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Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease
Get PDFApolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer’s disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD
Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics
Get PDFAllosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular-level understanding of the general principles that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M4 muscarinic acetylcholine receptor (M4 mAChR) is a validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders. In this study, we rigorously quantified the affinity, efficacy, and magnitude of modulation of two different positive allosteric modulators, LY2033298 (LY298) and VU0467154 (VU154), combined with the endogenous agonist acetylcholine (ACh) or the high-affinity agonist iperoxo (Ipx), at the human M4 mAChR. By determining the cryo-electron microscopy structures of the M4 mAChR, bound to a cognate Gi1 protein and in complex with ACh, Ipx, LY298-Ipx, and VU154-Ipx, and applying molecular dynamics simulations, we determine key molecular mechanisms underlying allosteric pharmacology. In addition to delineating the contribution of spatially distinct binding sites on observed pharmacology, our findings also revealed a vital role for orthosteric and allosteric ligand–receptor–transducer complex stability, mediated by conformational dynamics between these sites, in the ultimate determination of affinity, efficacy, cooperativity, probe dependence, and species variability. There results provide a holistic framework for further GPCR mechanistic studies and can aid in the discovery and design of future allosteric drugs
Impact of the Anatomical Accelerometer Placement on Vertical Jump Performance Characteristics
Get PDFWith rapid technological development over recent years, the use of wearable athlete monitoring devices has substantially gained popularity. Thus, the purpose of the present study was to examine the impact of the anatomical placement of an accelerometer on biomechanical characteristics of countermovement vertical jump with and without an arm swing when compared to the force plate as a criterion measure. Seventeen recreationally active individuals (ten males and seven females) volunteered to participate in the present study. Four identical accelerometers sampling at 100 Hz were placed at the following anatomical locations: upper-back (UB), chest (CH), abdomen (AB), and hip (HP). While standing on a uni-axial force plate system sampling at 1000 Hz, each participant completed three non-sequential maximal countermovement vertical jumps with and without an arm swing. All devices recorded the data simultaneously. The following variables of interest were obtained from ground reaction force curves: peak concentric force (PCF), peak landing force (PLF), and vertical jump height (VJH). The findings of the present study reveal that the most appropriate anatomical locations to place the accelerometer device when attempting to estimate PCF, PLF, and VJH during a countermovement vertical jump with no arm swing are CH, AB, and UB, and during a countermovement vertical jump with an arm swing are UB, HP, and UB, respectively. Overall, these findings may help strength and conditioning professionals and sports scientists to select appropriate anatomical locations when using innovative accelerometer technology to monitor vertical jump performance characteristics
The Impact of Specific Types of Trauma Exposure and Tolerance of Ambiguity on Loneliness Among Emerging Adults
No full textLoneliness is the aversive experience of perceiving one’s social relationships to be inadequate. While intermittent loneliness is common across the lifespan, persistent loneliness can be related to negative mental health outcomes. Trauma is a known correlate of loneliness, though less is known about the links between specific types of trauma exposures and loneliness. Further, the factors that may impact the influence of trauma on loneliness are not known. One such factor that may impact the link between trauma and loneliness is tolerance of ambiguity (TA), or the way an individual perceives and processes ambiguous situations. The current study sought to investigate links between exposure to specific types of potentially traumatic events (PTEs) and loneliness by examining the role of TA. The sample was comprised of 498 emerging adults attending a university in the Midwestern United States (M = 18.95, SD = 1.22, 49.4% male). Results from cross-sectional multiple regression analyses demonstrated that interpersonal violence and sexual victimization were both uniquely associated with high levels of loneliness, while exposure to non-interpersonal PTEs (other than war) was associated with low levels of loneliness. No moderating effects of TA in links between PTEs and loneliness were evident. These results suggest differential impacts of specific types of PTEs on loneliness. More research is required for understanding the factors that may influence the link between PTEs and loneliness
Sobre nuestros cuerpos negros: Pureza colonial y racialización en el México contemporáneo
No full textOver Our Black Bodies: Colonial Purity and Racialization in Contemporary Mexico explores the coloniality inscribed in the performance of blackness in contemporary Mexico. The chapters draw on black postcolonial studies, critical race theory, and black performance studies as well on my on archival research in Puebla, Veracruz, Ciudad de Mexico, and Oaxaca to juxtapose the history of Miguel, a boy from Africa sold as slave in Mexico in 1672, and his descendants with the life and work of three Afro-descendants artist. The central claim is that in mestizo societies, such as Mexico, the colonial inscription on Afro-descendants’ racialized bodies complicate the definition and limits of blackness. In other words, Afro-descendants’ bodies, memories and histories are still inscribed within a racial hierarchy hidden by mestizaje
A Trilogy on India’s Contemporary International Trade Policy: Part Three – Promise versus Reality
No full textIndia now is the most populous nation on earth, but its modern international trade policy remains an under-researched area. In contrast, the literature on the trade policy of the second largest nation, China, is voluminous. It is widely appreciated that China, since acceding to the World Trade Organization (WTO) on 11 December 2001, seeks – one way or the other – an ever-more powerful role in shaping the rules of the world trading system. That aspiration remains the lodestar of Chinese trade policy.
