Publications Resulting from CASIS-Sponsored Projects
Below, explore published research articles and book chapters that result from and acknowledge CASIS sponsorship of ISS National Lab R&D. For a more extensive list of spaceflight-related publications (not limited to CASIS sponsorship), see our ISS research publication database or International Space Station Research Results Citations on the NASA website.
SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm
Citation: Stashi E, Lanz R, Mao J, Michailidis G, Zhu B, Kettner N, Putluri N, Reineke E, Reineke L, Dasgupta S, Dean A, Stevenson C, Sivasubramanian N, Sreekumar A, DeMayo F, York B, Fu L, O'Malley B. SRC-2 is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm. Cell Rep.2014;6(4):633-645.
Publication Date: 2/13/14
Description: Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1: CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circa-dian clock.
In Vitro Organogenesis From Pluripotent Stem Cells
Citation: Li Y, Xu C, Ma T. In vitro organogenesis from pluripotent stem cells. Organogenesis. 2014;10(2):159-163.
Publication Date: 4/24/14
Description: Pluripotent stem cells (PSCs) have the ability to spontaneously generate structured tissues in vitro reminiscent of embryonic tissue development. Recently, complex organoids such as cortical tissues, cerebral brain organoids, optical cups, intestinal tissues, and liver buds have been generated from PSCs derived from healthy individuals and patients with genetic diseases, providing powerful tools to understand morphogenesis and disease pathology.
Microscale Generation of Cardiospheres Promotes Robust Enrichment of Cardiomyocytes Derived from Human Pluripotent Stem Cells
Citation: Nguyen DC, Hookway TA, Wu Q, Jha R, Preininger MK, Chen X, Easley CA, Spearman P, Deshpande SR, Maher K, Wagner MB, McDevitt TC, Xu C. Microscale Generation of Cardiospheres Promotes Robust Enrichment of Cardiomyocytes Derived from Human Pluripotent Stem Cells. Stem Cell Reports. 2014;3(2):260-268.
Publication Date: 8/12/14
Description: Cardiomyocytes derived from human pluripotent stem cells (hPSCs) are a promising cell source for regenerative medicine, diseasemodeling, and drug discovery, all of which require enriched cardiomyocytes, ideally ones with mature phenotypes. However, current methods are typically performed in 2D environments that produce immature cardiomyocytes within heterogeneous populations. Here, we generated 3D aggregates of cardiomyocytes (cardiospheres) from 2D differentiation cultures of hPSCs using micro
Leveraging electrokinetics for the active control of dendritic fullerene-1 release across a nanochannel membrane
Citation: Bruno G, Geninatti T, Hood RL, Fine D, Scorrano G, Schmulen J, Hosali S, Ferrari M, Grattoni A. Leveraging Electrokinetics for the Active Control of Dendritic Fullerene-1 Release Across a Nanochannel Membrane. Nanoscale. 2015;7(12):5240-5248.
Publication Date: 1/19/15
Description: General adoption of advanced treatment protocols such as chronotherapy will hinge on progress in drug delivery technologies that provide precise temporal control of therapeutic release. Such innovation is also crucial to future medicine approaches such as telemedicine. Here we present a nanofluidic membrane technology capable of achieving active and tunable control of molecular transport through nanofluidic channels. Control was achieved through application of an electric field between two platinum electrodes positioned on either surface of a 5.7 nm nanochannel membrane designed for zero-order drug delivery. Two electrode configurations were tested: laser-cut foils and electron beam deposited thin-films, configurations capable of operating at low voltage (?1.5 V), and power (100 nW). Temporal, reproducible tuning and interruption of dendritic fullerene 1 (DF-1) transport was demonstrated over multi-day release experiments. Conductance tests showed limiting currents in the low applied potential range, implying ionic concentration polarization (ICP) at the interface between the membrane?s micro- and nanochannels, even in concentrated solutions (? 1 M NaCl). The ability of this nanotechnology platform to facilitate controlled delivery of molecules and particles has broad applicability to next-generation therapeutics for numerous pathologies, including autoimmune diseases, circadian dysfunction, pain, and stress, among others.
