with SSD who have committed sex offenses from persons with SSD who have committed violent non-sex offenses could be relevant to the development of differentiated risk assessment, risk management and treatment approaches. This analysis included the patient records of 296 men with SSD convicted of at least one sex and/or violent offense who were admitted to the Centre for Inpatient Forensic Therapy at the University Hospital of Psychiatry Zurich between 1982 and 2016. Using supervised machine learning, data on 461 variables retrospectively collected from the records were compared with respect to their relative importance in differentiating between men who had committed sex offenses and men who had committed violent non-sex offenses. The final machine learning model was able to differentiate between the two types of offenders with a balanced accuracy of 71.5% (95% CI = [60.7, 82.1]) and an AUC of .80 (95% CI = [.67, .93]). The main distinguishing features included sexual behaviours and interests, psychopathological symptoms and characteristics of the index offense. Results suggest that when assessing and treating persons with SSD who have committed sex offenses, it appears to be relevant to not only address the core symptoms of the disorder, but to also take into account general risk factors for sexual recidivism, such as atypical sexual interests and sexual preoccupation.
RESUMEN
We studied the transleaflet coupling of compositionally asymmetric liposomes in the fluid phase. The vesicles were produced by cyclodextrin-mediated lipid exchange and contained dipalmitoyl phosphatidylcholine (DPPC) in the inner leaflet and different mixed-chain phosphatidylcholines (PCs) as well as milk sphingomyelin (MSM) in the outer leaflet. In order to jointly analyze the obtained small-angle neutron and X-ray scattering data, we adapted existing models of trans-bilayer structures to measure the overlap of the hydrocarbon chain termini by exploiting the contrast of the terminal methyl ends in X-ray scattering. In all studied systems, the bilayer-asymmetry has large effects on the lipid packing density. Fully saturated mixed-chain PCs interdigitate into the DPPC-containing leaflet and evoke disorder in one or both leaflets. The long saturated acyl chains of MSM penetrate even deeper into the opposing leaflet, which in turn has an ordering effect on the whole bilayer. These results are qualitatively understood in terms of a balance of entropic repulsion of fluctuating hydrocarbon chain termini and van der Waals forces, which is modulated by the interdigitation depth. Monounsaturated PCs in the outer leaflet also induce disorder in DPPC despite vestigial or even absent interdigitation. Instead, the transleaflet coupling appears to emerge here from a matching of the inner leaflet lipids to the larger lateral lipid area of the outer leaflet lipids.
Asunto(s)
Ciclodextrinas , Esfingomielinas , Esfingomielinas/química , 1,2-Dipalmitoilfosfatidilcolina , Membrana Dobles de Lípidos/química , Liposomas , Fosfatidilcolinas/químicaRESUMEN
High-accuracy mass measurements of neutron-deficient Yb isotopes have been performed at TRIUMF using TITAN's multiple-reflection time-of-flight mass spectrometer (MR-TOF-MS). For the first time, an MR-TOF-MS was used on line simultaneously as an isobar separator and as a mass spectrometer, extending the measurements to two isotopes further away from stability than otherwise possible. The ground state masses of ^{150,153}Yb and the excitation energy of ^{151}Yb^{m} were measured for the first time. As a result, the persistence of the N=82 shell with almost unmodified shell gap energies is established up to the proton drip line. Furthermore, the puzzling systematics of the h_{11/2}-excited isomeric states of the N=81 isotones are unraveled using state-of-the-art mean field calculations.
RESUMEN
We report on the response of asymmetric lipid membranes composed of palmitoyl oleoyl phosphatidylethanolamine and palmitoyl oleoyl phosphatidylglycerol, to interactions with the frog peptides L18W-PGLa and magainin 2 (MG2a), as well as the lactoferricin derivative LF11-215. In particular we determined the peptide-induced lipid flip-flop, as well as membrane partitioning of L18W-PGLa and LF11-215, and vesicle dye-leakage induced by L18W-PGLa. The ability of L18W-PGLa and MG2a to translocate through the membrane appears to correlate with the observed lipid flip-flop, which occurred at the fastest rate for L18W-PGLa. The higher structural flexibility of LF11-215 in turn allows this peptide to insert into the bilayers without detectable changes of membrane asymmetry. The increased vulnerability of asymmetric membranes to L18W-PGLa in terms of permeability, appears to be a consequence of tension differences between the compositionally distinct leaflets, but not due to increased peptide partitioning.
