Synthesis and Characterization of Long Acting Darunavir Prodrugs

Patient adherence is critical for ART success to ensure adequate viral suppression, therefore, long-acting antiretrovirals are soon replacing current daily regimens. In recent years, two drugs were successfully transformed into long-acting injectables; CAB LA and RPV LA. These long-acting nanoformulations made it possible to abandon the daily pill burden, instead approximately a bimonthly injection of both drugs is enough to suppress and maintain viral load suppression. Our laboratory has been instrumental in transforming FDA-approved and experimental-HIV medications into long-acting slow effective release drugs, also known as LASER ART. LASER ART consists of slow drug metabolism and high permeability and retention inside cellular reservoirs eventually increasing the apparent life of the drugs. In this work, we apply LASER strategies to darunavir, a protease inhibitor (PI). DRV is a preferred PI due to its potency against wild type HIV as well as many mutant resistant viral strains. Among other drugs from its class, DRV is considered to have the highest genetic barrier to HIV mutations. To transform DRV into a LASER DRV, we chemically modified DRV to a prodrug, an inactive form of the drug, by conjugation of different lengths of fatty acids/lipids; M1DRV and M2DRV. These prodrugs were encased in amphiphilic polymer, NM1DRV and NM2DRV, to increase nanoparticles stability and permeability across cell membranes. The prodrug nanoformulations improved uptake, retention, release and antiretroviral activities in macrophages and T cells. Pharmacokinetics studies in mice affirmed the advantage of the modifications in extending the apparent half-life of DRV in animal models. Long-acting DRV offers the option of a long-acting PI that does not require a booster to maintain high concentrations in plasma, blood, and tissues. Therefore, DRV prodrugs nanoformulations can eliminate heavy pill burden and reduce drug-drug interactions that are prominent with PI boosters such as ritonavir and cobicistat

Marine Fish Farming and the Blue Revolution: Culturing Cod Fisheries

The Blue Revolution promises to transform wild marine fish into docile domesticates, fish hunters into harvesters. As commercially fished marine species continue to face extinction in the wild due to overfishing, pollution, global climate change and a host of other anthropogenic assaults, ‘culture’ has emerged as a keyword in the field of marine fisheries management. Like the terrestrial dreams and grandiose visions of their Green comrades a half-century earlier, Blue revolutionaries advocate the application of scientific expertise, industrial technology and trans-national capital in their oceanic culturing projects. These culturing projects influence and seek to transform human identity and ways of living as much as the genetic make-up, behaviours and metabolism of the wild fish species that are targeted for domestication

Size Resistance to Infection with the Schistosome Parasite in the Vector Snail

Schistosomiasis is a parasitic disease that infects 200 million individuals, in mainly undeveloped countries, killing thousands. Schistosoma mansoni is one causative parasite, and it is transmitted by the freshwater snail Biomphalaria glabrata. B. glabrata snails of the BS-90 strain have shown neonatal susceptibility to the parasite, while adults are resistant, although the mechanism is unknown. Here we show that resistance to the parasite may be a function of snail size, since prevalence of infection is lower in larger snails, and since larval parasites (sporocysts) in larger snails have fewer germinal cells, are surrounded by a multilayered capsule of hemocytes, and elicit a strong mitotic response in the snail’s immune tissue. A lower germinal cell count in a sporocyst indicates that the parasite is in an unhealthy physiological state, inasmuch as these are reproductive cells. Additionally, encapsulation signifies that a host response is occurring, as hemocytes surround and constrict the sporocyst. Furthermore, the increase of mitotic figures in the snail immune tissue also suggests a stronger response against the infection in larger snails. Our results demonstrate that snails may develop a more robust immune system as they grow, thereby becoming resistant to infection. Subsequent studies could test for changes in gene expression as a function of size to better understand the mechanism underlying our findings

