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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 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Metformin ameliorates TGF-β1–induced osteoblastic differentiation of human aortic valve interstitial cells by inhibiting β-catenin signaling

Highlights: • β-catenin mediates TGF-β–induced osteoblastic differentiation of human AVICs. • Metformin ameliorates osteoblastic differentiation of AVICs by activating AMPKα. • Smad2/3 and JNK signaling mediates TGF-β1–induced activation of β-catenin in AVICs. • Metformin mitigates TGF-β1–induced β-catenin signaling by inhibiting Smad2/3 and JNK. Osteoblastic differentiation of aortic valve interstitial cells (AVICs) is the central process in the development of calcific aortic valve disease (CAVD). Metformin is a widely used first-line antidiabetic drug, and recently, pleiotropic benefits of metformin beyond hypoglycemia have been reported in the cardiovascular system. Here, we examined the effect of metformin on the osteoblastic differentiation of human AVICs. Our results showed that metformin ameliorated TGF-β1–induced production of osteogenic proteins Runx2 and osteopontin as well as calcium deposition in the cultured human AVICs. Experiments using AICAR, Compound C and AMPKα siRNA showed that the beneficial effect of metformin on TGF-β1–induced osteoblastic differentiation of human AVICs was mediated by AMPKα. Moreover, metformin inhibited the TGF-β1–induced activation of β-catenin, and β-catenin siRNA blocked TGF-β1–induced osteoblastic differentiation of AVICs. Smad2/3 and JNK were phosphorylated to promote the TGF-β1–induced activation of β-catenin and osteoblastic differentiation of AVICs, and metformin also alleviated TGF-β1–induced activation of Smad2/3 and JNK. In conclusion, our results suggest a beneficial effect of metformin based on the prevention of osteoblastic differentiation of human AVICs via inhibition of β-catenin, which indicates the therapeutic potential of metformin for CAVD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A novel role for PTK2B in cultured beige adipocyte differentiation

Highlights: • PTK2B protein levels are higher during cultured beige versus white adipogenesis. • Ptk2b knock-out SVF cells have poor white adipocyte differentiation. • Ptk2b knock-out beige adipocytes have elevated lipid accumulation. • Ptk2b knock-out beige adipocytes have a greatly diminished thermogenic gene program. • Ptk2b knock-out beige adipocytes have altered mitochondrial respiration. Adipocyte differentiation is a tightly regulated process which requires the sequential and organized expression of numerous genes and proteins. Phosphorylation of cytoplasmic proteins and key transcription factors represents a critical regulatory mechanism of the process leading to adipocyte maturation and modulation of associated metabolic pathways. Despite the recognition of the importance of protein phosphorylation in adipocyte biology, relatively little is known about the role of specific kinases in thermogenic (brown or beige) adipocyte differentiation and function. In this study, we demonstrate that the non-receptor protein tyrosine kinase 2 beta (PTK2B) plays a critical role in murine beige adipocyte differentiation. We observed that PTK2B protein expression is associated with beige adipocyte differentiation in cultured, immortalized, inguinal stromal vascular fraction cells. CRISPR/Cas9-mediated knock-out of Ptk2b results in non-differentiating white adipocytes, and differentiated beige adipocytes with significantly reduced thermogenic gene and protein expression, enlarged lipid droplet size, and altered mitochondrial respiration. Together, our data in a cell culture system provides evidence for a role of PTK2B in the differentiation of murine beige adipocytes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Pull down assay for GTP-bound form of Sar1a reveals its activation during morphological differentiation

