Stimuli-Responsive Nanoscale Hydrogels For The Improved Delivery Of Chemotherapeutic Agents

Cancer represents one of the largest public health concerns in the world. Current treatment methods for cancer – namely, chemotherapy – possess serious limitations, most notably the nonspecific biodistribution of the cytotoxic drugs, which leads to diminished drug efficacy and undesirable side effects. However, nanomedicines have recently demonstrated great promise in improving the target specificity of chemotherapeutic drugs and thus drug efficacy. Nanomedicines can be designed with ideal properties for drug delivery, and they are able to preferentially accumulate in the diseased site by the enhanced permeability and retention (EPR) effect. However, there are still numerous biological barriers to drug delivery that need to be considered when designing these nanomedicines. In order to overcome these barriers, the nanomedicines or nanoparticles must be rationally designed. By tuning such properties as size, shape, elasticity, hydrophobicity, and surface charge – these nanoparticles can be passively targeted to the diseased site, and even into the cancerous cells. However, it is also beneficial to actively target tumors by functionalizing the particles with target ligands that can preferentially bind to unique or overexpressed receptors or molecules at the tumor site, thereby improving target specificity, as well as facilitating uptake of the nanoparticles by the cell. In the original work of this thesis, the use of pH-sensitive nanogels as drug delivery agents for ovarian cancer was investigated. There were three aims of this investigation: (1) to elucidate the mechanism of internalization in order to determine if endosomal acidification could be leveraged to facilitate cytosolic delivery of the drug payload, (2) to evaluate the effect of stealth coating (PEG) surface density on cellular uptake, (3) and – expecting that the presence of a stealth coating would impede uptake – to design a stimuli responsive peptide linker that would facilitate the shedding of the stealth coating in the presence of a key enzyme that is over expressed in cancer cells – thereby improving uptake. Ultimately, it was determined that the nanogels were internalized via a clathrin-mediated endocytosis process. As a result, these nanogels can, in fact, leverage endosomal acidification to induce nanoparticle swelling, endosomal rupture, and cytosolic delivery. Additionally, particles with no PEG conjugated to the surface exhibited about 90% uptake, but this uptake diminished to about 10% or lower for particles with a PEG content of 10 mol% or higher, showing that the increase in PEG content severely hindered cellular uptake. However, nanoparticles with the enzyme degradable crosslinker that functionalized the PEG to the particle surfaces were successfully synthesized, and it was seen that – in the presence of the enzyme – shedding of the stealth coating was, in fact, observed, and uptake levels returned to those of the particles without PEG coatings. Therefore, it can be concluded that nanogels were rationally designed and successfully synthesized that possessed a multitude of functionalities, each of which contributed to the capacity of the nanogels to delivery drugs to a specific target with a controlled release of the drug payload

Kinematics of the Broad Line Region in M81

A new model is presented which explains the origin of the broad emission lines observed in the LINER/Seyfert nucleus of M81 in terms of a steady state spherically symmetric inflow, amounting to 1 x 10^-5 Msun/yr, which is sufficient to explain the luminosity of the AGN. The emitting volume has an outer radius of ~1 pc, making it the largest broad line region yet to be measured, and it contains a total mass of ~ 5 x 10^-2 Msun of dense, ~ 10^8 cm^-3, ionized gas, leading to a very low filling factor of ~ 5 x 10^-9. The fact that the BLR in M81 is so large may explain why the AGN is unable to sustain the ionization seen there. Thus, the AGN in M81 is not simply a scaled down quasar.Comment: Accepted for Publication in ApJ 7/21/0

The relative compliance of energy-storing tendons may be due to the helical fibril arrangement of their fascicles

T.S. acknowledges funding for this work from the EPSRC through grant no. EP/L017997/1

The Effect of Bone Quality on Treatment of Intertrochanteric Fractures with Helical Blade Versus Lag Screw Fixation in Cephalomedulary Nails

Introduction. The specific aim of this retrospective study was to determine whether bone quality has any effect on the complication rates or overall survivorship between helical blades and lag screws in cephalomedullary nails used for intertrochanteric hip fractures. Methods. Clinical charts and radiographic studies of patients between Jan 2012 through July 2019 were reviewed. Radiographic images (pre-, intra-, and post-operative) were reviewed to evaluate fracture fixation type, fracture reduction grade, and post-operative complications. DEXA scan results (T-score) and serum alkaline phosphatase (ALP) isoenzyme activity values were collected to evaluate patient bone quality. Results. 303 (helical: 197, screw: 106) cases were included. Complications were found in 31 helical blade cases (16%) and 23 lag screw cases (22%). No statistically significant difference was detected when comparing complication rates to patient bone quality between these two groups. These two groups had similar one-year implant survivorship with respect to T-score, the low ALP level group, and normal ALP level group. The helical blade had higher implant survivorship compared to lag screw in five-year survival rate with respect to osteoporotic group, high ALP level group, and normal ALP level group. (Osteoporotic: 77% vs 69%, High ALP: 73% vs 67%, normal ALP: 70% vs 64%). Conclusions. Similar complication rates were observed between helical blade and lag screw constructs in cephalomedullary femoral nails when accounting for patient bone quality. However, the bone quality had positive influence on the initial post-operative fracture reduction grade, and the five-year implant survivorship