Electron ionization mass spectrometry of difurfuryl diamines

Electron impact mass spectrometry (ei-ms) has aided the structural characterization of a novel series of synthetic difuranic diamines and permitted the comparison with a previous study employing electrospray ionization mass spectrometry. As expected, the molecular radical ion was inexistant in this series of compounds and the fragmentation routes of the molecular radical ion were governed either by homolytic cleavage of the radical R2• or by heterolytic loss of NH3 to give their respective base peaks

Gleasondale Village Revitalization Plan

In 2005, the Town of Stow received a Priority Development Fund Grant made available by MassHousing. The funds were used to develop zoning bylaws with the Metropolitan Area Planning Commission for a draft Mixed-Use Overlay District in town (Stow Lower Village 2011, 4). At that time, two of Stow’s villages, Gleasondale and the Lower Village, seemed like ideal candidates for the project. After focusing its initial efforts on the Lower Village, the Town is preparing to turn next to Gleasondale, in the southern edge of town. A classic mill village on the Assabet River, Gleasontdale is home to Stow’s contribution to the American Industrial Revolution. The purpose of this project is to create a revitalization plan for Gleasondale that will capitalize on the village’s remarkable characteristics. Today, Gleasondale is home to a variety of uses, including agriculture, outdoor recreation, housing, and light industry. At the center of the village are two mill buildings, which have housed Gleasondale’s industrial operations for generations. Throughout the spring of 2013, a team of graduate students from the University of Massachusetts Amherst has assessed the social and economic potential of the village and the town. As part of the Economic Development Practicum, the team was tasked with identifying key issues and developing recommendations for revitalization and preservation in accordance with Stow’s values. The project team has gathered information from a number of sources: Documents and Reports, Town Officials, Industry Professionals, and Local Stakeholders. Documents from municipal, regional, and state agencies were reviewed alongside reports from civic groups and non-profit organizations. Town officials were consulted for insights pertaining to the town and village, and the feasibility of potential recommendations. The team contacted industry professionals for in-depth guidance on larger-scale issues, in order to place particulars in their appropriate context. Local stakeholders were interviewed, as well, to gather the perspective of tenants and property owners at the Gleasondale Mill site. Following initial meetings with planning officials in Stow, the team drafted a project scope. The project was completed in three phases: inventory, assessment, and implementation. This report presents the output of each of these phases. The inventory examines the physical, social, cultural, legal, and commercial elements in the project area. The assessment identifies the major issues pertaining to the redevelopment potential of the site, gathered from the inventory. Guided by the assessment, the implementation presents the team’s recommendations, and strategies for realizing them. The report concludes with a vision for Gleasondale

The role of complement and complement regulators in peripheral nerve and neuromuscular disorders

This thesis describes the evaluation of the role of Complement (C) and C regulators (CRegs) in experimental models of peripheral neuropathy and neuromuscular disease. Although a role for C in mediating peripheral neuropathy has previously been demonstrated in Guillain-Barre Syndrome (GBS) and its well characterised animal model Experimnetal Autoimmune Neuritis (EAN), evaluation of the role of individual components is lacking. C activation has also been widely implicated in the pathology seen in myasthenia gravis (MG) and its associated animal model Experimental Autoimmune Myasthenia Gravis (EAMG), although the precise effectors are uncertain. Evaluation of the extent of protection conferred by CRegs in the peripheral nervous system (PNS), and the ability of the myelin-producing Schwann cell to synthesize C components was a vital first step in determining the susceptibility of the system to C attack, and for providing a method of targeting key C-related molecules for further study in vivo. This work demonstrated that the PNS is well protected from membrane attack complex (MAC) attack, with high expression of the terminal pathway regulator, CD59. Crry was also highly expressed, while CD55 had a limited expression, suggesting a possible alternative role for this protein. CD46 was not expressed in the PNS. Testing the susceptibility of C and CReg deficient and knockout animals to induction of EAN and EAMG would enable further clarification of the role of individual C components to disease pathogenesis. For EAN, various antigens derived from myelin protein zero (PO) were generated to induce disease in rodents. Using this panel of antigens, specific, reproducible EAN was not achieved, and the possible reasons for this are discussed. C activation at the neuromuscular junction (NMJ) contributes to pathology in MG, although the precise role of the MAC is undear. EAMG was used to test the susceptibility of wikHype rats versus rats deficient in the terminal pathway component C6, to disease induction. Wildtype rats demonstrated severe weakness following induction of passively transferred EAMG, while C6 deficient rats were completely protected, demonstrated by protection against clinical disease, reduction in acetylcholine receptor (nAChR) loss, absence of inflammatory infiltrates and lack of C9 deposition. Reconstitution of human C6 to the C6 deficient rats resulted in increased disease. Soluble and fusion protein forms of CRegs, and a novel C5 inhibitor were also tested for their ability to abrogate disease in this model. Preliminary studies of EAMG induction in CReg knockout mice revealed that a lack of CD55 and CD59 markedly enhanced disease, although this remains to be confirmed. In conclusion, this work demonstrates: 1 The potential susceptibility of the PNS to C-mediated pathology 2 The difficulties in inducing EAN in rodents using published protocols 3 That MAC is the major drive to NMJ destruction in EAMG CRegs tested in EAMG hold promise for treatment of inflammatory disease, and analysis of the role of CRegs in EAMG in the mouse may shed new light on the precise effectors mediating disease pathogenesis

