ReBuild: Reset Your Life, Renew Your Church, Reshape Your World. By Tommy “Urban D.” Kyllonen

REBUILD: RESET YOUR LIFE. RENEW YOUR CHURCH. RESHAPE YOUR WORLD. By Tommy “Urban D.” Kyllonen. Downers Grove, IL: Intervarsity Press (2015). Paperback, 176 pages. ReBuild offers not only guidance but encouragement for leaders who feel impressed to step out and be a change catalyst for God. Though the vision God sets before us often can seem overwhelming, We are reminded that if we persist, resist opposition and distraction, and persevere, God will see us through to the completion of the “wall.

Characterizing and exploiting the amyloid precursor protein-mint1 interaction as an Alzheimer’s disease therapeutic target

The generation of amyloid-β (Aβ) peptides through proteolytic processing of the amyloid precursor protein (APP) is a key pathogenic event in Alzheimer’s disease (AD). Aβ generation begins with APP endocytosis, which is mediated by the endocytic YENPTY sequence located in the cytoplasmic tail of APP. Mints, a family of cytosolic adaptor proteins, directly bind to the YENPTY motif of APP and facilitate APP endocytosis and amyloidogenic processing. In addition, loss of any one of the three Mint proteins decreases Aβ production in aging mouse models of AD, supporting the hypothesis that the APP-Mint interaction may provide a novel therapeutic target to selectively reduce Aβ production in AD. Characterizing the biochemical and cellular dynamics of the APP-Mint interaction is critical for understanding Aβ generation. Thus, we generated Mint1 mutants that bind with high affinity (Mint1Y633A) or low affinity (Mint1Y549A/F610A) to APP. These Mint1 mutants exhibited profound alterations in cellular localization, APP endocytosis, and Aβ production. Therapeutically, we generated a novel cell-permeable APP mimetic peptide (APPMP) that interferes with the APP-Mint interaction. This APPMP was designed to outcompete endogenous APP binding, with a 46-fold improved affinity to Mint. Treatment of primary neurons from an AD mouse model with several cell permeable APPMP variants reduced Aβ production with minimal cellular toxicity, supporting Mints as a promising novel therapeutic target for AD. The PTB domain of Mint1 that mediates APP binding is autoinhibited by an adjacent C-terminal α-helix. However, the molecular mechanisms underlying the relief of Mint1 autoinhibition are unclear. Since post-translational modification is one mechanism for alleviating protein autoinhibition, and Mint1 is highly regulated by phosphorylation, we performed mass spectrometry and identified several Mint1 phosphosites. In addition, we found constitutively-active Src kinase, a kinase implicated in Mint phosphorylation, enhanced APP-Mint1 binding. These results suggest that Src kinase-mediated phosphorylation of Mint1 may relieve Mint1 autoinhibition and promote APP-Mint1 interaction. Overall, this work biochemically characterized the Mint-APP interaction and how it affects amyloidogenic processing, provided a proof of concept for targeting the APP-Mint1 interaction as an AD therapeutic target, and suggested a novel mechanism for the relief of Mint1 autoinhibition

Vaccine Hesitancy at Andrews University

In February 2022, using the Class Climate platform, we investigated reasons why students, staff and faculty at Andrews University received or did not receive the COVID-19 vaccine. Three hundred ninety-four (394) participated: students (47.4%), staff and faculty (48.4%), and others (4.1%). Significant differences in reasons were found between vaccinated and unvaccinated

06 Effect of Empathy Development on Service-Learning - Andrews University Nursing School/Community Partnership – Benton Harbor Program.

