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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 199 records · Page 11
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

Slow and sustained nitric oxide releasing compounds inhibit multipotent vascular stem cell proliferation and differentiation without causing cell death

Highlights: • Multipotent vascular stem cells (MVSCs) proliferate and differentiate. • Nitric oxide inhibits proliferation of MVSCs. • Nitric oxide inhibits MVSC differentiation to mesenchymal-like stem cells (MSCs). • Smooth muscle cells (SMCs) neither de-differentiate nor proliferate. - Abstract: Atherosclerosis is the leading cause of cerebral and myocardial infarction. It is believed that neointimal growth common in the later stages of atherosclerosis is a result of vascular smooth muscle cell (SMC) de-differentiation in response to endothelial injury. However, the claims of the SMC de-differentiation theory have not been substantiated by monitoring the fate of mature SMCs in response to such injuries. A recent study suggests that atherosclerosis is a consequence of multipotent vascular stem cell (MVSC) differentiation. Nitric oxide (NO) is a well-known mediator against atherosclerosis, in part because of its inhibitory effect on SMC proliferation. Using three different NO-donors, we have investigated the effects of NO on MVSC proliferation. Results indicate that NO inhibits MVSC proliferation in a concentration dependent manner. A slow and sustained delivery of NO proved to inhibit proliferation without causing cell death. On the other hand, larger, single-burst NO concentrations, inhibits proliferation, with concurrent significant cell death. Furthermore, our results indicate that endogenously produced NO inhibits MVSC differentiation to mesenchymal-like stem cells (MSCs) and subsequently to SMC as well.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

DNA–PKcs–SIN1 complexation mediates low-dose X-ray irradiation (LDI)-induced Akt activation and osteoblast differentiation

Highlights: • LDI increases ALP activity, promotes type I collagen (Col I)/Runx2 mRNA expression. • LDI induces DNA–PKcs activation, which is required for osteoblast differentiation. • Akt activation mediates LDI-induced ALP activity and Col I/Runx2 mRNA increase. • DNA–PKcs–SIN1 complexation mediates LDI-induced Akt Ser-473 phosphorylation. • DNA–PKcs–SIN1 complexation is important for osteoblast differentiation. - Abstract: Low-dose irradiation (LDI) induces osteoblast differentiation, however the underlying mechanisms are not fully understood. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA–PKcs)–Akt signaling in LDI-induced osteoblast differentiation. We confirmed that LDI promoted mouse calvarial osteoblast differentiation, which was detected by increased alkaline phosphatase (ALP) activity as well as mRNA expression of type I collagen (Col I) and runt-related transcription factor 2 (Runx2). In mouse osteoblasts, LDI (1 Gy) induced phosphorylation of DNA–PKcs and Akt (mainly at Ser-473). The kinase inhibitors against DNA–PKcs (NU-7026 and NU-7441) or Akt (LY294002, perifosine and MK-2206), as well as partial depletion of DNA–PKcs or Akt1 by targeted-shRNA, dramatically inhibited LDI-induced Akt activation and mouse osteoblast differentiation. Further, siRNA-knockdown of SIN1, a key component of mTOR complex 2 (mTORC2), also inhibited LDI-induced Akt Ser-473 phosphorylation as well as ALP activity increase and Col I/Runx2 expression in mouse osteoblasts. Co-immunoprecipitation (Co-IP) assay results demonstrated that LDI-induced DNA–PKcs–SIN1 complexation, which was inhibited by NU-7441 or SIN1 siRNA-knockdown in mouse osteoblasts. In summary, our data suggest that DNA–PKcs–SIN1 complexation-mediated Akt activation (Ser-473 phosphorylation) is required for mouse osteoblast differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

