Development of Macromolecular Prodrugs for the Treatment of Chronic Inflammatory Pain

Chronic pain afflicts millions of people worldwide. Particularly, the inflammatory conditions in the incurable disease rheumatoid arthritis (RA) generate persistent pain in its sufferers, for which a number of different analgesics have been prescribed, such as glucocorticoids (GCs) and opioids. However, administration of these pain- mitigating pharmaceutics is implicated in the development of adverse systemic effects due to their non-specific tissue distribution and quick excretion, eliciting the need for high dosing frequencies. To address this issue, this thesis is focused on the development of prodrugs based on a macromolecular design approach to instill preferential inflammation-targeting and retentive properties to common analgesics. Previously within our lab, an HPMA copolymer prodrug of the common GC dexamethasone (P-Dex) was tested for its antirheumatic properties in a rodent model of adjuvant-induced arthritis (AIA). The first part of this project, therefore, involved further evaluation of the pain-alleviating properties of P-Dex. We demonstrated that a single systemically-administered dose of the prodrug significantly reduced the pain response for a duration of twenty-one days, versus equivalent doses of free Dex given daily. It was confirmed that both the sustained analgesia and anti-inflammatory effects conferred by P-Dex is due to its enhanced uptake within inflamed tissue and subsequent retention by phagocytosing immune cells within the arthritic synovium and synovial cavity. Moreover, the macromolecular P-Dex copolymer greatly tempered the co-morbidity of enhanced bone turnover, as is often observed in RA. To expand the clinical repertoire of improved analgesic therapies for RA, we then synthesized and tested the pain-alleviating properties of an HPMA copolymer of the opioid hydromorphone (HMP), a very potent drug that has been implicated in deleterious effects on the central nervous system (CNS) by crossing the blood-brain barrier (BBB). Though the analgesic effects lasted only throughout the dosing day, there was sustained presence of this prodrug (P-HMP) for up to seven days within the AIA knee joint, confirmed to be mediated by the resident inflammatory cells. In contrast to the free drug, the spinal cord analgesic effects of P-HMP were greatly attenuated. Therefore, it can be reasoned that opioid-induced CNS depressive effects could be mitigated by way of the polymeric scaffold’s inability to cross the BBB. Though there remain optimization strategies to be implemented in the design of these macromolecular analgesics, we have successfully demonstrated their improved therapeutic efficacies in the treatment of pain related to RA. Through instilling arthrotropic and retentive properties to small molecule drugs, the prodrug approach can not only more effectively relieve pain versus free drugs alone, but may also curtail harmful systemic side effects associated with off-target biodistribution. In conclusion, macromolecular prodrugs demonstrate great potential as a clinically-relevant approach to mitigate the pain accompanying such chronic inflammatory conditions as those present in the pathology of RA

The frequency of infection caused by Chlamydia trachomatis in pregnant women attended at Hospital Gineco-obstétrico Isidro Ayora, Hospital Vozandes de Quito, and the Cínica Universitaria USFQ in Quito, Ecuador.

Genital infection with Chlamydia trachomatis is one of the most common sexually transmitted infections affecting reproductive population worldwide. As infection may be asymptomatic in majority of cases, annual screening is vital for population at risk. Untreated infection may cause complications not only in the non-pregnant population, but also in the pregnant population, producing risk for preterm rupture of membranes and labor, endometritis, neonatal conjunctivitis, and pneumonia. After obtaining informed consent, 60 endocervical samples were obtained from pregnant women (less than 14 weeks of gestation age) between the ages of 18-36, with no history of use of antibiotics or ovules within the previous 6 weeks. Samples were collected from three health care centers in Quito, Ecuador. Endocervical samples were processed using PCR.Infección genital con Chlamydia trachomatis es una de las infecciones de transmisión sexualmás frecuentes, afectando a la poblaciónfértil en todo el mundo. La infección puede ser asintomática por lo que en algunos países se recomienda realizar tamizaje anual para la población en riesgo. La infección no tratada puede causar complicaciones no solamente en la población no embarazada, sino que también afecta a la población embarazada, produciendo riesgo para rupturaprematura de membranas, partoprematuro, endometritis, conjuntivitis neonatal y neumonía. Después de obtener el consentimiento informado, 60 muestras endocervicales fueron obtenidas de mujeres embarazadas cursando hasta 14 semanas de edad gestacional, entre las edades de 18 a 36 años, sin historia previa del uso de antibióticos u óvulos adentro de las seis semanas previas. Las muestras fueron recolectadas de tres centros de salud en Quito, Ecuador. Las muestras endocervicales fueron procesadas usando PCR

Local Labor Market Conditions and the Jobless Poor: How Much Does Local Job Growth Help in Rural Areas?

