PRELP secreted from mural cells protects the function of blood brain barrier through regulation of endothelial cell-cell integrity

INTRODUCTION: Proline/arginine-rich end leucine-rich repeat protein (PRELP), is a small secreted proteoglycan expressed by pericytes and vascular smooth muscle cells surrounding the brain vasculature of adult mouse. METHODS: We utilised a Prelp knockout (Prelp−/−) mouse model to interrogate vasculature integrity in the brain alongside performing in vitro assays to characterise PRELP application to endothelial cells lines. Our findings were supplemented with RNA expression profiling to elucidate the mechanism of how PRELP maintains neurovasculature function. RESULTS: Prelp−/− mice presented with neuroinflammation and reducedneurovasculature integrity, resulting in IgG and dextran leakage in the cerebellum and cortex. Histological analysis of Prelp−/− mice revealed reducedcell-cell integrity of the blood brain barrier, capillary attachment of pericytes andastrocyte end-feet. RNA-sequencing analysis found that cell-cell adhesion andinflammation are affected in Prelp−/− mice and gene ontology analysis as well as gene set enrichment analysis demonstrated that inflammation related processes and adhesion related processes such as epithelial-mesenchymal transition and apical junctions were significantly affected, suggesting PRELP is a regulator of cell-cell adhesion. Immunofluorescence analysis showed that adhesion junction protein expression levels of cadherin, claudin-5, and ZO-1, was suppressed in Prelp−/− mice neurovasculature. Additionally, in vitro studies revealed that PRELP application to endothelial cells enhances cell-cell integrity, induces mesenchymal-endothelial transition and inhibits TGF-β mediated damage to cell-cell adhesion. DISCUSSION: Our study indicates that PRELP is a novel endogenous secreted regulator of neurovasculature integrity and that PRELP application may be a potential treatment for diseases associated with neurovascular damage

Teleradiology as a Foundation for an Enterprise-wide Health Care Delivery System

An effective, integrated telemedicine system has been developed that allows (a) teleconsultation between local primary health care providers (primary care physicians and general radiologists) and remote imaging subspecialists and (b) active patient participation related to his or her medical condition and patient education. The initial stage of system development was a traditional teleradiology consultation service between general radiologists and specialists; this established system was expanded to include primary care physicians and patients. The system was developed by using a well-defined process model, resulting in three integrated modules: a patient module, a primary health care provider module, and a specialist module. A middle agent layer enables tailoring and customization of the modules for each specific user type. Implementation by using Java and the Common Object Request Broker Architecture standard facilitates platform independence and interoperability. The system supports (a) teleconsultation between a local primary health care provider and an imaging subspecialist regardless of geographic location and (b) patient education and online scheduling. The developed system can potentially form a foundation for an enterprise-wide health care delivery system. In such a system, the role of radiologist specialists is enhanced from that of a diagnostician to the management of a patient’s process of care

Sophisticated Framework between Cell Cycle Arrest and Apoptosis Induction Based on p53 Dynamics

The tumor suppressor, p53, regulates several gene expressions that are related to the DNA repair protein, cell cycle arrest and apoptosis induction, which activates the implementation of both cell cycle arrest and induction of apoptosis. However, it is not clear how p53 specifically regulates the implementation of these functions. By applying several well-known kinetic mathematical models, we constructed a novel model that described the influence that DNA damage has on the implementation of both the G2/M phase cell cycle arrest and the intrinsic apoptosis induction via its activation of the p53 synthesis process. The model, which consisted of 32 dependent variables and 115 kinetic parameters, was used to examine interference by DNA damage in the implementation of both G2/M phase cell cycle arrest and intrinsic apoptosis induction. A low DNA damage promoted slightly the synthesis of p53, which showed a sigmoidal behavior with time. In contrast, in the case of a high DNA damage, the p53 showed an oscillation behavior with time. Regardless of the DNA damage level, there were delays in the G2/M progression. The intrinsic apoptosis was only induced in situations where grave DNA damage produced an oscillation of p53. In addition, to wreck the equilibrium between Bcl-2 and Bax the induction of apoptosis required an extreme activation of p53 produced by the oscillation dynamics, and was only implemented after the release of the G2/M phase arrest. When the p53 oscillation is observed, there is possibility that the cell implements the apoptosis induction. Moreover, in contrast to the cell cycle arrest system, the apoptosis induction system is responsible for safeguarding the system that suppresses malignant transformations. The results of these experiments will be useful in the future for elucidating of the dominant factors that determine the cell fate such as normal cell cycles, cell cycle arrest and apoptosis