Asunto(s)
Péptidos Antimicrobianos , Membrana Dobles de Lípidos , Membrana Celular , MagaininasRESUMEN
Small-angle X-ray and neutron scattering are well-established, non-invasive experimental techniques to interrogate global structural properties of biological membrane mimicking systems under physiologically relevant conditions. Recent developments, both in bottom-up sample preparation techniques for increasingly complex model systems, and in data analysis techniques have opened the path toward addressing long standing issues of biological membrane remodelling processes. These efforts also include emerging quantitative scattering studies on live cells, thus enabling a bridging of molecular to cellular length scales. Here, we review recent progress in devising compositional models for joint small-angle X-ray and neutron scattering studies on diverse membrane mimics - with a specific focus on membrane structural coupling to amphiphatic peptides and integral proteins - and live Escherichia coli. In particular, we outline the present state-of-the-art in small-angle scattering methods applied to complex membrane systems, highlighting how increasing system complexity must be followed by an advance in compositional modelling and data-analysis tools.
Asunto(s)
Difracción de Neutrones , Neutrones , Membrana Celular , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Rayos XRESUMEN
Atherosclerosis is a major burden for all societies, and there is a great need for a deeper understanding of involved key inflammatory, immunological and biomechanical processes. A decisive step for the prevention and medical treatment of atherosclerosis is to predict what conditions determine whether early atherosclerotic plaques continue to grow, stagnate or become regressive. The driving biological and mechanobiological mechanisms that determine the stability of plaques are yet not fully understood. We develop a spatially resolved and quantitative mathematical model of key contributors of early atherosclerosis. The stability of atherosclerotic model plaques is assessed to identify and classify progression-prone and progression-resistant atherosclerotic regions based on measurable or computable in vivo inputs, such as blood cholesterol concentrations and wall shear stresses. The model combines Darcy's law for the transmural flow through vessels walls, the Kedem-Katchalsky equations for endothelial fluxes of lipoproteins, a quantitative model of early plaque formation from a recent publication and a novel submodel for macrophage recruitment. The parameterization and analysis of the model suggest that the advective flux of lipoproteins through the endothelium is decisive, while the influence of the advective transport within the artery wall is negligible. Further, regions in arteries with an approximate wall shear stress exposure below 20% of the average exposure and their surroundings are potential regions where progression-prone atherosclerotic plaques develop.
Asunto(s)
Aterosclerosis/etiología , Modelos Cardiovasculares , Aterosclerosis/patología , Aterosclerosis/fisiopatología , Transporte Biológico Activo , Movimiento Celular/fisiología , Progresión de la Enfermedad , Endotelio Vascular/fisiología , Endotelio Vascular/fisiopatología , Análisis de Elementos Finitos , Hemodinámica/fisiología , Hemorreología/fisiología , Humanos , Lipoproteínas/fisiología , Macrófagos/patología , Macrófagos/fisiología , Conceptos Matemáticos , Placa Aterosclerótica/etiología , Placa Aterosclerótica/patología , Placa Aterosclerótica/fisiopatologíaRESUMEN
OBJECTIVE: Neutrophils accumulate in early atherosclerotic lesions and promote lesion growth. In this study, we evaluated an elastase-specific near-infrared imaging agent for molecular imaging using hybrid fluorescence molecular tomography/x-ray computed tomography. APPROACH AND RESULTS: Murine neutrophils were isolated from bone marrow and incubated with the neutrophil-targeted near-infrared imaging agent Neutrophil Elastase 680 FAST for proof of principle experiments, verifying that the elastase-targeted fluorescent agent is specifically cleaved and activated by neutrophil content after lysis or cell stimulation. For in vivo experiments, low-density lipoprotein receptor-deficient mice were placed on a Western-type diet and imaged after 4, 8, and 12 weeks by fluorescence molecular tomography/x-ray computed tomography. Although this agent remains silent on injection, it produces fluorescent signal after cleavage by neutrophil elastase. After hybrid fluorescence molecular tomography/x-ray computed tomography imaging, mice were euthanized for whole-body cryosectioning and histological analyses. The in vivo fluorescent signal in the area of the aortic arch was highest after 4 weeks of high-fat diet feeding and decreased at 8 and 12 weeks. Ex vivo whole-body cryoslicing confirmed the fluorescent signal to locate to the aortic arch and to originate from the atherosclerotic arterial wall. Histological analysis demonstrated the presence of neutrophils in atherosclerotic lesions. CONCLUSIONS: This study provides evidence that elastase-targeted imaging can be used for in vivo detection of early atherosclerosis. This imaging approach may harbor potential in the clinical setting for earlier diagnosis and treatment of atherosclerosis.