MEK5 suppresses osteoblastic differentiation

Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and is activated by its upstream kinase, MAPK kinase 5 (MEK5), which is a member of the MEK family. Although the role of MEK5 has been investigated in several fields, little is known about its role in osteoblastic differentiation. In this study, we have demonstrated the role of MEK5 in osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells and bone marrow stromal ST2 cells. We found that treatment with BIX02189, an inhibitor of MEK5, increased alkaline phosphatase (ALP) activity and the gene expression of ALP, osteocalcin (OCN) and osterix, as well as it enhanced the calcification of the extracellular matrix. Moreover, osteoblastic cell proliferation decreased at a concentration of greater than 0.5 μM. In addition, knockdown of MEK5 using siRNA induced an increase in ALP activity and in the gene expression of ALP, OCN, and osterix. In contrast, overexpression of wild-type MEK5 decreased ALP activity and attenuated osteoblastic differentiation markers including ALP, OCN and osterix, but promoted cell proliferation. In summary, our results indicated that MEK5 suppressed the osteoblastic differentiation, but promoted osteoblastic cell proliferation. These results implied that MEK5 may play a pivotal role in cell signaling to modulate the differentiation and proliferation of osteoblasts. Thus, inhibition of MEK5 signaling in osteoblasts may be of potential use in the treatment of osteoporosis. - Highlights: • MEK5 inhibitor BIX02189 suppresses proliferation of osteoblasts. • MEK5 knockdown and MEK5 inhibitor promote differentiation of osteoblasts. • MEK5 overexpression inhibits differentiation of osteoblasts.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

miR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1 and promoting SOD2 expression

miR-140-5p is down-regulated in patients with pulmonary arterial hypertension (PAH) and experimental models of PAH, and inhibits hypoxia-mediated pulmonary artery smooth muscle cell (PASMC) proliferation in vitro. Delivery of synthetic miR-140-5p prevents and treats established, experimental PAH. DNA methyltransferase 1 (Dnmt1) is up-regulated in PAH associated human PASMCs (HPASMCs), which promotes the development of PAH by hypermethylation of CpG islands within the promoter for superoxide dismutase 2 (SOD2) and down-regulating SOD2 expression. We searched for miR-140-5p targets using TargetScan, PicTar and MiRanda tools, and found that Dnmt1 is a potential target of miR-140-5p. Based on these findings, we speculated that miR-140-5p might target Dnmt1 and regulate SOD2 expression to regulate hypoxia-mediated HPASMC proliferation, apoptosis and differentiation. We detected the expression of miR-140-5p, Dnmt1 and SOD2 by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays, respectively, and found down-regulation of miR-140-5p and SOD2 and up-regulation of Dnmt1 exist in PAH tissues and hypoxia-mediated HPASMCs. Cell proliferation, apoptosis and differentiation detection showed that miR-140-5p inhibits proliferation and promotes apoptosis and differentiation of HPASMCs in hypoxia, while the effect of Dnmt1 on hypoxia-mediated HPASMCs is reversed. Luciferase assay confirmed that miR-140-5p targets Dnmt1 directly. An inverse correlation is also found between miR-140-5p and Dnmt1 in HPASMCs. In addition, we further investigated whether miR-140-5p and Dnmt1 regulate HPASMC proliferation, apoptosis and differentiation by regulating SOD2 expression, and the results confirmed our speculation. Taken together, these results indicated that miR-140-5p at least partly targets Dnmt1 and regulates SOD2 expression to inhibit proliferation and promote apoptosis and differentiation of HPASMCs in hypoxia. - Highlights: • miR-140-5p and SOD2 are down-regulated in PAH tissues and hypoxia-mediated HPASMCs. • Dnmt1 is up-regulated in PAH tissues and hypoxia-mediated HPASMCs. • miR-140-5p regulates HPASMC proliferation, apoptosis and differentiation. • Dnmt1 and SOD2 regulates HPASMC proliferation, apoptosis and differentiation. • miR-140-5p targets Dnmt1 and regulates SOD2 expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MiR-449 overexpression inhibits osteogenic differentiation of bone marrow mesenchymal stem cells via suppressing Sirt1/Fra-1 pathway in high glucose and free fatty acids microenvironment