Spaceflight and simulated microgravity cause a significant reduction of key gene expression in early T-cell activation
Citation: Martinez EM, Yoshida MC, Candelario TLT, Hughes-Fulford M. Am J Physiol Regul Integr Comp Physiol. 2015;308(6):R480-R488.
Publication Date: 3/15/15
Description: Healthy immune function depends on precise regulation of lymphocyte activation. During the National Aeronautics and Space Administration (NASA) Apollo and Shuttle eras, multiple spaceflight studies showed depressed lymphocyte activity under microgravity (?g) conditions. Scientists on the ground use two models of simulated ?g (s?g): 1) the rotating wall vessel (RWV) and 2) the random positioning machine (RPM), to study the effects of altered gravity on cell function before advancing research to the true ?g when spaceflight opportunities become available on the International Space Station (ISS). The objective of this study is to compare the effects of true ?g and s?g on the expression of key early T-cell activation genes in mouse splenocytes from spaceflight and ground animals. For the first time, we compared all three conditions of microgravity spaceflight, RPM, and RWV during immune gene activation of Il2, Il2r?, Ifn?, and Tagap; moreover, we confirm two new early T-cell activation genes, Iigp1 and Slamf1. Gene expression for all samples was analyzed using quantitative real-time PCR (qRT-PCR). Our results demonstrate significantly increased gene expression in activated ground samples with suppression of mouse immune function in spaceflight, RPM, and RWV samples. These findings indicate that s?g models provide an excellent test bed for scientists to develop baseline studies and augment true ?g in spaceflight experiments. Ultimately, s?g and spaceflight studies in lymphocytes may provide insight into novel regulatory pathways, benefiting both future astronauts and those here on earth suffering from immune disorders.
Large-volume protein crystal growth for neutron macromolecular crystallography
Citation: Ng JD, Baird JK, Coates L, Garcia-Ruiz JM, Hodge TA, and Huang S. Large-volume Protein Crystal Growth for Neutron Macromolecular Crystallography. Acta Crystallographica Section F Structural Biology Communications. 2015;71(4):358-370.
Publication Date: 3/30/15
Description: Neutron macromolecular crystallography (NMC) is the prevailing method for the accurate determination of the positions of H atoms in macromolecules. As neutron sources are becoming more available to general users, finding means to optimize the growth of protein crystals to sizes suitable for NMC is extremely important. Historically, much has been learned about growing crystals for X-ray diffraction. However, owing to new-generation synchrotron X-ray facilities and sensitive detectors, protein crystal sizes as small as in the nano-range have become adequate for structure determination, lessening the necessity to grow large crystals. Here, some of the approaches, techniques and considerations for the growth of crystals to significant dimensions that are now relevant to NMC are revisited. These include experimental strategies utilizing solubility diagrams, ripening effects, classical crystallization techniques, microgravity and theoretical considerations.
Collective Search by Ants in Microgravity
Citation: Countryman S, Stumpe M, Crow S, Adler F, Greene M., Vonshak M, and Gordon D. Collective Search by Ants in Microgravity. Front Ecol Evol. 2015;3(25).
Publication Date: 3/30/15
Description: The problem of collective search is a tradeoff between searching thoroughly and covering as much area as possible. This tradeoff depends on the density of searchers. Solutions to the problem of collective search are currently of much interest in robotics and in the study of distributed algorithms, for example to design ways that without central control robots can use local information to perform search and rescue operations. Ant colonies operate without central control. Because they can perceive
Pulse transit time measured by photoplethysmography improves the accuracy of heart rate as a surrogate measure of cardiac output, stroke volume and oxygen uptake in response to graded exercise
Citation: Pollonini L, Padhye NS, Re R, Torricelli A, Simpson RJ, Dacso, CC. Pulse transit time measured by photoplethysmography improves the accuracy of heart rate as a surrogate measure of cardiac output, stroke volume and oxygen uptake in response to graded exercise. Physiol Meas. 2015;36(5):911-924.