As for India, it is understood that from the August 1947 British Partition to the ballyhooed 1991 First Generation Reforms, India’s trade policy was that of import substitution. Following the semi-Socialist path chalked out by its founding Prime Minister, Jawaharlal Nehru, India kept tariff and non-tariff barriers high, mandated licenses for importation, and mollycoddled domestic champions favoured by the government in the hopes of transforming its traditional agriculture into modern industry. All the while, as a founding contracting party to the General Agreement on Tariffs and Trade (GATT), and founding Member of the WTO, India put its faith in multilateralism.
After 1991, import substitution seemed no longer to be the Indian lodestar. By the early 2000s, protectionism seemed back in vogue. But India also explored free trade agreements (FTAs). That, too, was irregular: India opted for a few bilateral FTAs, but stayed out of mega-deals like the Regional Comprehensive Economic Partnership (RCEP) and Trans-Pacific Partnership (TPP). With Prime Minister (PM) Narendra Modi came expectations of liberalization, but also Hindutva. Redolent of America First advocated by former U.S. President Donald J. Trump, for this Hindu nationalist sentiment, words like ‘globalization’ and ‘cosmopolitan’ are pejorative, and hopes for enhancing peace through cross-border commercial interdependence undermines national security So, what is India’s trade policy about? What word best characterizes India’s international trade policy since the watershed year of 1991? This trilogy of articles argues that word is ‘inconstant’. Since the ballyhooed 1991 First Generation Reforms, India’s approach to its trade measures, be they tariff or non-tariff barriers, and to potential FTAs, has been irregular. The lodestar is that there is no lodestar.
Part One of this Trilogy might be colloquially sub-titled, ‘It all started off so well, but then …’ The 1991 reforms promised a genuinely new Indian approach to cross-border trade, foreign exchange (FX) rates, and foreign direct investment (FDI). The reforms sputtered amidst governance problems. India faced no less than 12 serious challenges, and desperately needed a political apparatus that reinforced open trade and investment regime.
Parts Two and Three advance this argument by, respectively, critically analysing the twists and turns in Indian trade policy during the first and second terms (2014-2019, and 2019-present) of Prime Minister. Together, the three Parts indicate that if India’s post-1991 past is prologue, then future Indian trade policy is uncertain and thus unpredictable. Or to put the conclusion differently, as the U.S. and its Allies navigate the many variables of de-coupling (i.e., euphemistically, de-risking) from China amidst the Sino-American trade war, they would do well to see India’s trade policy as a variable, too
Personalize Campaign or Voting? : Electoral Personalization in South Korean General Elections
No full textThis dissertation is about the electoral behaviors of candidates and voters in South Korean General Elections with the wish to suggest a generalizable concept and theory of electoral personalization. Electoral personalization occurs when political actors (i.e., candidates and voters) rely on candidate-related factors instead of party-related factors as they campaign or vote.In this dissertation, I attempt to theorize how electoral personalization progresses. Despite the importance and frequent usage of the concept, scholars still need to achieve a precise and unified definition of personalization. Hence, in Chapter 2, I conceptualized personalization concerning electoral behavior, such as candidates’ campaign personalization and voters’ voting personalization. To do so, I created a typology of electoral personalization with two conceptual dimensions – candidate individuality vs. party collectivity and district localization vs. country nationalization. The former dimension categorizes electoral behaviors in terms of candidate-centered vs. party-centered, which resembles the categorization of the previous campaign studies. The latter dimension categorizes electoral behaviors in regard to policy orientation, which has often been neglected. Based on this categorization, I established four ideal types of electoral behavior that exist on a continuum between depersonalized and personalized. Thus, I consider candidates’ campaign personalization and voters’ voting personalization as a matter of degree rather than a kind.Based on the conceptualization, I generated a theoretical framework to analyze electoral behavior, including candidates’ campaign behavior and voters’ voting behavior in Chapter 3. The reason to generate a somewhat ambitious framework that covers a full election cycle is that campaigning and voting do not occur in a contextual vacuum. Also, candidates’ campaigns are not independent of voters’ voting and vice versa; these two stages are interactional. Hence, I argue that we need to analyze the connection from the political and socio-economic setting/context to the candidates’ campaign stage and from the campaign stage to the voters’ voting stage to understand under what conditions electoral personalization progresses. This theoretical framework of electoral personalization is generalizable and applicable to other countries or institutional contexts, even though I focus on the case of Korea in this dissertation.Understanding Korean electoral personalization is critical to fill the theoretical, methodological, and empirical gap in the study of personalization of politics. As one of the most-likely cases, understanding the Korean electoral personalization case is theoretically beneficial. It allows us to closely examine the scope of conditions and identify the causal necessity or sufficiency of electoral personalization. With much constituency candidate behavior data based on Korean Candidate Advertisements, I constructed an original candidate campaign behavior dataset, as explained in Chapter 4. The new datasets allow us to explore electoral personalization in Korea from the generally overlooked Asian region. By doing so, it is possible to investigate further whether we observe any differences and similarities compared to the previously examined country cases in the view of personalization of politics. Furthermore, as a new democracy, the Korean case can shed light on comparative electoral personalization between old and new democracies.From various statistical tests, this dissertation shows that country-, district-, and individual-level political and socio-economic factors influence candidates’ campaign personalization. Particularly, political factors, such as the national political scandal, party system (e.g., party’s ideological position), and incumbency, significantly impact campaign personalization, as shown in Chapter 5. Although the district-level socio-economic factors, such as the district’s urbanization, play a significant role in campaign personalization when I ran a bivariable test, the impact disappeared when it was tested with other political factors. Similarly, the influence of candidates’ socio-economic factors, such as age and education, also disappeared when they were statistically tested with other political factors.Voters’ voting personalization also progressed in Korea. Voters tend to reward candidates who personalized campaigns. Statistical tests with conditional logit models in Chapter 6 confirmed that voters prefer candidates who adopted personalized strategies, such as emphasizing the connection to the district or district specific issues/policy. Furthermore, the pattern or degree of voters’ voting personalization changes by an outbreak of a national political scandal and voters’ partisan status. Interestingly, even partisan voters personalized their voting by choosing candidates who emphasized their district specific policy/development; party-focused strategies did not attract partisan voters. I discuss the possible reason for the counterintuitive outcome in Chapter 6.All in all, this dissertation found expected and unexpected outcomes throughout the empirical analyses. The unexpected outcomes are discussed in detail in both Chapters 5 and 6. The counterintuitive outcomes suggest interesting future research, as discussed in Chapter 7. Among the future studies, the following research can be quite beneficial: comparative country studies on electoral personalization, including the case of Japan and Taiwan; studies on independents – campaign and voting personalization of independent candidates and independent voters; transferring text into data using computerized content analysis of Korean Candidate Advertisement to cover entire candidates over the six democratic elections
Making sense of adaptive leadership: Elevating sensemaking to help students learn leadership
No full textThis qualitative study explores how the communicative process of sensemaking can help equip students to lead. Combining evidence from literature on adaptive leadership and sensemaking, a semi-structured interview protocol was developed. Following five days of observer-participant data collection, 32 participants engaged in semi-structured interviews with students (n = 12), facilitators (n = 11), and expert leadership practitioners (n = 9) and data was analyzed using the phronetic iterative approach (Tracy, 2019). Findings offer insights into how leadership facilitators and experts can help students make better sense of adaptive leadership to then more effectively tackle adaptive challenges in their communities and organizations. This study contributes to the growing body of empirical research on adaptive leadership and extends our current understanding of how sensemaking manifests in leadership contexts. Findings show sensemaking is a necessary and crucial component and should be framed as a leadership skill within the teaching of adaptive leadership. This study found that sensemaking is both an individual and collective endeavor which requires intentionality and does not happen by accident. Facilitators and experts of adaptive leadership teaching and training should seek to include significant, purposeful