Fundamental Chemistry Advances Toward the Development of Degradable Polymer-Based Nanoparticles for the Treatment of Infectious Diseases

Microorganisms, including bacteria, viruses, fungi, or parasites, give rise to infectious diseases, which can spread between people, and can even transfer from animals or insects to humans. Infectious diseases are common, sometimes fatal, health issues. To date, the treatment of infectious diseases has largely relied on antibiotics. However, the therapeutic outcomes of current treatments need to be enhanced due to the emergence of drug-resistant microorganisms and the decline in the development of new antibiotics. Nanotechnology could help improve the efficacy of currently available antibiotics via changing the pharmacokinetics and biodistribution of drugs, which could enhance bioavailability, reduce side effects, help overcome physical and biological barriers for the efficient delivery to the site of infection, and so on. This dissertation aims to explore a novel treatment method to treat infectious diseases using degradable polymer-based nanoparticles. In a first project, bacterial adhesin, FimHA-targeted polymeric nanoparticles were developed for the delivery of antimicrobials to bacteria hiding inside the cells by mimicking the bacterial mode of cell invasion in order to treat and eradicate recurrent urinary tract infections. Amidation between carboxylic acids located in the shell of the poly(acrylic acid)-block-polystyrene-based polymeric nanoparticles and primary amine groups of lysine residues on FimHA was employed as the conjugation method. We prepared FimHA-polymeric nanoparticle conjugates with varying amounts of adhesins on the surface without free and/or physically-associated proteins under the improved coupling conditions. In a second direction involving a series of projects, functional polycarbonates were developed in order to expand the pool of degradable polymers and their self-assembled nanostructures, which can be utilized as drug-delivery vehicles. Degradable polycarbonates were synthesized by metal-free organocatalytic ring-opening polymerization of cyclic carbonate monomers. Postpolymerization modifications were also employed to introduce new functionalities onto the same degradable polymer backbone. Water-soluble polycarbonate formed a hydrophilic shell domain of polymeric nanostructures, and reactive aldehyde- and vinyl ether-functionalized polycarbonates were synthesized and their potential for drug delivery systems were demonstrated. In a third direction, advanced mechanistic understanding of organocatalytic ring-opening polymerization (ROP), which is widely used for syntheses of degradable polymers, was gained by specialized NMR spectroscopy studies. The collection of 13C NMR data in real time during polymerization was enhanced via hyperpolarization of nuclear spins. The “living” characteristics of ring-opening polymerization enabled the observation of NMR resonances associated with an intermediate formed during ROP

Multiparametric immunoimaging maps inflammatory signatures in murine myocardial infarction models

In the past 2 decades, research on atherosclerotic cardiovascular disease has uncovered inflammation to be a key driver of the pathophysiological process. A pressing need therefore exists to quantitatively and longitudinally probe inflammation, in preclinical models and in cardiovascular disease patients, ideally using non-invasive methods and at multiple levels. Here, we developed and employe

Ketosis prevents abdominal aortic aneurysm rupture through C-C chemokine receptor type 2 downregulation and enhanced extracellular matrix balance

Abdominal aortic aneurysms (AAAs) are prevalent with aging, and AAA rupture is associated with increased mortality. There is currently no effective medical therapy to prevent AAA rupture. The monocyte chemoattractant protein (MCP-1)/C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA inflammation, matrix-metalloproteinase (MMP) production, and extracellular matrix (ECM) stability. We therefore hypothesized that a diet intervention that can modulate CCR2 axis may therapeutically impact AAA risk of rupture. Since ketone bodies (KBs) can trigger repair mechanisms in response to inflammation, we evaluated whether systemic ketosis in vivo could reduce CCR2 and AAA progression. Male Sprague-Dawley rats underwent surgical AAA formation using porcine pancreatic elastase and received daily β-aminopropionitrile to promote AAA rupture. Rats with AAAs received either a standard diet, ketogenic diet (KD), or exogenous KBs (EKB). Rats receiving KD and EKB reached a state of ketosis and had significant reduction in AAA expansion and incidence of rupture. Ketosis also led to significantly reduced aortic CCR2 content, improved MMP balance, and reduced ECM degradation. Consistent with these findings, we also observed that Ccr2-/- mice have significantly reduced AAA expansion and rupture. In summary, this study demonstrates that CCR2 is essential for AAA expansion, and that its modulation with ketosis can reduce AAA pathology. This provides an impetus for future clinical studies that will evaluate the impact of ketosis on human AAA disease

Kinematics Characteristic of Lower Extremity during Simulated Skiing Exercise

We analyze the kinematic factors of sectional and total movements in healthy participants to providing group dependent information during simulated exercise. Participants in this study's experiment were 26 male adults, the elapsed times in each phase, the difference in the lower extremity angles, and muscle activity were computed through analysis of kinematic factors. We revealed that motions of the experts took shorter to perform than non-experts, and showed larger variation of lower limb joint angle in most events during simulated skiing. There were also significant group dependent differences in the peak and mean EMG values during simulated skiing. Referring to these results, such a non-expert's posture leads to enhance muscle activity to keep the lower body in balance. Non-experts should maintain appropriate ROM with lower-intensity exercise to improve muscle endurance initially, and it can be useful in providing preliminary data for future training and rehabilitation studies, as well as improvements in muscle strength

