Developmentally Regulated Sphingolipid Degradation in Leishmania major

Leishmania parasites alternate between extracellular promastigotes in sandflies and intracellular amastigotes in mammals. These protozoans acquire sphingolipids (SLs) through de novo synthesis (to produce inositol phosphorylceramide) and salvage (to obtain sphingomyelin from the host). A single ISCL (Inositol phosphoSphingolipid phospholipase C-Like) enzyme is responsible for the degradation of both inositol phosphorylceramide (the IPC hydrolase or IPCase activity) and sphingomyelin (the SMase activity). Recent studies of a L. major ISCL-null mutant (iscl−) indicate that SL degradation is required for promastigote survival in stationary phase, especially under acidic pH. ISCL is also essential for L. major proliferation in mammals. To further understand the role of ISCL in Leishmania growth and virulence, we introduced a sole IPCase or a sole SMase into the iscl− mutant. Results showed that restoration of IPCase only complemented the acid resistance defect in iscl− promastigotes and improved their survival in macrophages, but failed to recover virulence in mice. In contrast, a sole SMase fully restored parasite infectivity in mice but was unable to reverse the promastigote defects in iscl−. These findings suggest that SL degradation in Leishmania possesses separate roles in different stages: while the IPCase activity is important for promastigote survival and acid tolerance, the SMase activity is required for amastigote proliferation in mammals. Consistent with these findings, ISCL was preferentially expressed in stationary phase promastigotes and amastigotes. Together, our results indicate that SL degradation by Leishmania is critical for parasites to establish and sustain infection in the mammalian host

A high-order FEM formulation for free and forced vibration analysis of a nonlocal nonlinear graded Timoshenko nanobeam based on the weak form quadrature element method

The purpose of this paper is to provide a high-order finite element method (FEM) formulation of nonlocal nonlinear nonlocal graded Timoshenko based on the weak form quadrature element method (WQEM). This formulation offers the advantages and flexibility of the FEM without its limiting low-order accuracy. The nanobeam theory accounts for the von Kármán geometric nonlinearity in addition to Eringen’s nonlocal constitutive models. For the sake of generality, a nonlinear foundation is included in the formulation. The proposed formulation generates high-order derivative terms that cannot be accounted for using regular first- or second-order interpolation functions. Hamilton’s principle is used to derive the variational statement which is discretized using WQEM. The results of a WQEM free vibration study are assessed using data obtained from a similar problem solved by the differential quadrature method (DQM). The study shows that WQEM can offer the same accuracy as DQM with a reduced computational cost. Currently the literature describes a small number of high-order numerical forced vibration problems, the majority of which are limited to DQM. To obtain forced vibration solutions using WQEM, the authors propose two different methods to obtain frequency response curves. The obtained results indicate that the frequency response curves generated by either method closely match their DQM counterparts obtained from the literature, and this is despite the low mesh density used for the WQEM systems

Comparative Expression Profiling of Leishmania: Modulation in Gene Expression between Species and in Different Host Genetic Backgrounds

The single-celled parasite Leishmania, transmitted by sand flies in more than 88 tropical and sub-tropical countries globally, infects man and other mammals, causing a spectrum of diseases called the leishmaniases. Over 12 million people are currently infected worldwide with 2 million new cases reported each year. The type of leishmaniasis that develops in the mammalian host is dependent on the species of infecting parasite and the immune response to infection (that can be influenced by host genetic variation). Our research is focused on identifying parasite factors that contribute to pathogenicity in the host and understanding how these might differ between parasite species that give rise to the different clinical forms of leishmaniasis. Molecules of this type might lead to new therapeutic tools in the longer term. In this paper, we report a comparative analysis of gene expression profiles in three Leishmania species that give rise to different types of disease, focusing on the intracellular stages that reside in mammalian macrophages. Our results show that there are only a small number of differences between these parasite species, with host genetics playing only a minor role in influencing the parasites' response to their intracellular habitat. These small changes may be significant, however, in determining the clinical outcome of infection

Instability Characteristics of Free-Standing Nanowires Based on the Strain Gradient Theory with the Consideration of Casimir Attraction and Surface Effects

