Molecular evolution of the porcine type I interferon family: subtype-specific expression and antiviral activity

Type I interferons (IFNs), key antiviral cytokines, evolve to adapt with ever-changing viral threats during vertebrate speciation. Due to novel pathogenic pressure associated with Suidae speciation and domestication, porcine IFNs evolutionarily engender both molecular and functional diversification, which have not been well addressed in pigs, an important livestock species and animal model for biomedical sciences. Annotation of current swine genome assembly Sscrofa10.2 reveals 57 functional genes and 16 pseudogenes of type I IFNs. Subfamilies of multiple IFNA, IFNW and porcine-specific IFND genes are separated into four clusters with ~60 kb intervals within the IFNB/IFNE bordered region in SSC1, and each cluster contains mingled subtypes of IFNA, IFNW and IFND. Further curation of the 57 functional IFN genes indicates that they include 18 potential artifactual duplicates. We performed phylogenetic construction as well as analyses of gene duplication/conversion and natural selection and showed that porcine type I IFN genes have been undergoing active diversification through both gene duplication and conversion. Extensive analyses of the non-coding sequences proximal to all IFN coding regions identified several genomic repetitive elements significantly associated with different IFN subtypes. Family-wide studies further revealed their molecular diversity with respect to differential expression and restrictive activity on the resurgence of a porcine endogenous retrovirus. Based on predicted 3-D structures of representative animal IFNs and inferred activity, we categorized the general functional propensity underlying the structure-activity relationship. Evidence indicates gene expansion of porcine type I IFNs. Genomic repetitive elements that associated with IFN subtypes may serve as molecular signatures of respective IFN subtypes and genomic mechanisms to mediate IFN gene evolution and expression. In summary, the porcine type I IFN profile has been phylogenetically defined family-wide and linked to diverse expression and antiviral activity, which is important information for further biological studies across the porcine type I IFN family

A New Materials and Design Approach for Roads, Bridges, Pavement, and Concrete

Increased understanding of demand for transport energy and how to improve road pavement materials would enable decision makers to make environmental, financial, and other positive changes in future planning and design of roads, bridges, and other important transportation structures. This research comprises three studies focused on pavement materials and a fourth study that examines energy demand within the road transportation sector. These studies are as follows: 1. A techno-economic study of ground tire rubber as an asphalt modifier; 2. A computational fluid dynamics analysis comparing the urban heat island effect of two different pavement materials – asphalt and Portland Cement Concrete; 3. A new approach that modifies the surface of ground tire rubber using low-cost chemicals and treatment methods to be used in asphalt applications; and 4. Analysis of road transport energy demand in California and the United States. The findings of these studies include that 1. GTR is an effective and economically suitable additive for modified asphalt, 2. the suitability of PCC pavements in urban settings should be reexamined, 3. Surface modification of GTR materials can improve compatibilization of particles for the manufacture of asphalt materials, and 4. gasoline sales are generally price inelastic in both the U.S. and California. Ultimately, these four studies improve understanding of road pavement materials and transport energy demand. They lay out important information about the future of the relationship between materials and design in the transportation industry. These findings may be used by engineers, policymakers, and others in the industry to better consider implications of decisions involved in design, creation, and modification of structures using pavement and concrete, including roads, bridges, etc

Tugging at the root of oppression: Infusing social justice across doctoral level clinical psychology curriculum

Most professional associations and accrediting bodies in psychology and counseling make the aspirational call to graduate training programs to integrate social justice throughout their curriculum. Although a laudable goal, there appear to be no clear guidelines or best practices for cultivating this aspiration in psychology trainees preparing for entry-level practice. This case study will summarize a comprehensive process of integrating social justice principles into a doctoral program in clinical psychology accredited by the American Psychological Association. This programmatic, descriptive case study will describe specific program revisions to internal curriculum components and reorganization of the program trajectory, which were implemented to assist students in the reconciliation process. Modified curriculum components included lecture topics, readings and empirical research, in-class activities, and assignments in the core classes. The result was a more coherent and sequential program that infuses social justice concepts across all aspects of learning and training. The goal of this investigation was to (1) inspire other programs to engage in the important work of moving the exploration of social justice from one mandatory class to a concept that permeates all training aspects, and (2) cultivate a new generation of psychologists that know not just how to effectively treat people from different cultural perspectives, but to dismantle the oppressive systems that cause psychological suffering

Talent Assessment in Soccer:predicting Performance Through the Lens of Selection Psychology

Professional soccer clubs are always searching for talented soccer players. Based on match observations or results on performance tests, soccer coaches and scouts strive to identify players who have the potential to participate at the professional soccer level. By doing so, they (implicitly) make performance predictions. However, making such predictions is hard: youth players are often selected at an early age for clubs’ professional academies, which means that predictions cover large time intervals and are uncertain. How can soccer clubs improve talent selection decisions? Or in other words: how can we optimize performance predictions in soccer? In his PhD thesis ‘Talent Assessment in Soccer: Predicting Performance Through the Lens of Selection Psychology’ Tom Bergkamp aimed to answer these questions. In collaboration with the KNVB and FC Groningen, he examined which methods yield better predictions among soccer scouts, coaches, and from soccer specific tests. He used insights from psychological research on selection (i.e. selection psychology), which had previously not been applied in the sports literature. The thesis offers new insights on predicting soccer performance. For example, it presents a large-scale survey on the decision-making process of soccer scouts; a population which had received little interest in the sport sciences so far. In addition, it includes an experiment – involving nearly one hundred scouts and coaches of professional soccer clubs – examining whether a structured assessment approach improves the predictions of these decision-makers. Finally, the thesis examines whether soccer performance in small-sided soccer games can be used as a predictor of performance in regular 11v11 games. The findings in this thesis may raise awareness among soccer- and sport organizations on the importance of evidence-based talent selection methods

