Synthesis of Glycopharmaceuticals for the Treatment of Microbial sepsis

Carbohydrates (glycans) form the basis of all living organisms and, consequently, are ubiquitous both in nature as biologically active compounds and in medicine as pharmaceuticals. One important application of carbohydrate-based drugs (glycopharmaceuticals) is the treatment of microbial sepsis, an acute illness that causes 100,000+ human deaths annually in the US alone. Exposure of the patient’s blood system to E. coli bacteria causes a massive, and often fatal, immune response. One important cellular receptor that senses the bacterium and is critically involved in triggering the immune response is CD14. Significant efforts by our team and others have been made to develop carbohydrate-based drugs called anti-microbial antagonists that target and block the CD14 receptor, thus terminating the infection/immune response cascade. Nevertheless, microbial sepsis remains a long-standing, difficult-to-solve problem that requires innovative approaches since progress in this unmet medical need has been difficult to achieve. Among new promising developments is antagonist AM-12 that is an attractive drug candidate due to its relatively simple structure, stability, potent activity, and lack of toxicity, discovered by Drs. Demchenko and Nichols (UMSL). To capitalize on this discovery of this promising anti-microbial receptor antagonist and extend this development to new therapeutic avenues, my project aims to develop a range of novel carbohydrate-derived drugs. At the completion of this projects, my synthetic compounds with superior pharmaceutical properties will help to accelerate discovery in many scientific disciplines with significant public health impact

Silver Salt-Mediate Benzylation of Carbohydrates Under Mildly Acidic Conditions

When looking at biomolecules, carbohydrate represent a large group of macromolecules that play an important role in the body. Most importantly, carbohydrates provide an energy supply for organisms, but it is proven that they are also involved in a myriad of other processes. Furthermore, synthesizing these molecules leads to advancements in chemistry, such as drug design, and other structures such as glycolipids play important roles in the immune system. Understanding this, an efficient and reliable way to create these carbohydrates is needed. The protection and deprotection manipulations of carbohydrates play an essential role in synthetic carbohydrate chemistry.1 Using benzyl ethers as protecting groups for hydroxyls is a standard way of obtaining efficient building blocks in carbohydrate chemistry.2Uniform benzylation of carbohydrates can be efficiently achieved, but it typically requires excess reagents and/or harsh reaction conditions.3 Methods for mild and regioselective benzylation are not available at all. Herein, we report the investigation of a new benzylation reaction that makes use of mildly acidic conditions. The main focus of this study is to identify suitable silver salts that would provide high regioselectivity, excellent yields, and help minimize side reactions

Digital Dance-theatre as a Multidimensional Romance Notes on the production of C8's Flatland

This paper is an account of practice-based research and artistic work carried out by the authors in the field of digital dance theatre (C8’s Flatland). The work addresses the question of body-machine interaction from the point of view of a relationship (or digital romance), involving continuous and discontinuous processes of movement characteristic both to humans and technological machines. The essay explores Andre Leroi-Gourhan’s notion of ‘multidimensional graphism’ to speak of a type of digital writing that does not give prevalence to textual writing, to choreographic writing (or the virtual embodied writing of dance), to visuals, or code, but which functions as an amalgam of all these. We speak to Brian Rotman’a idea of gesturo-haptic language, as a kind of lingua franca that enables machines and bodies to relate to one another as part of the same intercommunictaional transaction, and as part of the same creative process for the emergence, and self-emergence of multidimensional artistic form

Comparison of echocardiographic methods for calculating left ventricular mass in elite rugby football league athletes and the impact on chamber geometry

Background: Recommendations for the echocardiographic assessment of left ventricular (LV) mass in the athlete suggest the use of the linear method using a two-tiered classification system (2TC). The aims of this study were to compare the linear method and the area-length (A-L) method for LV mass in elite rugby football league (RFL) athletes and to establish how any differences impact the classification of LV geometry using 2TC and four-tier (4TC) classification systems. Methods: Two hundred and twenty (220) male RFL athletes aged 25 ± 5 (14–34 years) were recruited. All athletes underwent echocardiography and LV mass was calculated by the American Society of Echocardiography (ASE) corrected Linear equation (2D) and the A-L method. Left ventricular mass Index (LVMi) was used with relative wall thickness to determine geometry in the 2TC and with concentricity and LV end diastolic volume index for the 4TC. Method specific recommended cut-offs were utilised. Results: Higher values of absolute (197 ± 34 vs. 181 ± 34 g; p < 0.0001) and indexed (92 ± 13 vs. 85 ± 13 g/m2; p < 0.0001) measures of LV mass were obtained from A-L compared to the linear method. Normal LV geometry was demonstrated in 98.2% and 80% of athletes whilst eccentric hypertrophy in 1.4% and 19.5% for linear and A-L respectively. Both methods provided 0.5% as having concentric remodelling and 0% as having concentric hypertrophy. Allocation to the 4TC resulted in 97% and 80% with normal geometry, 0% and 8.6% with eccentric dilated hypertrophy, 0% and 7.7% with eccentric non-dilated hypertrophy, 1.4% and 0.5% with concentric remodelling and 1.4% and 3% with concentric non-dilated hypertrophy for linear and A-L methods respectively. No participants had concentric dilated hypertrophy from either methods. Conclusion: The linear and A-L method for calculation of LV mass in RFL athletes are not interchangeable with significantly higher values obtained using A-L method impacting on geometry classification. More athletes present with eccentric hypertrophy using 2TC and eccentric dilated/non-dilated using 4TC. Further studies should be aimed at establishing the association of A-L methods of LV mass and application of the 4TC to the multi-factorial demographics of the athlete