Highlights: • The C-terminal region of Sec23B is available for a Sar1a pull down assay. • Neuronal differentiation correlates to an increase in GTP-bound Sar1a. • Oligodendrocyte differentiation correlates to an increase in GTP-bound Sar1a. • PREB binding to nucleotide-free Sar1a also increases during differentiation. The intracellular molecular transport system is a basic and general cellular mechanism that is regulated by an array of signaling molecules. Sar1 small GTPases are molecules that play a key role in controlling vehicle transport between the endoplasmic reticulum (ER) and Golgi bodies. Like other small GTPases, the activities of Sar1a depend on their guanine-nucleotide-binding states, which are regulated by guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Despite the well-known function of mammalian Sar1 in the intracellular transport system, little is known about when and how Sar1 is activated during cell morphological changes. Here we show that the C-terminal, but not the N-terminal, regions of Sec23A and Sec23B, the effector proteins of Sar1a, specifically bind to the active, GTP-bound form of Sar1a. An affinity precipitation (pull-down) assay using a recombinant C-terminal region of Sec23B reveals that Sar1a is activated following differentiation in neuronal cell lines. In neuronal N1E-115 cells, GTP-bound Sar1a is increased when cells elongate neuronal processes. Similar results are observed in morphological differentiation in oligodendroglial FBD-102b cells. Additionally, prolactin regulatory element binding (PREB), the GEF for Sar1 (Sar1 activator), increases the binding ability to the nucleotide-free form of Sar1a when morphological differentiation occurs. Nucleotide-free small GTPases preferentially interact with the cognate, active GEFs. These results provide evidence that using previously unreported pull down assays reveals that Sar1 and PREB are upregulated following the induction of morphological differentiation, suggesting the potential role of signaling through Sar1a during morphological differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Zoledronate and high glucose levels influence osteoclast differentiation and bone absorption via the AMPK pathway

Highlights: • High glucose suppresses osteoclast differentiation and bone absorption. • ZOL suppresses osteoclast differentiation and bone absorption in high glucose. • The influences on osteoclast above realize via the AMPK pathway. • The expression of NFATc1, SYK, CTSK and TRAP is regulated by AMPK. Bisphosphonates, the main drugs to treat osteoporosis, have been shown to protect against bone loss in diabetic osteoporosis. However, the effects of the bisphosphonate zoledronate (ZOL) on osteoclast differentiation and function in a high glucose environment as well as the involvement of the adenosine activated protein kinase (AMPK) pathway remain unclear. In the current study, RAW264.7 cells were induced into osteoclasts, divided into low glucose, high glucose, low glucose + ZOL, and high glucose + ZOL groups, which were tested for cell proliferation, cell migration, integrity of the osteoclast sealing zone, osteoclast differentiation, bone absorption, and protein and mRNA expression of genes in the AMPK pathway. We demonstrated that high glucose promoted the expression of AMPK, p-AMPK, while inhibited nuclear factor of activated T cells 1 (NFATc1), spleen tyrosine kinase (SYK), cathepsin K (CTSK), and tartrate-resistant acid phosphatase (TRAP), which influenced osteoclast differentiation and bone absorption. Upon addition of ZOL to high glucose, the expression of AMPK, p-AMPK increased and the expression of NFATc1, SYK, CTSK, TRAP decreased, while osteoclast differentiation and bone absorption were further inhibited. Further more, when added Compound C (AMPK antagonist), we found the expression of AMPK, p-AMPK, decreased, whereas NFATc1, SYK, and TRAP increased. In contrast, AMPK and p-AMPK increased and NFATc1, SYK, CTSK and TRAP decreased upon addition of AICAR, an AMPK agonist. In conclusion, the results suggest AMPK has potential as a new target for the treatment of osteoporosis, the high glucose environment promoted RAW264.7 cell migration, but suppressed osteoclast differentiation and bone absorption, and ZOL suppressed osteoclast migration, differentiation, and bone absorption via the AMPK pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Optogenetic manipulation of intracellular calcium by BACCS promotes differentiation of MC3T3-E1 cells

Highlights: • Intracellular Ca{sup 2+} signaling changes before and after differentiation of osteoblasts. • An optogenetic tool can control intracellular Ca{sup 2+} signaling of osteoblasts. • Using the optogenetic tool, differentiation of osteoblasts was enhanced. Bone remodeling is maintained through the balance between bone formation by osteoblasts and bone resorption by osteoclasts. Previous studies suggested that intracellular Ca{sup 2+} signaling plays an important role in the differentiation of osteoblasts; however, the molecular mechanism of Ca{sup 2+} signaling in the differentiation of osteoblasts remains unclear. To elucidate the effect of Ca{sup 2+} signaling in osteoblasts, we employed an optogenetic tool, blue light-activated Ca{sup 2+} channel switch (BACCS). BACCS was used to spatiotemporally control intracellular Ca{sup 2+} with blue light stimulation. MC3T3-E1 cells, which have been used as a model of differentiation from preosteoblast to osteoblast, were promoted to differentiate by BACCS expression and rhythmical blue light stimulation. The results indicated that intracellular Ca{sup 2+} change from the outside of the cells can regulate signaling for differentiation of MC3T3-E1 cells. Our findings provide evidence that Ca{sup 2+} could cause osteoblast differentiation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Glucocorticoids suppressed osteoblast differentiation by decreasing Sema3A expression via the PIK3/Akt pathway