Background: Andrews University’s administration acknowledges the university’s obligation to seek higher levels of community engagement. The relatively recent adoption of the motto—Seek knowledge, Affirm faith, Change the world—speaks to the intent of the organization to become an agent for positive change. Consequently, educators are encouraged to understand and support community engagement efforts to mold students into World Changers. It is with this backdrop that Andrews University embarked on a pilot project with the School of Nursing to see the effect of empathy development on a service-learning program at Benton Harbor High School. Aim of Project: To determine the level of empathy among selected nursing students; evaluate the effectiveness of community engagement activities on nursing students’ level of empathy, and to evaluate the effect of Andrews University’s nursing students’ community engagement activities on the community’s perception of empathy or readiness to engage. Method: Andrews University School of Nursing sought partnership with Benton Harbor High School (BHHS) through Andrews University Community Engagement Office. With the approval of the BHHS and parents of BHHS students, School of Nursing Students (NS) completed 5 visits to BHHS for the service-learning project. The project consisted of Ice breaker sessions, Hands-only CPR training; one to one bonding experiences; First Aid Training; and project completion celebration event. NS completed cultural competency, mentoring, and applicable health training before the start of the project implementation. They also completed the Empathy Quotient (EQ) questionnaire pre and post-project implementation. BHHS student volunteers completed pre and post knowledge questions related to first aid and hands-only CPR. Both groups had focus group interviews pre and post-project. Pre and post-test scores for EQ and knowledge questions were compared by the t-test. Focus groups interviews manually analyzed by themes. The project was completed during 1-hour sessions on 5 Fridays in the Fall 2018 semester. Results: 15 NS participated in the project and 13 successfully complete the project. Though 23 BHHS students volunteered for the project, only three completed the project. Initial analysis revealed no significant difference in the NS EQ scores for empathy. The number of BHHS students who completed the project (3) versus 15 made knowledge scores comparison difficult. There was an observed increase in scores from pre to post knowledge tests for the three students that completed the project. NS and BHHS students made positive and encouraging comments about the service-learning project via the focus interviews. Limitations and plans: Empathy is part of the nursing profession, so this may account for the lack of increase in NS EQ scores observed in the project. There were competing activities during the project implementation at BHHS, and this may account for decreased participation. The number of interactions may not be sufficient to see tangible results. We plan to conduct a needs assessment at BHHS, increase the number of NS-BHHS Students’ interactions, and utilize a more sensitive indicator to measure the effect in future projects

CLASP2 links Reelin to the cytoskeleton during neocortical development

Published in final edited form as: Neuron. 2017 March 22; 93(6): 1344–1358.e5. doi:10.1016/j.neuron.2017.02.039.INTRODUCTION The complex architecture of the brain requires precise control over the timing of neurogenesis, neuron migration, and differentiation. These three developmental processes are exquisitely controlled during the expansion of the mammalian neocortex. The six morphologically distinct layers of the neocortex form in an “inside-out” pattern with early-born neurons forming deeper layers and later-born neurons migrating past them to form superficial layers of the cortical plate (Rakic, 1974). The Reelin signaling pathway plays a crucial role in cortical lamination. Reelin is a secreted glycoprotein that exerts its function by binding to the lipoprotein receptors ApoER2 and VLDLR and inducing tyrosine phosphorylation of the intracellular adaptor protein Disabled (Dab1) (Howell et al., 2000, Bock and Herz, 2003). Phosphorylated Dab1 then recruits downstream signaling molecules to promote cytoskeletal changes necessary for neuronal migration, final positioning, and morphology (D’Arcangelo, 2005). Mutations of Reelin, the dual ApoER2/VLDLR receptor, or Dab1 lead to an inversion of the normal inside-out pattern of cortex development (D’Arcangelo et al., 1995, Howell et al., 1997, Trommsdorff et al., 1999). In addition, a number of mutations in cytoskeletal-encoded genes produce deficits in neuron migration and cortical lamination phenotypically similar to Reelin mutants, firmly establishing a mechanistic and developmentally critical connection between Reelin and the cytoskeleton. For example, human mutations in lissencephaly-1, doublecortin, and tubulin, integral components of the microtubule cytoskeleton, cause severe cortical lamination defects with later-born neurons failing to migrate past previously born neurons (Reiner et al., 1993, Gleeson et al., 1998, Romaniello et al., 2015). The culmination of these genetic studies indicates that several signaling pathways, including the Reelin pathway, converge on downstream cytoskeletal proteins to affect proper neuronal migration and brain development. However, the molecular effectors of these pathways have not been fully characterized. CLASPs (cytoplasmic linker associated proteins) belong to a heterogeneous family of plus-end tracking proteins (+TIPs) that specifically accumulate at the growth cone. This localization strategically places them in a position to control neurite growth, directionality, and the crosstalk between microtubules and the actin cytoskeleton (Akhmanova and Hoogenraad, 2005, Basu and Chang, 2007, Akhmanova and Steinmetz, 2008). Previous evidence showed that CLASPs accumulate asymmetrically toward the leading edge of migrating fibroblasts, indicating a role for CLASPs in cell polarity and movement (Akhmanova et al., 2001, Wittmann and Waterman-Storer, 2005). We found that CLASP2 protein levels steadily increase throughout neuronal development and are specifically enriched at the growth cones of extending neurites. In particular, short-hairpin RNA (shRNA)-mediated knockdown of CLASP2 in primary mouse neurons decreases neurite length, whereas overexpression of human CLASP2 causes the formation of multiple axons, enhanced dendritic branching, and Golgi condensation (Beffert et al., 2012). These results implicate a role for CLASP2 in neuronal morphogenesis and polarization; however, the function of CLASP2 during brain development is unknown. Here we demonstrate that CLASP2 is a modifier of the Reelin signaling pathway during cortical development. In vivo knockdown experiments demonstrate that CLASP2 plays significant roles in neural precursor proliferation, neuronal migration, and morphogenesis. In addition, we show that GSK3β-mediated phosphorylation of CLASP2 controls its binding to the Reelin adaptor protein Dab1, a required molecular step governing CLASP2’s regulatory effects on neuron morphology and movement. RESULTS CLASP2 Expression Is Functionally Associated with the Reelin Signaling Pathway To identify novel genes downstream of Reelin signaling, we examined the expression of mRNA transcripts by microarray between adult brain cortices from mice deficient in either Reelin, the double ApoER2/VLDLR receptor mutant, or Dab1 and compared Affymetrix gene expression profiles against age-matched, wild-type mice. Importantly, each of these mutant mouse models present a similar phenotype that includes severe neuronal migration defects (D’Arcangelo et al., 1995, Howell et al., 1997, Trommsdorff et al., 1999). We defined a large network of genes perturbed above a threshold of 1.5-fold in response to deficient Reelin signaling, identifying 832 upregulated and 628 downregulated genes that were common to all three mouse models (Figure 1A). Ingenuity Pathway Analysis revealed a network of genes that is functionally related to cytoskeleton organization, microtubule dynamics, neurogenesis, and migration of cells (Figure 1B). Of the few cytoskeletal candidate genes identified, CLASP2 was the only microtubule +TIP. Specifically, CLASP2 mRNA expression was increased in all three Reelin mutant phenotypes, while CLASP1 mRNA expression remained unchanged (Figure 1B). Consistent with the microarray data, CLASP2 protein levels were ∼2.8-fold higher in Dab1 knockout mice (Figure 1C). These findings suggest that Reelin signaling controls CLASP2 expression and establishes the first molecular link between a plus-end, microtubule binding protein downstream of extracellular Reelin signaling.We thank Drs. Thomas C. Sudhof, Joachim Herz, Santos Franco, and Torsten Wittmann for plasmids and antibodies. We thank Alicia Dupre, Elias Fong, and Christine Learned for technical support. This work was supported by grants from the National Institutes of Health (R21 MH100581 to T.F.H., U.B., and A.H.). (R21 MH100581 - National Institutes of Health)Accepted manuscrip

