Despite important empirical findings, current models of the oral glucose tolerance test (OGTT) do not incorporate the essential contributions of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, to glucose-stimulated insulin secretion. In order to address this deficiency, a model was, therefore, developed in which the incretins, as well as a term reflecting net hepatic glucose balance, were included. Equations modeling the changes in incretins, hepatic glucose balance, insulin and glucose were used to simulate the responses to 50 and 100 g oral glucose loads under normal conditions. The model successfully captures main trends in mean data from the literature using a simple 'lumped-parameter,' single-compartment approach in which the majority of the parameters were matched to known clinical data. The accuracy of the model and its applicability to understanding fundamental mechanisms was further assessed using a variety of glycemic and insulinemic challenges beyond those which the model was originally created to encompass, including hyper- and hypoinsulinemia, changes in insulin sensitivity, and the insulin infusion-modified intravenous glucose tolerance test.

Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.

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Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood–brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.

Background:The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) causes various neurological manifestations including neuroinflammation. Neuroinflammation is also present in Alzheimer's Disease and Related Dementias (ADRD).Despite the widespread and devastating impact of these conditions, the full causal mechanisms leading to neuroinflammation and its impact on outcomes remain elusive.Here we examine neuroinflammation in COVID-19 and ADRD in order to identify similarities, differences and interactions that could aid in addressing the biopsychosocial mechanisms and consequences in both conditions.Method: Using an expanded Adverse Outcome Pathway (AOP) approach we constructed a framework to compare the similarities and differences in key events leading to neuroinflammation. The framework is based on a meta-survey of the literature as well as existing AOPs. Key findings were assessed for similarities and differences regarding the clinical presentation, biological mechanisms, risk, protective factors, and treatment interventions. Additionally, we considered health disparities that may contribute to the worsening progression of both COVID-19 and ADRD. Result:The comparison and intersections of COVID-19 and ADRD show various overlapping factors across scales. An overlap of immune system and inflammatory processes exacerbate both conditions, potentially leading to increased mortality rates.Although there are major differences in the initiating events, timelines and molecular cascades, there are significant pathway commonalities across scales. Furthermore, commonalities in underlying conditions, such as obesity, Type 2 diabetes, cardiovascular disease, hypertension, and metabolic disorders, are major risk factors in both COVID-19 and ADRD, which worsen the outcomes. Additionally, lifestyle risk factors, such as poor nutrition, physical inactivity and cognitive status, may further exacerbate the deadly prognosis for both conditions. Conclusion:Given the crucial role of inflammation and immune system functioning in both these conditions, implementing preventative measures to strengthen the immune system and decrease comorbid conditions and lifestyle risk factors is imperative, especially for vulnerable populations. Mapping approaches such as AOPs can be particularly helpful in evaluating the weight of current evidence and knowledge gaps in a rapidly evolving scientific data landscape, such as the COVID-19 pandemic. These approaches can also serve as a foundation to further probe the complexities of multiscale interactions in diseases that may otherwise initially appear unrelated.

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Human‐induced pluripotent stem cells (iPSCs) and their differentiated derivatives are a powerful way to study disease processes and healthy function in conditions ranging from Alzheimer's disease (AD) to COVID‐19. However, these models often remain limited due to their contamination with non‐human animal‐derived components. As such, there is a need for a major shift to entirely xenofree methodologies so experimental conditions are free of non‐human animal contaminants. Here, we evaluate the availability of xenofree stem cell lines and the extent of xenogenicity in major public sources of AD and control cell lines that could also be used in COVID‐19 iPSC‐related research. In order to assess the extent of xenogenicity, we analyzed three primary catalogs of stem cell repositories for AD and control cell lines. The iPSC catalogs were chosen based on their efforts to create accessible, high quality cell lines and recognition of the need to improve reproducibility in stem cell research. These public collections included the Coriell Institute for Medical Research, the California Institute for Regenerative Medicine (CIRM), and the European Bank for induced Pluripotent Stem Cells (EBiSC). Over 300 cell lines were reviewed in this study. Although all cells were obtained from human donors, none of the collections were determined to meet fully verifiable xenofree criteria. A large numbers of cell lines were generated with one or more known xenogenic components (e.g., fetal bovine serum, Matrigel). Others lines were classified as 'suspected exposure to xenogenic components', based on the composition of the culture reagent and/or lack of manufacturer product information to verify whether animal‐free reagents were used (e.g., Eagle's Minimum Essential Medium). Even CIRM, a repository clearly dedicated to producing xenofree cell lines, included Vitronectin (VTN‐N) Recombinant Human Protein that was manufactured using Casein Peptone Type I derived from bovine milk. The results show that major stem cell collections ‐‐ despite substantial efforts to improve accessibility, consistency and reproducibility ‐‐ either fail to be xenofree or make it difficult to establish truly xenofree research conditions. The absence of xenofree resources fundamentally undermines the clinical, scientific and ethical integrity of stem cell research and raises specific concerns for readiness to study AD and COVID‐19 using iPSCs. There is a clear need for xenofree sources, not only for clinical applications but also for the discovery and testing phases of research. This will likely require the development of open and transparent xenofree certification. By establishing truly xenofree research criteria, the field can build a foundation for accurately and effectively studying conditions that affect large parts of the population, including AD and COVID‐19. Xenofree conditions for the study of long‐term sequelae will be important in COVID‐19 research as sources for iPSC cells from recovered and vaccinated individuals become available. Beyond population impact ...