Highlights: • Dex decreased Sema3A expression by suppressing the PI3K/Akt pathway. • Sema3A reversed Dex-induced suppression of osteoblast differentiation. • Sema3A reversed the Dex-mediated reduced transcriptional activity of β-catenin. Glucocorticoids(GCs) are extensively used to treat inflammatory and autoimmune diseases. Excessive prolonged exposure to glucocorticoids is associated with an increased risk of osteoporosis. The inhibition of osteoblast differentiation by GCs is suggested as a major cause for GCs-induced osteoporosis (GIO). However, the precise mechanism underlying the role of GCs in osteoblasts differentiation is not fully elucidated. Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, enhances bone formation and promotes fracture healing, which is known to increase osteoblastic differentiation and stimulate osteogenesis in bone metabolism. Here, the present study explored the effect of Sema3A in osteoblast differentiation using dexamethasone (Dex) treatment of bone marrow stromal cells (BMSCs). Dex treatment decreased Sema3A expression in BMSCs in a dose-dependent manner. Moreover, Dex stimulation suppressed the differentiation of osteoblasts by reducing alkaline phosphatase (ALP) activity, osteoblastic marker genes expression and mineralization, but all of these effects were ameliorated by exogenous recombinant Sema3A administration. Furthermore, exogenous Sema3A administration reversed the Dex-mediated decrease in nuclear accumulation of β-catenin and β-catenin activity in BMSCs. Meanwhile, Dex was capable of simultaneously suppressing the phosphorylation of protein kinase B(Akt) and the expression level of Sema3A in BMSCs. These changes were significantly abolished by the PI3K/Akt agonist. These results suggest that Dex inhibits osteoblast differentiation by suppressing Sema3A expression via the PI3K/Akt pathway. These data provide new insights into the molecular mechanisms of Dex-induced osteoblast differentiation inhibition.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Ferredoxin reductase regulates proliferation, differentiation, cell cycle and lipogenesis but not apoptosis in SZ95 sebocytes

Highlights: • FDXR expression is increased in sebaceous cells of acne lesions. • FDXR may enhance sebocyte differentiation and lipogenesis via ROS production. • FDXR might inhibit proliferation through inducing G2/S blockade. • IGF-1 could facilitate sebaceous differentiation and lipogenesis via PI3K/Akt/FDXR pathway. Ferredoxin reductase (FDXR), a mitochondrial membrane-associated flavoprotein, is essential for electron transfer and modulates p53-dependent apoptosis in cancer cells.FDXR may be implicated in epidermal and sebocytic differentiation, but its explicit function in sebocytes remains to be elucidated. In the present study, immunohistochemistry revealed that FDXR expression was increased in sebaceous cells of acne lesions. FDXR, PPARγ, LXRα/β, SREBP1 and Sox9 expression was incremental during sebocyte differentiation. FDXR overexpression induced by Ad-GFP-FDXR infection enhanced differentiation, reactive oxygen species (ROS), lipogenesis and PPARγ expression, and consequnently inhibited proliferation in SZ95 sebocytes. Flow cytometry showed that FDXR overexpression induced significant blockade of G2/M phase but had no effect on sub-G1 (apoptotic) sebocytes. Insulin-like growth factor-1 (IGF-1)-induced FDXR and PPARγ expression and lipogenesis were abolished by pretreatment with PI3K inhibitor LY294002. These results suggest that FDXR overexpression might promote differentiation and lipogenesis via ROS production and suppress proliferation via G2/S blockade in SZ95 sebocytes. IGF-1 could facilitate differentiation and lipogenesis through PI3K/Akt/FDXR pathway. FDXR could serve as a potential marker of advanced sebaceous differentiation, and its overexpression may be involved in the development of acne lesions.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2001