Asunto(s)
Aorta Torácica/diagnóstico por imagen , Enfermedades de la Aorta/diagnóstico por imagen , Aterosclerosis/diagnóstico por imagen , Elastasa de Leucocito/metabolismo , Imagen Molecular/métodos , Imagen Multimodal/métodos , Neutrófilos/enzimología , Imagen Óptica , Tomografía Computarizada por Rayos X , Animales , Aorta Torácica/enzimología , Aorta Torácica/patología , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/enzimología , Aterosclerosis/genética , Aterosclerosis/patología , Biomarcadores/metabolismo , Células Cultivadas , Dieta Occidental , Modelos Animales de Enfermedad , Diagnóstico Precoz , Colorantes Fluorescentes/administración & dosificación , Predisposición Genética a la Enfermedad , Ratones Noqueados , Neutrófilos/patología , Fenotipo , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de TiempoRESUMEN
There are a growing number of studies that model immunological processes in the artery wall that lead to the development of atherosclerotic plaques. However, few of these models use parameters that are obtained from experimental data even though data-driven models are vital if mathematical models are to become clinically relevant. We present the development and analysis of a quantitative mathematical model for the coupled inflammatory, lipid and macrophage dynamics in early atherosclerotic plaques. Our modeling approach is similar to the biologists' experimental approach where the bigger picture of atherosclerosis is put together from many smaller observations and findings from in vitro experiments. We first develop a series of three simpler submodels which are least-squares fitted to various in vitro experimental results from the literature. Subsequently, we use these three submodels to construct a quantitative model of the development of early atherosclerotic plaques. We perform a local sensitivity analysis of the model with respect to its parameters that identifies critical parameters and processes. Further, we present a systematic analysis of the long-term outcome of the model which produces a characterization of the stability of model plaques based on the rates of recruitment of low-density lipoproteins, high-density lipoproteins and macrophages. The analysis of the model suggests that further experimental work quantifying the different fates of macrophages as a function of cholesterol load and the balance between free cholesterol and cholesterol ester inside macrophages may give valuable insight into long-term atherosclerotic plaque outcomes. This model is an important step toward models applicable in a clinical setting.
Asunto(s)
Modelos Cardiovasculares , Placa Aterosclerótica/etiología , Animales , Colesterol/metabolismo , Simulación por Computador , Humanos , Técnicas In Vitro , Lipoproteínas/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Conceptos Matemáticos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologíaRESUMEN
We study single- and multiquantum transitions of the nuclear spins of an ensemble of ionized arsenic donors in silicon and find quadrupolar effects on the coherence times, which we link to fluctuating electrical field gradients present after the application of light and bias voltage pulses. To determine the coherence times of superpositions of all orders in the 4-dimensional Hilbert space, we use a phase-cycling technique and find that, when electrical effects were allowed to decay, these times scale as expected for a fieldlike decoherence mechanism such as the interaction with surrounding ^{29}Si nuclear spins.
RESUMEN
Real-time feedback from iterative electronic structure calculations requires to mediate between the inherently unpredictable execution times of the iterative algorithm used and the necessity to provide data in fixed and short time intervals for real-time rendering. We introduce the concept of a mediator as a component able to deal with infrequent and unpredictable reference data to generate reliable feedback. In the context of real-time quantum chemistry, the mediator takes the form of a surrogate potential that has the same local shape as the first-principles potential and can be evaluated efficiently to deliver atomic forces as real-time feedback. The surrogate potential is updated continuously by electronic structure calculations and guarantees to provide a reliable response to the operator for any molecular structure. To demonstrate the application of iterative electronic structure methods in real-time reactivity exploration, we implement self-consistent semiempirical methods as the data source and apply the surrogate-potential mediator to deliver reliable real-time feedback.