Highlights: • MiR-449 expression was up-regulated during osteogenic differentiation. • MiR-449 mediates osteogenic differentiation of HG-FFA-treated hBMSCs. • MiR-449 directly targets Sirt1 by binding to its 3′-UTR. • MiR-449 regulates osteogenic differentiation via suppressing Sirt1/Fra-1 pathway. Diabetic osteoporosis is a chronic complication caused by diabetes mellitus, and However, the exact mechanism of diabetes mellitus-induced osteoporosis is still unknown. In this study, we investigate the effect of miR-449 on osteogenic differentiation and its underlying mechanism in human bone marrow-derived mesenchymal stem cells (hBMSCs) with high glucose (HG) and free fatty acids (FFA) treatment. Results showed that after culturing for 14 days, high glucose (HG) and free fatty acids (FFA) treatment dramatically decreased mineralization of human bone marrow-derived mesenchymal stem cells (hBMSCs) compared with cells treated with osteogenic medium (OM) alone. We also found that miR-449 expression was up-regulated during osteogenic differentiation of hBMSCs with HG and FFA treatment. Moreover, during osteogenic differentiation of hBMSCs with HG and FFA treatment, miR-449 mimics notably decreased the alkaline phosphatase (ALP) activity and the mRNA and protein expression levels of runt-related transcription factor 2 (Runx2), ALP, collagen I, osteocalcin (OCN), and bone sialoprotein (BSP), which was remarkably increased by miR-449 inhibitors. Furthermore, miR-449 directly targets Sirt1 by binding to its 3′-UTR. Sirt1 overexpression reverses the suppressive effect of miR-449 mimics on Fra-1 mRNA and protein expression, which was also alleviated by Fra-1 overexpression. In addition, Fra-1 overexpression alleviates the inhibitory effect of miR-449 mimics on the ALP activity and the mRNA and protein of Runx2, collagen I, OCN and BSP. Taken together, our results indicated that miR-449 overexpression inhibited osteogenic differentiation of HG-FFA-treated hBMSCs through the Sirt1/Fra-1 signal pathway. It is conceivable that modulating miR-449 might provide a new therapy for intervention in diabetic osteoporosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

GSK126 alleviates the obesity phenotype by promoting the differentiation of thermogenic beige adipocytes in diet-induced obese mice

Highlights: • GSK126, a chemical inducer of beige adipocytes, was identified in mice. • GSK126 induced the browning phenotype in subcutaneous and visceral WAT in mice. • Ezh2 and H3K27me3 promoted the differentiation of white adipocytes in mice. • Ezh2 and H3K27me3 inhibited the differentiation of beige adipocytes in mice. • Ezh2 and H3K27me3 played complex roles in brown adipocytes differentiation in mice. A close relationship between epigenetic regulation and obesity has been demonstrated in several recent studies. Histone methyltransferase enhancer of Zeste homolog 2 (Ezh2), which mainly catalyzes trimethylation of histone H3K27 to form H3K27me3 was found to be required for the differentiation of white and brown adipocytes in vitro. Here, we investigated the effects of the Ezh2-specific inhibitor GSK126 in a mouse model of obesity induced by a high-fat diet (HFD). We found that GSK126 treatment reduced body fat, improved glucose tolerance, increased lipolysis and improved cold tolerance in mice by promoting the differentiation of thermogenic beige adipocytes. Moreover, we discovered that GSK126 inhibited the differentiation of white adipocytes, and the decrease of Ezh2 enzymatic activity and H3K27me3 also changed the morphology of brown adipocytes but did not alter the expression of thermogenic genes in these cells. Our results indicated that GSK126 was a novel chemical inducer of beige adipocytes and may be a potential therapeutic agent for the management of obesity. Furthermore, they also prompted that Ezh2 and H3K27me3 play different roles in the differentiation of the white, brown, and beige adipocytes in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibitory effect of celastrol on adipogenic differentiation of human adipose-derived stem cells

Highlights: • Celastrol has therapeutic potential against obesity- and aging-related diseases. • Anti-adipogenic effect of celatrol in human ADSCs depended on dose and duration. • Celatrol inhibited adipogenesis in human ADSCs by regulating PPARG and CEBPA. • Celastrol inhibited adipogenesis in hADSCs derived from 12 donors with various ages. • Celastrol also inhibited osteogenic and chondrogenic differentiation in hADSCs. Control of adipogenesis in mesenchymal stem cells (MSCs) offers enormous potential for management of obesity- and aging-related diseases. Celastrol, the traditional Chinese medicine extracted from Tripterygium wilfordi, exhibits anti-obesity effects in in vitro and in vivo murine models. This study describes how celastrol affects multilineage differentiation potential of human adipose-derived stem cells (hADSCs). We performed in vitro adipogenic differentiation of hADSCs and investigated how celastrol-induced lipid accumulation and expression of adipocyte differentiation markers varied with dose, duration, and donor age. In addition, we assessed the effect of celastrol on osteogenic and chondrogenic differentiation of hADSCs. During adipogenic induction of hADSCs, the inhibitory effect of celastrol on lipid accumulation and adipogenesis depended on dose, duration, time of administration, and individual donor. Inhibition was mediated by proliferator-activated receptor-γ (PPARG) and CCAAT/enhancer-binding protein alpha (CEBPA). Celastrol also suppressed differentiation of hADSCs into the osteogenic and chondrogenic lineages. Celastrol plays a regulatory role in multilineage differentiation of human MSCs. Our findings provide important insights regarding management of obesity and stem cell therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Human papillomavirus 16E6 and NFX1-123 potentiate notch signaling and differentiation without activating cellular arrest