Host stress drives Salmonella recrudescence

Host stress is well known to result in flare-ups of many bacterial, viral and parasitic infections. The mechanism by which host stress is exploited to increase pathogen loads, is poorly understood. Here we show that Salmonella enterica subspecies enterica serovar Typhimurium employs a dedicated mechanism, driven by the scsA gene, to respond to the host stress hormone cortisol. Through this mechanism, cortisol increases Salmonella proliferation inside macrophages, resulting in increased intestinal infection loads in DBA/2J mice. ScsA directs overall Salmonella virulence gene expression under conditions that mimic the intramacrophagic environment of Salmonella, and stimulates the host cytoskeletal alterations that are required for increased Salmonella proliferation inside cortisol exposed macrophages. We thus provide evidence that in a stressed host, the complex interplay between a pathogen and its host endocrine and innate immune system increases intestinal pathogen loads to facilitate pathogen dispersal

Plasma enhanced vortex fluidic device manipulation of graphene oxide

Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.A vortex fluid device (VFD) with non-thermal plasma liquid processing within dynamic thin films has been developed. This plasma–liquid microfluidic platform facilitates chemical processing which is demonstrated through the manipulation of the morphology and chemical character of colloidal graphene oxide in water

Stress induced Salmonella Typhimurium re-excretion by pigs is associated with cortisol induced increased intracellular proliferation in porcine macrophages

Infections of pigs with Salmonella enterica subspecies enterica serovar Typhimurium (Salmonella Typhimurium) often result in the development of carriers that intermittently excrete Salmonella in very low numbers. During periods of stress, recrudescence of Salmonella may occur

Stress induced Salmonella Typhimurium recrudescence in pigs coincides with cortisol induced increased intracellular proliferation in macrophages

Salmonella Typhimurium infections in pigs often result in the development of carriers that intermittently excrete Salmonella in very low numbers. During periods of stress, for example transport to the slaughterhouse, recrudescence of Salmonella may occur, but the mechanism of this stress related recrudescence is poorly understood. Therefore, the aim of the present study was to determine the role of the stress hormone cortisol in Salmonella recrudescence by pigs. We showed that a 24 h feed withdrawal increases the intestinal Salmonella Typhimurium load in pigs, which is correlated with increased serum cortisol levels. A second in vivo trial demonstrated that stress related recrudescence of Salmonella Typhimurium in pigs can be induced by intramuscular injection of dexamethasone. Furthermore, we found that cortisol, but not epinephrine, norepinephrine and dopamine, promotes intracellular proliferation of Salmonella Typhimurium in primary porcine alveolar macrophages, but not in intestinal epithelial cells and a transformed cell line of porcine alveolar macrophages. A microarray based transcriptomic analysis revealed that cortisol did not directly affect the growth or the gene expression or Salmonella Typhimurium in a rich medium, which implies that the enhanced intracellular proliferation of the bacterium is probably caused by an indirect effect through the cell. These results highlight the role of cortisol in the recrudescence of Salmonella Typhimurium by pigs and they provide new evidence for the role of microbial endocrinology in host-pathogen interactions

How should we measure psychological resilience in sport performers?

Psychological resilience is important in sport because athletes must constantly withstand a wide range of pressures to attain and sustain high performance. To advance psychologists’ understanding of this area, there exists an urgent need to develop a sport-specific measure of resilience. The purpose of this paper is to review psychometric issues in resilience research and to discuss the implications for sport psychology. Drawing on the wider general psychology literature to inform the discussion, the narrative is divided into three main sections relating to resilience and its assessment: adversity, positive adaptation, and protective factors. The first section reviews the different ways that adversity has been measured and considers the potential problems of using items with varying degrees of controllability and risk. The second section discusses the different approaches to assessing positive adaptation and examines the issue of circularity pervasive in resilience research. The final section explores the various issues related to the assessment of protective factors drawing directly from current measures of resilience in other psychology sub-disciplines. The commentary concludes with key recommendations for sport psychology researchers seeking to develop a measure of psychological resilience in athletes

EcoCyc: fusing model organism databases with systems biology.

EcoCyc (http://EcoCyc.org) is a model organism database built on the genome sequence of Escherichia coli K-12 MG1655. Expert manual curation of the functions of individual E. coli gene products in EcoCyc has been based on information found in the experimental literature for E. coli K-12-derived strains. Updates to EcoCyc content continue to improve the comprehensive picture of E. coli biology. The utility of EcoCyc is enhanced by new tools available on the EcoCyc web site, and the development of EcoCyc as a teaching tool is increasing the impact of the knowledge collected in EcoCyc