The employment outcomes of a group of jobless poor Oregonians are tracked in order to analyze the relative importance of local labor market conditions on their employment outcomes. Local job growth increases the probability that a jobless poor adult will get a job and shortens the length of time until she finds a job. After accounting for both the effects of personal demographic characteristics and local job growth, there is little evidence that the probability of employment or the duration of joblessness differs in rural compared with urban areas.employment, local labor markets, rural labor markets, rural poverty, unemployment, welfare reform, Labor and Human Capital,

EMPLOYMENT OUTCOMES FOR LOW-INCOME ADULTS IN RURAL AND URBAN LABOR MARKETS

This study analyzes the impact of local labor market conditions on the probability of employment and duration of employment for low-income adults in Oregon. We find that economic conditions (lower employment growth and higher unemployment rates) help to explain the less successful employment outcomes for low-income adults in non-metro areas.rural labor markets, employment, low-income workers, Labor and Human Capital,

Ammonia oxidation is not required for growth of Group 1.1c soil Thaumarchaeota

© FEMS 2015. FUNDING EBW is funded by Centre for Genome Enabled Biology and Medicine, University of Aberdeen.Peer reviewedPublisher PD

Mungo and StMungo: tools for typechecking protocols in Java

We present two tools that support static typechecking of communica- tion protocols in Java. Mungo associates Java classes with typestate specifications, which are state machines defining permitted sequences of method calls. StMungo translates a communication protocol specified in the Scribble protocol description language into a typestate specification for each role in the protocol by following the message sequence. Role implementations can be typechecked by Mungo to ensure that they satisfy their protocols, and then compiled as usual with javac. We demonstrate the Scribble, StMungo and Mungo toolchain via a typechecked POP3 client that can communicate with a real-world POP3 server

Digitization and New Work: A Qualitative Guide for Small and Medium-Sized Enterprises to Take Action

The Western world is currently facing a persistent shortage of skilled workers. Well-trained employees are difficult to find and even more challenging to retain. Employees, therefore, expect the best working conditions. Companies initiate New Work approaches in response to dynamic changes. This study examines the requirements for New Work design from the perspective of commercial employees to offer small and medium-sized enterprises (SMEs) guidance to find the optimal workplace development for their employees. A qualitative research method in the form of guided interviews was used to explore the needs of employees. The results suggest that employees desire an adapted work structure and change in the sense of New Work. Based on the study results, seven design areas were derived and recommendations for action were developed for the respective areas. Requirements and patterns are identified across several principles and design areas. Based on the results, strategies for implementation were developed

Optimization of DNA extraction for advancing coral microbiota investigations

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Microbiome 5 (2017): 18, doi:10.1186/s40168-017-0229-y.We designed a two-phase study in order to propose a comprehensive and efficient method for DNA extraction from microbial cells present in corals and investigate if extraction method influences microbial community composition. During phase I, total DNA was extracted from seven coral species in a replicated experimental design using four different MO BIO Laboratories, Inc., DNA Isolation kits: PowerSoil®, PowerPlant® Pro, PowerBiofilm®, and UltraClean® Tissue & Cells (with three homogenization permutations). Technical performance of the treatments was evaluated using DNA yield and amplification efficiency of small subunit ribosomal RNA (SSU ribosomal RNA (rRNA)) genes. During phase II, potential extraction biases were examined via microbial community analysis of SSU rRNA gene sequences amplified from the most successful DNA extraction treatments. In phase I of the study, the PowerSoil® and PowerPlant® Pro extracts contained low DNA concentrations, amplified poorly, and were not investigated further. Extracts from PowerBiofilm® and UltraClean® Tissue and Cells permutations were further investigated in phase II, and analysis of sequences demonstrated that overall microbial community composition was dictated by coral species and not extraction treatment. Finer pairwise comparisons of sequences obtained from Orbicella faveolata, Orbicella annularis, and Acropora humilis corals revealed subtle differences in community composition between the treatments; PowerBiofilm®-associated sequences generally had higher microbial richness and the highest coverage of dominant microbial groups in comparison to the UltraClean® Tissue and Cells treatments, a result likely arising from using a combination of different beads during homogenization. Both the PowerBiofilm® and UltraClean® Tissue and Cells treatments are appropriate for large-scale analyses of coral microbiota. However, studies interested in detecting cryptic microbial members may benefit from using the PowerBiofilm® DNA treatment because of the likely enhanced lysis efficiency of microbial cells attributed to using a variety of beads during homogenization. Consideration of the methodology involved with microbial DNA extraction is particularly important for studies investigating complex host-associated microbiota.This project was supported by NSF award OCE-1233612 to AA and NSF GRFP award to LW

The Explanation Matters: Enhancing AI Adoption in Human Resource Management

Artificial intelligence (AI) has ubiquitous applications in companies, permeating multiple business divisions like human resource management (HRM). Yet, in these high-stakes domains where transparency and interpretability of results are of utmost importance, the black-box characteristic of AI is even more of a threat to AI adoption. Hence, explainable AI (XAI), which is regular AI equipped with or complemented by techniques to explain it, comes in. We present a systematic literature review of n=62 XAI in HRM papers. Further, we conducted an experiment among a German sample (n=108) of HRM personnel regarding a turnover prediction task with or without (X)AI-support. We find that AI-support leads to better task performance, self-assessment accuracy and response characteristics toward the AI, and XAI, i.e., transparent models allow for more accurate self-assessment of one’s performance. Future studies could enhance our research by employing local explanation techniques on real-world data with a larger and international sample