Photocurable Bioink for the Inkjet 3D Pharming of Hydrophilic Drugs.

Novel strategies are required to manufacture customized oral solid dosage forms for personalized medicine applications. 3D Pharming, the direct printing of pharmaceutical tablets, is an attractive strategy, since it allows for the rapid production of solid dosage forms containing custom drug dosages. This study reports on the design and characterization of a biocompatible photocurable pharmaceutical polymer for inkjet 3D printing that is suitable for hydrophilic active pharmaceutical ingredients (API). Specifically, hyaluronic acid was functionalized with norbornene moieties that, in the presence of poly(ethylene) glycol dithiol, Eosin Y as a photoinitiator, and a visible light source, undergoes a rapid step-growth polymerization reaction through thiol-ene chemistry. The engineered bioink was loaded with Ropinirole HCL, dispensed through a piezoelectric nozzle onto a blank preform tablet, and polymerized. Drug release analysis of the tablet resulted in 60% release within 15 min of tablet dissolution. The study confirms the potential of inkjet printing for the rapid production of tablets through the deposition of a photocurable bioink designed for hydrophilic APIs

Resummed Quantum Gravity

We present the current status of the a new approach to quantum general relativity based on the exact resummation of its perturbative series as that series was formulated by Feynman. We show that the resummed theory is UV finite and we present some phenomenological applications as well.Comment: 4 pages, 1 figure; presented at ICHEP0

The energy spectrum observed by the AGASA experiment and the spatial distribution of the sources of ultra-high energy cosmic rays

Seven and a half years of continuous monitoring of giant air showers triggered by ultra high-energy cosmic rays have been recently summarized by the AGASA collaboration. The resulting energy spectrum indicates clearly that the cosmic ray spectrum extends well beyond the Greisen-Zatsepin-Kuzmin (GZK) cut-off at $\sim 5 \times 10^{19}$ eV. Furthermore, despite the small number statistics involved, some structure in the spectrum may be emerging. Using numerical simulations, it is demonstrated in the present work that these features are consistent with a spatial distribution of sources that follows the distribution of luminous matter in the local Universe. Therefore, from this point of view, there is no need for a second high-energy component of cosmic rays dominating the spectrum beyond the GZK cut-off.Comment: 14 pages, 4 figures, Astrophys. J. Letters (submitted

Effect of Xpcl1 Activation and p27Kip1 Loss on Gene Expression in Murine Lymphoma

Mice lacking the p27Kip1 Cdk inhibitor (Cdkn1b) exhibit increased susceptibility to lymphomas from the Maloney murine leukemia virus (M-MuLV), and exhibit a high frequency of viral integrations at Xpcl1 (Kis2), a locus on the X-chromosome. Xpcl1 encodes miR-106a∼363, a cluster of microRNAs that are expressed in response to adjacent retroviral integrations. We report the first large-scale profile of microRNA expression in MuLV-induced lymphomas, in combination with microarray gene expression analysis. The source material was T-cell lymphomas induced by M-MuLV in p27Kip1 knockout mice and normal thymus. Surprisingly, the overall levels of miRNA expression were equivalent in lymphomas and normal thymus. Nonetheless, the expression of specific microRNAs was altered in tumors. The miR-106a∼363 miRNA were over-expressed in lymphomas, particularly those with viral integrations at the Xpcl1 locus. In contrast, p27Kip1 deletion itself was associated with a different pattern of microRNA expression. Gene expression was dramatically altered in lymphomas, yet paralleled data from T-cell lymphomas induced by other mechanisms. Genes with altered expression in association with the p27Kip1 null genotype were of similar functional classes to those associated with Xpcl1 integration, but with the opposite pattern of expression. Thus, the effect of p27Kip1 deletion may be to oppose an anti-oncogenic effect of Xpcl1 rather than enhancing its oncogenic functions. A subset of miR-106a∼363 target genes was consistently reduced in lymphomas with Xpcl1 integrations, particularly genes with cell cycle and immune functions. We identify four predicted target genes of miR-106a∼363 miRNA, including N-Myc (Mycn), and the TGF-beta receptor (Tgfbr2) using 3'UTR reporter assays. Still, bioinformatic miRNA target predictions were poor predictors of altered gene expression in lymphomas with Xpcl1 integration. Confirmation of miR-106a∼363 gene targeting relevant to the tumor phenotype requires in vivo validation, because only a subset of predicted targets are consistently reduced in tumors that overexpress miR-106a∼363

