Quasi-diffusion magnetic resonance imaging (QDI): A fast, high b-value diffusion imaging technique.

To enable application of non-Gaussian diffusion magnetic resonance imaging (dMRI) techniques in large-scale clinical trials and facilitate translation to clinical practice there is a requirement for fast, high contrast, techniques that are sensitive to changes in tissue structure which provide diagnostic signatures at the early stages of disease. Here we describe a new way to compress the acquisition of multi-shell b-value diffusion data, Quasi-Diffusion MRI (QDI), which provides a probe of subvoxel tissue complexity using short acquisition times (1-4 min). We also describe a coherent framework for multi-directional diffusion gradient acquisition and data processing that allows computation of rotationally invariant quasi-diffusion tensor imaging (QDTI) maps. QDI is a quantitative technique that is based on a special case of the Continuous Time Random Walk model of diffusion dynamics and assumes the presence of non-Gaussian diffusion properties within tissue microstructure. QDI parameterises the diffusion signal attenuation according to the rate of decay (i.e. diffusion coefficient, D in mm2 s-1) and the shape of the power law tail (i.e. the fractional exponent, α). QDI provides analogous tissue contrast to Diffusional Kurtosis Imaging (DKI) by calculation of normalised entropy of the parameterised diffusion signal decay curve, Hn, but does so without the limitations of a maximum b-value. We show that QDI generates images with superior tissue contrast to conventional diffusion imaging within clinically acceptable acquisition times of between 84 and 228 s. We show that QDI provides clinically meaningful images in cerebral small vessel disease and brain tumour case studies. Our initial findings suggest that QDI may be added to routine conventional dMRI acquisitions allowing simple application in clinical trials and translation to the clinical arena

Fractional compartmental models and multi-term Mittag–Leffler response functions

Systems of fractional differential equations (SFDE) have been increasingly used to represent physical and control system, and have been recently proposed for use in pharmacokinetics (PK) by (J Pharmacokinet Pharmacodyn 36:165–178, 2009) and (J Phamacokinet Pharmacodyn, 2010). We contribute to the development of a theory for the use of SFDE in PK by, first, further clarifying the nature of systems of FDE, and in particular point out the distinction and properties of commensurate versus non-commensurate ones. The second purpose is to show that for both types of systems, relatively simple response functions can be derived which satisfy the requirements to represent single-input/single-output PK experiments. The response functions are composed of sums of single- (for commensurate) or two-parameters (for non-commensurate) Mittag–Leffler functions, and establish a direct correspondence with the familiar sums of exponentials used in PK

Fractional dynamics pharmacokinetics–pharmacodynamic models

While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics–pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior. The families represent extensions of frequently used PK link and PD direct and indirect action models, using the tools of fractional calculus. In addition the PD models can be a function of a variable, the active drug, which can smoothly transition from concentration to exposure, to hyper-exposure, according to a fractional integral transformation. To investigate the behavior of the models we propose, we implement numerical algorithms for fractional integration and for the numerical solution of a system of fractional differential equations. For simplicity, in our investigation we concentrate on the pharmacodynamic side of the models, assuming standard (integer order) pharmacokinetics

Towards the Formalization of Fractional Calculus in Higher-Order Logic

Fractional calculus is a generalization of classical theories of integration and differentiation to arbitrary order (i.e., real or complex numbers). In the last two decades, this new mathematical modeling approach has been widely used to analyze a wide class of physical systems in various fields of science and engineering. In this paper, we describe an ongoing project which aims at formalizing the basic theories of fractional calculus in the HOL Light theorem prover. Mainly, we present the motivation and application of such formalization efforts, a roadmap to achieve our goals, current status of the project and future milestones.Comment: 9 page

Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis

Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy

HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis

Molecular chaperones play key roles during growth, development, and stress survival. The ability to induce chaperone expression enables cells to cope with the accumulation of nonnative proteins under stress and complete developmental processes with an increased requirement for chaperone assistance. Here we generate and analyze transgenic mice that lack the cochaperone HSPBP1, a nucleotide-exchange factor of HSP70 proteins and inhibitor of chaperone-assisted protein degradation. Male HSPBP1(−/−) mice are sterile because of impaired meiosis and massive apoptosis of spermatocytes. HSPBP1 deficiency in testes strongly reduces the expression of the inducible, antiapoptotic HSP70 family members HSPA1L and HSPA2, the latter of which is essential for synaptonemal complex disassembly during meiosis. We demonstrate that HSPBP1 affects chaperone expression at a posttranslational level by inhibiting the ubiquitylation and proteasomal degradation of inducible HSP70 proteins. We further provide evidence that the cochaperone BAG2 contributes to HSP70 stabilization in tissues other than testes. Our findings reveal that chaperone expression is determined not only by regulated transcription, but also by controlled degradation, with degradation-inhibiting cochaperones exerting essential prosurvival functions