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At least 1,783 records · Page 99

Characterization of γδ regulatory T cells from peripheral blood in patients with multiple myeloma

γδ regulatory T cells are able to inhibit the activation and function of T cells involved in antigen-specific immune responses. This study aimed to investigate the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in patients diagnosed as multiple myeloma (MM). We measured the levels of γδ T cells, the distribution and clonally amplified TCR Vγ and VδT cells in peripheral blood of healthy donors, patients recently diagnosed with MM, and MM patients in remission cohorts. In addition, we evaluated the ability of γδ regulatory T cells to inhibit the proliferation of CD4+CD25- T cells and detected the expression of immunoregulatory-associated molecules. We found that the levels of γδ regulatory T cells from the peripheral blood in patients of MM were significantly higher than those in healthy donors. Comparison of γδT regulatory cells function in MM and healthy donors showed similarly inhibitory effects on the proliferation of T cells. Additionally, TLR8 expression level increased significantly in MM patients compared to healthy donors, while the expression levels of Foxp3, CD25, CTLA4, GITR, GATA3 and Tbet in MM patients and healthy donors showed no significant difference. Taken together, our study reveals the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in MM patients.

60 APPLIED LIFE SCIENCES↗

CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model

Multiple myeloma (MM) is characterized by the clonal proliferation of neoplastic plasma cells. Despite a stream of new molecular targets based on better understanding of the disease, MM remains incurable. Epigenomic abnormalities contribute to the pathogenesis of MM. bromodomain 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, binds to acetylated histones during M/G1 transition in the cell cycle promoting progression to S phase. In this study, we investigated the effects of a novel BET inhibitor CG13250 on MM cells. CG13250 inhibited ligand binding to BRD4 in a dose-dependent manner and with an IC{sub 50} value of 1.1 μM. It inhibited MM proliferation in a dose-dependent manner and arrested cells in G1, resulting in the induction of apoptosis through caspase activation. CG13250 inhibited the binding of BRD4 to c-MYC promoter regions suppressing the transcription of the c-MYC gene. Administered in vivo, CG13250 significantly prolonged survival of an orthotopic MM-bearing mice. In conclusion, CG13250 is a novel bromodomain inhibitor that is a promising molecular targeting agent against MM. - Highlights: • A novel bromodomain inhibitor CG13250 suppresses MM cell proliferation. • CG13250 decreases C-MYC expression, resulting in the induction of apoptosis. • CG13250 prolongs the survivals of MM-bearing mice.

60 APPLIED LIFE SCIENCES↗

CTP synthase knockdown during early development distorts the nascent vertebral column and causes fluid retention in multiple tissues in zebrafish

Highlights: • Morpholino-based knockdown of ctps during early development produces zebrafish embryos with curved spines and tissue oedema. • Knockdown of ctps1a, and not ctps1b, induces more severe, longer-lasting defects. • Phenotypes are exacerbated when morpholinos against both gene variants are supplied together at uneven ratios. • The same phenotypes were recovered from embryos treated with DON, a CTPS activity-inhibiting drug. CTP Synthase (CTPS) is a metabolic enzyme that is recognized as a catalyst for nucleotide, phospholipid and sialoglycoprotein production. Though the structural characteristics and regulatory mechanisms of CTPS are well-understood, little is known regarding the extent of its involvement during the early developmental stages of vertebrates. Zebrafish carries two CTPS genes, annotated as ctps1a and ctps1b. Phylogenetic analyses show that both genes had diverged from homologues in the ancestral Actinopterygii, Oreochromis niloticus. Conservation of common CTPS-catalytic regions further establishes that both proteins are likely to be functionally similar to hsaCTPS. Here, we show that ctps1a is more critical throughout the initial period of embryonic development than ctps1b. The effects of concurrent partial knockdown are dependent on ctps1a vs ctps1b dosage ratios. When these are equally attenuated, abnormal phenotypes acquired prior to the pharyngula period disappear in hatchlings (48hpf); however, if either gene is more attenuated than the other, these only become more pronounced in advanced stages. Generally, disruption to normal ctps1a or ctps1b expression levels by morpholinos culminates in the distortion of the early spinal column as well as multiple-tissue oedema. Other effects include slower growth rates, increased mortality rates and impaired structural formation of the young fish's extremities. Embryos grown in DON, a glutamine-analogue drug and CTPS antagonist, also exhibit similar characteristics, thus strengthening the validity of the morpholino-induced phenotypes observed. Together, our results demonstrate the importance of CTPS for the development of zebrafish embryos, as well as a disparity in activity and overall importance amongst isozymes.

