Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions

Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression

A new dimension for magnetosensitive e-skins: active matrix integrated micro-origami sensor arrays

Magnetic sensors are widely used in our daily life for assessing the position and orientation of objects. Recently, the magnetic sensing modality has been introduced to electronic skins (e-skins), enabling remote perception of moving objects. However, the integration density of magnetic sensors is limited and the vector properties of the magnetic field cannot be fully explored since the sensors can only perceive field components in one or two dimensions. Here, we report an approach to fabricate high-density integrated active matrix magnetic sensor with three-dimensional (3D) magnetic vector field sensing capability. The 3D magnetic sensor is composed of an array of self-assembled micro-origami cubic architectures with biased anisotropic magnetoresistance (AMR) sensors manufactured in a wafer-scale process. Integrating the 3D magnetic sensors into an e-skin with embedded magnetic hairs enables real-time multidirectional tactile perception. We demonstrate a versatile approach for the fabrication of active matrix integrated 3D sensor arrays using micro-origami and pave the way for new electronic devices relying on the autonomous rearrangement of functional elements in space

Nano-biosupercapacitors enable autarkic sensor operation in blood

Today’s smallest energy storage devices for in-vivo applications are larger than 3 mm3 and lack the ability to continuously drive the complex functions of smart dust electronic and microrobotic systems. Here, we create a tubular biosupercapacitor occupying a mere volume of 1/1000 mm3 (=1 nanoliter), yet delivering up to 1.6 V in blood. The tubular geometry of this nano-biosupercapacitor provides efficient self-protection against external forces from pulsating blood or muscle contraction. Redox enzymes and living cells, naturally present in blood boost the performance of the device by 40% and help to solve the self-discharging problem persistently encountered by miniaturized supercapacitors. At full capacity, the nano-biosupercapacitors drive a complex integrated sensor system to measure the pH-value in blood. This demonstration opens up opportunities for next generation intravascular implants and microrobotic systems operating in hard-to-reach small spaces deep inside the human body

Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si-OTP) Alkylating Reagents

The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBPn) and triazole phosphates (Si-OTPn) using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBPn and Si-OTPn, can be used to carry out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated products in good yield and high purity

Visual target tracking for rover-based planetary exploration

Abstract-To command a rover to go to a location of scientific interest on a remote planet, the rover must be capable of reliably tracking the target designated by a scientist from about ten rover lengths away. The rover must maintain lock on the target while traversing rough terrain and avoiding obstacles without the need for communication with Earth. Among the challenges of tracking targets from a rover are the large changes in the appearance and shape of the selected target as the rover approaches it, the limited frame rate at which images can be acquired and processed, and the sudden changes in camera pointing as the rover goes over rocky terrain. We have investigated various techniques for combining 2D and 3D information in order to increase the reliability of visually tracking targets under Mars like conditions. We will present the approaches that we have examined on simulated data and tested onboard the Rocky 8 rover in the JPL Mars Yard and the K9 rover in the ARC Marscape. These techniques include results for 2D trackers, ICP, visual odometry, and 2D/3D trackers

Constraints on the Onset of Color Transparency from Quasielastic ¹²C(e, e′p) up to Q² = (14.2 GeV /c)²

Quasielastic scattering on 12C(e,e′p) was measured in Hall C at Jefferson Lab for spacelike four-momentum transfer squared Q2 in the range of 8–14.2(GeV/c)2 with proton momenta up to 8.3GeV/c. The experiment was carried out in the upgraded Hall C at Jefferson Lab. It used the existing high-momentum spectrometer and the new super-high-momentum spectrometer to detect the scattered electrons and protons in coincidence. The nuclear transparency was extracted as the ratio of the measured yield to the yield calculated in the plane wave impulse approximation. Additionally, the transparency of the 1s1/2 and 1p3/2 shell protons in 12C was extracted, and the asymmetry of the missing momentum distribution was examined for hints of the quantum chromodynamics prediction of color transparency. All of these results were found to be consistent with traditional nuclear physics and inconsistent with the onset of color transparency

Prevalence of type 2 diabetes in Nepal: a systematic review and meta-analysis from 2000 to 2014

Background: Understanding the prevalence of type 2 diabetes in Nepal can help in planning for health services and recognising risk factors. This review aims to systematically identify and collate studies describing the prevalence of type 2 diabetes, to summarise the findings, and to explore selected factors that may influence prevalence estimates. Design: This systematic review was conducted in adherence to the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies. Medical Literature Analysis and Retrieval System (MEDLINE) database from 1 January 2000 to 31 December 2014 was searched for the prevalence of type 2 diabetes among Nepalese populations with a combination of search terms. We exploded the search terms to include all possible synonyms and spellings obtained in the search strategy. Additionally, we performed a manual search for other articles and references of published articles. Results: We found 65 articles; ten studies fulfilled the inclusion criteria and were included in the analyses. These ten studies comprised a total of 30,218 subjects. The sample size ranged from 489 to 14,009. All the studies used participants older than age 15, of whom 41.5% were male and 58.5% female. All the studies were cross-sectional and two were hospital-based. Prevalence of type 2 diabetes ranged from a minimum of 1.4% to a maximum of 19.0% and pooled prevalence of type 2 diabetes was 8.4% (95% CI: 6.2 10.5%). Prevalence of type 2 diabetes in urban and rural populations was 8.1% (95% CI: 7.3 8.9%) and 1.0% (95% CI: 0.7 1.3%), respectively. Conclusions: This is, to our knowledge, the first study to systematically evaluate the literature of prevalence of type 2 diabetes in Nepal. Results showed that type 2 diabetes is currently a high-burden disease in Nepal, suggesting a possible area to deliberately expand preventive interventions as well as efforts to control the disease

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen