Faculty Bibliography

BACKGROUND CONTEXT/BACKGROUND:Mathematical modelling for creating computer spine models is one of the basic methods underlying many scientific publications. The accuracy of strength parameters of tissues introduced into such models translates directly into the reliability of obtained results. Experimental determination of Young's modulus (E) in various areas of spongy bone tissue seems to be crucial for creating a reliable spine model without excessive simplifications in the form of a single E value for the whole vertebral body. PURPOSE/OBJECTIVE:The aim of the study was to determine Young's modulus in different parts of the lumbar vertebral column for samples subjected to compression and bending. STUDY DESIGN/METHODS:Cylindrical spongy bone tissue samples were subjected to bending and compression strength tests. METHODS:The study included 975 pathologically unchanged samples of spongy bone tissue harvested from the lumbar vertebrae of 15 male donors. The samples were subjected to compression or bending strength tests and then Young's modulus was determined for each sample depending on its location in the vertebral body. The samples were tested differently between given locations within one vertebra as well as between vertebrae. RESULTS:Compressed specimens are characterized by highly significantly different Young's modulus values depending on the location in the vertebral body. Samples No. 7 and No. 9 in the anterior part of the vertebral body have highly significantly higher Young's modulus values compared to those in the posterior part of the vertebral body for all lumbar vertebrae. Samples subjected to bending showed significant differences (p<0.05) between samples located closer to the vertebral canal (No.16, No.17) and samples located further away (No.14, No.15) with higher values for the samples located in the posterior part of the vertebral body. CONCLUSIONS:Accommodating the anisotropic structure of spongy bone in computer models and the application of different Young's module values for areas within one vertebral body will allow one to obtain realistic results of computer simulations used.

BACKGROUND: Modeling suggests that climate change mitigation actions can have substantial human health benefits that accrue quickly and locally. Documenting the benefits can help drive more ambitious and health-protective climate change mitigation actions; however, documenting the adverse health effects can help to avoid them. Estimating the health effects of mitigation (HEM) actions can help policy makers prioritize investments based not only on mitigation potential but also on expected health benefits. To date, however, the wide range of incompatible approaches taken to developing and reporting HEM estimates has limited their comparability and usefulness to policymakers.
OBJECTIVE(S): The objective of this effort was to generate guidance for modeling studies on scoping, estimating, and reporting population health effects from climate change mitigation actions.
METHOD(S): An expert panel of HEM researchers was recruited to participate in developing guidance for conducting HEM studies. The primary literature and a synthesis of HEM studies were provided to the panel. Panel members then participated in a modified Delphi exercise to identify areas of consensus regarding HEM estimation. Finally, the panel met to review and discuss consensus findings, resolve remaining differences, and generate guidance regarding conducting HEM studies.
RESULT(S): The panel generated a checklist of recommendations regarding stakeholder engagement: HEM modeling, including model structure, scope and scale, demographics, time horizons, counterfactuals, health response functions, and metrics; parameterization and reporting; approaches to uncertainty and sensitivity analysis; accounting for policy uptake; and discounting. DISCUSSION: This checklist provides guidance for conducting and reporting HEM estimates to make them more comparable and useful for policymakers. Harmonization of HEM estimates has the potential to lead to advances in and improved synthesis of policy-relevant research that can inform evidence-based decision making and practice. https://urldefense.proofpoint.com/v2/url?u=https-3A__doi.org_10.1289_EHP6745&d=DwIBAg&c=j5oPpO0eBH1iio48DtsedeElZfc04rx3ExJHeIIZuCs&r=CY_mkeBghQnUPnp2mckgsNSbUXISJaiBQUhM-Uz9W58&m=TyoCBAKzCpBZ4-uIICybN67eGKr9ePdBC-WexDhSuSM&s=kbJNEKvonPZ_U5Fg0iIhLmyB5CB-fH6dvKuB5m4mioI&e= .
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It is now widely recognized that carcinoma-associated fibroblasts which are believed to be myofibroblasts, promote the transformation of prostate epithelial cells to cancer cells, enhance their proliferation and invasiveness, and induce the acquisition of resistance to cancer therapy and immune evasiveness. Prostate-associated gene 4 (PAGE4) is an intrinsically disordered protein that is remarkably prostate-specific. PAGE4 is also a stress-response protein that functions as a transcriptional regulator and is upregulated in early-stage prostate cancer (PCa) and its precursor lesions. However, PAGE4 is downregulated in high-grade PCa and metastatic disease. Here, we show that PAGE4 is highly expressed in the stromal cells surrounding the cancer-adjacent "normal" glands and low-grade PCa lesions but not in lesions proximal to high-grade PCa. Overexpression of PAGE4 in a stromal cell line inhibits the migration and invasion of PCa epithelial cells in multiple coculture systems. PAGE4 overexpression also inhibits the downregulation of E-cadherin in PCa epithelial cells when cocultured with stromal cells. Furthermore, signaling via tumor necrosis factor-α and transforming growth factor-β pathways is decreased in the stromal cells overexpressing PAGE4 suggesting that PAGE4 appears to play a protective role against disease progression by perturbing interactions between epithelial cells and stromal cells in PCa. Taken together, these findings support previous observations that upregulation of PAGE4 in PCa correlates with a better prognosis and highlight PAGE4 as a novel therapeutic target for early-stage "low-risk" disease.

Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia. Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with lifespan extension. A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.

Recently, the nuclear receptor farnesoid X receptor (FXR) has been considered to be a liver tumor suppressor. However, the role of FXR in liver cancer invasion and metastasis remains unclear. The results of the current study demonstrated that FXR suppressed the migratory and invasive capacities of SK-Hep-1 cells in vitro and that FXR overexpression inhibited local invasion and lung metastasis of SK-Hep-1 ×enografts in vivo. Bioinformatics analysis of the gene expression profile of SK-Hep-1 cells with different FXR levels indicated that FXR may regulate the Wnt/β-catenin pathway. Compared with controls, FXR-overexpressing SK-Hep-1 cells exhibited decreased expression of β-catenin target genes and reduced nuclear translocation of β-catenin proteins in vitro and in vivo. In conclusion, these results indicated that FXR may suppress SK-Hep-1 cell invasion and metastasis by suppressing the Wnt/β-catenin signaling pathway. The current study provided novel insight into the diagnosis and treatment of liver cancer.

Animal embryogenesis requires a precise coordination between morphogenesis and cell fate specification. During mesoderm induction, mesodermal fate acquisition is tightly coordinated with the morphogenetic process of epithelial-to-mesenchymal transition (EMT). In zebrafish, cells exist transiently in a partial EMT state during mesoderm induction. Here, we show that cells expressing the transcription factor Sox2 are held in the partial EMT state, stopping them from completing the EMT and joining the mesoderm. This is critical for preventing the formation of ectopic neural tissue. The mechanism involves synergy between Sox2 and the mesoderm-inducing canonical Wnt signaling pathway. When Wnt signaling is inhibited in Sox2-expressing cells trapped in the partial EMT, cells exit into the mesodermal territory but form an ectopic spinal cord instead of mesoderm. Our work identifies a critical developmental checkpoint that ensures that morphogenetic movements establishing the mesodermal germ layer are accompanied by robust mesodermal cell fate acquisition.

Pondering on pandemics and the promise of purification from the plethora of problems that it has spawned, the paper builds on a game-theoretic model of host-pathogen interaction, and... moves beyond. It highlights how quickly this 'wicked' problem has led to deceptive Nash equilibria of certain information-asymmetric games as well as their sequels of more complex intertwined games at human scale but without an exit strategy in sight. In the absence of clarity (e.g., access to complete information) and yet facing a capricious and complex conspirator, we overview an exemplary solution, created by RxCovea, and examine how it might help.

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ's indispensable roles in adaptive immunity.