Analytical approximation to the multidimensional Fokker--Planck equation with steady state

The Fokker--Planck equation is a key ingredient of many models in physics, and related subjects, and arises in a diverse array of settings. Analytical solutions are limited to special cases, and resorting to numerical simulation is often the only route available; in high dimensions, or for parametric studies, this can become unwieldy. Using asymptotic techniques, that draw upon the known Ornstein--Uhlenbeck (OU) case, we consider a mean-reverting system and obtain its representation as a product of terms, representing short-term, long-term, and medium-term behaviour. A further reduction yields a simple explicit formula, both intuitive in terms of its physical origin and fast to evaluate. We illustrate a breadth of cases, some of which are `far' from the OU model, such as double-well potentials, and even then, perhaps surprisingly, the approximation still gives very good results when compared with numerical simulations. Both one- and two-dimensional examples are considered.Comment: Updated version as publishe

Temporal endogenous gene expression profiles in response to polymer-mediated transfection and profile comparison to lipid-mediated transfection

Background Design of efficient nonviral gene delivery systems is limited by the rudimentary understanding of specific molecules that facilitate transfection. Methods Polyplexes using 25-kDa polyethylenimine (PEI) and plasmid encoding green fluorescent protein (GFP) were delivered to HEK 293T cells. After treating cells with polyplexes, microarrays were used to identify endogenous genes differentially expressed between treated and untreated cells (2 h of exposure) or between flow-separated transfected cells (GFP+) and treated, untransfected cells (GFP–) at 8, 16 and 24 h after lipoplex treatment. Cell priming studies were conducted using pharmacologic agents to alter endogenous levels of the identified differentially expressed genes to determine effect on transfection levels. Differentially expressed genes in polyplex-mediated transfection were compared with those differentially expressed in lipoplex transfection to identify DNA carrier-dependent molecular factors. Results Differentially expressed genes were RGS1, ARHGAP24, PDZD2, SNX24, GSN and IGF2BP1 after 2 h; RAP1A and ACTA1 after 8 h; RAP1A, WDR78 and ACTA1 after 16 h; and RAP1A, SCG5, ATF3, IREB2 and ACTA1 after 24 h. Pharmacologic studies altering endogenous levels for ARHGAP24, GSN, IGF2BP1, PDZD2 and RGS1 were able to increase or decrease transgene production. Comparing differentially expressed genes for polyplexes and lipoplexes, no common genes were identified at the 2-h time point, whereas, after the 8-h time point, RAP1A, ATF3 and HSPA6 were similarly expressed. SCG5 and PGAP1 were only upregulated in polyplex-transfected cells. Conclusions The identified genes and pharmacologic agents provide targets for improving transfection systems, although polyplex or lipoplex dependencies must be considered. Includes supplementary materials

Temporal endogenous gene expression profiles in response to lipid-mediated transfection

Background — Design of efficient nonviral gene delivery systems is limited as a result of the rudimentary understanding of the specific molecules and processes that facilitate DNA transfer. Methods — Lipoplexes formed with Lipofectamine 2000 (LF2000) and plasmid-encoding green fluorescent protein (GFP) were delivered to the HEK 293T cell line. After treating cells with lipoplexes, HG-U133 Affymetrix microarrays were used to identify endogenous genes differentially expressed between treated and untreated cells (2 h exposure) or between flow-separated transfected cells (GFP+) and treated, untransfected cells (GFP–) at 8, 16 and 24 h after lipoplex treatment. Cell priming studies were conducted using pharmacologic agents to alter endogenous levels of the identified differentially expressed genes to determine effect on transfection levels. Results — Relative to untreated cells 2 h after lipoplex treatment, only downregulated genes were identified ≥ 30-fold: ALMS1, ITGB1, FCGR3A, DOCK10 and ZDDHC13. Subsequently, relative to GFP– cells, the GFP+ cell population showed at least a five-fold upregulation of RAP1A and PACSIN3 (8 h) or HSPA6 and RAP1A (16 and 24 h). Pharmacologic studies altering endogenous levels for ALMS1, FCGR3A, and DOCK10 (involved in filopodia protrusions), ITGB1 (integrin signaling), ZDDHC13 (membrane trafficking) and PACSIN3 (proteolytic shedding of membrane receptors) were able to increase or decrease transgene production. Conclusions — RAP1A, PACSIN3 and HSPA6 may help lipoplex-treated cells overcome a transcriptional shutdown due to treatment with lipoplexes and provide new targets for investigating molecular mechanisms of transfection or for enhancing transfection through cell priming or engineering of the nonviral gene delivery system. Includes supporting materials

