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Collagenase‐treated, explanted human trabecular‐bone chips are an excellent source of osteoblast‐like cells. We have recently shown the multiple differentiation potential of these cells; in addition to osteogenesis and adipogenesis, these cells also undergo chondrogenesis when maintained as high‐density pellet cultures (250,000 cells/pellet) in a serum‐free, chemically defined medium stimulated with TGF‐β1 (10 ng/mL). In this investigation, we have analyzed how transactivating nuclear transcription factors, specifically AP‐2 and SP‐1, may interact with common cis‐acting elements found in the regulatory region of cartilage‐specific genes as part of the signal transduction mechanism of TGF‐β1 and p38 during chondrogenesis of human trabecular bone‐derived multipotential cells. Both TGF‐β1 stimulation and p38 MAP kinase activation affect the binding of AP‐2 as well as SP‐1 to oligonucleotides with sequence similarity to the overlapping AP‐2/SP‐1 sites found in the putative 52‐bp immediate upstream regulatory region and the 5′‐untranslated region of the human aggrecan gene. Electrophoretic mobility shift assays show that TGF‐β1 treatment of the bone‐derived cells inhibits AP‐2 DNA binding but enhances the DNA binding ability of SP‐1. Additionally, treatment of these TGF‐β1‐stimulated cells with p38 MAP kinase inhibitor, SB203580, rescued the AP‐2 DNA binding but did not affect SP‐1 DNA binding. These findings indicate that AP‐2 DNA binding is the target of both TGF‐β1 and p38 MAP kinase signaling pathways and suggest a possible signal transduction cascade whereby TGF‐β1 induction of chondrogenesis involves the activation of p38 MAP kinase and the subsequent inhibition of DNA binding by AP‐2, thereby preventing the transcriptional repression of the aggrecan gene.

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Specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4, and the orphan nuclear receptor 4A1 (NR4A1) are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival. Results of knockdown and overexpression of Sp1, Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members. NR4A1 is also a pro-oncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth, survival, migration and invasion. There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin, epidermal growth factor receptor, PAX3-FOXO1, α5- and α6-integrins, β1-, β3- and β4-integrins; this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites. Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells, and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.

If the accelerated expansion of the universe is due to a modification of general relativity at late times, it is likely that the growth of structure on large scales would also display deviations from the standard cosmology. We investigate the statistics of the distribution of galaxy cluster-sized halos as a probe of gravity. We analyze the output of several matched N-body simulations with the same initial conditions and expansion histories but using both DGP and f (R) gravity with various parameters. From each simulation we extract the cluster mass function, power spectrum, and mean pairwise velocity at redshifts 1, 0.3, and 0. All three statistics display systematic differences between gravity theories. The mean pairwise velocity provides an important consistency test for any posited departure from general relativity suggested by measurements of the power spectrum and cluster mass function. Upcoming microwave background experiments, including Simons Observatory and CMB-S4, will detect tens of thousands of galaxy clusters via the thermal Sunyaev-Zeldovich effect, probe their masses with lensing of the microwave background, and potentially measure velocities using the transverse lensing effect or the kinematic Sunyaev-Zeldovich effect. These cluster measurements promise to be a substantial probe of modified gravity.