Descent Via Isogeny on Elliptic Curves with Large Rational Torsion Subgroups.

We outline PARI programs which assist with various algorithms related to descent via isogeny on elliptic curves. We describe, in this context, variations of standard inequalities which aid the computation of members of the Tate-Shafarevich group. We apply these techniques to several examples: in one case we use descent via 9-isogeny to determine the rank of an elliptic curve; in another case we find nontrivial members of the 9-part of the Tate-Shafarevich group, and in a further case, nontrivial members of the 13-part of the Tate-Shafarevich group

Nanochanneled Device and Related Methods

A capsule configured for in vivo refilling of a therapeutic agent. In certain embodiments, the capsule may contain methotrexate

The Influence of Surface Protein Adsorption on Gold Nanoparticle Intratumoral Distribution and Retention

Nanomedicines’ inability to penetrate throughout the entire volume of a tumor due to heterogeneous distribution within the tumor mass remains a crucial limiting factor for a vast range of theranostic applications, including image-guided radiation therapy. Despite many studies conducted on the topic having shown the efficacy and biocompatibility of colloidal gold nanoparticles (GNPs), the biological effects of GNPs in the tumor microenvironment, including the particle–protein interaction and the consequent impact on cellular pathways and contrast enhancement remain unclear. In this regard, further investigations on how GNP surface passivation affects X-ray attenuation as well as in vivo biodistribution will clarify several aspects still under discussion in the scientific community, which so far have limited the clinical translation of their cancer-related applications. We aim to evaluate the influence of protein surface adsorption on the GNP biodistribution in Lewis lung carcinoma (LLC) tumor-bearing mice using high-resolution computed tomography (CT) pre-clinical imaging. We hypothesize that, by controlling the adsorption of proteins on the GNP surface, we can influence the intratumoral distribution and retention of the particles. GNPs approximately 34 nm in diameter were synthesized with a surface plasmon peak at ~530 nm, surface passivated with bovine serum albumin (BSA) to reduce opsonization and improve colloidal stability, and characterized with standard methods. Modulation of BSA adsorption on the GNPs was observed by tuning the pH of the immobilization medium from acidic to alkaline, which we quantified using Langmuir isotherms. CT phantom imaging was used to determine X-ray attenuation as a function of GNP concentration and surface functionalization. The in vitro study for evaluating the uptake of GNPs by LLC cells highlighted a difference in the internalization depending on the surface functionalization. In both cases, macropinocytosis was the trafficking mechanism, but while endosomes with citrate-GNPs can be found in different stages of maturation, cells treated with BSA-GNPs presented larger vesicles up to 1 μm in diameter. The in vivo study was performed by injecting intratumorally, concentrating GNPs into LLC solid tumors grown on the right flank of 6-week-old female C57BL/6 mice. Ten days post-injection, follow-up assessments with CT imaging showed the distribution and retention of the particles in the tumor. CT attenuation quantification based on bioimaging analysis for each time point was conducted. In vivo results showed significant heterogeneity in the intratumoral biodistribution of GNPs dependent on surface passivation. BSA-GNPs perfused predominately along the tumor periphery with few depositions throughout the entire tumor volume. This response can be explained by the abnormal and heterogeneous vascular structure of the LLC tumor, suggesting perfusion rather than permeability as the limiting factor for tumor accumulation of the GNPs. Despite the perivascular cluster accumulation, the BSA-GNP distribution diverged from that obtained after unpassivated, citrate-GNP intratumoral injections. In conclusion, our investigations have shown that surface passivation of GNPs is able to influence the mechanism of cellular uptake in vitro and their in vivo intratumoral diffusion, highlighting the spatial heterogeneity of the solid tumor

STRESS SENSITIVITY OF MERCURY INJECTION MEASUREMENTS

Many petrophysical properties (e.g. permeability, electrical resistivity etc.) of tight rocks are very stress sensitive. However, most mercury injection measurements are made using an instrument that does not apply a confining pressure to the samples. Here we further explore the implications of the use and analysis of data from mercury injection porosimetry or mercury capillary pressure measurements (MICP). Two particular aspects will be discussed. First, the effective stress acting on samples analysed using standard MICP instruments (i.e. Micromeritics Autopore system) is described. Second, results are presented from a new mercury injection porosimeter that is capable of injecting mercury at up to 60,000 psi into 1.5 or 1 in core plugs while keeping a constant net stress up to 15,000 psi. This new instrument allows monitoring of the electrical conductivity across the core during the test so that an accurate threshold pressure can be determined. Although no external confining pressure is applied (unconfined) when using the standard MICP instrument, this doesn’t mean that the measurements can be considered as unstressed. Instead, the sample is under isostatic compression by the mercury until it enters the pore space of the sample. As an approximation, the stress that the mercury places on the sample is equal to its threshold pressure. Thus, the permeability calculated from standard MICP data is equivalent to that measured at its threshold pressure. Not all the samples have the same stress dependency thus comparing measured permeabilities at a single stress with values calculated from standard MICP data, corresponding at different threshold pressures, can lead to erroneous correlations. Therefore, the estimation of permeabilities from standard MICP data can be flawed and uncertain unless the stress effect is included. Results obtained from the new mercury injection system, porosimeter under net stress, are radically different from those obtained from standard MICP instruments such as the Autopore IV. In particular, the measurements at reservoir conditions produce threshold pressures that are three times higher and pore throat sizes that are 1/3rd of those measured by the standard MICP instrument. The results clearly indicate that calculating capillary height functions, sealing capacity, etc. from the standard instrument can lead to large errors that can have significant impact on subsurface characterization