RESUMEN
Elucidating chemical reactivity in complex molecular assemblies of a few hundred atoms is, despite the remarkable progress in quantum chemistry, still a major challenge. Black-box search methods to find intermediates and transition-state structures might fail in such situations because of the high-dimensionality of the potential energy surface. Here, we propose the concept of interactive chemical reactivity exploration to effectively introduce the chemist's intuition into the search process. We employ a haptic pointer device with force feedback to allow the operator the direct manipulation of structures in three dimensions along with simultaneous perception of the quantum mechanical response upon structure modification as forces. We elaborate on the details of how such an interactive exploration should proceed and which technical difficulties need to be overcome. All reactivity-exploration concepts developed for this purpose have been implemented in the samson programming environment.
RESUMEN
Small-angle X-ray and neutron scattering (SAXS/SANS) techniques excel in unveiling intricate details of the internal structure of lipid membranes under physiologically relevant temperature and buffer conditions, all without the need to resort to bulky labels. By concurrently conducting and analyzing neutron and X-ray data, these methods harness the complete spectrum of contrast and resolution from various components constituting lipid membranes. Despite this, the literature exhibits only a sparse presence of applications compared to other techniques in membrane biophysics. This chapter serves as a primer for conducting joint SAXS/SANS analyses on symmetric and asymmetric large unilamellar vesicles, elucidating fundamental elements of the analysis process. Specifically, we introduce the basics of interactions of X-rays and neutrons with matter that lead to the scattering contrast and a description of membrane structure in terms of scattering length density profiles. These profiles allow fitting of the experimentally observed scattering intensity. We further integrate practical insights, unveiling strategies for successful data acquisition and providing a comprehensive assessment of the technique's advantages and drawbacks. By amalgamating theoretical underpinnings with practical considerations, this chapter aims to dismantle barriers hindering the adoption of joint SAXS/SANS approaches, thereby encouraging an influx of studies in this domain.
Asunto(s)
Difracción de Neutrones , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Difracción de Neutrones/métodos , Difracción de Rayos X/métodos , Lípidos de la Membrana/química , Liposomas Unilamelares/química , Membrana Dobles de Lípidos/químicaRESUMEN
How can an animal learn from experience? How can it train sensors, such as the auditory or tactile system, based on other sensory input such as the visual system? Supervised spike-timing-dependent plasticity (supervised STDP) is a possible answer. Supervised STDP trains one modality using input from another one as "supervisor." Quite complex time-dependent relationships between the senses can be learned. Here we prove that under very general conditions, supervised STDP converges to a stable configuration of synaptic weights leading to a reconstruction of primary sensory input.
Asunto(s)
Algoritmos , Encéfalo/fisiología , Aprendizaje/fisiología , Plasticidad Neuronal/fisiología , Redes Neurales de la ComputaciónRESUMEN
We present the software package M(O)V(I)P(AC) for calculations of vibrational spectra, namely infrared, Raman, and Raman Optical Activity (ROA) spectra, in a massively parallelized fashion. M(O)V(I)P(AC) unites the latest versions of the programs SNF and AKIRA alongside with a range of helpful add-ons to analyze and interpret the data obtained in the calculations. With its efficient parallelization and meta-program design, M(O)V(I)P(AC) focuses in particular on the calculation of vibrational spectra of very large molecules containing on the order of a hundred atoms. For this purpose, it also offers different subsystem approaches such as Mode- and Intensity-Tracking to selectively calculate specific features of the full spectrum. Furthermore, an approximation to the entire spectrum can be obtained using the Cartesian Tensor Transfer Method. We illustrate these capabilities using the example of a large π-helix consisting of 20 (S)-alanine residues. In particular, we investigate the ROA spectrum of this structure and compare it to the spectra of α- and 3(10)-helical analogs.