Path Selection for Quantum Repeater Networks

Quantum networks will support long-distance quantum key distribution (QKD) and distributed quantum computation, and are an active area of both experimental and theoretical research. Here, we present an analysis of topologically complex networks of quantum repeaters composed of heterogeneous links. Quantum networks have fundamental behavioral differences from classical networks; the delicacy of quantum states makes a practical path selection algorithm imperative, but classical notions of resource utilization are not directly applicable, rendering known path selection mechanisms inadequate. To adapt Dijkstra's algorithm for quantum repeater networks that generate entangled Bell pairs, we quantify the key differences and define a link cost metric, seconds per Bell pair of a particular fidelity, where a single Bell pair is the resource consumed to perform one quantum teleportation. Simulations that include both the physical interactions and the extensive classical messaging confirm that Dijkstra's algorithm works well in a quantum context. Simulating about three hundred heterogeneous paths, comparing our path cost and the total work along the path gives a coefficient of determination of 0.88 or better.Comment: 12 pages, 8 figure

A Randomized Trial Evaluating Prosaptide™ for HIV-Associated Sensory Neuropathies: Use of an Electronic Diary to Record Neuropathic Pain

Objectives: To examine the efficacy and safety of Prosaptide™ (PRO) for the treatment of painful HIV-associated sensory neuropathies (HIV-SN). Design: A randomized, double-blind, placebo-controlled, multicenter study in participants with sensory neuropathy. Pain modulating therapy was discontinued prior to baseline. Participants were stratified by sural sensory nerve action potential (SNAP) amplitude. Participants were trained to use an electronic diary (ED) to record pain. Setting: Peripheral neuropathies are common complications of HIV infection. The pathogenesis is unknown and currently treatments are restricted to symptomatic measures. We examined PRO against placebo (PBO) for treatment of painful HIV-SN and performed a post-hoc evaluation of an electronic diary (ED) to record HIV-associated neuropathic pain. Participants: Eligible participants included adults with neurologist-confirmed painful HIV-SN.Interventions 2, 4, 8, or 16 mg/d PRO or PBO administered via subcutaneous (SC) injection for six weeks. Neurotoxic antiretroviral drug usage was held constant.Outcome Measures Changes from baseline in the weekly average of evaluable daily random prompts measuring pain using the Gracely pain scale and adverse events. Results: 237 participants were randomized. The study was stopped after a planned futility analysis. There were no between-group differences in the frequency of adverse events or laboratory toxicities. The 6-week mean (sd) Gracely pain scale changes were −0.12 (0.23), −0.24 (0.35), −0.15 (0.32), −0.18 (0.34), and −0.18 (0.32) for the 2, 4, 8, 16 mg, and PBO arms respectively. A similar variability of pain changes recorded using the ED were noted compared to previous trials that used paper collection methods.Conclusions 6-week treatment with PRO was safe but not effective at reducing HIV-associated neuropathic pain. Use of an ED to record neuropathic pain is novel in HIV-SN, resulted in reasonable compliance in recording pain data, but did not decrease the variability of pain scores compared to historical paper collection methods. Trial Registration: Current Controlled Trials NCT0028637

Effect of curing time on the microstructure and mechanical strength development of alkali activated binders based on vitreous calcium aluminosilicate (VCAS)