COMPUTATIONAL MODELING OF INTRAOCULAR DRUG TRANSPORT

In this work we present computational model for intraocular drug transport using coupled convective-diffusive equations. Model can simulate drug transport using either injection or by state of the art implant devices. We are using Navier-Stokes equation for fluid flow in vitreous humor, and composite smeared finite element (CSFE) for convection in rest of the eye and also for diffusion within the whole model. CSFE takes into account blood vessel properties, such as hydraulic and diffusive components. User interface tool CAD for pre- and post- processing is constructed which enables generation of geometries for patient specific purposes. Computational model provides results in a form convenient for investigation of effects of the drugs on different diseases, such as diabetic macular edema, uveitis, etc. This computational platform has potentials to become a powerful tool for optimization of therapies and simulation of different drugs.Publishe

Wireless Power Transfer Closed-Loop Control for Low-Power Active Implantable Medical Devices

Near-field resonant inductive coupling is the most mature wireless power transfer (WPT) method for implantable medical devices. Common commercial WPT components are not optimized neither to deliver small amounts of power nor to work with other than small air gaps. In this paper, a closed-loop control is integrated with commercial off-the-shelf WPT components to efficiently recharge and power an implantable device for controlled active drug delivery. The system keeps the transmitted power stable and reliable, achieving a 26 % transfer efficiency with delivered power of tens of milliwatts, guaranteeing an autonomy of 5 days with a 4-hour recharge. Overheating is kept around the 2 °C safety limit

Implication of heterogeneities on core porosity measurements

Heterogeneities within core samples affect the accuracy of the laboratory measured core plug interconnected porosity. The laboratory measures the volume averaged porosity of the interconnected pores, . For homogeneous cores this is the correct porosity ± any experimental error. However for heterogeneous cores when any embedded material (unknown or ignored) has a differing porosity, ϕi, to that of the containing outer shell, ϕo, there will be increased uncertainty. We show that the difference between the measured volume averaged porosity, , and the porosity of the outer shell of the core, ϕo can be quantified by our Heterogeneity Factor, H. H is defined as ( - ϕo)/ϕo and given by H = F(R-1), where F is the ratio of the bulk volume of the embedded material to the total core bulk volume (measured), VBi/VBm, and R is the ratio of the embedded and the host outer porosity, ϕi/ϕo. The core plug homogeneous model can create increased error bounds in porosity for heterogeneous plugs. When H is zero there is no error in the porosity measurement due to heterogeneity, but when H≠ 0 then the differences can be significant and increases the experimental error bound. We present graphs for relevant industry scenarios to demonstrate the effect of any inclusions in the measured porosity. We find that when F is ∼0.1 i.e., inner included porosity is 10% of bulk volume, the relative error between and ϕo can reach ∼30% and even larger differences when F > 0.1. We then give a real example from a faulted vuggy outcrop carbonate which demonstrates extra porosity uncertainties, even for a very small vug. Finally we discuss the possible effect of embedded clay intrusions emitting adsorbed gas on grain/pore volume determinations of porosity using gas expansion, a common laboratory method of porosity determination. Appreciation of core heterogeneity on the precision of the laboratory porosity measurements is essential to improve the confidence in the error bounds for the quality control of laboratory core porosity measurements, and of the porosity distribution frequency for inputs to statistical methods such as Monte Carlo analysis for oil-in-place estimations, STOIIP

Hyaluronate-Thiol Passivation Enhances Gold Nanoparticle Peritumoral Distribution When Administered Intratumorally in Lung Cancer

Biofouling is the unwanted adsorption of cells, proteins, or intracellular and extracellular biomolecules that can spontaneously occur on the surface of metal nanocomplexes. It represents a major issue in bioinorganic chemistry because it leads to the creation of a protein corona, which can destabilize a colloidal solution and result in undesired macrophage-driven clearance, consequently causing failed delivery of a targeted drug cargo. Hyaluronic acid (HA) is a bioactive, natural mucopolysaccharide with excellent antifouling properties, arising from its hydrophilic and polyanionic characteristics in physiological environments which prevent opsonization. In this study, hyaluronate-thiol (HA-SH) (MW 10 kDa) was used to surface-passivate gold nanoparticles (GNPs) synthesized using a citrate reduction method. HA functionalized GNP complexes (HA-GNPs) were characterized using absorption spectroscopy, scanning electron microscopy, zeta potential, and dynamic light scattering. GNP cellular uptake and potential dose-dependent cytotoxic effects due to treatment were evaluated in vitro in HeLa cells using inductively coupled plasma—optical emission spectrometry (ICP-OES) and trypan blue and MTT assays. Further, we quantified the in vivo biodistribution of intratumorally injected HA functionalized GNPs in Lewis Lung carcinoma (LLC) solid tumors grown on the flank of C57BL/6 mice and compared localization and retention with nascent particles. Our results reveal that HA-GNPs show overall greater peritumoral distribution (** p < 0.005, 3 days post-intratumoral injection) than citrate-GNPs with reduced biodistribution in off-target organs. This property represents an advantageous step forward in localized delivery of metal nano-complexes to the infiltrative region of a tumor, which may improve the application of nanomedicine in the diagnosis and treatment of cancer