Targeted Nanocarriers for Systemic Delivery of IRAK4 Inhibitors to Inflamed Tissues

Persistent and uncontrolled inflammation is the root cause of various debilitating diseases. Given that interleukin-1 receptor–associated kinase 4 (IRAK4) is a critical modulator of inflammation, inhibition of its activity with selective drug molecules (IRAK4 inhibitors) represents a promising therapeutic strategy for inflammatory disorders. To exploit the full potential of this treatment approach, drug carriers for efficient delivery of IRAK4 inhibitors to inflamed tissues are essential. Herein, the first nanoparticle-based platform for the targeted systemic delivery of a clinically tested IRAK4 inhibitor, PF-06650833, with limited aqueous solubility (57 μg mL-1) is presented. The developed nanocarriers increase the intrinsic aqueous dispersibility of this IRAK4 inhibitor by 40 times. A targeting peptide on the surface of nanocarriers significantly enhances their accumulation after intravenous injection in inflamed tissues of mice with induced paw edema and ulcerative colitis when compared to non-targeted counterparts. The delivered IRAK4 inhibitor markedly abates inflammation and dramatically suppresses paw edema, mitigates colitis symptoms, and reduces proinflammatory cytokine levels in the affected tissues. Importantly, repeated injections of IRAK4 inhibitor-loaded nanocarriers have no acute toxic effect on major organs of mice. Therefore, the developed nanocarriers have the potential to significantly improve the therapeutic efficacy of IRAK4 inhibitors for different inflammatory diseases

Generalized higher gauge theory

We study a generalization of higher gauge theory which makes use of generalized geometry and seems to be closely related to double field theory. The local kinematical data of this theory is captured by morphisms of graded manifolds between the canonical exact Courant Lie 2-algebroid $TM\oplus T^*M$ over some manifold $M$ and a semistrict gauge Lie 2-algebra. We discuss generalized curvatures and their infinitesimal gauge transformations. Finite gauge transformation as well as global kinematical data are then obtained from principal 2-bundles over 2-spaces. As dynamical principle, we consider first the canonical Chern-Simons action for such a gauge theory. We then show that a previously proposed 3-Lie algebra model for the six-dimensional (2,0) theory is very naturally interpreted as a generalized higher gauge theory.Comment: 24 pages, minor corrections, typos fixed, published versio

Relative Susceptibility of Pima S-5 and Pima S-6 Bolls to Pink Bollworm Larval Infestations

The 1985 and 1986 Cotton Reports have the same publication and P-Series numbers

Embedded ultrasonic transducer design and wireless communication for intelligent monitoring of structures

This paper describes a wireless demonstrator system designed for generation and detection of fundamental symmetrical Lamb waves (So) characterized by high velocity and low attenuation. The demonstrator comprises two piezoceramic transducers embedded within an epoxy plate, drive and pre-amplification electronics, a microcontroller and a communications interface. This arrangement can be configured to operate in an active pitch-catch or pulse-echo interrogation mode or as a passive acoustic emission (AE) sensor. The history of AE incidents, for example, may then be transmitted by Wireless link

Systemically Delivered Magnetic Hyperthermia for Prostate Cancer Treatment

Herein, we report a novel therapy for prostate cancer based on systemically delivered magnetic hyperthermia. Conventional magnetic hyperthermia is a form of thermal therapy where magnetic nanoparticles delivered to cancer sites via intratumoral administration produce heat in the presence of an alternating magnetic field (AMF). To employ this therapy for prostate cancer tumors that are challenging to inject intratumorally, we designed novel nanoclusters with enhanced heating efficiency that reach prostate cancer tumors after systemic administration and generate desirable intratumoral temperatures upon exposure to an AMF. Our nanoclusters are based on hydrophobic iron oxide nanoparticles doped with zinc and manganese. To overcome the challenges associated with the poor water solubility of the synthesized nanoparticles, the solvent evaporation approach was employed to encapsulate and cluster them within the hydrophobic core of PEG-PCL (methoxy poly(ethylene glycol)-b-poly(ε-caprolactone))-based polymeric nanoparticles. Animal studies demonstrated that, following intravenous injection into mice bearing prostate cancer grafts, the nanoclusters efficiently accumulated in cancer tumors within several hours and increased the intratumoral temperature above 42 °C upon exposure to an AMF. Finally, the systemically delivered magnetic hyperthermia significantly inhibited prostate cancer growth and did not exhibit any signs of toxicity

Evaluating the performances of gridded satellite/reanalysis products in representing the rainfall climatology of Ethiopia

This study evaluated performances of the Climate Hazard Group Infrared Precipitation with stations version 2.0 (CHIRPS v2.0) and Multi-Source Weighted-Ensemble Precipitation version 2.8 (MSWEP v2.8) products against observed data. Rainfall climatology was simulated for different agro-ecological zones (AEZs) of Ethiopia during 1991–2020 at different temporal scales. Performance evaluations were made using continuous and statistical performance measures as well as Probability Density Function (PDF). CHIRPS v2.0 for estimating monthly, seasonal, and annual rainfall totals, and MSWEP v2.8 for daily rainfall have shown better performance over all AEZs. The two products display comparable performance for detecting daily rainfall occurrences over alpine AEZ, but MSWEP v2.8 is superior in the rest four AEZs. CHIRPS v2.0 outperforms MSWEP v2.8 for detecting most of the daily rainfall intensity classes over all AEZs. The findings will play a noteworthy role to improve the quality of hydro-climate studies in Ethiopia