Effects of NSTEMI on Patients with Eating Disorders: Insights from the National Inpatient Sample

Introduction: Eating disorders (ED) such as bulimia and anorexia nervosa have detrimental implications on the health and wellbeing of children and young adults across the country. Cardiovascular implications are known to accompany these conditions, however there is a paucity of data looking specifically on the effects of NSTEMI on patients with these disorders. We sought to analyze this relationship further by examining these disorders within the national inpatient sample database to describe in-hospital trends and outcomes among those patients. Methods: Data were extracted from the National Inpatient Sample (NIS) Database for the years 2019 and 2020. The NIS was searched for hospitalizations of adult patients with eating disorder(s) with and without a concomitant diagnosis of NSTEMI using international classification of diseases-10th revision codes. Multivariate logistic was used to adjust for confounders. The primary outcome was inpatient mortality. Secondary outcomes were hospital length of stay (LOS), and total hospital charges (TOTHCG). SPSS software was used for statistical analysis. Results: This study included 16,889 patients who were diagnosed with eating disorders, of which only 56 (0.3%) patients were diagnosed with NSTEMI. ED patients with NSTEMI had higher prevalence of hypertension, diabetes mellitus and chronic kidney disease but not statistically different compared to patients with ED only. Multivariate regression showed that patients with both ED and NSTEMI had higher inpatient mortality compared to those with ED alone (OR 1.013, CI 1.011-1.015, p Conclusion: In this nationally representative population‐based retrospective cohort study, we concluded that ED patients hospitalized with NSTEMI have increased in-hospital mortality and worse outcomes. More research is needed in this area

A Vision for the Pioneer Valley Riverfront Club

The goal of Planning Studio is to develop a student’s techniques for collecting, analyzing, synthesizing spatial and non-spatial data and presenting that collective data in a manner (i.e., report, video, presentation, charettes) that is understandable to academics, professionals, and the public. Planning Studio allows students to integrate knowledge from coursework and research, and apply such knowledge to resolving representative planning problems. At UMASS Amherst, these problems are found in neighborhood, rural, urban, and/or regional settings. In Fall 2013, the course completed three projects: Master Plans & Land-Use Elements, the Revitalization of the Lower Worthington Street District (Springfield, MA), a Vision for the Pioneer Valley Riverfront Club (Springfield, MA). For a Vision for the Pioneer Valley Riverfront Club, the Studio Team of six students was tasked with helping the newly invigorated nonprofit rowing club write a plan that implements their vision and expands their programs the next five years. Historically, the rowing club was an organization with a small budget and devoted following. Recently, the organization experienced an influx of revenue in the form of a public health grant. This new budget presents opportunities for organizational prosperity and sustainability and the Studio Team provides strategies to sustain the organization. The client was Pioneer Valley Riverfront Club