Nonhuman Primate Models of Respiratory Disease: Past, Present, and Future.

The respiratory system consists of an integrated network of organs and structures that primarily function for gas exchange. In mammals, oxygen and carbon dioxide are transmitted through a complex respiratory tract, consisting of the nasal passages, pharynx, larynx, and lung. Exposure to ambient air throughout the lifespan imposes vulnerability of the respiratory system to environmental challenges that can contribute toward development of disease. The importance of the respiratory system to human health is supported by statistics from the Centers for Disease Control and Prevention; in 2015, chronic lower respiratory diseases were the third leading cause of death in the United States. In light of the significant mortality associated with respiratory conditions that afflict all ages of the human population, this review will focus on basic and preclinical research conducted in nonhuman primate models of respiratory disease. In comparison with other laboratory animals, the nonhuman primate lung most closely resembles the human lung in structure, physiology, and mucosal immune mechanisms. Studies defining the influence of inhaled microbes, pollutants, or allergens on the nonhuman primate lung have provided insight on disease pathogenesis, with the potential for elucidation of molecular targets leading to new treatment modalities. Vaccine trials in nonhuman primates have been crucial for confirmation of safety and protective efficacy against infectious diseases of the lung in a laboratory animal model that recapitulates pathology observed in humans. In looking to the future, nonhuman primate models of respiratory diseases will continue to be instrumental for translating biomedical research for improvement of human health

Crime and punishment in Post-War Britain: “Mob rule” as democratic corrective?

Conventional wisdom amongst scholars, as well as much of the public, sees crime as an attractive and easy political issue for politicians seeking to expand their popularity. Regardless of whether crime is on the rise, mass publics are believed to be poor risk assessors, predisposed to react to perceived criminal behaviour with support for singularly punitive policies. However, drawing on her forthcoming book The Myth of Mob Rule: Violent Crime and Democratic Politics, Lisa Miller challenges this view, arguing the public perception of crime is close to reality, and politicians are often acting responsively, not opportunistically, to these trends

Impact of Vegetative Treatment Systems on Multiple Measures of Antibiotic Resistance in Agricultural Wastewater

Wastewater is an important vector of antibiotic resistant bacteria and antibiotic resistance genes (ARB/G). While there is broad agreement that ARB/G from agricultural (ag) wastewaters can be transported through the environment and may contribute to untreatable infectious disease in humans and animals, there remain large knowledge gaps surrounding applied details on the types and amounts of ARB/G associated with different agricultural wastewater treatment options and different ag production systems. This study evaluates a vegetative treatment system (VTS) built to treat the wastewater from a beef cattle feedlot. Samples were collected for three years, and plated on multiple media types to enumerate tetracycline and cefotaxime-resistant bacteria. Enterobacteriaceae isolates (n = 822) were characterized for carriage of tetracycline resistance genes, and E. coli isolates (n = 673) were phenotyped to determine multi-drug resistance (MDR) profiles. Tetracycline resistance in feedlot runoff wastewater was 2-to-3 orders of magnitude higher compared to rainfall runoff from the VTS fields, indicating efficacy of the VTA for reducing ARB over time following wastewater application. Clear differences in MDR profiles were observed based on the specific media on which a sample was plated. This result highlights the importance of method, especially in the context of isolate-based surveillance and monitoring of ARB in agricultural wastewaters

The genus Sipha Passerini (Hemiptera: Aphididae) in North America

Five species of the aphid genus Sipha Passerini (Hemiptera: Aphididae) are reported in North America and are reviewed herein. Of these species, three are adventive species and include: Sipha elegans del Guercio, Sipha glyceriae (Kaltenbach), and Sipha maydis Passerini. Sipha maydis was discovered in California in 2007 and now has been found in Georgia. The genus also includes two native species: Sipha agropyronensis (Gillette) and Sipha flava (Forbes). Sipha maydis can be distinguished easily from all the other species in the genus that occur in North America because it is black. All the species except S. agropyronensis have been implicated in damage to crop plants. A key to the apterae and alatae of Sipha found in North America is included

Peer Coaching and the Perceived Impact on Fostering Positive Relationships, Knowledge Creation and Sharing Among Nursing Personnel