Micro- and nanoparticulates for DNA vaccine delivery

DNA vaccination has emerged as a promising alternative to traditional protein-based vaccines for the induction of protective immune responses. DNA vaccines offer several advantages over traditional vaccines, including increased stability, rapid and inexpensive production, and flexibility to produce vaccines for a wide variety of infectious diseases. However, the immunogenicity of DNA vaccines delivered as naked plasmid DNA is often weak due to degradation of the DNA by nucleases and inefficient delivery to immune cells. Therefore, biomaterial-based delivery systems based on micro- and nanoparticles that encapsulate plasmid DNA represent the most promising strategy for DNA vaccine delivery. Microparticulate delivery systems allow for passive targeting to antigen presenting cells through size exclusion and can allow for sustained presentation of DNA to cells through degradation and release of encapsulated vaccines. In contrast, nanoparticle encapsulation leads to increased internalization, overall greater transfection efficiency, and the ability to increase uptake across mucosal surfaces. Moreover, selection of the appropriate biomaterial can lead to increased immune stimulation and activation through triggering innate immune response receptors and target DNA to professional antigen presenting cells. Finally, the selection of materials with the appropriate properties to achieve efficient delivery through administration routes conducive to high patient compliance and capable of generating systemic and local (i.e. mucosal) immunity can lead to more effective humoral and cellular protective immune responses. In this review, we discuss the development of novel biomaterial- based delivery systems to enhance the delivery of DNA vaccines through various routes of administration and their implications for generating immune responses

A Variable Kinematic One-Dimensional Model for the Hygro-Mechanical Analysis of Composite Materials

Composite materials are widely used in many engineering fields. Their mechanical properties allow very stiff structures to be obtained with a mass reduction with respect to metallic materials. These materials are built using a polymeric matrix reinforced with high strength fibres, e.g. carbon fibres. The use of a polymeric matrix makes composite materials subject to aging effects and in particular their properties and performances may be reduced because of the moisture absorption. An accurate prediction of the deformations and of the internal stress field due to the hygro-mechanical effects is mandatory in the design of a composite structure exposed to a moisture concentration. Classical structural models, beams and plates, cannot provide a complete three-dimensional stress field because their kinematic assumption, e.g. rigid crosssection for the beam of constant thickness for the plates. These limitations make the classical models inaccurate when complex three-dimensional stress fields have to be evaluated as in the case of the hygro-mechanical problem, that is, a full three-dimensional model must be used. The present paper proposes to use a refined one-dimensional model with variable kinematic, developed in the frameworks of the Carrera Unified Formulation (CUF), for the hygromechanical analysis of composite structures. Refined one-dimensional models are able to overcome the limitations of the classical beam models thanks to a refined kinematic fields, used over the cross-section, able to provide a full three-dimensional solution. In this work a model based on Lagrange functions is used. The hygro-mechanical model has been derived in the CUF frameworks, that is, the moisture concentration can be considered as a variable of the problem. The moisture concentration has been evaluated solving analytically the Fick law that is able to provide the moisture distribution after a certain time of exposure. The moisture concentration has been used as boundary condition in the hygro-mechanical problem in order to evaluate the displacement and stress fields. The model has been assessed and the results have been compare with those from classical threedimensional FE models. Displacements field, stress field and the volume variation have been used to compare the accuracy of the solution. The results show that the refined one-dimensional models are able to provide an accurate solution with a lower computational cost with respect to the full three-dimensional FE models