Publication Date: 4/9/15
Description: Heart rate (HR) is a valuable and widespread measure for physical training programs, although its description of conditioning is limited to the cardiac response to exercise. More comprehensive measures of exercise adaptation include cardiac output (Q? ), stroke volume (SV) and oxygen uptake (V? O2), but these physiological parameters can be measured only with cumbersome equipment installed in clinical settings. In this work, we explore the ability of pulse transit time (PTT) to represent a valuable pairing with HR for indirectly estimating Q? , SV and V? O2 non-invasively. PTT was measured as the time interval between the peak of the electrocardiographic (ECG) R-wave and the onset of the photoplethysmography (PPG) waveform at the periphery (i.e., fingertip) with a portable sensor. Fifteen healthy young subjects underwent a graded incremental cycling protocol after which HR and PTT were correlated with Q? , SV and V? O2using linear mixed models. The addition of PTT significantly improved the modeling of Q? , SV and V? O2 at the individual level (R1 2 = 0.419 for SV, 0.548 for Q? , and 0.771 for V? O2) compared to predictive models based solely on HR (R12 = 0.379 for SV, 0.503 for Q? , and 0.745 for V? O2). While challenges in sensitivity and artifact rejection exist, combining PTT to HR holds potential for development of novel wearable sensors that provide exercise assessment largely superior to HR monitors.
Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1
Citation: Owens G, New D, West A, Bjorkman P. Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1. J Mol Biol. 2015;427(15):2507-2519.
Publication Date: 6/3/15
Description: Huntington's disease is caused by expansion of a polyglutamine (polyQ) repeat in the huntingtin protein. A structural basis for the apparent transition between normal and disease-causing expanded polyQ repeats of huntingtin is unknown. The "linear lattice" model proposed random-coil structures for both normal and expanded polyQ in the preaggregation state. Consistent with this model, the affinity and stoichiometry of the anti-polyQ antibody MW1 increased with the number of glutamines. An opposing "structural toxic threshold" model proposed a conformational change above the pathogenic polyQ threshold resulting in a specific toxic conformation for expanded polyQ. Support for this model was provided by the anti-polyQ antibody 3B5H10, which was reported to specifically recognize a distinct pathologic conformation of soluble expanded polyQ. To distinguish between these models, we directly compared binding of MW1 and 3B5H10 to normal and expanded polyQ repeats within huntingtin exon 1 fusion proteins. We found similar binding characteristics for both antibodies. First, both antibodies bound to normal, as well as expanded, polyQ in huntingtin exon 1 fusion proteins. Second, an expanded polyQ tract contained multiple epitopes for fragments antigen-binding (Fabs) of both antibodies, demonstrating that 3B5H10 does not recognize a single epitope specific to expanded polyQ. Finally, small-angle X-ray scattering and dynamic light scattering revealed similar binding modes for MW1 and 3B5H10 Fab-huntingtin exon 1 complexes. Together, these results support the linear lattice model for polyQ binding proteins, suggesting that the hypothesized pathologic conformation of soluble expanded polyQ is not a valid target for drug design.
Simulated Microgravity Exerts an Age Dependent Effect on the Differentiation of Cardiovascular Progenitors Isolated From Human Heart
Citation: Fuentes TI, Appleby N, Raya M, Bailey L, Hasaniya N, Stodieck L, Kearns-Jonker M. Simulated Microgravity Exerts an Age-Dependent Effect on the Differentiation of Cardiovascular Progenitors Isolated from the Human Heart. PLoS ONE. 2015;10(7).
Publication Date: 7/10/15
Description: Microgravity has a profound effect on cardiovascular function, however, little is knownabout the impact of microgravity on progenitors that reside within the heart. We investigatedthe effect of simulated microgravity exposure on progenitors isolated from the neonatal and adult human heart by quantifying changes in functional parameters, gene expression and protein levels after 6-7 days of 2D clinorotation. Utilization of neonatal and adult cardiovascular progenitors in ground-based studies has