time for sensemaking through a variety of mechanisms including debriefs, small groups, reflection assignments and practical application. Intentionality when including sensemaking as part of leadership curriculum makes teaching adaptive leadership less risky and mitigates uncertainty experienced by students. This study also extends existing metaphors for understanding the inherent uncertainty and disequilibrium present within adaptive leadership by including a metaphor of a barometer to both attend to pressure and make predictions about future needs within adaptive leadership learning environments. Facilitators and experts of leadership should pay close attention to the pressures students feel within adaptive leadership classrooms and trainings, and seek to engage wholeheartedly to offer both challenge and support. Sensemaking is a key communicative ingredient to solidify learning and productive application of adaptive leadership concepts and should be elevated in adaptive leadership scholarship and pedagogy
Effects of Total Internal Water Content on Freeze-Thaw Durability and Scaling Resistance of Internally-Cured Concrete
Get PDFThe effects of total internal (TI) water, provided by normalweight coarse and fine aggregates and pre-wetted fine lightweight aggregate (LWA), in the range of 6.8 to 17.3%, corresponding to internal curing (IC) water in the LWA ranging from 0 to 15.1%, by weight of cementitious materials, on the freeze-thaw durability and scaling resistance of 12 concrete mixtures are evaluated. Cementitious materials consist of portland cement only or portland cement with a 30% weight replacement by slag cement. The coarse aggregate consists of limestone (with an oven-dry absorption of 1.8%) or granite (with an oven-dry absorption of 0.6%), which provide 5.5 to 5.6% or 1.9% internal curing water by the weight of cementitious materials, respectively.All of the mixtures with the limestone coarse aggregate failed the test, with the average dynamic modulus of elasticity (EDYN) dropping below 95% of the initial value well before the 660 freeze-thaw cycles specified by the Kansas Department of Transportation, demonstrating that the limestone itself is susceptible to freeze-thaw damage. The mixtures containing granite coarse aggregate had an average relative EDYN above 95% of the initial value at 660 freeze-thaw cycles in the test of freeze-thaw durability at TI water contents up to 15.7% (corresponding to an IC water content of 13.4% from the LWA) by the weight of cementitious materials. The only mixture with granite coarse aggregate that failed the test had a 30% weight replacement of portland cement with slag cement and a TI water content of 17.3% by weight of the cementitious materials (corresponding to 15.1% IC water from LWA). This result indicates that it is possible to have too much internal curing water. In the scaling test, the mixtures with granite coarse aggregate, all of which contained LWA, had lower mass losses than mixtures with limestone coarse aggregate, although all but one of the 12 mixtures passed the test with a cumulative 56-day mass loss below 0.1 lb/ft2. For concrete with granite coarse aggregate, the mass loss increased slightly with increased TI water content when portland cement was used as the only cementitious material. When a 30% weight replacement of portland cement with slag cement was used, the mass loss increased for a TI water content above 12.5% (corresponding to 9.9% IC water from LWA), but remained below the failure limit, suggesting no benefits for a TI water content above 12.5% by the weight of cementitious materials. The mixtures with portland cement as the only cementitious material had lower mass losses than the mixtures with a 30% weight replacement of portland cement with slag cement for the same coarse aggregate. Pre-wetted fine lightweight aggregate (LWA) for internal curing (IC) should equal 7 to 8% by weight of cementitious materials. The results provide no evidence that it would be advantageous to stray much above these values and demonstrate that high TI/ IC water contents can be deleterious
Data-driven learning beyond English: Insights and implications from three monographs
No full textThis paper stems from the 2023 CorpusCALL SIG Symposium on Data-Driven Learning (DDL) for Languages Other Than English (LOTE). Three monographs on DDL for LOTE were presented and are briefly illustrated in this paper (Forti, 2023; Vyatkina, 2024; Schaeffer-Lacroix, 2019).Despite the growth of DDL in second language (L2) research and education in many languages, its focus has largely been on English. As a result, the knowledge about the applicability of DDL for learning LOTE remains limited. This hinders the validity and generalizability of DDL as a whole, and conceals the important implications related to bridging the research vs. practice gap in such contexts where the focus is on LOTEs. The monographs introduced in this paper demonstrate the relevance of DDL for learning LOTEs by discussing corpus-based resources, pedagogical applications, and empirical research from three perspectives