Membrane pores can significantly alter not only the permeation dynamics of biological membranes but also their elasticity. Large membrane pores able to transport macromolecular contents represent an ...interesting model to test theoretical predictions that assign active-like (non-equilibrium) behavior to the permeability contributions to the enhanced membrane fluctuations existing in permeable membranes Maneville et al. Phys. Rev. Lett. 82, 4356 (1999). Such high-amplitude active contributions arise from the forced transport of solvent and solutes through the open pores, which becomes even dominant at large permeability. In this paper, we present a detailed experimental analysis of the active shape fluctuations that appear in highly permeable lipid vesicles with large macromolecular pores inserted in the lipid membrane, which are a consequence of transport permeability events occurred in an osmotic gradient. The experimental results are found in quantitative agreement with theory, showing a remarkable dependence with the density of membrane pores and giving account of mechanical compliances and permeability rates that are compatible with the large size of the membrane pore considered. The presence of individual permeation events has been detected in the fluctuation time-series, from which a stochastic distribution of the permeation events compatible with a shot-noise has been deduced. The non-equilibrium character of the membrane fluctuations in a permeation field, even if the membrane pores are mere passive transporters, is clearly demonstrated. Finally, a bio-nano-technology outlook of the proposed synthetic concept is given on the context of prospective uses as active membrane DNA-pores exploitable in gen-delivery applications based on lipid vesicles.
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•Membrane pores alter the permeation dynamics of biological membranes and their elasticity.•DNA-translocating pores can be used to transport macromolecular contents across membranes.•They represent an interesting model to test theoretical predictions of active-like (non-equilibrium) behavior to membrane permeability•Individual permeation events have been detected in the time-series of the membrane fluctuations.•The membrane fluctuations in a permeation field are out-of-equilibrium
We study thermal undulations of giant bilayer vesicles by flickering spectroscopy. The experimental fluctuation spectra are scrutinized in view of the classical Helfrich theory. Pure bending modes ...are revealed to be unable to predict the large fluctuations systematically found at a high wave vector. Hybrid curvature-dilational modes are then invoked as a more efficient mode of motion in producing high curvatures. A bimodal spectrum of the thermal undulations has been theoretically developed for the shell-like topology. Reconciliation between experiments and theory is achieved when this bimodal spectrum is considered.
Although classically classified as a non-inflammatory condition, an inflammatory basis for keratoconus (KC) appears to be a growing evidence. Recently, it has been shown that KC patients have an ...increased choroidal thickness (CT). Among inflammatory disorders, atopy has been associated with KC development; therefore, the aim of this study was to evaluate if the increased CT in patients with KC is related to atopy.
This is an analytical cross-sectional study of patients with KC. Patients were classified as atopic and non-atopic according to their atopy history (allergic rhinoconjunctivitis (AR), asthma (AA) and/or atopic dermatitis (AD)) and were also classified based on their eye rubbing habits. Choroidal profile of all subjects was evaluated using a Spectralis optical coherence tomography (OCT) device with enhanced depth imaging (EDI) mode. CT was measured and compared between groups at the center of the fovea and at 500 µm intervals along a horizontal section. A multivariable analysis, adjusted for sex, age, spherical equivalent, history of medication and atopy, was performed to assess the influence of atopy in CT.
Of the 80 patients included, 51 were atopic and 29 non-atopic. Atopic patients showed a thicker choroid in every measured location than the non-atopic patients (mean subfoveal CT 391.53 µm vs 351.17 µm, respectively), although the differences were not statistically different. The multivariable analysis revealed that being atopic makes the choroid statistically thicker, on average, 55.14 µm, when compared to non-atopic patients (p=0.043). Furthermore, patients who are frequent eye rubbers have significantly thicker choroids than non-rubbers (p=0.004).
Although some results do not reach statistical significance, atopic KC patients seem to have thicker choroids compared with non-atopic KC patients, suggesting a possible role for atopy in the choroidal profile of KC. This constitutes a completely new sight in this field of research that needs further investigation.
Abstract
Background
Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to ...develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment.
Methods
The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model.
Results
The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in all its different definitions, when adjusted for several confounding factors (Fig. 1). Additionally, alongside FC, both IFX and C-reactive protein demonstrated a significant impact on the temporal aspect of disease progression.
Conclusion
In this 2-year prospective real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that persistent gut damage, as mirrored by FC, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of the progression of the underlying disease. These findings underscore the imperative need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.
Age-related white matter changes have been associated with cognitive functioning, even though their role is not fully understood. This work aimed to test a 3-factor model of the neuropsychological ...assessment battery and evaluate how the model fit the data longitudinally. Confirmatory factor analysis (CFA) was used to investigate the dimensions of a structured set of neuropsychological tests administered to a multicenter, international sample of independent older adults (LADIS study). Six hundred and thirty-eight older adults completed baseline neuropsychological, clinical, functional and motor assessments, which were repeated each year for a 3-year follow-up. CFA provided support for a 3-factor model. These factors involve the dimensions of executive functions, memory functions, and speed and motor control abilities. Performance decreased in most neuropsychological measures. Results showed that executive functioning, memory and speed of motor abilities are valid latent variables of neuropsychological performance among older adults, and that this structure is relatively consistent longitudinally, even though performance decreases with time.
Objectives To explore the behaviors of parents and nurses during the immunization process and their association with children's distress and coping in a sample of Portuguese preschool-aged children; ...to identify similarities and differences in the behavior of parents, nurses, and children, as well as in the relation between adults’ behaviors and child distress and coping, with those previously identified by the Interactive Model of Acute Child Distress, from Blount et al. (1992). Method A total of nine nurses, 89 children aged 3–6, and their parents participated. Behaviors were videotaped and scored according to CAMPIS-R operational definitions. Measures of parents and nurses’ ratings of children's distress and of child-rated distress were obtained. Results Our results show not only similarities, but also important divergences from previous research. New adult codes were proposed. Only two new codes, and another code previously considered neutral, significantly contributed to explain the association between adult and child behavior. Conclusions Portuguese nurses and parents’ behaviors during immunization show some important cultural differences.
The portal connector of bacteriophage viruses constitutes a robust molecular machine for DNA translocation. In this paper we propose an optimized reconstitution method for efficient orthogonal ...integration of native viral connectors into lipid bilayers, particularly of giant unilamellar vesicles. Our nanoengineering plan considers the hydrophilic connector protein of the bacteriophage virus ϕ29 integrated into a specifically engineered bilayer made of “hydrophylized” lipids. From the precise knowledge of the connector structure, the membrane chemistry was designed by tuning reactivity in the bilayer using specific functional lipids. We show details on the reconstitution methods and experimental evidence about the integration of the portal protein in the engineered membrane. The proposed route provides an efficient method for orthogonal integration of native viral connectors into lipid bilayers in conditions adequate for functional DNA translocation. This concept could be potentially exploited in advanced nanotechnological realizations, particularly for the integration of these powerful machines into giant lipid vesicles with the aim of building a cargo-device useful for gene delivery applications.
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