Nanobodies targeting human and viral chemokine receptors

G protein-coupled receptors (GPCRs) control many physiological processes by converting input from the extracellular environment (e.g., light, neurotransmitters, hormones, or other ligands) into intracellular signal transduction. Due to their crucial role in various disease states and their tractability (e.g., predominant plasma membrane localization), GPCRs represent a major therapeutic class. CXCR4 is a member of the chemokine receptors, a family of GPCRs with a central role in the development and homeostasis of the immune system. Additionally, CXCR4 is overexpressed in many cancers, in which the receptor is implicated in oncogenic processes like proliferation and metastasis. It became clear that some GPCRs not only exist as monomeric entities but also form interactions among themselves or with other receptors, a process called oligomerization. In artificial systems, CXCR4 switches from mainly monomeric at low expression levels to predominantly dimeric or higher-order oligomeric at high expression levels. The human cytomegalovirus (HCMV) is a widespread pathogen that has infected a large fraction of the population. In immunocompetent individuals, this herpesvirus establishes latent and asymptomatic infections. However, in organ-transplant or immunocompromised settings, HCMV may reactivate with severe consequences. HCMV infections are associated with several malignancies, including glioblastoma. In this most aggressive type of brain cancer, HCMV is believed to be oncomodulatory. HCMV encodes four viral GPCRs, human chemokine receptor homologs, of which US28 is the best-studied one. This receptor is vital for the establishment and maintenance of latency as well as the oncomodulatory effects. Yet, there are outstanding questions regarding US28 conformations and mechanisms underlying the oncomodulatory effects. Nanobodies or VHHs are the single variable fragments of heavy chain-only antibodies found in camelids. The long CDR3 and protruding paratope make nanobodies ideal for targeting discontinuous cryptic epitopes, such as the binding pockets of GPCRs. This thesis describes the development of nanobodies to study the mechanisms underlying oncogenic signaling by CXCR4 and US28. The first study introduces fluorescently labeled nanobodies as probes for BRET-based binding studies with Nanoluciferase-tagged GPCRs. In the second study, we report on VUN103, a nanobody that targets the intracellular site of US28. A comparison of VUN103 with a previously published US28-targeting nanobody, Nb7, demonstrates the existence of different active conformations. While VUN103 recognizes the apo constitutively active state of US28, Nb7 recognizes the ligand-bound active state. By interfering with G protein binding, VUN103 could fully inhibit US28 signaling and associated oncomodulatory effects in glioblastoma cells. The third study sheds light on how US28 rewires and relocalizes cellular signaling networks in glioblastoma cells, thereby contributing to HCMV-mediated oncomodulatory effects. US28 activates the sphingosine kinase-1 (SK1)/sphingosine-1-phosphate receptor 1 (S1P1) signaling axis, apparently from intracellular sites, thereby engaging in malignant feed-forward loops that exert proliferative and anti-apoptotic effects. The fourth study describes the characterization of a series of CXCR4-targeting nanobodies to study the role of receptor oligomerization in downstream signal transduction. Using nanobodies that modulate CXCR4 oligomerization, we corroborate the role of receptor oligomerization in activating the oncogenic JAK-STAT pathway. In the fifth study, we detected endogenous CXCR4 oligomers in B-cell malignancies using nanobodies. Identifying non-competitive CXCR4-targeting nanobodies and small molecules allowed the demonstration of pharmacological disruption of endogenous CXCR4 clusters. Eventually, malignant signaling and phenotypes could be associated with CXCR4 clusters, highlighting the potential of ligands that can selectively interfere with this process. Overall, the research described in this thesis provides insights into the mechanisms underlying the oncogenic signaling of human and viral chemokine receptors. The existence and functional relevance of GPCR oligomers and multiple active conformations, as well as malignant intracellular signaling complexes, are key findings. Furthermore, this thesis highlights the versatility of nanobodies to study and modulate various aspects of GPCR interactions and signaling

The Paradox of Emotionality & Competence in Multicultural Competency Training: A Grounded Theory

The American Psychological Association mandates multicultural competency training as a requirement of accredited doctoral programs. The tripartite model of knowledge, skills, and awareness has been the most consistently cited framework in the last two decades. Although multiple pedagogical methods have been researched, there has yet to be a unified theory developed to link educational techniques to the tripartite domain competencies. Furthermore, there is a dearth of research exploring the various learning factors involved in multicultural competency training. Emotionality is an important factor in obtaining multicultural competency. No unified theory of multicultural education can be developed without incorporating the element of emotional triggering. This grounded theory study found that the emotional construct, termed Agent Shame, served as a barrier to multicultural competency. Further, a curriculum construct coined Oppression Mechanics, offers powerful implications for future multicultural competency training