60 APPLIED LIFE SCIENCES↗

Enhanced antitumor effect of combination of annexin A1 knockdown and bortezomib treatment in multiple myeloma in vitro and in vivo

Highlights: • ANXA1 knockdown suppresses secretion of inflammatory factors in MM cells. • ANXA1 knockdown enhances BTZ-mediated antitumor effect in MM cells in vitro. • ANXA1 knockdown enhances BTZ-mediated antitumor effect in MM cells in vivo. • Combination of ANXA1 silencing and BTZ combination inhibits STAT3 phosphorylation. Bortezomib (BTZ) is one of the most frequently used drugs in treatment of multiple myeloma (MM), but drug-resistance often occurs and limits its clinical efficacy. Annexin A1 (ANXA1) is upregulated in MM, and its knockdown enhances chemosensitivity in MM. However, whether ANXA1 inhibition can increase antitumor activity of BTZ in MM cells remains unknown. In the present study, Cell Counting Kit-8 (CCK-8) and colony formation assays showed that ANXA1 silencing combined with BTZ treatment led to a more significant inhibition of MM cell proliferation than each treatment alone. Cell apoptosis was dramatically promoted in MM cells following silencing of ANXA1 and BTZ administration versus that in ANXA1-silenced alone or BTZ-treated alone cells, as evidenced by decreased expression of phosphorylated signal transducers and activators of transcription 3 and BCL2, and increased expression of BAX. Moreover, we demonstrated that the levels of IL-6 and IL-23 were markedly downregulated in ANXA1-silenced and BTZ-treated MM cells. Furthermore, the combination of ANXA1 knockdown and BTZ treatment distinctly suppressed tumor growth in vivo compared with BTZ treatment alone. Taken together, our results show that downregulation of ANXA1 enhances antitumor activity of BTZ in MM in vitro and in vivo, indicating that ANXA1 may be a promising target for enhancing the chemosensitivity of MM to BTZ.

60 APPLIED LIFE SCIENCES↗

Chemical-free production of multiple high-value bioproducts from metabolically engineered transgenic sugarcane ‘oilcane’ bagasse and their recovery using nanofiltration

Bioenergy crops have potential for being a sustainable and renewable feedstock for biofuels and various value- added bioproducts. The study utilizes recently developed transgenic sugarcane (‘oilcane’) bagasse for chemical- free coproduction of high-value bioproducts, i.e., furfurals, HMF, acetic acid, cellulosic sugars, and vegetative lipids. Hydrothermal pretreatment was optimized at 210°C for 5 min to coproduce 6.91%, 2.67%, 5.07%, 2.42% and 37.82% (w/w) furfurals, HMF, acetic acid, vegetative lipids, and cellulosic sugars, respectively from lignocellulosic biomass. Additionally, nanofiltration system in-series was successfully established to recover sugars, furfurals, HMF, and acetic acid from the pretreatment liquor. 1st nanofiltration with Duracid NF mem- brane rejected ~99% sugars. Concentrated sugars with significantly reduced inhibitory products were obtained in retentate for fermentation. 2nd nanofiltration with NF90 membrane used permeate of 1st nanofiltration as feed and rejected ~ 86% furfurals. Furthermore, the work demonstrates the feasibility of coproducing and recovering multiple biochemicals from lignocellulosic biomass.

09 BIOMASS FUELS↗

Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single-Molecule Imaging

Localization of the Ca2þ/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIa (a) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIb (b). The bE0 splice variant bound more weakly than a, showing that binding by b depends critically on the interdomain linker. The mutations bT287D and aT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (bK43R and aK42M) or Ca2þ/calmodulin (bA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the aT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIa isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F-actin cytoskeleton that stabilize the initial weak (micromolar) monovalent interaction.

59 BASIC BIOLOGICAL SCIENCES↗

Optical properties and carrier dynamics of GaAs/GaInAs multiple-quantum-well shell grown on GaAs nanowire by molecular beam epitaxy

GaAs/GaInAs multiple-quantum-well (MQW) shells having different GaInAs shell width formed on the surface of self-catalyzed GaAs core nanowires (NWs) are grown on (100) Si substrate using molecular beam epitaxy. The photoluminescence emission from GaAs/GaInAs MQW shells and the carrier lifetime could be varied by changing the width of GaInAs shell. Time-resolved photoluminescence measurements showed that the carrier lifetime had a fast and slow decay owing to the mixing of wurtzite and zinc-blende structures of the NWs. Furthermore, strain relaxation caused the carrier lifetime to decrease beyond a certain thickness of GaInAs quantum well shells.