The aim of this paper is to study the influence of curing time on the microstructure and mechanical strength development of alkali activated binders based on vitreous calcium aluminosilicate (VCAS). Mechanical strength of alkali activated mortars cured at 65 °C was assessed for different curing times (4¿168 h) using 10 molal NaOH solution as alkaline activator. Compressive strength values around 77 MPa after three days of curing at 65 °C were obtained. 1·68 MPa/h compressive strength gain rate was observed in the first 12 h, decreasing to 0·95 MPa/h for the period of 12¿72 h. The progress of geopolymeric reaction was monitored by means of TGA and, electrical conductivity and pH measurements in an aqueous suspension. Significant decrease in pH and electrical conductivity were observed in the 4¿72 h period, demonstrating the geopolymerization process. Furthermore, SEM images showed an important amount of (N, C)ASH gel and low porosity of the developed matrix.To the Ministerio de Ciencia e Innovacion (MICINN) of the Spanish Government (BIA2011-26947) and also to FEDER for funding and to Vitrominerals company for supplying VCAS samples.Mitsuuchi Tashima, M.; Soriano Martínez, L.; Borrachero Rosado, MV.; Monzó Balbuena, JM.; Paya Bernabeu, JJ. (2013). Effect of curing time on the microstructure and mechanical strength development of alkali activated binders based on vitreous calcium aluminosilicate (VCAS). Bulletin of Materials Science. 36:245-249. https://doi.org/10.1007/s12034-013-0466-zS24524936Bernal S A, Gutiérrez R M, Pedraza A L, Provis J L, Rodriguez E D and Delvasto S 2011 Cem. Concr. Res. 41 1Criado M, Fernández-Jiménez A, Sobrados I, Palomo A and Sanz J 2011 J. Eur. Ceram. Soc. avaiable onlineDavidovits J 2008 Geopolymer chemistry and applications Institute Geopolymere, Saint-Quentin, FranceDuxson P, Fernández-Jiménez A, Provis J L, Lukey G C, Palomo A and van Deventer J S J 2007 J. Mater. Sci. 47 2917Fernández-Jiménez A, Palomo A and Criado M 2005 Cem. Concr. Res. 35 1204Hossain A B, Shrazi S A, Persun J and Neithalath N 2008 J. Transp. Res. Board 2070 32Komnitsas K and Zaharaki D 2007 Miner. Eng. 20 1261Lampris C, Lupo R and Cheeseman C R 2009 Waste Manage. 29 368Lin T, Jia D, Wang M, He P and Liang D 2009 Bull. Mater. Sci. 32 77Lloyd R R, Provis J L and van Deventer J S J 2009 J. Mater. Sci. 44 608Marín-López C, Reyes Araiza J L, Manzano-Ramírez A, Rubio Avalos J C, Perez-Bueno J J, Muñiz-Villareal M S, Ventura-Ramos E and Vorobiev Y 2009 Inorg. Mater. 45 1429Najafi Kani E, Allahverdi A and Provis J L 2012 Cem. Concr. Comp. 34 25Neithalath N, Persun J and Hossain A 2009 Cem. Concr. Res. 39 473Pacheco-Torgal F, Castro-Gomes J and Jalali S 2008a Constr. Build. Mater. 22 1315Pacheco-Torgal F, Castro-Gomex J and Jalali S 2008b Constr. Build. Mater. 22 1201Pacheco-Torgal F, Castro-Gomex J and Jalali S 2008c Constr. Build. Mater. 22 2212Payá J, Borrachero M V, Monzó J, Soriano L and Tashima M M 2012 Mater. Lett. 74 223Puertas F, Martínez-Ramírez S, Alonso S and Vázquez T 2000 Cem. Concr. Res. 30 1625Puertas F, Barba A, Gazulla M F, Gómez M P, Palacios M and Martínez-Ramírez S 2006 Mater. Construc. 56 73Reig L, Tashima M M, Borrachero M V, Monzó J and Payá J 2010 II Simposio aprovechamiento de residuos agro-industriales como fuente sostenible de materiales de construcción p. 83Rodriguez E D, Bernal S A, Provis J, Payá J, Monzó J and Borrachero M V 2012 Cem. Concr. Comp. (submitted)Tashima M M, Borrachero M V, Monzó J, Soriano L and Payá J 2009 COMATCOMP09 p.421Tashima M M, Akasaki J L, Castaldelli V N, Soriano L, Monzó J, Payá J and Borrachero M V 2012 Mater. Lett. 80 50Xu H and van Deventer J S J 2000 Int. J. Miner. Process. 59 247Yao X, Zhang Z, Zhu H and Chen Y 2009 Thermochim. Acta 493 49Zivica V 2004 Bull. Mater. Sci. 27 179Zivica V, Balkovic S and Drabik M 2011 Constr. Build. Mater. 25 220

Electrophysiological features of familial amyloid polyneuropathy in endemic area

The process of deterioration of peripheral nerve function in familial amyloid polyneuropathy (FAP) with amyloidogenic transthyretin (ATTR) Val30Met has not been systematically evaluated hitherto. We performed nerve conduction studies in 69 patients with FAP with ATTR Val30Met from one of the endemic areas in Japan. Sensory conduction velocity (SCV), motor conduction velocity (MCV), the size of the compound muscle action potential (CMAP) and distal latency (DL) were measured in the ulnar and tibial nerves. SCV was evaluated using the orthodromic method with needle recording electrodes. These electrophysiological parameters were compared with clinical stage of FAP and duration of neuropathy. When subjects noted minimal neuropathic symptoms only in the feet, motor and sensory nerve function in both the hands and feet had already been disturbed. Sensory nerve action potential on the foot disappeared more rapidly than CMAP. CMAP on foot muscle rapidly decreased during the initial 2 years and completely disappeared within 10 years. The duration of illness and deterioration parameters (CMAP of the abductor digiti minimi muscle, MCV and SCV of the ulnar nerve and DL of both ulnar and tibial nerves) were linearly correlated. CMAP was the most sensitive and reliable parameter to evaluate motor nerve degeneration in FAP.</.ArticleAMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS. 18(1):10-18 (2011)journal articl

A randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: Week 96 results

In 2 double-blinded Phase 3 trials, 1733 antiretroviralnaive participants were randomized to tenofovir alafenamide (TAF), a tenofovir prodrug versus tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 96 weeks, 86.6% in the TAF arm and 85.2% in the TDF arm had HIV-1 RNA<50 c/mL [difference 1.5%; (95% CI: 21.8% to 4.8%)]. With TAF, there are smaller declines in bone mineral density and more favorable changes in proteinuria, albuminuria, and tubular proteinuria, and no cases of proximal tubulopathy compared with 2 for TDF. These longer-term data support E/C/F/TAF as a safe, welltolerated, and durable regimen for initial HIV-1 treatment