High-risk human papillomavirus (HR HPV) oncoproteins bind host cell proteins to dysregulate and uncouple apoptosis, senescence, differentiation, and growth. These pathways are important for both the viral life cycle and cancer development. HR HPV16 E6 (16E6) interacts with the cellular protein NFX1-123, and they collaboratively increase the growth and differentiation master regulator, Notch1. In 16E6 expressing keratinocytes (16E6 HFKs), the Notch canonical pathway genes Hes1 and Hes5 were increased with overexpression of NFX1-123, and their expression was directly linked to the activation or blockade of the Notch1 receptor. Keratinocyte differentiation genes Keratin 1 and Keratin 10 were also increased, but in contrast their upregulation was only indirectly associated with Notch1 receptor stimulation and was fully unlinked to growth arrest, increased p21{sup Waf1/CIP1}, or decreased proliferative factor Ki67. This leads to a model of 16E6, NFX1-123, and Notch1 differently regulating canonical and differentiation pathways and entirely uncoupling cellular arrest from increased differentiation. - Highlights: • 16E6 and NFX1-123 increased the Notch canonical pathway through Notch1. • 16E6 and NFX1-123 increased the differentiation pathway indirectly through Notch1. • 16E6 and NFX1-123 increased differentiation gene expression without growth arrest. • Increased NFX1-123 with 16E6 may create an ideal cellular phenotype for HPV.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Retinoic acid receptor signalling directly regulates osteoblast and adipocyte differentiation from mesenchymal progenitor cells

Low and high serum retinol levels are associated with increased fracture risk and poor bone health. We recently showed retinoic acid receptors (RARs) are negative regulators of osteoclastogenesis. Here we show RARs are also negative regulators of osteoblast and adipocyte differentiation. The pan-RAR agonist, all-trans retinoic acid (ATRA), directly inhibited differentiation and mineralisation of early osteoprogenitors and impaired the differentiation of more mature osteoblast populations. In contrast, the pan-RAR antagonist, IRX4310, accelerated differentiation of early osteoprogenitors. These effects predominantly occurred via RARγ and were further enhanced by an RARα agonist or antagonist, respectively. RAR agonists similarly impaired adipogenesis in osteogenic cultures. RAR agonist treatment resulted in significant upregulation of the Wnt antagonist, Sfrp4. This accompanied reduced nuclear and cytosolic β-catenin protein and reduced expression of the Wnt target gene Axin2, suggesting impaired Wnt/β-catenin signalling. To determine the effect of RAR inhibition in post-natal mice, IRX4310 was administered to male mice for 10 days and bones were assessed by µCT. No change to trabecular bone volume was observed, however, radial bone growth was impaired. These studies show RARs directly influence osteoblast and adipocyte formation from mesenchymal cells, and inhibition of RAR signalling in vivo impairs radial bone growth in post-natal mice. - Graphical abstract: Schematic shows RAR ligand regulation of osteoblast differentiation in vitro. RARγ antagonists±RARα antagonists promote osteoblast differentiation. RARγ and RARα agonists alone or in combination block osteoblast differentiation, which correlates with upregulation of Sfrp4, and downregulation of nuclear and cytosolic β-catenin and reduced expression of the Wnt target gene Axin2. Red arrows indicate effects of RAR agonists on mediators of Wnt signalling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

miR-675 promotes odontogenic differentiation of human dental pulp cells by epigenetic regulation of DLX3

