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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 739 records · Page 41
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524)

Purpose: Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. Methods and Materials: Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival. Results: A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. Conclusions: In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Mercury induces proliferation and reduces cell size in vascular smooth muscle cells through MAPK, oxidative stress and cyclooxygenase-2 pathways

Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl{sub 2} affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl{sub 2} (first dose 4.6 mg kg{sup −1}, subsequent doses 0.07 mg kg{sup −1} day{sup −1}, 30 days) and cultured aortic VSMC stimulated with HgCl{sub 2} (0.05–5 μg/ml) were used. Treatment of rats with HgCl{sub 2} decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl{sub 2}: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl{sub 2}. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl{sub 2}-induced Nox1 and COX-2 expression and normalized the alterations induced by mercury in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease. - Highlights: ► Chronic HgCl{sub 2} exposure induces vascular remodeling. ► HgCl{sub 2} induces proliferation and decreased cell size in vascular smooth muscle cells. ► HgCl{sub 2} induces MAPK activation, oxidative stress and COX-2 expression. ► Inhibition of MAPK reduces HgCl{sub 2}-induced oxidative stress and COX-2 expression. ► Inhibition of MAPK, oxidative stress and COX-2 restores the altered cell proliferation and size.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. The cellular repressor of E1A-stimulated genes (CREG) has been shown to play an important role in phenotypic modulation of VSMCs. However, the mechanism regulating CREG upstream signaling remains unclear. MicroRNAs (miRNAs) have recently been found to play a critical role in cell differentiation via target-gene regulation. This study aimed to identify a miRNA that binds directly to CREG, and may thus be involved in CREG-mediated VSMC phenotypic modulation. Computational analysis indicated that miR-31 bound to the CREG mRNA 3′ untranslated region (3′-UTR). miR-31 was upregulated in quiescent differentiated VSMCs and downregulated in proliferative cells stimulated by platelet-derived growth factor and serum starvation, demonstrating a negative relationship with the VSMC differentiation marker genes, smooth muscle α-actin, calponin and CREG. Using gain-of-function and loss-of-function approaches, CREG and VSMC differentiation marker gene expression levels were shown to be suppressed by a miR-31 mimic, but increased by a miR-31 inhibitor at both protein and mRNA levels. Notably, miR-31 overexpression or inhibition affected luciferase expression driven by the CREG 3′-UTR containing the miR-31 binding site. Furthermore, miR-31-mediated VSMC phenotypic modulation was inhibited in CREG-knockdown human VSMCs. We also determined miR-31 levels in the serum of patients with coronary artery disease (CAD), with or without in stent restenosis and in healthy controls. miR-31 levels were higher in the serum of CAD patients with restenosis compared to CAD patients without restenosis and in healthy controls. In summary, these data demonstrate that miR-31 not only directly binds to its target gene CREG and modulates the VSMC phenotype through this interaction, but also can be an important biomarker in diseases involving VSMC phenotypic modulation. These novel findings may have extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases. - Highlights: ► MiR-31 modulates CREG expression by binding directly to the human CREG mRNA 3′-UTR. ► MiR-31 mediates the human VSMC phenotypic modulation by regulating the expression of human CREG. ► Serum miR-31 may act as an important biomarker in diseases involving in stent restenosis after PCI.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

High-performance polyvinyl chloride gel artificial muscle actuator with graphene oxide and plasticizer

A transparent and electroactive plasticized polyvinyl chloride (PVC) gel was investigated to use as a soft actuator for artificial muscle applications. PVC gels were prepared with varying plasticizer (dibutyl adipate, DBA) content. The prepared PVC gels were characterized using Fourier-transform infrared spectroscopy, thermogravimetric analysis, and dynamic mechanical analysis. The DBA content in the PVC gel was shown to have an inverse relationship with both the storage and loss modulus. The electromechanical performance of PVC gels was demonstrated for both single-layer and stacked multi-layer actuators. When voltage was applied to a single-layer actuator and then increased, the maximum displacement of PVC gels (for PVC/DBA ratios of 1:4, 1:6, and 1:8) was increased from 105.19, 123.67, and 135.55µm (at 0.5kV) to 140.93, 157.13, and 172.94µm (at 1.0kV) to 145.03, 191.34, and 212.84µm (at 1.5kV), respectively. The effects of graphene oxide (GO) addition in the PVC gel were also investigated. The inclusion of GO (0.1 wt.%) provided an approximate 20% enhancement of displacement and 41% increase in force production, and a 36% increase in power output for the PVC/ GO gel over traditional plasticizer only PVC gel. The proposed PVC/GO gel actuator may have promising applications in artificial muscle, small mechanical devices, optics, and various opto-electro-mechanical devices due to its low-profile, transparency, and electrical response characteristics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure

In striated muscle, the sarcomeric protein myosin-binding protein-C (MyBP-C) is bound to the myosin thick filament and is predicted to stabilize myosin heads in a docked position against the thick filament, which limits crossbridge formation. Here, we use the homozygous Mybpc2 knockout (C2 -/- ) mouse line to remove the fast-isoform MyBP-C from fast skeletal muscle and then conduct mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2 -/- fibers present deficits in force production and calcium sensitivity. Structurally, passive C2 -/- fibers present altered sarcomere length-independent and -dependent regulation of myosin head conformations, with a shift of myosin heads towards actin. At shorter sarcomere lengths, the thin filament is axially extended in C2 -/- , which we hypothesize is due to increased numbers of low-level crossbridges. These findings provide testable mechanisms to explain the etiology of debilitating diseases associated with MyBP-C.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

In vitro terahertz monitoring of muscle tissue dehydration under the action of hyperosmotic agents

Dehydration of muscle tissue in vitro under the action of biologically compatible hyperosmotic agents is studied using a laser terahertz spectrometer in the frequency range from 0.25 to 2.5 THz. Broadband terahertz absorption and reflection spectra of the bovine skeletal muscle tissue were obtained under the action of glycerol, polyethylene glycol with the molecular weight 600 (PEG-600), and propylene glycol. The presented results are proposed for application in developing the methods of image contrast enhancement and increasing the depth of biological tissue probing with terahertz radiation. (laser biophotonics)

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2018

Deciphering the super relaxed state of human β-cardiac myosin and the mode of action of mavacamten from myosin molecules to muscle fibers

Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human β-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Kv2.1 channels play opposing roles in regulating membrane potential, Ca 2+ channel function, and myogenic tone in arterial smooth muscle

The accepted role of the protein Kv2.1 in arterial smooth muscle cells is to form K + channels in the sarcolemma. Opening of Kv2.1 channels causes membrane hyperpolarization, which decreases the activity of L-type Ca V 1.2 channels, lowering intracellular Ca 2+ ([Ca 2+ ] i ) and causing smooth muscle relaxation. A limitation of this model is that it is based exclusively on data from male arterial myocytes. Here, we used a combination of electrophysiology as well as imaging approaches to investigate the role of Kv2.1 channels in male and female arterial myocytes. We confirmed that Kv2.1 plays a canonical conductive role but found it also has a structural role in arterial myocytes to enhance clustering of Ca V 1.2 channels. Less than 1% of Kv2.1 channels are conductive and induce membrane hyperpolarization. Paradoxically, by enhancing the structural clustering and probability of Ca V 1.2–Ca V 1.2 interactions within these clusters, Kv2.1 increases Ca 2+ influx. These functional impacts of Kv2.1 depend on its level of expression, which varies with sex. In female myocytes, where expression of Kv2.1 protein is higher than in male myocytes, Kv2.1 has conductive and structural roles. Female myocytes have larger Ca V 1.2 clusters, larger [Ca 2+ ] i , and larger myogenic tone than male myocytes. In contrast, in male myocytes, Kv2.1 channels regulate membrane potential but not Ca V 1.2 channel clustering. We propose a model in which Kv2.1 function varies with sex: in males, Kv2.1 channels control membrane potential but, in female myocytes, Kv2.1 plays dual electrical and Ca V 1.2 clustering roles. This contributes to sex-specific regulation of excitability, [Ca 2+ ] i , and myogenic tone in arterial myocytes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Homologous mutations in human β, embryonic, and perinatal muscle myosins have divergent effects on molecular power generation

Mutations at a highly conserved homologous residue in three closely related muscle myosins cause three distinct diseases involving muscle defects: R671C in β-cardiac myosin causes hypertrophic cardiomyopathy, R672C and R672H in embryonic skeletal myosin cause Freeman–Sheldon syndrome, and R674Q in perinatal skeletal myosin causes trismus-pseudocamptodactyly syndrome. It is not known whether their effects at the molecular level are similar to one another or correlate with disease phenotype and severity. To this end, we investigated the effects of the homologous mutations on key factors of molecular power production using recombinantly expressed human β, embryonic, and perinatal myosin subfragment-1. We found large effects in the developmental myosins but minimal effects in β myosin, and magnitude of changes correlated partially with clinical severity. The mutations in the developmental myosins dramatically decreased the step size and load-sensitive actin-detachment rate of single molecules measured by optical tweezers, in addition to decreasing overall enzymatic (ATPase) cycle rate. In contrast, the only measured effect of R671C in β myosin was a larger step size. Our measurements of step size and bound times predicted velocities consistent with those measured in an in vitro motility assay. Finally, molecular dynamics simulations predicted that the arginine to cysteine mutation in embryonic, but not β, myosin may reduce pre-powerstroke lever arm priming and ADP pocket opening, providing a possible structural mechanism consistent with the experimental observations. This paper presents direct comparisons of homologous mutations in several different myosin isoforms, whose divergent functional effects are a testament to myosin’s highly allosteric nature.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila

Dilated cardiomyopathy (DCM), a life-threatening disease characterized by pathological heart enlargement, can be caused by myosin mutations that reduce contractile function. To better define the mechanistic basis of this disease, we employed the powerful genetic and integrative approaches available in Drosophila melanogaster. To this end, we generated and analyzed the first fly model of human myosin–induced DCM. The model reproduces the S532P human β-cardiac myosin heavy chain DCM mutation, which is located within an actin-binding region of the motor domain. In concordance with the mutation’s location at the actomyosin interface, steady-state ATPase and muscle mechanics experiments revealed that the S532P mutation reduces the rates of actin-dependent ATPase activity and actin binding and increases the rate of actin detachment. The depressed function of this myosin form reduces the number of cross-bridges during active wing beating, the power output of indirect flight muscles, and flight ability. Further, S532P mutant hearts exhibit cardiac dilation that is mutant gene dose–dependent. Our study shows that Drosophila can faithfully model various aspects of human DCM phenotypes and suggests that impaired actomyosin interactions in S532P myosin induce contractile deficits that trigger the disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

CCL2 release by airway smooth muscle is increased in asthma and promotes fibrocyte migration

Background: Asthma is characterized by variable airflow obstruction, airway inflammation, airway hyper-responsiveness and airway remodelling. Airway smooth muscle (ASM) hyperplasia is a feature of airway remodelling and contributes to bronchial wall thickening. We sought to investigate the expression levels of chemokines in primary cultures of ASM cells from asthmatics vs healthy controls and to assess whether differentially expressed chemokines (i) promote fibrocyte (FC) migration towards ASM and (ii) are increased in blood from subjects with asthma and in sputum samples from those asthmatics with bronchial wall thickening. Methods: Chemokine concentrations released by primary ASM were measured by MesoScale Discovery platform. The chemokine most highly expressed by ASM from asthmatics compared with healthy controls was confirmed by ELISA, and expression of its cognate chemokine receptor by FCs was examined by immunofluorescence and flow cytometry. The role of this chemokine in FC migration towards ASM was investigated by chemotaxis assays. Results: Chemokine (C-C motif) ligand 2 (CCL2) levels were increased in primary ASM supernatants from asthmatics compared with healthy controls. CCR2 was expressed on FCs. Fibrocytes migrated towards recombinant CCL2 and ASM supernatants. These effects were inhibited by CCL2 neutralization. CCL2 levels were increased in blood from asthmatics compared with healthy controls, and sputum CCL2 was increased in asthmatics with bronchial wall thickening. Conclusions: Airway smooth muscle-derived CCL2 mediates FC migration and potentially contributes to the development of ASM hyperplasia in asthma.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

THE MUSCLES TREASURY SURVEY. II. INTRINSIC LY α AND EXTREME ULTRAVIOLET SPECTRA OF K AND M DWARFS WITH EXOPLANETS

The ultraviolet (UV) spectral energy distributions (SEDs) of low-mass (K- and M-type) stars play a critical role in the heating and chemistry of exoplanet atmospheres, but are not observationally well-constrained. Direct observations of the intrinsic flux of the Ly α line (the dominant source of UV photons from low-mass stars) are challenging, as interstellar H i absorbs the entire line core for even the closest stars. To address the existing gap in empirical constraints on the UV flux of K and M dwarfs, the MUSCLES Hubble Space Telescope Treasury Survey has obtained UV observations of 11 nearby M and K dwarfs hosting exoplanets. This paper presents the Ly α and extreme-UV spectral reconstructions for the MUSCLES targets. Most targets are optically inactive, but all exhibit significant UV activity. We use a Markov Chain Monte Carlo technique to correct the observed Ly α profiles for interstellar absorption, and we employ empirical relations to compute the extreme-UV SED from the intrinsic Ly α flux in ∼100 Å bins from 100–1170 Å. The reconstructed Ly α profiles have 300 km s{sup −1} broad cores, while >1% of the total intrinsic Ly α flux is measured in extended wings between 300 and 1200 km s{sup −1}. The Ly α surface flux positively correlates with the Mg ii surface flux and negatively correlates with the stellar rotation period. Stars with larger Ly α surface flux also tend to have larger surface flux in ions formed at higher temperatures, but these correlations remain statistically insignificant in our sample of 11 stars. We also present H i column density measurements for 10 new sightlines through the local interstellar medium.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2013

Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin/+ mouse

Cancer cachexia is a muscle wasting condition that occurs in response to a malignant growth in the body. The mechanisms regulating cardiac muscle mass with cachexia are not well understood. Using the ApcMin/+ mouse model of colorectal cancer, we investigated how cachexia affects the regulation of 5'-adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling in the heart. Compared to age-matched C57BL/6 (BL6) mice, ApcMin/+ body mass and heart mass were lower at 12 (11±5 and 8±3%, respectively) and 20 weeks (26±3 and 6±4%, respectively) of age (P<0.05). Diminished heart mass in the 20-week-old ApcMin/+ mice coincided with a decreased rate of myofibrillar protein synthesis and increased AMPKα phosphorylation. Cachexia decreased mTOR phosphorylation and the phosphorylation of the mTOR substrates, S6 ribosomal protein and 4EBP1 independent of Akt activation. These changes in mTOR-related protein signaling were accompanied by modest increases in the amount of Beclin1 but not protein ubiquitination or cardiomyocyte apoptosis. Taken together, these data suggest that loss of cardiac mass during cachexia progression in the ApcMin/+ mouse is associated with an Akt-independent suppression of anabolic signaling and evidence of increased autophagy.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1972

Middle ear muscle contractions and their relation to pulse and echo evoked potentials in the bat

An analysis is made of pulse and echo orientation cries of the Mustache Bat. That bat's cries are characterized by a long, 60 to 30 msec, pure tone component and brief beginning and terminal FM sweeps. In addition to obvious echo overlap and middle ear muscle contractions, the following are examined: (1) characteristics of pulse- and echo-evoked potential under various conditions, (2) evidence of changes in hearing sensitivity during and after pulse emission, and (3) the role of the middle ear muscles in bringing about these changes.

Henson, O. W., Jr.↗
NASA NTRS1975

Bioelectric activity of skeletal muscle under conditions of alternating action of g-Forces and weightlessness

The bioelectric activity of the musculature of animals and man was studied during alternating g-forces and weightlessness. The appropriate conditions were reproduced in flight along a parabolic curve; in this case, weightlessness lasting 25-30 sec alternated with g-forces of about 2 g magnitude. Quite regular changes in the bioelectric activity of various groups of muscles were disclosed under g-forces and in weightlessness. Thus, muscle biopotential amplitudes of 130-180 microvolt in horizontal flight, increased to 190-330 microvolt under g-forces. In the subsequent weightlessness, an abrupt reduction in oscillation voltage was observed and, in a number of cases, phenomena, similar to the picture of bioelectric silence were noted.

Yuganov, Y. M.↗
NASA NTRS1977

The effects of prolonged spaceflight on the regional distribution of fluid, muscle and fat: Biostereometric results from Skylab

Biostereometric analysis of body form was performed several times preflight and postflight on the astronauts of all three skylab flights. The analysis was made by deriving the three-dimensional coordinates of numerous points on the body surface from stereoscopic pairs of photographs of the subject, using a stereoplotter. The volume of segments of the body, and of the body as a whole, was calculated by integration of cross sectional areas derived from the coordinate data. All nine astronauts demonstrated regional changes in volume distribution which could be related to changes in total body water, muscle mass, and fat deposits. The change in water resulted from a redistribution of fluid in response to zero gravity. Changes in muscle mass resulted from an alternation in patterns of musclar activity in the absence of gravity, and changes in fat resulted from discrepancies between the individual's caloric needs and his food consumption.

Whittle, M. W.↗
NASA NTRS1977

Investigate methods for measuring muscle and bone mass changes in astronauts and animals which occur during space flight

Sodium-22 is being used as a tracer for bone mineral metabolism studies. Dogs are being grown from puppies to adulthood on a diet containing a constant level of sodium-22 in order to uniformly tag the entire skeleton with a long lived radionuclide. This study is still in progress and the dogs are still growing. Potassium-40 measurements were made on people, who are replacing muscle mass lost due to leg injuries, in a second study. It appears that potassium-40 measurements provide an accurate and convenient method for determining relative changes in the muscle content of the leg.

Palmer, H. E.↗
NASA NTRS1980

Cyclic AMP system in muscle tissue during prolonged hypokinesia

Components of the cyclic Adenosine-cyclic-35-monophosphate (AMP) system in the muscle tissue of white rats were studied during 70-75 days of hypokinesia, created by placing the animals in small booths which restricted their movements, and during the readaptation period. In the initial period, cyclic AMP levels and the activities of phosphodiesterase and adenylate cyclase in muscle tissue were increased. The values for these indices were roughly equal for controls and experimental animals during the adaptation period, but on the 70th day of the experiment cAMP levels dropped, phosphodiesterase activity increased, and the stimulative effect of epinephrine on the activity of adenylate cyclase decreased. The indices under study normalized during the readaptation period.

Antipenko, Y. A.↗