The Obesity-Breast Cancer Conundrum: An Analysis of the Issues

Breast cancer develops over a timeframe of 2–3 decades prior to clinical detection. Given this prolonged latency, it is somewhat unexpected from a biological perspective that obesity has no effect or reduces the risk for breast cancer in premenopausal women yet increases the risk for breast cancer in postmenopausal women. This conundrum is particularly striking in light of the generally negative effects of obesity on breast cancer outcomes, including larger tumor size at diagnosis and poorer prognosis in both pre- and postmenopausal women. This review and analysis identifies factors that may contribute to this apparent conundrum, issues that merit further investigation, and characteristics of preclinical models for breast cancer and obesity that should be considered if animal models are used to deconstruct the conundrum

The Psychic Distance Paradox

Companies tend to begin their internationalization process in countries that are ‘psychically’ close. Researchers describe the sequence of entry that firms follow and the mode of entry they choose. They suggest that psychically close countries are more easily understood than distant ones; and offer more familiar operating environments. Although not prescriptive, an unstated conclusion can be drawn linking sequence of entry to performance. Evidence from thirty-two Canadian retail companies shows that only seven (22%) were functioning successfully in the United States. The psychic distance paradox is that operations in psychically close countries are not necessarily easy to manage, because assumptions of similarity can prevent executives from learning about critical differences. Moreover, empirical evidence from 271 CEOs confirms greater cultural differences between Canada and the U.S. than assumed previously. Modifications are suggested to improve the psychic distance concept.© 1996 JIBS. Journal of International Business Studies (1996) 27, 309–333

Development of a core collection of <it>Triticum</it> and <it>Aegilops</it> species for improvement of wheat for activity against chronic diseases

Abstract Background The objective of this study was to develop a core collection of Triticum and Aegilops species as a resource for the identification and characterization of wheat lines with preventive activity against chronic diseases. Given that cancer is the leading cause of mortality in the world and shares risk factors with obesity, type-2 diabetes, and cardiovascular disease, and given that wheat has been reported to protect against these diseases, the core collection was developed based on cancer prevalence. Methods The Germplasm Resources Information Network (GRIN) database was used to identify Triticum and Aegilops species grown in regions of the world that vary in cancer prevalence based on the International Agency for Cancer Research GLOBOCAN world map of cancer statistics (2008). Cancer incidence data drove variety selection with secondary consideration of ploidy, center of origin, and climate. Results Analysis indicated that the geographic regions from which wheat is considered to have originated have a lower incidence of cancer than other geographic regions (P Conclusions A diverse core collection of wheat germplasm has been established from a range of regions worldwide. This core collection will be used to identify wheat lines with activity against chronic diseases using anticancer activity as a screening tool.</p