Highlights: • miR-675 promotes the odontogenic differentiation of human dental pulp cells (hDPCs). • miR-675 regulates the odontogenic differentiation of hDPCs by epigenetic regulating DLX3. • Our findings shed light on the regulatory mechanism of dentin hypoplasia in TDO patients. In a previous study, we showed that microRNA-675 (miR-675) was significantly down-regulated in patients with tricho-dento-osseous (TDO) syndrome. One of the main features of TDO syndrome is dentin hypoplasia. Thus, we hypothesize that miR-675 plays a role in dentin development. In this study, we determined the role of miR-675 in the odontogenic differentiation of human dental pulp cells (hDPCs). Stable overexpression and knockdown of miR-675 in hDPCs were performed using recombinant lentiviruses containing U6 promoter-driven miR-675 and short hairpin-miR675 expression cassettes, respectively. Alkaline phosphatase (ALP) assay, Alizarin red staining assay, quantitative polymerase chain reaction (qPCR), Western blot analysis, and immunofluorescent staining revealed the promotive effects of miR-675 on the odontogenic differentiation of hDPCs. Further, we found that miR-675 facilitates the odontogenic differentiation process of hDPCs by epigenetic regulation of distal-less homeobox (DLX3). Thus, for the first time, we determined that miR-675 regulates the odontogenic differentiation of hDPCs by inhibiting the DNA methyltransferase 3 beta (DNMT3B)-mediated methylation of DLX3. Our findings uncover an unanticipated regulatory role for miR-675 in the odontogenic differentiation of hDPCs by epigenetic changes in DLX3 and provide novel insight into dentin hypoplasia feature in TDO patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Commonly used thiol-containing antioxidants reduce cardiac differentiation and alter gene expression ratios of sarcomeric isoforms

Highlights: • β-mercaptoethanol (BME) and monothiolglycerol (MTG) reduce cardiac differentiation. • BME and MTG treatments decrease TNNI3/TNNI1 and MLC2V/MLC2A expression ratios. • BME and MTG treatments reduce beating rates and contraction/relaxation velocities. • Trolox, a strong ROS scavenger, does not inhibit cardiac differentiation. Reactive oxygen species (ROS) scavengers such as beta-mercaptoethanol (BME) and monothiol glycerol (MTG) are extensively used in stem cell research to prevent cellular oxidative stress. However, how these antioxidant supplements impact stem cell cardiac differentiation, a process regulated by redox-signaling remains unknown. In this study, we found that removal of BME from the conventional high-glucose, serum-based differentiation medium improved cardiac differentiation efficiency by 2-3 fold. BME and MTG treatments during differentiation significantly reduced mRNA expression of cardiac progenitor markers (NKX2.5 and ISL1) as well as sarcomeric markers (MLC2A, MLC2V, TNNI3, MYH6 and MYH7), suggesting reduced cardiomyogenesis by BME or MTG. Moreover, BME and MTG altered the expression ratios between the sarcomeric isoforms. In particular, TNNI3 to TNNI1 ratio and MLC2V to MLC2A ratio were significantly lower in BME or MTG treated cells than untreated cells, implying altered cardiomyocyte phenotype and maturity. Lastly, BME and MTG treatments resulted in less frequent beating, slower contraction and relaxation velocities than untreated cells. Interestingly, none of the above-mentioned effects was observed with Trolox, a non-thiol based antioxidant, despite its strong antioxidant activity. This work demonstrates that commonly used antioxidant supplements may cause considerable changes to cellular redox state and the outcome of differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Nrf2 activation is involved in osteogenic differentiation of periodontal ligament stem cells under cyclic mechanical stretch

Highlights: • Cyclic mechanical stretch increases the nuclear accumulation of Nrf2 in PDLSCs. • T-BHQ promotes osteogenic differentiation under cyclic mechanical stretch. • Nrf2 activation may improve alveolar bone remodeling during orthodontic treatment. During orthodontic treatment, mechanical stretch serves a crucial function in osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Up-regulated reactive oxygen species (ROS) level is a result of cyclic mechanical stretch in many cell types. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a master regulator in various antioxidants expression. However, it is not known whether cyclic mechanical stretch could induce the ROS generation in PDLSCs and whether Nrf2 participated in this process. The present study was aimed to investigate the role of Nrf2 in PDLSCs under cyclic mechanical stretch. Our results showed that cyclic mechanical stretch increased ROS level and the nuclear accumulation of Nrf2 during osteoblast differentiation. Knocking down Nrf2 by siRNA transfection increased ROS formation and suppressed osteogenic differentiation in PDLSCs. T-BHQ, a Nrf2 activator, promoted the osteogenic differentiation in PDLSCs under cyclic mechanical stretch, and improved the microstructure of alveolar bone during orthodontic tooth movement in rats by employing micro-CT system. Taken together, Nrf2 activation was involved in osteogenic differentiation under cyclic mechanical stretch in PDLSCs. T-BHQ could promote the osteogenic differentiation in vitro and in vivo, suggesting a promising option for the remodeling of the alveolar bone during orthodontic tooth movement.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Differential rotation in main-sequence solar-like stars: Qualitative inference from asteroseismic data