Creating a team on which caregivers consistently deliver safe and compassionate care requires ongoing developmental attention, not just for excellent technical skills, but also for exceptional interpersonal, relational, and service skills. Supportive and encouraging peer-developmental relationships have the potential to augment the role of a nurse manager in addressing soft skill learning and development needs. The specific construct of peer coaching represents a small but emerging focus in the scholarly literature. In the healthcare setting, there are relatively few studies of the use of peer coaching outside the classroom setting. There are no scholarly reports documenting the study of peer coaching in a hospital setting for the intended purpose of supporting service, communication, and interpersonal skill development. It was the intent of the study to explore whether peer coaches trained in an intentionally positive model of peer coaching were perceived as facilitating high-quality connections with their coachees, and to determine if the peer-coaching process was perceived as benefiting team knowledge, skills, and innovation with regard to patient/family-centered interpersonal communication, relational, and service skills. This was a mixed-methods descriptive and correlational study using a a non experimental, cross-sectional survey design with intact groups. The practice being investigated was receiving training in positive peer coaching. Two preexisting survey instruments were adapted and modified for the study setting and combined into one instrument that also included study-specific and participant-specific questions. The instrument was made available to volunteer participants who received positive peer-coaching training, their managers, and the nursing-staff participants of the coaching groups (coachees), and included open-ended questions and three subscales. The survey period followed training in peer coaching and a subsequent period of practical experience. Data collected from 187 participants provided empirical evidence, from both a quantitative and qualitative standpoint, that despite some reported constraints such as time and availability, the majority of peer coaches, managers, and coachees perceived the experience of peer coaching to be both positive and effective. Beneficial impacts were perceived for the team as a whole, the individual participants, and for the patients and their families. There was a strong and direct correlation between perceived positive peer-coaching competencies and the development of high-quality connections. Both were also directly and strongly correlated to knowledge creation and sharing among the team

The development of small molecule inhibitors for fibrosis drug discovery

PDF of supporting information as well as thesis. Previously restricted to Strathclyde users from 1 May 2017 until 1 May 2022Fibrotic diseases can be attributed to approximately 45% of deaths within western developed countries. This category of disease can affect nearly every tissue in the body, predominantly liver, kidney, and lung. The severity of fibrotic diseases is widely recognised but currently there is no accepted effective disease modifying treatment. There have been a number of potential drug targets identified in recent years, including the enzyme autotaxin (ATX) and the RGD integrins, which are known to play a key role in the pathogenesis. In collaboration with GlaxoSmithKline, the projects detailed in this report were aimed to develop small molecule inhibitors with drug like physicochemical properties for fibrosis drugdiscovery.;Chapter 1 focusses on the secreted enzyme ATX, which is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognised therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, Chapter 1 details the structure-activity relationship (SAR) exploration of a previously reported small molecule ATX inhibitor through the design, synthesis, and biological evaluation of aseries of analogues.;Furthermore, using enzyme kinetics studies it is shown that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX the discrete binding mode was confirmed. This work has provided valuable insight into the binding of this chemotype, which could aid the design of novel ATX inhibitors with non-lipid-like scaffolds.;Chapter 2 describes a lead-optimisation project targeting the RGD subfamily of the integrin receptors. The RGD integrins are recognised therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence of the natural ligands (arginine-glycine-aspartic acid); however, the RGD-mimetic antagonists for one particular RGD integrin (αIIbβ3) have been shown to cause partial agonism, leading to the opposite pharmacological effect.The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrintherapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic.;The work detailed herein aimed to build on this emerging area, with the design, synthesis, and biological evaluation of novel small molecule inhibitors targeting the αvβ3 integrin. These compounds are shown to be accessed via synthetically divergent routes, allowing for the quick exploration of adiverse set of potential lead compounds. Initial efforts led to the identification offour promising lead-like inhibitors with pIC50 values ranging from 4.1-5.5 for the target integrin αvβ3. Unfortunately, the initial hit compound, that the subsequent compound design stemmed from, was later determined to be a false positive, and as a result work on the project ceased. Thus, Chapter 2 details a project that was misled due to false positive assay results.Fibrotic diseases can be attributed to approximately 45% of deaths within western developed countries. This category of disease can affect nearly every tissue in the body, predominantly liver, kidney, and lung. The severity of fibrotic diseases is widely recognised but currently there is no accepted effective disease modifying treatment. There have been a number of potential drug targets identified in recent years, including the enzyme autotaxin (ATX) and the RGD integrins, which are known to play a key role in the pathogenesis. In collaboration with GlaxoSmithKline, the projects detailed in this report were aimed to develop small molecule inhibitors with drug like physicochemical properties for fibrosis drugdiscovery.;Chapter 1 focusses on the secreted enzyme ATX, which is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signalling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognised therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, amongst others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, Chapter 1 details the structure-activity relationship (SAR) exploration of a previously reported small molecule ATX inhibitor through the design, synthesis, and biological evaluation of aseries of analogues.;Furthermore, using enzyme kinetics studies it is shown that analogues of this chemotype are noncompetitive inhibitors, and using a crystal structure with ATX the discrete binding mode was confirmed. This work has provided valuable insight into the binding of this chemotype, which could aid the design of novel ATX inhibitors with non-lipid-like scaffolds.;Chapter 2 describes a lead-optimisation project targeting the RGD subfamily of the integrin receptors. The RGD integrins are recognised therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence of the natural ligands (arginine-glycine-aspartic acid); however, the RGD-mimetic antagonists for one particular RGD integrin (αIIbβ3) have been shown to cause partial agonism, leading to the opposite pharmacological effect.The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrintherapeutics in need of a new strategy. Recently, a new generation of inhibitor has emerged that lacks the RGD-mimetic.;The work detailed herein aimed to build on this emerging area, with the design, synthesis, and biological evaluation of novel small molecule inhibitors targeting the αvβ3 integrin. These compounds are shown to be accessed via synthetically divergent routes, allowing for the quick exploration of adiverse set of potential lead compounds. Initial efforts led to the identification offour promising lead-like inhibitors with pIC50 values ranging from 4.1-5.5 for the target integrin αvβ3. Unfortunately, the initial hit compound, that the subsequent compound design stemmed from, was later determined to be a false positive, and as a result work on the project ceased. Thus, Chapter 2 details a project that was misled due to false positive assay results