Expression of the B7/BB1 Activation Antigen and its Ligand CD28 in T-Cell-Mediated Skin Diseases

Interactions of CD28 (on T cells) with its recently identified ligand B7/BB1 (on antigen-presenting cells) have been shown to activate T cells via a major histocompatibility complex/Ag-independent “alternative” pathway, leading to an amplification of T- cell – mediated immune responses. The in vivo relevance of these molecules for cutaneous immunity is presently unknown. These findings prompted us to study the expression of B7/BB1 and CD28 in normal human skin and in selected T-cell – mediated inflammatory skin diseases. Biopsies were obtained from lesional skin of patients with allergic contact dermatitis, lichen planus, and, as control, from basal cell carcinoma and from healthy controls. Serial cryostat sections were stained with a panel of MoAbs directed against CD28, B7/BB1, CD3, CD1a, and KiM8 using immunohistochemistry (ABC technique). CD28 expression was observed in the majority of dermal and epidermal CD3+ T cells in contact dermatitis and lichen planus. In normal skin and basal cell carcinoma, CD28 was expressed only occasionally by perivascular T cells. In allergic contact dermatitis and lichen planus, B7/BB1-expression was found on dermal dendritic cells, on dermal macrophages, on Langerhans cells, focally on keratinocytes, and occasionally on dermal T cells. No B7/BB1 immunoreactivity was detected in normal skin and basal cell carcinoma. These findings indicate that T-cell – mediated skin diseases are accompanied by an influx of CD28+ T cells and an upregulation of B7/BB1 on cutaneous antigen- presenting cells, keratinocytes, and on some T cells. We speculate that “alternative” T cell-activation via the B7/CD28 pathway may contribute to the pathogenesis of these skin diseases

On the Discovery of the GZK Cut-off

The recent claim of the '5 sigma' observation of the Greisen and Zatzepin and Kuzmin cut-off by the HiRes group based on their nine years data is a significant step toward the eventual solution of the one of the most intriguing questions which has been present in physics for more than forty years. However the word 'significance' is used in the mentioned paper in the sense which is not quite obvious. In the present paper we persuade that this claim is a little premature.Comment: 10 page

Ultra high energy neutrinos from gamma ray bursts

Protons accelerated to high energies in the relativistic shocks that generate gamma ray bursts photoproduce pions, and then neutrinos in situ. I show that ultra high energy neutrinos (> 10^19 eV) are produced during the burst and the afterglow. A larger flux, also from bursts, is generated via photoproduction off CMBR photons in flight but is not correlated with currently observable bursts, appearing as a bright background. Adiabatic/synchrotron losses from protons/pions/muons are negligible. Temporal and directional coincidences with bursts detected by satellites can separate correlated neutrinos from the background.Comment: Adiabatic/synchrotron losses from protons/pions/muons shown to be negligible. Accepted for publication in Phys. Rev. Letters. RevTe

Spatial and temporal robustness of Sr/Ca‐SST calibrations in Red Sea corals : evidence for influence of mean annual temperature on calibration slopes