Understanding differential rotation of Sun-like stars is of great importance for insight into the angular momentum transport in these stars. One means of gaining such information is that of asteroseismology. By a forward modeling approach we analyze in a qualitative manner the impact of different differential rotation profiles on the splittings of p-mode oscillation frequencies. The optimum modes for inference on differential rotation are identified along with the best value of the stellar inclination angle. We find that in general it is not likely that asteroseismology can be used to make an unambiguous distinction between a rotation profile such as a conical Sun-like profile and a cylindrical profile. In addition, it seems unlikely that asteroseismology of Sun-like stars will result in inferences on the radial profile of the differential rotation, such as can be done for red giants. At best, one could possibly obtain the sign of the radial differential rotation gradient. Measurements of the extent of the latitudinal differential from frequency splitting are, however, more promising. One very interesting aspect that could likely be tested from frequency splittings is whether the differential rotation is solar-like or anti-solar-like in nature, in the sense that a solar-like profile has an equator rotating faster than the poles.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2022

Keratin Promotes Differentiation of Keratinocytes Seeded on Collagen/Keratin Hydrogels

Keratinocytes undergo a complex process of differentiation to form the stratified stratum corneum layer of the skin. In most biomimetic skin models, a 3D hydrogel fabricated out of collagen type I is used to mimic human skin. However, native skin also contains keratin, which makes up 90% of the epidermis and is produced by the keratinocytes present. We hypothesized that the addition of keratin (KTN) in our collagen hydrogel may aid in the process of keratinocyte differentiation compared to a pure collagen hydrogel. Keratinocytes were seeded on top of a 100% collagen or 50/50 C/KTN hydrogel cultured in either calcium-free (Ca-free) or calcium+ (Ca+) media. Our study demonstrates that the addition of keratin and calcium in the media increased lysosomal activity by measuring the glucocerebrosidase (GBA) activity and lysosomal distribution length, an indication of greater keratinocyte differentiation. We also found that the presence of KTN in the hydrogel also increased the expression of involucrin, a differentiation marker, compared to a pure collagen hydrogel. We demonstrate that a combination (i.e., containing both collagen and kerateine or “C/KTN”) hydrogel was able to increase keratinocyte differentiation compared to a pure collagen hydrogel, and the addition of calcium further increased the differentiation of keratinocytes. This multi-protein hydrogel shows promise in future models or treatments to increase keratinocyte differentiation into the stratum corneum.

Zuniga, Kameel (ORCID:0000000196674007)↗
DOE OSTI2014

Evaluating single-scale and/or non-planar diagrams by differential equations

We apply a recently suggested new strategy to solve differential equations for Feynman integrals. We develop this method further by analyzing asymptotic expansions of the integrals. We argue that this allows the systematic application of the differential equations to single-scale Feynman integrals. Moreover, the information about singular limits significantly simplifies finding boundary constants for the differential equations. To illustrate these points we consider two families of three-loop integrals. The first are form-factor integrals with two external legs on the light cone. We introduce one more scale by taking one more leg off-shell, $p_2^2\neq 0$. We analytically solve the differential equations for the master integrals in a Laurent expansion in dimensional regularization with $\epsilon=(4-D)/2$. Then we show how to obtain analytic results for the corresponding one-scale integrals in an algebraic way. An essential ingredient of our method is to match solutions of the differential equations in the limit of small $p_2^2$ to our results at $p_2^2\neq 0$ and to identify various terms in these solutions according to expansion by regions. The second family consists of four-point non-planar integrals with all four legs on the light cone. We evaluate, by differential equations, all the master integrals for the so-called $K_4$ graph consisting of four external vertices which are connected with each other by six lines. We show how the boundary constants can be fixed with the help of the knowledge of the singular limits. We present results in terms of harmonic polylogarithms for the corresponding seven master integrals with six propagators in a Laurent expansion in $\epsilon$ up to weight six.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2025

