Permeabilization of the Blood-Brain Barrier via Mucosal Engrafting: Implications for Drug Delivery to the Brain

Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson’s disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS

From DNA Nanotechnology to Material Systems Engineering

In the past 35 years, DNA nanotechnology has grown to a highly innovative and vibrant field of research at the interface of chemistry, materials science, biotechnology, and nanotechnology. Herein, a short summary of the state of research in various subdisciplines of DNA nanotechnology, ranging from pure “structural DNA nanotechnology” over protein–DNA assemblies, nanoparticle-based DNA materials, and DNA polymers to DNA surface technology is given. The survey shows that these subdisciplines are growing ever closer together and suggests that this integration is essential in order to initiate the next phase of development. With the increasing implementation of machine-based approaches in microfluidics, robotics, and data-driven science, DNA-material systems will emerge that could be suitable for applications in sensor technology, photonics, as interfaces between technical systems and living organisms, or for biomimetic fabrication processes

The age of Wolfe Creek meteorite crater (Kandimalal), Western Australia

Wolfe Creek crater lies in northwestern Australia at the edge of the Great Sandy Desert. Together with Meteor Crater, it is one of the two largest craters on Earth from which meteorite fragments have been recovered. The age of the impact is poorly constrained and unpublished data places the event at about 300,000 years ago. In comparison, Meteor Crater is well constrained by exposure dating. In this paper, we present new ages for Wolfe Creek Crater from exposure dating using the cosmogenic nuclides 10Be and 26Al, together with optically stimulated luminescence ages (OSL) on sand from a site created by the impact. We also present a new topographic survey of the crater using photogrammetry. The exposure ages range from ~86 to 128 ka. The OSL ages indicate that the age of the impact is most likely to be ~120 ka with a maximum age of 137 ka. Considering the geomorphic setting, the most likely age of the crater is 120 ± 9 ka. Last, we review the age of Meteor Crater in Arizona. Changes in production rates and scaling factors since the original dating work revise the impact age to 61.1 ± 4.8 ka, or ~20% older than previously reported

CDZNTE ROOM-TEMPERATURE SEMICONDUCTOR GAMMA-RAY DETECTOR FOR NATIONAL-SECURITY APPLICATIONS.

One important mission of the Department of Energy's National Nuclear Security Administration is to develop reliable gamma-ray detectors to meet the widespread needs of users for effective techniques to detect and identify special nuclear- and radioactive-materials. Accordingly, the Nonproliferation and National Security Department at Brookhaven National Laboratory was tasked to evaluate existing technology and to develop improved room-temperature detectors based on semiconductors, such as CdZnTe (CZT). Our research covers two important areas: Improving the quality of CZT material, and exploring new CZT-based gamma-ray detectors. In this paper, we report on our recent findings from the material characterization and tests of actual CZT devices fabricated in our laboratory and from materials/detectors supplied by different commercial vendors. In particular, we emphasize the critical role of secondary phases in the current CZT material and issues in fabricating the CZT detectors, both of which affect their performance

Peak oxygen consumption and long-term all-cause mortality in nonsmall cell lung cancer

Identifying strong markers of prognosis is critical to optimize treatment and survival outcomes in patients with non-small cell lung cancer (NSCLC). We investigated the prognostic significance of preoperative cardiorespiratory fitness (VO2peak) among operable candidates with NSCLC

Performance-Limiting Defects in CdZnTe Detectors.

We studied the effects of small, <20 {micro}m, Te inclusions on the energy resolution of CdZnTe gamma-ray detectors using a highly collimated X-ray beam and gamma-rays, and modeled them via a simplified geometrical approach. Previous reports demonstrated that Te inclusions of about a few microns in diameter degraded the charge-transport properties and uniformity of CdZnTe detectors. The goal of this work was to understand the extent to which randomly distributed Te-rich inclusions affect the energy resolution of CZT detectors, and to define new steps to overcome their deleterious effects. We used a phenomenological model, which depends on several adjustable parameters, to reproduce the experimentally measured effects of inclusions on energy resolution. We also were able to hound the materials-related problem and predict the enhancement in performance expected by reducing the size and number of Te inclusions within the crystals

High Spatial-Resolution Imaging of Te Inclusions in CZT Material.

We present new results from our studies of defects in current single-crystal CdZnTe material. Our previous measurements, carried out on thin ({approx}1 mm) and long (>12 mm) CZT detectors, indicated that small (1-20 {micro}m) Te inclusions can significantly degrade the device's energy resolution and detection efficiency. We are conducting detailed studies of the effects of Te inclusions by employing different characterization techniques with better spatial resolution, such as quantitative fluorescence mapping, X-ray micro-diffraction, and TEM. Also, IR microscopy and gamma-mapping with pulse-shape analysis with higher spatial resolution generated more accurate results in the areas surrounding the micro-defects (Te inclusions). Our results reveal how the performance of CdZnTe detectors is influenced by Te inclusions, such as their spatial distribution, concentration, and size. We also discuss a model of charge transport through areas populated with Te inclusions

Expanding homogeneous culture of human primordial germ cell-like cells maintaining germline features without serum or feeder layers.

In vitro expansion of human primordial germ cell-like cells (hPGCLCs), a pluripotent stem cell-derived PGC model, has proved challenging due to rapid loss of primordial germ cell (PGC)-like identity and limited cell survival/proliferation. Here, we describe long-term culture hPGCLCs (LTC-hPGCLCs), which actively proliferate in a serum-free, feeder-free condition without apparent limit as highly homogeneous diploid cell populations maintaining transcriptomic and epigenomic characteristics of hPGCLCs. Histone proteomics confirmed reduced H3K9me2 and increased H3K27me3 marks in LTC-hPGCLCs compared with induced pluripotent stem cells (iPSCs). LTC-hPGCLCs established from multiple human iPSC clones of both sexes were telomerase positive, senescence-free cells readily passaged with minimal cell death or deviation from the PGC-like identity. LTC-hPGCLCs are capable of differentiating to DAZL-positive M-spermatogonia-like cells in the xenogeneic reconstituted testis (xrTestis) organ culture milieu as well as efficiently producing fully pluripotent embryonic germ cell-like cells in the presence of stem cell factor and fibroblast growth factor 2. Thus, LTC-hPGCLCs provide convenient access to unlimited amounts of high-quality and homogeneous hPGCLCs

Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al

Te Inclusions and Their Relationship to the Performance of CdZnTe Detectors.

Te-rich secondary phases existing in CdZnTe (CZT) single crystals degrade the spectroscopic performance of these detectors. An unpredictable number of charges are trapped, corresponding to the abundance of these microscopic defects, thereby leading to fluctuations in the total collected charge and strongly affecting the uniformity of charge-collection efficiency. These effects, observed in thin planar detectors, also were found to be the dominant cause of the low performance of thick detectors, wherein the fluctuations accumulate along the charge's drift path. Reducing the size of Te inclusions from a virtual diameter of 10-20 {micro}m down to less than 5 {micro}m already allowed us to produce Frisch-ring detectors with a resolution as good as {approx}0.8% FWHM at 662 keV: Understanding and modeling the mechanisms involving Te-rich secondary phases and charge loss requires systematic studies on a spatial scale never before realized. Here, we describe a dedicated beam-line recently established at BNL's National Synchrotron Light Source for characterizing semiconductor detectors along with a IR system with counting capability that permits us to correlate the concentration of defects with the devices' performances