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Paleoceanography and Paleoclimatology 33 (2018): 443-456, doi:10.1029/2017PA003276.Sr/Ca ratios recorded in the aragonite skeleton of massive coral colonies are commonly used to reconstruct seasonal‐ to centennial‐scale variability in sea surface temperature (SST). While the Sr/Ca paleothermometer is robust in individual colonies, Sr/Ca‐SST relationships between colonies vary, leading to questions regarding the utility of the proxy. We present biweekly‐resolution calibrations of Sr/Ca from five Porites spp. corals to satellite SST across 10° of latitude in the Red Sea to evaluate the Sr/Ca proxy across both spatial and temporal scales. SST is significantly correlated with coral Sr/Ca at each site, accounting for 69–84% of Sr/Ca variability (P ≪ 0.01). Intercolony variability in Sr/Ca‐SST sensitivities reveals a latitudinal trend, where calibration slopes become shallower with increasing mean annual temperature. Mean annual temperature is strongly correlated with the biweekly‐resolution calibration slopes across five Red Sea sites (r2 = 0.88, P = 0.05), while also correlating significantly to Sr/Ca‐SST slopes for 33 Porites corals from across the entire Indo‐Pacific region (r2 = 0.26, P < 0.01). Although interannual summer, winter, and mean annual calibrations for individual Red Sea colonies are inconsistently robust, combined multicoral calibrations are significant at summer (r2 = 0.53, P ≪ 0.01), winter (r2 = 0.62, P ≪ 0.01), and mean annual time scales (r2 = 0.79, P ≪ 0.01). Our multicoral, multisite study indicates that the Sr/Ca paleothermometer is accurate across both temporal and spatial scales in the Red Sea and also potentially explains for the first time variability in Sr/Ca‐SST calibration slopes across the Indo‐Pacific region. Our study provides strong evidence supporting the robustness of the coral Sr/Ca proxy for examining seasonal to multicentury variability in global climate phenomena.Singapore Ministry of Education; National Research Foundation Singapore Grant Number: NRFF‐2012‐03; U.S. National Science Foundation Grant Number: OCE‐1031288; King Abdullah University of Science and Technology Grant Numbers: USA 00002, KSA 0001

Features of Muon Arrival Time Distributions of High Energy EAS at Large Distances From the Shower Axis

In view of the current efforts to extend the KASCADE experiment (KASCADE-Grande) for observations of Extensive Air Showers (EAS) of primary energies up to 1 EeV, the features of muon arrival time distributions and their correlations with other observable EAS quantities have been scrutinised on basis of high-energy EAS, simulated with the Monte Carlo code CORSIKA and using in general the QGSJET model as generator. Methodically various correlations of adequately defined arrival time parameters with other EAS parameters have been investigated by invoking non-parametric methods for the analysis of multivariate distributions, studying the classification and misclassification probabilities of various observable sets. It turns out that adding the arrival time information and the multiplicity of muons spanning the observed time distributions has distinct effects improving the mass discrimination. A further outcome of the studies is the feature that for the considered ranges of primary energies and of distances from the shower axis the discrimination power of global arrival time distributions referring to the arrival time of the shower core is only marginally enhanced as compared to local distributions referring to the arrival of the locally first muon.Comment: 24 pages, Journal Physics G accepte

Learning to be Waste Wise

The Learning to be Waste Wise Activity Guide is a series of curriculum-linked activity packs written for the Waste Wise Schools Program. Each booklet covers a different topic including a general introduction to waste, the ‘3Rs’ (Reduce, Reuse and Recycle), ‘Worms’ and ‘Compost’. The activities are designed to complement the school’s ongoing waste minimisation projects, and to support learning at every stage of a school’s Waste Wise journey. In turn, Waste Wise projects provide real life context to curriculum outcomes while directly involving students in their own learning. By reinforcing Waste Wise principles through the curriculum in an engaging and practical way, teachers will find it easier to incorporate waste reduction practices in their school. In addition, the involvement of students and the modelling of positive behaviours, reinforces the environmental principles and curriculum outcomes. The activities are designed to be fun; to promote life-long learning; to empower and enable students, teachers and the rest of the school community to take responsibility for their waste minimisation actions; to develop positive environmental values and to promote long-term behaviour change