Asunto(s)
Programas Informáticos , Adenina/química , Algoritmos , Aminoácidos/química , Teoría Cuántica , Espectrofotometría Infrarroja , Espectrometría Raman , Timina/químicaRESUMEN
We report the real-time response of Escherichia coli to lactoferricin-derived antimicrobial peptides (AMPs) on length scales bridging microscopic cell sizes to nanoscopic lipid packing using millisecond time-resolved synchrotron small-angle X-ray scattering. Coupling a multiscale scattering data analysis to biophysical assays for peptide partitioning revealed that the AMPs rapidly permeabilize the cytosolic membrane within less than 3 s-much faster than previously considered. Final intracellular AMP concentrations of â¼80-100 mM suggest an efficient obstruction of physiologically important processes as the primary cause of bacterial killing. On the other hand, damage of the cell envelope and leakage occurred also at sublethal peptide concentrations, thus emerging as a collateral effect of AMP activity that does not kill the bacteria. This implies that the impairment of the membrane barrier is a necessary but not sufficient condition for microbial killing by lactoferricins. The most efficient AMP studied exceeds others in both speed of permeabilizing membranes and lowest intracellular peptide concentration needed to inhibit bacterial growth.
Asunto(s)
Antibacterianos , Péptidos Catiónicos Antimicrobianos , Membrana Celular , Escherichia coli , Lactoferrina , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/metabolismo , Péptidos Catiónicos Antimicrobianos/farmacología , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Espacio Intracelular/química , Espacio Intracelular/microbiología , Lactoferrina/metabolismo , Lactoferrina/farmacología , Factores de TiempoRESUMEN
A method is proposed for the automated generation of potential energy surfaces in high dimensions. It combines the existing algorithm for the definition of new energy data points, based on the interpolating moving least-squares algorithm with a simulated annealing procedure. This method is then studied in a haptic quantum chemistry environment that requires a fast evaluation of gradients on a potential energy surface with automatic improvement of its accuracy. As an example we investigate the nitrogen binding pathway in the Schrock dinitrogen fixation complex with this set-up.
RESUMEN
We developed a global X-ray data analysis method to determine the intrinsic curvatures of lipids hosted in inverted hexagonal phases. In particular, we combined compositional modelling with molecular shape-based arguments to account for non-linear mixing effects of guest-in-host lipids on intrinsic curvature. The technique was verified by all-atom molecular dynamics simulations and applied to sphingomyelin and a series of phosphatidylcholines and ceramides with differing composition of the hydrocarbon chains. We report positive lipid curvatures for sphingomyelin and all phosphatidylcholines with disaturated and monounsaturated hydrocarbons. Phosphatidylcholines with diunsaturated hydrocarbons in turn yielded intrinsic lipid curvatures with negative values. All ceramides, with chain lengths varying between C2:0 and C24:0, displayed significant negative lipid curvature values. Moreover, we report non-additive mixing for C2:0 ceramide and sphingomyelin. This suggests for sphingolipids that in addition to lipid headgroup and hydrocarbon chain volumes also lipid-specific interactions are important contributors to membrane curvature stress.
Asunto(s)
Ceramidas/química , Lípidos/química , Membrana Celular/química , Simulación de Dinámica Molecular , Dispersión del Ángulo Pequeño , Esfingomielinas/química , Difracción de Rayos XRESUMEN
BACKGROUND AND AIMS: Recent research has identified higher prevalence of offending behavior in patients with comorbid schizophrenia spectrum disorder (SSD) and substance use disorder (SUD) compared to patients with SSD only and to the general population. However, findings on the subgroup of patients with SUD, SSD and offending behavior in forensic psychiatric care are scarce and inconsistent. The present study used machine learning to uncover more detailed characteristics of offender patients in forensic psychiatric care with comorbid SSD and SUD. METHODS: Using machine learning algorithms, 370 offender patients (91.6 % male, mean age of M = 34.1, SD = 10.2) and 558 variables were explored in order to build three models to differentiate between no substance use disorder, cannabis use disorder and any other substance use disorder. To counteract the risk of overfitting, the dataset was split, employing variable filtering, machine learning model building and selection embedded in a nested resampling approach on one subset. The best model was then selected and validated on the second data subset. RESULTS: Distinguishing between SUD vs. no drug use disorder yielded models with an AUC of 70 and 78. Variables assignable to demographics, social disintegration, antisocial behavior and illness were identified as most influential for the distinction. The model comparing cannabis use disorder with other substance use disorders provided no significant differences. CONCLUSIONS: From a clinical perspective, offender patients suffering from schizophrenia spectrum and comorbid substance use disorder seem particularly challenging to treat, but initial differences in psychopathology will dissipate over inpatient treatment. Our data suggest that offender patients may benefit from appropriate treatment that focuses on illicit drug abuse to reduce criminal behavior and improve social integration.