Airborne Differential Doppler Weather Radar

The Precipitation Radar aboard the Tropical Rain Measuring Mission (TRMM) Satellite has shown the potential for spaceborne sensing of snow and rain by means of an incoherent pulsed radar operating at 13.8 GHz. The primary advantage of radar relative to passive instruments arises from the fact that the radar can image the 3-dimensional structure of storms. As a consequence, the radar data can be used to determine the vertical rain structure, rain type (convective/stratiform) effective storm height, and location of the melting layer. The radar, moreover, can be used to detect snow and improve the estimation of rain rate over land. To move toward spaceborne weather radars that can be deployed routinely as part of an instrument set consisting of passive and active sensors will require the development of less expensive, lighter-weight radars that consume less power. At the same time, the addition of a second frequency and an upgrade to Doppler capability are features that are needed to retrieve information on the characteristics of the drop size distribution, vertical air motion and storm dynamics. One approach to the problem is to use a single broad-band transmitter-receiver and antenna where two narrow-band frequencies are spaced apart by 5% to 10% of the center frequency. Use of Ka-band frequencies (26.5 GHz - 40 GHz) affords two advantages: adequate spatial resolution can be attained with a relatively small antenna and the differential reflectivity and mean Doppler signals are directly related to the median mass diameter of the snow and raindrop size distributions. The differential mean Doppler signal has the additional property that this quantity depends only on that part of the radial speed of the hydrometeors that is drop-size dependent. In principle, the mean and differential mean Doppler from a near-nadir viewing radar can be used to retrieve vertical air motion as well as the total mean radial velocity. In the paper, we present theoretical calculations for the differential reflectivity and Doppler as functions of the center frequency, frequency difference, and median mass diameter. For a fixed pair of frequencies, the detectability of the differential signals can be expressed as the number of independent samples required to detect rain or snow with a particular median mass diameter. Because sampling numbers on the order of 1000 are needed to detect the differential signal over a range of size distributions, the instrument must be confined to a near-nadir, narrow swath. Radar measurements from a zenith directed radar operated at 9.1 GHz and 10 GHz are used to investigate the qualitative characteristics of the differential signals. Disdrometer and rain gauge data taken at the surface, just below the radar, are used to test whether the differential signals can be used to estimate characteristics of the raindrop size distribution.

Meneghini, R.↗
NASA NTRS2009

Differential InP HEMT MMIC Amplifiers Embedded in Waveguides

Monolithic microwave integrated-circuit (MMIC) amplifiers of a type now being developed for operation at frequencies of hundreds of gigahertz contain InP high-electron-mobility transistors (HEMTs) in a differential configuration. The differential configuration makes it possible to obtain gains greater than those of amplifiers having the single-ended configuration. To reduce losses associated with packaging, the MMIC chips are designed integrally with, and embedded in, waveguide packages, with the additional benefit that the packages are compact enough to fit into phased transmitting and/or receiving antenna arrays. Differential configurations (which are inherently balanced) have been used to extend the upper limits of operating frequencies of complementary metal oxide/semiconductor (CMOS) amplifiers to the microwave range but, until now, have not been applied in millimeter- wave amplifier circuits. Baluns have traditionally been used to transform from single-ended to balanced configurations, but baluns tend to be lossy. Instead of baluns, finlines are used to effect this transformation in the present line of development. Finlines have been used extensively to drive millimeter- wave mixers in balanced configurations. In the present extension of the finline balancing concept, finline transitions are integrated onto the affected MMICs (see figure). The differential configuration creates a virtual ground within each pair of InP HEMT gate fingers, eliminating the need for inductive vias to ground. Elimination of these vias greatly reduces parasitic components of current and the associated losses within an amplifier, thereby enabling more nearly complete utilization of the full performance of each transistor. The differential configuration offers the additional benefit of multiplying (relative to the single-ended configuration) the input and output impedances of each transistor by a factor of four, so that it is possible to use large transistors that would otherwise have prohibitively low impedances. Yet another advantage afforded by the virtual ground of the differential configuration is elimination of the need for a ground plane and, hence, elimination of the need for back-side metallization of the MMIC chip. In turn, elimination of the back-side metallization simplifies fabrication, reduces parasitic capacitances, and enables mounting of the MMIC in the electric-field plane ("E-plane") of a waveguide. E-plane mounting is consistent with (and essential for the utility of) the finline configuration, in which transmission lines lie on a dielectric sheet in the middle of a broad side of the waveguide. E-plane mounting offers a combination of low loss and ease of assembly because no millimeter-wave wire bonds or transition substrates are required. Moreover, because there is no ground plane behind the MMIC, the impedance for the detrimental even (single-ended) mode is high, suppressing coupling to that mode. Still another advantage of E-plane mounting is that the fundamental waveguide mode is inherently differential, eliminating the need for a balun to excite the differential mode.