Transgendered in Alaska: Navigating the Changing Legal Landscape for Change in Gender Petitions

Background: Detecting intracellular bacterial symbionts can be challenging when they persist at very low densities. Wolbachia, a widespread bacterial endosymbiont of invertebrates, is particularly challenging. Although it persists at high titers in many species, in others its densities are far below the detection limit of classic end-point Polymerase Chain Reaction (PCR). These low-titer infections can be reliably detected by combining PCR with DNA hybridization, but less elaborate strategies based on end-point PCR alone have proven less sensitive or less general. Results: We introduce a multicopy PCR target that allows fast and reliable detection of A-supergroup Wolbachia -even at low infection titers -with standard end-point PCR. The target is a multicopy motif (designated ARM: A-supergroup repeat motif) discovered in the genome of wMel (the Wolbachia in Drosophila melanogaster). ARM is found in at least seven other Wolbachia A-supergroup strains infecting various Drosophila, the wasp Muscidifurax and the tsetse fly Glossina. We demonstrate that end-point PCR targeting ARM can reliably detect both high-and low-titer Wolbachia infections in Drosophila, Glossina and interspecific hybrids. Conclusions: Simple end-point PCR of ARM facilitates detection of low-titer Wolbachia A-supergroup infections. Detecting these infections previously required more elaborate procedures. Our ARM target seems to be a general feature of Wolbachia A-supergroup genomes, unlike other multicopy markers such as insertion sequences (IS)

Behavior Management in Children with Autism and Related Disorders

Children with autism and related disorders commonly suffer from developmental delays and physical impairments. These often require services such as physical and occupational therapy. The behavioral symptoms these children display can pose an additional challenge to therapy sessions, requiring therapists to spend time dealing with the behaviors rather than focusing on the treatment. The purpose of the study is to review the literature on autism and related disorders and to provide effective means of behavior management to achieve more effective therapy sessions. This paper will discuss physical therapy interventions such as sensory integration and deep touch proprioception, and how these can be used to help keep students with autism and related disorders more focused and cooperative during therapy sessions