Electrical conductivity enhancement of epitaxially grown TiN thin films

Titanium nitride (TiN) presents superior electrical conductivity with mechanical and chemical stability and compatibility with the semiconductor fabrication process. Here, we fabricated epitaxial and polycrystalline TiN (111) thin films on MgO (111), sapphire (001), and mica substrates at 640oC and room temperature by using a DC sputtering, respectively. The epitaxial films show less amount of surface oxidation than the polycrystalline ones grown at room temperature. The epitaxial films show drastically reduced resistivity (~30 micro-ohm-cm), much smaller than the polycrystalline films. Temperature-dependent resistivity measurements show a nearly monotonic temperature slope down to low temperature. These results demonstrate that high temperature growth of TiN thin films leads to significant enhancement of electrical conductivity, promising for durable and scalable electrode applications.Comment: 14 pages, 3 figure

Translation and validation of the Korean confusion assessment method for the intensive care unit

<p>Abstract</p> <p>Background</p> <p>Delirium is a common problem and associated with poor outcomes in intensive care unit (ICU) patients. Diagnosis of delirium in ICU patients is limited and usually underdiagnosed by physicians. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is one of the most widely used screening methods for detection of ICU delirium. Our goal was to translate and validate the CAM-ICU for use in the Korean ICU setting.</p> <p>Methods</p> <p>Translation of the CAM-ICU was done according to the guidelines suggested by the Translation and Cultural Adaptation Group. For validation and interrater reliability assessment of the Korean CAM-ICU, two nurses independently assessed delirium in ICU patients and the results were compared with the reference evaluation, which was done by a psychiatrist using the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV).</p> <p>Results</p> <p>Twenty-two patients were evaluated by two nurses and one psychiatrist expert independently. During the study period, we have continuously educated study nurses. Based on DSM-IV criteria, 16 out of 22 (72.7%) patients developed delirium. The sensitivities of the two nurses' evaluations using the Korean CAM-ICU were 89.80% for nurse 1 and 77.40% for nurse 2. Their specificities were 72.40% and 75.80% and their overall accuracy was 83.33% and 88.37% respectively. The Korean CAM-ICU was done with reasonable interrater reliability between nurse 1 and nurse 2 (κ = 0.81, <it>p </it>< 0.001).</p> <p>Conclusions</p> <p>The Korean CAM-ICU showed good validity and could be incorporated into clinical practice in Korean ICUs.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN50265663">ISRCTN50265663</a></p

The presence of high level soluble herpes virus entry mediator in sera of gastric cancer patients

The development of gastric cancer (GC) is closely related to chronic inflammation caused by Helicobacter pylori infection, and herpes virus entry mediator (HVEM) is a receptor expressed on the surface of leukocytes that mediates potent inflammatory responses in animal models. However, the role of HVEM in human GC has not been studied. Previously, we showed that the interaction of HVEM on human leukocytes with its ligand LIGHT induces intracellular calcium mobilization, which results in inflammatory responses including induction of proinflammatory cytokine production and anti-bacterial activities. In this study, we report that leukocytes from GC patients express lower levels of membrane HVEM (mHVEM) and have lower LIGHT-induced bactericidal activities than those from healthy controls (HC). In contrast, levels of soluble HVEM (sHVEM) in the sera of GC patients were significantly higher than in those of HC. We found that monocyte membrane-bound HVEM is released into the medium when cells are activated by proinflammatory cytokines such as TNF-α and IL-8, which are elevated in the sera of GC patients. mHVEM level dropped in parallel with the release of sHVEM, and release was completely blocked by the metalloprotease inhibitor, GM6001. We also found that the low level of mHVEM on GC patient leukocytes was correlated with low LIGHT-induced bactericidal activities against H. pylori and S. aureus and production of reactive oxygen species. Our results indicate that mHVEM on leukocytes and sHVEM in sera may contribute to the development and/or progression of GC

Cardiac immune cell infiltration associates with abnormal lipid metabolism

CD36 mediates the uptake of long-chain fatty acids (FAs), a major energy substrate for the myocardium. Under excessive FA supply, CD36 can cause cardiac lipid accumulation and inflammation while its deletion reduces heart FA uptake and lipid content and increases glucose utilization. As a result, CD36 was proposed as a therapeutic target for obesity-associated heart disease. However, more recent reports have shown that CD36 deficiency suppresses myocardial flexibility in fuel preference between glucose and FAs, impairing tissue energy balance, while CD36 absence in tissue macrophages reduces efferocytosis and myocardial repair after injury. In line with the latter homeostatic functions, we had previously reported that CD3