Kangaslahti, Pekka↗
NASA NTRS2010

Differential Resonant Ring YIG Tuned Oscillator

A differential SiGe oscillator circuit uses a resonant ring-oscillator topology in order to electronically tune the oscillator over multi-octave bandwidths. The oscillator s tuning is extremely linear, because the oscillator s frequency depends on the magnetic tuning of a YIG sphere, whose resonant frequency is equal to a fundamental constant times the DC magnetic field. This extremely simple circuit topology uses two coupling loops connecting a differential pair of SiGe bipolar transistors into a feedback configuration using a YIG tuned filter creating a closed-loop ring oscillator. SiGe device technology is used for this oscillator in order to keep the transistor s 1/f noise to an absolute minimum in order to achieve minimum RF phase noise. The single-end resonant ring oscillator currently has an advantage in fewer parts, but when the oscillation frequency is greater than 16 GHz, the package s parasitic behavior couples energy to the sphere and causes holes and poor phase noise performance. This is because the coupling to the YIG is extremely low, so that the oscillator operates at near the unloaded Q. With the differential resonant ring oscillator, the oscillation currents are just in the YIG coupling mechanisms. The phase noise is even better, and the physical size can be reduced to permit monolithic microwave integrated circuit oscillators. This invention is a YIG tuned oscillator circuit making use of a differential topology to simultaneously achieve an extremely broadband electronic tuning range and ultra-low phase noise. As a natural result of its differential circuit topology, all reactive elements, such as tuning stubs, which limit tuning bandwidth by contributing excessive open loop phase shift, have been eliminated. The differential oscillator s open-loop phase shift is associated with completely non-dispersive circuit elements such as the physical angle of the coupling loops, a differential loop crossover, and the high-frequency phase shift of the n-p-n transistors. At the input of the oscillator s feedback loop is a pair of differentially connected n-p-n SiGe transistors that provides extremely high gain, and because they are bulk-effect devices, extremely low 1/f noise (leading to ultralow RF phase noise). The 1/f corner frequency for n-p-n SiGe transistors is approximately 500 Hz. The RF energy from the transistor s collector output is connected directly to the top-coupling loop (the excitation loop) of a single-sphere YIG tuned filter. A uniform magnetic field to bias the YIG must be at a right angle to any vector associated with an RF current in a coupling loop in order for the precession to interact with the RF currents.

Parrott, Ronald A.↗
DOE OSTI2018

Mitochondrial dynamics coordinate cell differentiation

Highlights: • Mitochondrial fusion and fission are essential in mouse embryogenesis, and cell differentiation. • The mitochondrial shape changes in differentiation and dedifferentiation. • Mitochondrial dynamics act as a hub to consolidate intra-and-extracellular signals in cell differentiation. Cells differentiate into specific and functional lineages to build up tissues. It has been shown in several tissues that mitochondrial morphology, levels of “mitochondria-shaping” proteins, and mitochondrial functions change upon differentiation. In this review, we highlight the significance of mitochondrial dynamics and functions in tissue development, cell differentiation, and reprogramming processes. Signalling cascades are critical for tissue stem cell maintenance and cell fate determination, and growing evidence demonstrates mitochondria could act as a centre of intra and extracellular signals to coordinate signalling pathways, such as Notch, Wnt, and YAP/TAZ signalling. Just an organelle, however, emerges as a master regulator of cell differentiation, and can be a target to manipulate cell fates.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Knockdown of laminin α5 stimulates intestinal cell differentiation

Highlights: • Knockdown of laminin α5 accelerates early intestinal cell differentiation. • Laminin α5 depletion triggers precocious sucrase-isomaltase expression. • A transient increase of dipeptidylpeptidase IV, villin, CDX2 and HNF-1α is noted. • Dome formation and trans-epithelial resistance are also transiently enhanced. Interactions between cells and the extracellular matrix regulate a wide range of cell processes such as proliferation and differentiation. Laminins are major components of the basement membrane that actively participate in most biological functions via their interactions with a variety of specific cell receptors. The α5-containing laminins (LAMA5) are one of the three main types of laminins identified at the epithelial basal lamina in the adult intestine. The aim of the present study was to investigate the role of α5-containing laminins on intestinal cell proliferation and differentiation. Using an shRNA targeting approach, the effects of knocking down the expression of LAMA5 were investigated in the enterocytic-like Caco-2/15 cell line, a well-characterized model for intestinal cell differentiation. Surprisingly, the abolition of the laminin α5 chain resulted in a drastic increase in the differentiation marker sucrase-isomaltase which was correctly expressed at the apical pole of the cells as observed by indirect immunofluorescence. Transient increases of dipeptidylpeptidase IV, villin, CDX2, HNF-1α, HNF-4α and transepithelial resistance as well as an apparent redistribution of the junctional components ZO-1 and E-cadherin were also observed at early stages of differentiation but no specific effect was observed on cell proliferation as evaluated by BrdU incorporation. Taken together, these data suggest that α5-containing laminins repress intestinal differentiation in its early stages.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MBD2-mediated Th17 differentiation in severe asthma is associated with impaired SOCS3 expression

