Microbial and Haemagglutinins from the Serum of Estuarine Crab Portunus sanguinolentus

A naturally occurring haemagglutinin (HA), with activity against bacteria and yeast cells were detected in the serum of Portunus sanguinolentus using mammalian erythrocytes (RBC), various bacteria and yeast as indicator cells. The serum gave highest HA titer with buffalo RBC, tripsinized yeast, Vibrio fluvialis and Vibrio alginolyticus. An analysis of the biological properties of the HA showed it to be specifically dependent on the presence of Ca2+ for its activity. Further studies demonstrated that the HA- inhibition assays performed with carbohydrates revealed that the serum HA was specific for non-reducing terminal glucose with 1-2 glucosidic linkages. Thus this agglutinin appears to be unique among all the known crustacean agglutinins

Support Vector Machine for Photovoltaic System Efficiency Improvement

Photovoltaic panels are promising source for renewable energy. They serve as a clean source of electricity by converting the radiation coming from the sun to electric energy. However, the amount of energy produced by the photovoltaic panels is dependent on many variables including the irradiation and the ambient temperature, leading to nonlinear characteristics. Finding the optimal operating point in the photovoltaic characteristic curve and operating the photovoltaic panels at that point ensures improved system efficiency. This paper introduces a unique method to improve the efficiency of the photovoltaic panel using Support Vector Machines. The dataset, which is obtained from a real photovoltaic setup in Spain, include temperature, radiation, output current, voltage and power for a period of one year. The results obtained show that the system is capable of accurately driving the photovoltaic panel to produce optimal output power for a given temperature and irradiation levels

Evaluation of the Novel Folate Receptor Ligand [18F] Fluoro-PEG-Folate for Macrophage Targeting in a Rat Model of Arthritis.

Introduction Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[11C]PK11195 and positron emission tomography (PET). Images, however, also showed significant peri-articular background activity. The folate receptor (FR)-β is a potential alternative target for imaging activated macrophages. Therefore, the PET tracer [18F]fluoro-PEG-folate was synthesized and evaluated in both in vitro and ex vivo studies using a methylated BSA induced arthritis model. Methods [18F]fluoro-PEG-folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5-methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo [18F]fluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic and normal rats and results were compared with those of the established macrophage tracer (R)-[11C]PK11195. Results [18F]fluoro-PEG-folate was synthesized with a purity \u3e97%, a yield of 300 to 1,700 MBq and a specific activity between 40 and 70 GBq/µmol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8-fold lower than that of folic acid, but 3-fold higher than that of 5-Me-THF. In the rat model, [18F]fluoro-PEG-folate uptake in arthritic knees was increased compared with both contralateral knees and knees of normal rats. Uptake in arthritic knees could be blocked by an excess of glucosamine-folate, consistent with [18F]fluoro-PEG-folate being specifically bound to FR. Arthritic knee-to-bone and arthritic knee-to-blood ratios of [18F]fluoro-PEG-folate were increased compared with those of (R)-[11C]PK11195. Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels increased absolute [18F]fluoro-PEG-folate uptake in arthritic joints, but without improving target-to-background ratios. Conclusions The novel PET tracer [18F]fluoro-PEG-folate, designed to target FR on activated macrophages provided improved contrast in a rat model of arthritis compared with the accepted macrophage tracer (R)-[11C]PK11195. These results warrant further exploration of [18F]fluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients

Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs

Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRβ) within the TME and its restriction to the TME. This FRβ+ subpopulation could be selectively targeted with folate-linked drugs. Delivery of a folate-targeted TLR7 agonist to these cells (i) reduced their immunosuppressive function, (ii) increased CD8+ T-cell infiltration, (iii) enhanced M1/M2 macrophage ratios, (iv) inhibited tumor growth, (v) blocked tumor metastasis, and (vi) improved overall survival without demonstrable toxicity. These data reveal a broadly applicable strategy across tumor types for reprogramming MDSCs and TAMs into antitumorigenic immune cells using a drug that would otherwise be too toxic to administer systemically. The data also establish FRβ as the first marker that distinguishes immunosuppressive from nonimmunosuppressive subsets of MDSCs and TAMs. Because all solid tumors accumulate MDSCs and TAMs, a general strategy to both identify and reprogram these cells should be broadly applied in the characterization and treatment of multiple tumors

CXCR4 Expression in Prostate Cancer Progenitor Cells

Tumor progenitor cells represent a population of drug-resistant cells that can survive conventional chemotherapy and lead to tumor relapse. However, little is known of the role of tumor progenitors in prostate cancer metastasis. The studies reported herein show that the CXCR4/CXCL12 axis, a key regulator of tumor dissemination, plays a role in the maintenance of prostate cancer stem-like cells. The CXCL4/CXCR12 pathway is activated in the CD44+/CD133+ prostate progenitor population and affects differentiation potential, cell adhesion, clonal growth and tumorigenicity. Furthermore, prostate tumor xenograft studies in mice showed that a combination of the CXCR4 receptor antagonist AMD3100, which targets prostate cancer stem-like cells, and the conventional chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors as compared to monotherapy