Differential equations for cosmological correlators

Cosmological fluctuations retain a memory of the physics that generated them in their spatial correlations. The strength of correlations varies smoothly as a function of external kinematics, which is encoded in differential equations satisfied by cosmological correlation functions. In this work, we provide a broader perspective on the origin and structure of these differential equations. As a concrete example, we study conformally coupled scalar fields in a power-law cosmology. The wavefunction coefficients in this model have integral representations, with the integrands being the product of the corresponding flat-space results and “twist factors” that depend on the cosmological evolution. Similar twisted integrals arise for loop amplitudes in dimensional regularization, and their recent study has led to the discovery of rich mathematical structures and powerful new tools for computing multi-loop Feynman integrals in quantum field theory. The integrals of interest in cosmology are also part of a finite-dimensional basis of master integrals, which satisfy a system of first-order differential equations. We develop a formalism to derive these differential equations for arbitrary tree graphs. The results can be represented in graphical form by associating the singularities of the differential equations with a set of graph tubings. Upon differentiation, these tubings grow in a local and predictive fashion. In fact, a few remarkably simple rules allow us to predict — by hand — the equations for all tree graphs. While the rules of this “kinematic flow” are defined purely in terms of data on the boundary of the spacetime, they reflect the physics of bulk time evolution. We also study the analogous structures in tr ϕ 3 theory, and see some glimpses of hidden structure in the sum over planar graphs. This suggests that there is an autonomous combinatorial or geometric construction from which cosmological correlations, and the associated spacetime, emerge.

Cosmological models↗
DOE OSTI2015

Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation

The p53 tumor suppressor gene plays a critical role in regulation of proliferation, cell death and differentiation. The MDM2 oncoprotein is a major negative regulator for p53 by binding to and targeting p53 for proteasome-mediated degradation. The small molecule inhibitor, nutlin-3, disrupts MDM2-p53 interaction resulting in stabilization and activation of p53 protein. We have previously shown that nutlin-3 activates p53, leading to MDM2 accumulation as concomitant of reduced retinoblastoma (Rb) protein stability. It is well known that Rb is important in muscle development and myoblast differentiation and that rhabdomyosarcoma (RMS), or cancer of the skeletal muscle, typically harbors MDM2 amplification. In this study, we show that nutlin-3 inhibited myoblast proliferation and effectively prevented myoblast differentiation, as evidenced by lack of expression of muscle differentiation markers including myogenin and myosin heavy chain (MyHC), as well as a failure to form multinucleated myotubes, which were associated with dramatic increases in MDM2 expression and decrease in Rb protein levels. These results indicate that nutlin-3 can effectively inhibit muscle cell differentiation. - Highlights: • Nutlin-3 inhibits myoblast proliferation and prevents differentiation into myotubes. • Nutlin-3 increases MDM2 expression and down-regulates Rb protein levels. • This study has implication in nutlin-3 treatment of rhabdomyosarcomas.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Effect of molecular weight and concentration of hyaluronan on cell proliferation and osteogenic differentiation in vitro

Hyaluronan (HA), the simplest glycosaminoglycan and a major component of the extracellular matrix, exists in various tissues. It is involved in some critical biological procedures, including cellular signaling, cell adhesion and proliferation, and cell differentiation. The effect of molecular weight (MW) and concentration of HA on cell proliferation and differentiation was controversial. In this study, we investigated the effect of MW and concentration of HA on the proliferation and osteogenic differentiation of rabbit bone marrow-derived stem cells in vitro. Results showed that high MW HA decreased the cell adhesion rate in a concentration-dependant manner. The cell adhesion rate was decreased by increasing MW of HA. Cell proliferation was significantly enhanced by low MW HA (P < 0.05). The factorial analysis indicated that MW and concentration had an interactive effect on the cell adhesion rate and cell proliferation (P < 0.05). High MW HA increased the mRNA expressions of ALP, RUNX-2 and OCN. The higher the MW was, the higher the mRNA expressions were. The factorial analysis indicated that MW and concentration had an interactive effect on ALP mRNA expression (P < 0.05). HA of higher MW and higher concentration promoted bone formation. These findings provide some useful information in understanding the mechanism underlying the effect of MW and concentration of HA on cell proliferation and differentiation. - Highlights: • Effect of hyaluronan on cell proliferation and differentiation is evaluated in vitro. • Hyaluronan of low molecular weight increases cell proliferation. • Hyaluronan of high molecular weight promotes cell osteogenic differentiation. • Molecular weight and concentration of hyaluronan show interactive effect.

60 APPLIED LIFE SCIENCES↗