T helper 17 (Th17) cells has proven to be crucial in the pathogenesis of severe asthma. Although it is known that Suppressor of cytokine signaling 3 (SOCS3) is involved in differentiation of Th17 cells but, how it affects severe asthma is uncertain. Since previous studies indicated that Methtyl-CpG binding domain protein 2 (MBD2) null mice was deficient in Th17 cell differentiation, the aim of the present study was to understand how MBD2 interacts with SOCS3 to regulate Th17 cell differentiation in severe asthma. Here, we show that SOCS3 expression was significantly decreased in Th17-mediated severe asthmatic mice, accompanied by elevated STAT3 phosphorylation and RORγt expression. Knock-down of SOCS3 promoted the differentiation of naïve T cells into Th17 cells through STAT3/RORγt pathway. Meanwhile, MBD2 was overexpressed in Th17-mediated severe asthmatic mice. Intervention of MBD2 expression lead to a negative change of SOCS3 expression, whereas the differentiation of Th17 cells showed positive change. In addition, MBD2 knockout (MBD2-KO) mice displayed increased SOCS3 expression and decreased Th17 differentiation after severe asthma modeling. Taken together, our results suggest that MBD2 might facilitate Th17 cell differentiation via down-regulating SOCS3 expression in severe asthma. These findings uncover new roles for SOCS3 and MBD2, and provide a potential target for treatment of severe asthma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Differential methods for assessing sensitivity in biological models

Differential sensitivity analysis is indispensable in fitting parameters, understanding uncertainty, and forecasting the results of both thought and lab experiments. Although there are many methods currently available for performing differential sensitivity analysis of biological models, it can be difficult to determine which method is best suited for a particular model. In this paper, we explain a variety of differential sensitivity methods and assess their value in some typical biological models. First, we explain the mathematical basis for three numerical methods: adjoint sensitivity analysis, complex perturbation sensitivity analysis, and forward mode sensitivity analysis. We then carry out four instructive case studies. (a) The CARRGO model for tumor-immune interaction highlights the additional information that differential sensitivity analysis provides beyond traditional naive sensitivity methods, (b) the deterministic SIR model demonstrates the value of using second-order sensitivity in refining model predictions, (c) the stochastic SIR model shows how differential sensitivity can be attacked in stochastic modeling, and (d) a discrete birth-death-migration model illustrates how the complex perturbation method of differential sensitivity can be generalized to a broader range of biological models. Finally, we compare the speed, accuracy, and ease of use of these methods. We find that forward mode automatic differentiation has the quickest computational time, while the complex perturbation method is the simplest to implement and the most generalizable.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Identifying Differential Equations in Fourier Domain (FourierIdent)

We investigate identifying differential equations in the frequency domain. Fourier analysis is an important tool in theoretical analysis and numerical solvers of differential equations, yet there is limited work in exploring this connection in the identification of differential equations. This paper aims to identify the underlying differential equation in the frequency domain, from a given single realization of the differential equation perturbed by noise. Such setting imposes difficulties which are different from other identification methods where computation is carried out in the physical domain. We propose several ways to mitigate the challenges arising from noise in data and large differences in the magnitudes of frequency responses. The main takeaways are that identifying differential equations solely in the frequency domain is challenging, the method we propose is based on a form of domain partitions in the frequency domain, and this method shows benefits for complex data even with high level of noise. We introduce a Fourier feature denoising, and define the meaningful data region and the core regions of features to reduce the effect of noise in the frequency domain and to enhance the accuracy in coefficient identification. The proposed method is tested on various differential equations with linear, nonlinear, and high-order derivative feature terms, and shows advantages on complex data with many frequency modes, even under high level of noise.

97 MATHEMATICS AND COMPUTING↗
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↗