Size-dependent dynamic instability of cylindrical nanowires incorporating the effects of Casimir attraction and surface energy is presented in this research work. To develop the attractive intermolecular force between the nanowire and its substrate, the proximity force approximation (PFA) for small separations, and the Dirichlet asymptotic approximation for large separations with a cylinder-plate geometry are employed. A nonlinear governing equation of motion for free-standing nanowires – based on the Gurtin-Murdoch model – and a strain gradient elasticity theory are derived. To overcome the complexity of the nonlinear problem in hand, a Garlerkin-based projection procedure for construction of a reduced-order model is implemented as a way of discretization of the governing differential equation. The effects of length-scale parameter, surface energy and vacuum fluctuations on the dynamic instability threshold and adhesion of nanowires are examined. It is demonstrated that in the absence of any actuation, a nanowire might behave unstably, due to the Casimir induction force

Modal interaction in a levitation force MEMS based resonator

This work aims to examine the possibility of internal resonances (modal interactions) among the vibration modes of a levitation force Micro-electro-mechanical Systems (MEMS) based resonator. The actuating levitation force is generated through a special arrangement consisting of two stationary side electrodes (both electrically charged) and a middle grounded unit consisting of the stationary electrode located beneath a moving electrode (micro-beam). Both “cantilever” (CL) and “clamped-clamped” (CC) microbeams are analysed as the moving element of this especial design in which the applied voltage pushes away the micro beam from the underneath substrate. All possible commensurable relations between the frequencies are inspected. We use the numerical bifurcation toolbox MatCont to capture the computed frequency response branches and examine their stability. A period-doubling bifurcation for the possible onset of chaotic attractors is inspected as well. A preliminary eigenvalue problem analysis suggests the internal resonance may exist in both (CC and CL) cases. However, an extended dynamical analysis shows that just a 3-to-1 modal interaction (between the first and third modes) in the CC arrangement is possible. The effects of dominant force-related terms are plotted through associated plots. These diagrams demonstrated that this design exhibits a rich internal resonance behavior that can be controlled with different geometrical and actuating parameters. Overall, this effort provides a systematic methodology and simple guidelines for in-depth exploration of internal resonances in levitation force-based microbeams. The outcomes of this work could also assist in the development of MEMS sensors based on the internal resonance phenomenon

Dynamic Analysis of Multilayers Based MEMS Resonators

The dynamic behavior of a microelectromechanical system (MEMS) parallel and electrically coupled double-layers (microbeams) based resonator is investigated. Two numerical methods were used to solve the dynamical problem: the reduced-order modeling (ROM) and the perturbation method. The ROM was derived using the so-called Galerkin expansion with considering the linear undamped mode shapes of straight beam as the basis functions. The perturbation method was generated using the method of multiple scales by direct attack of the equations of motion. Dynamic analyses, assuming the above two numerical methods were performed, and a comparison of the results showed good agreement. Finally, a parametric study was performed using the perturbation on different parameters and the results revealed different interesting features, which hopefully can be useful for some MEMS based applications

Nonlocal study of the vibration and stability response of small-scale axially moving supported beams on viscoelastic-Pasternak foundation in a hygro-thermal environment

This paper aims at studying the vibrational behavior and dynamical stability of small-scale axially moving beams resting on the viscoelastic-Pasternak foundation in a hygro-thermal environment, according to a nonlocal strain gradient Rayleigh beam model. The Galerkin procedure is applied to determine the eigenvalues of the dynamic system of equations together with the stability regions of the system. A comparison study of the proposed method is performed, first, against the available literature. Thus, we examine the effect of the rotary inertia, flexural stiffness, boundary conditions, scale parameters, foundation conditions, and environmental loads, on the vibrational frequencies and stability boundaries of the system. Based on the numerical results, an increased flexural stiffness and strain gradient parameter enhance the vibrational frequencies of the system. It is also demonstrated that the destructive effects of hygro-thermal conditions can be alleviated by a fine-tuning of the foundation characteristics. The outcomes of the present research can represent a useful benchmark for optimization design purposes of moving nanosystems in complex environmental conditions