Monitoring mountains in a changing world: new horizons for the Global Network for Observations and Information on Mountain Environments (GEO-GNOME)

Mountains are globally distributed environments that provide significant societal benefits, a function that is increasingly compromised by climatic change, environmental stress, political and socioeconomic transformations, and unsustainable use of natural resources. Gaps in our understanding of these processes and their interactions limit our capacity to inform decisions, where both generalities of mountain regions (eg climate processes) and specificities (eg context-specific manifestations of climate risks) matter. The Global Network for Observations and Information on Mountain Environments (GEO-GNOME), a Group on Earth Observations initiative, aims to fill these gaps through accessible Earth Observation (EO) as well as in-situ data and information on global change drivers, conditions, and trends. A workshop convened by the Mountain Research Initiative (MRI) revised GEO-GNOME's work plan, galvanizing a network that promotes relevant monitoring of global change in mountains and is responsive to the integrated knowledge needs of policy, research, and management

Labrador retrievers under primary veterinary care in the UK: demography, mortality and disorders

Abstract Background Labrador retrievers are reportedly predisposed to many disorders but accurate prevalence information relating to the general population are lacking. This study aimed to describe demography, mortality and commonly recorded diseases in Labrador retrievers under UK veterinary care. Methods The VetCompass™ programme collects electronic patient record data on dogs attending UK primary-care veterinary practices. Demographic analysis covered all33,320 Labrador retrievers in the VetCompass™ database under veterinary care during 2013 while disorder and mortality data were extracted from a random sample of 2074 (6.2%) of these dogs. Results Of the Labrador retrievers with information available, 15,427 (46.4%) were female and 15,252 (53.6%) were male. Females were more likely to be neutered than males (59.7% versus 54.8%, P <  0.001). The overall mean adult bodyweight was 33.0 kg (SD 6.1). Adult males were heavier (35.2 kg, SD 5.9 kg) than adult females (30.4 kg, SD 5.2 kg) (P <  0.001). The median longevity of Labrador retrievers overall was 12.0 years (IQR 9.9–13.8, range 0.0–16.0). The most common recorded colours were black (44.6%), yellow (27.8%) and liver/chocolate (reported from hereon as chocolate) (23.8%). The median longevity of non-chocolate coloured dogs (n = 139, 12.1 years, IQR 10.2–13.9, range 0.0–16.0) was longer than for chocolate coloured animals (n = 34, 10.7 years, IQR 9.0–12.4, range 3.8–15.5) (P = 0.028). Of a random sample of 2074 (6.2%) Labrador retrievers under care in 2013 that had full disorder data extracted, 1277 (61.6%) had at least one disorder recorded. The total number of dogs who died at any date during the study was 176. The most prevalent disorders recorded were otitis externa (n = 215, prevalence 10.4%, 95% CI: 9.1–11.8), overweight/obesity (183, 8.8%, 95% CI: 7.6–10.1) and degenerative joint disease (115, 5.5%, 95% CI: 4.6–6.6). Overweight/obesity was not statistically significantly associated with neutering in females (8.3% of entire versus 12.5% of neutered, P = 0.065) but was associated with neutering in males (4.1% of entire versus 11.4% of neutered, P < 0.001). The prevalence of otitis externa in black dogs was 12.8%, in yellow dogs it was 17.0% but, in chocolate dogs, it rose to 23.4% (P < 0.001). Similarly, the prevalence of pyo-traumatic dermatitis in black dogs was 1.1%, in yellow dogs it was 1.6% but in chocolate dogs it rose to 4.0% (P = 0.011). Conclusions The current study assists prioritisation of health issues within Labrador retrievers. The most common disorders were overweight/obesity, otitis externa and degenerative joint disease. Males were significantly heavier females. These results can alert prospective owners to potential health issues and inform breed-specific wellness checks

Glucocorticoids Acutely Increase Brown Adipose Tissue Activity in Humans, Revealing Species-Specific Differences in UCP-1 Regulation

SummaryThe discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased 18fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C–17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health

Integrated HIV Testing, Malaria, and Diarrhea Prevention Campaign in Kenya: Modeled Health Impact and Cost-Effectiveness

Efficiently delivered interventions to reduce HIV, malaria, and diarrhea are essential to accelerating global health efforts. A 2008 community integrated prevention campaign in Western Province, Kenya, reached 47,000 individuals over 7 days, providing HIV testing and counseling, water filters, insecticide-treated bed nets, condoms, and for HIV-infected individuals cotrimoxazole prophylaxis and referral for ongoing care. We modeled the potential cost-effectiveness of a scaled-up integrated prevention campaign.We estimated averted deaths and disability-adjusted life years (DALYs) based on published data on baseline mortality and morbidity and on the protective effect of interventions, including antiretroviral therapy. We incorporate a previously estimated scaled-up campaign cost. We used published costs of medical care to estimate savings from averted illness (for all three diseases) and the added costs of initiating treatment earlier in the course of HIV disease.Per 1000 participants, projected reductions in cases of diarrhea, malaria, and HIV infection avert an estimated 16.3 deaths, 359 DALYs and $85,113 in medical care costs. Earlier care for HIV-infected persons adds an estimated 82 DALYs averted (to a total of 442), at a cost of$37,097 (reducing total averted costs to $48,015). Accounting for the estimated campaign cost of$32,000, the campaign saves an estimated $16,015 per 1000 participants. In multivariate sensitivity analyses, 83$20.A mass, rapidly implemented campaign for HIV testing, safe water, and malaria control appears economically attractive