Simulation Supported Estimation of End-to-End Transmission Parameters in Non-Viral Gene Delivery

Communications, in general, involve delivery of information from a source to a sink. At nano-scale, an example of a man-made communications involving interfacing with biological systems at intra-cellular level is non-viral gene delivery. From a telecommunications engineering perspective, important end-to-end parameters of such a system are: the endto- end delay, system capacity, and packet loss rate. There are neither known methods to estimate those parameters theoretically nor they are ready available from standard measurements. The paper provides estimates for those parameters based on the simulation of non-viral gene delivery system based on the queuing theory. The simulator used has been validated through the series of in-vitro laboratory experiments

Oral health in relation to all-cause mortality: the IPC cohort study

We evaluated the association between oral health and mortality. The study population comprised 76,188 subjects aged 16–89 years at recruitment. The mean follow-up time was 3.4 ± 2.4 years. Subjects with a personal medical history of cancer or cardiovascular disease and death by casualty were excluded from the analysis. A full-mouth clinical examination was performed in order to assess dental plaque, dental calculus and gingival inflammation. The number of teeth and functional masticatory units 10 missing teeth and functional masticatory units 10 missing teeth (HR = 2.31, [95% CI: 1.40–3.82]) and functional masticatory units <5 (HR = 2.40 [95% CI 1.55–3.73]). Moreover, when ≥3 oral diseases were cumulated in the model, the risk increased for all-cause mortality (HR = 3.39, [95% CI: 2.51–5.42]), all-cancer mortality (HR = 3.59, [95% CI: 1.23–10.05]) and non-cardiovascular and non-cancer mortality (HR = 4.71, [95% CI: 1.74–12.7]). The present study indicates a postive linear association between oral health and mortality

METHOD OFOBTAINING MICROGRAPHS OF TRANSPARENT OR SEMI-TRANSPARENT SPECIMENS USING ANISOTROPIC CONTRAST

Anisotropic contrast methodology in combination with use of sample investigating polarized electromagnetic radiation to provide Jones or Mueller Matrix imaging data corresponding to areas on samples

Approche multifactorielle et typologique du concept de fragilité chez les patients hypertendus non contrôlés. Enquête Eclat

Objective The aim of the Eclat survey was to evaluate the frequency of frailty in uncontrolled hypertensives and to individualize different frailty profiles. Patients and methods This was an observational, prospective, longitudinal survey conducted in the cohort of uncontrolled hypertensive patients aged 55 years or more. Morbid events having occurred between two visits at a 6-month interval were reported. Patients with at least one event were considered to be frail. Predictive factors of at least one event were identified (logistic regression). The analysis was completed by a typological analysis (principal components analysis and clustering). Results At least one event occurred in 211 (9%) of 2306 patients (males 55%, 67 ± 9 years old, blood pressure [BP] = 160 ± 11/93 ± 8 mmHg, diabetes 23%): cardiovascular (1.7%), gerontological (5.5%), onset of diabetes (1.3%), worsening of renal impact (2%). Three frailty profiles were identified: patients at low risk (n = 1507, event rate = 6%), with neither cardiovascular risk factors nor target organ damage; patients at moderate risk (n = 335, event rate = 12%) with numerous risk factors but no target organ damage and patients at high risk (n = 243, event rate = 23%), the older ones, in bad general condition, with target organ damage, sensorial deficits and cognitive disorders. In a population of uncontrolled hypertensives aged 55 years or more, 9% could be considered as frailty. Conclusion Therapeutic measures might be adapted according to the frailty profile of the patient. With respect to treatment management, healthcare behaviour could differ depending on these frailty profiles