Targeted drugs for cancer and inflammatory diseases

Therapies that exploit targeting ligands to deliver attached cytotoxic drugs selectively to diseased cells are currently receiving significant attention. While antibody-targeted drugs have been the first to enter the clinic, recent studies demonstrate that low molecular weight ligands can also be used to deliver attached imaging and therapeutic agents selectively to malignant cells in human cancer patients. Prostate cancer (PCa) is a major cause of mortality and morbidity in Western society today. Current methods for detecting PCa are limited, leaving most early malignancies undiagnosed and sites of metastasis in advanced disease undetected. Major deficiencies also exist in treatment of PCa, especially metastatic disease. Guided by in silico docking studies using the crystal structure of prostate-specific membrane antigen (PSMA), we have developed a PSMA-targeted ligand, namely DUPA, that delivers attached imaging and therapeutic agents selectively to PCa cells without targeting normal cells. The PSMA-targeted radioimaging agent (DUPA-99mTc) was found to bind PSMA-positive human PCa cells (LNCaP cell line) with nanomolar affinity (KD = 14 nM). Imaging and bio-distribution studies revealed that DUPA-99mTc localizes primarily to LNCaP cell tumor xenografts in nu/nu mice (%injected dose/gram = 11.3 at 4 h post-injection; tumor-to-muscle ratio = 75:1). PSMA-targeted optical imaging agents (DUPA-FITC, DUPA-rhodamine B, DUPA-Alexaflour 647, etc.) were also shown to efficiently label PCa cells and to internalize and traffic to intracellular endosomes. The PSMA-targeted fluorophore (DUPA-FITC) is shown to selectively label circulating prostate tumor cells in fresh peripheral blood samples from PCa patients and no fluorescent cells were detected in blood samples from healthy volunteers. Further, DUPA was able to selectively deliver siRNA conjugates to PCa cells in vitro and to tumor xenograft animal model. A PSMA-targeted chemotherapeutic agent (DUPA-TubH) was demonstrated to kill PSMA-positive LNCaP cells in culture (IC50 = 3 nM) and to eliminate established tumor xenografts in nu/nu mice with no detectable weight loss. Blockade of tumor targeting upon administration of excess PSMA inhibitor (PMPA) and the absence of targeting to PSMA-negative tumors confirmed the specificity of each of the above targeted reagents for PSMA. Tandem use of the imaging and therapeutic agents targeted to the same receptor could allow detection, staging, monitoring, and treatment of PCa with improved accuracy and efficacy. The vitamin folic acid and folate conjugates bind to folate receptors (FR) that are over-expressed on ∼40% of human cancers (primarily FR-alpha) and mediate internalization of their attached drugs by receptor-mediated endocytosis. For these reasons, anticancer drugs have been tethered to folate via releasable disulfide linker that is susceptible to controlled drug release upon endocytosis. Based on this strategy, six folate-targeted drugs are currently in human clinical trials. Since FR is also abundant on the apical membrane of the proximal tubule of the kidney, the effect of folate-targeted drugs on kidney toxicity remains unclear. Therefore, we have developed a two-photon FRET imaging method to monitor in vivo efficiency of drug release mechanism in the kidney and tumor. The disulfide-bridged folate-FRET conjugate was found to remain intact in the blood circulation system, but drug (rhodamine) was efficiently released in the tumor via redox-mediated disulfide bond reduction. Moreover, the folate-FRET conjugate was released (within 7 - 24 h) during FR transcytosis in the kidney proximal tubule. Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes immune system to attack synovium of the joints by mistaken identity theory. Although the exact causes of RA remain unknown, activated macrophages are thought to play a pivotal role in its pathogenesis. Moreover, trace macrophage infiltration of the synovial tissue is characteristic of the earliest stages of RA. Since activated macrophages, but not resting macrophages or most other healthy cells, express FR-beta, we have developed FR-beta targeted PET imaging agents (folate-DOTA-68Ga-PET and Folate- 18F) and immunotherapeutic agents (folate-haptens) to early diagnosis and treatment of RA. Imaging studies revealed that folate-targeted PET imaging agents localize significantly into a rodent hind paw inflammation model suggesting that folate tracers might be equivalent to FDG-18F-PET to monitor inflammation. FR-beta targeted immunotherapeutic agents, namely folate-TNP and folate-FITC, constitute promising haptens for use in FR-targeted immunotherapy of RA

Climate variability and its impact on the spatial distribution of mangroves in Qatar

Mangroves are a unique vegetation community that can adapt to harsh climatic conditions, including in areas of high temperature and high salinity levels. It is an important coastal wetland community in many countries that provide a multitude of ecosystem services. Qatar has a small mangrove community covering about 21 km2 and it is probably the only natural vegetation type found in Qatar. They are important because of their aesthetic value, as a buffer zone protecting the lowland coastal area as well as its role in storing carbons. Therefore, it is important to understand mangroves response to global climatic variability. This is particularly important as Avicennia, which is the only mangrove species found in Qatar has limited elevation range and less able to resist extreme physical and environmental changes. Species distribution models combined with GIS and Remote Sensing are some of the tools that can be used to project the potential change of mangrove vegetation communities. These spatial information technologies can be used to extract and map current distribution of mangrove vegetation while species distribution model can be used to predict the potential geographical distribution of suitable habitats and species occurrence. In the current research, MaxEnt, GIS and high resolution World View 3 satellite data were used to classify, map and predict mangrove vegetation. The preliminary findings show the potential habitats in the east and the northwest part of Qatar. This research is important as there are no current studies examining the spatial distribution of mangroves or assessing the potential impact of climate variability on mangrove communities in Qatar.qscienc