14 SOLAR ENERGY↗

Hydrogen cluster/network in tobermorite as studied by multiple-quantum spin counting {sup 1}H NMR

Proton multiple-quantum (MQ) spin-counting experiment has been employed to study arrangement of hydrogen atoms in 9 Å/11 Å natural/synthetic tobermorites. Even though all tobermorite samples give similar characterless, broad static-powder {sup 1}H NMR spectra, their MQ spin-counting spectra are markedly different; higher quanta in 11 Å tobermorite do not grow with the MQ excitation time, while those in 9 Å one do. A statistical analysis of the MQ results recently proposed [26] is applied to show that hydrogens align in 9 Å tobermorite one dimensionally, while in 11 Å tobermorite they exist as a cluster of 5–8 hydrogen atoms.

36 MATERIALS SCIENCE↗

The multiple depleted mantle components in the Hawaiian-Emperor chain

Oceanic island basalts are targeted for geochemical study because they provide a direct window into mantle composition and a wealth of information on the dynamics and timescales associated with Earth mixing. Previous studies mainly focused on the shield volcanic stage of oceanic islands and the more fusible, enriched mantle components that are easily distinguished in those basalts. Mantle depleted compositions are typically more difficult to resolve unless large amounts of this material participated in mantle melting (e.g., mid-ocean ridges), or unique processes allow for their compositions to be erupted undiluted, such as very small degrees of melting of a source with minimal fusible enriched components (e.g., rejuvenated basalts) or as xenoliths (e.g., abyssal peridotites). Mantle depleted components, defined here as material with low time-integrated Rb/Sr (low 87 Sr/ 86 Sr) and high time-integrated Sm/Nd and Lu/Hf ratios (high 143 Nd/ 144 Nd and 176 Hf/ 177 Hf) relative to primitive mantle, derive from a potentially very large volume reservoir (up to 80% of the mantle), and therefore need adequate characterization in order estimate the composition of the Earth and mantle-derived melts. Here, this review focuses on mantle depleted compositions in oceanic island basalts using the Hawaiian-Emperor chain as a case study. The Hawaiian-Emperor chain is the ~6000 km long geological record of the deeply sourced Hawaiian mantle plume, active for >81 Myr. Hawaiian volcanism evolves through four volcanic stages as a volcano traverses the Hawaiian plume: alkalic preshield, tholeiitic shield (80–90% volcano volume), alkalic postshield (~1%), and silica undersaturated rejuvenated (<0.1%). We report Pb-Sr-Nd-Hf isotope compositions and trace element concentrations of three rejuvenated Northwest Hawaiian Ridge basalts and compare them to an exhaustive compiled dataset of basalts from the Hawaiian Islands to the Emperor Seamounts. The Northwest Hawaiian Ridge (NWHR) includes 51 volcanoes spanning ~42 m.y. between the bend in the Hawaiian-Emperor chain and the Hawaiian Islands where there is no high-precision isotopic data published on the rejuvenated-stage over ~47% of the chain. NWHR and Hawaiian Island rejuvenated basalts are geochemically similar, indicating a consistent source for rejuvenated volcanism over ~12.5 million years. In contrast, shield-stage basalts from the oldest Emperor Seamounts are more depleted in isotopic composition (i.e., higher 176 Hf/ 177 Hf, and 143 Nd/ 144 Nd with lower 87 Sr/ 86 Sr and 208 Pb*/ 206 Pb*) and trace element concentrations (i.e., much lower concentrations of highly incompatible elements) than all other depleted Hawaiian basalts younger than the bend, including NWHR rejuvenated basalts. The strongly depleted source for the oldest Emperor Seamounts (>70 Ma) was likely related to interaction with the Kula-Pacific-Izanagi mid-ocean ridge spreading system active near the Hawaiian plume in the Late Cretaceous. In contrast, the incompatible trace element ratios of NWHR rejuvenated basalts require a distinct source in the Hawaiian mantle plume that was imprinted by ancient (>1 Ga) partial melting, likely ancient recycled oceanic lithosphere. This review of the geochemistry of Hawaiian depleted components documents the need for the sampling of multiple distinctive depleted compositions, each preferentially melted during specific periods of Hawaiian plume activity. This suggests that the composition of depleted components can evolve during the lifetime of the mantle plume, as observed for enriched components in the Hawaiian mantle plume. Changes in the composition of depleted components are dominantly controlled by the upper mantle tectonic configurations at the time of eruption (i.e., proximity to a mid-ocean ridge), as this effect overwhelms the signal imparted by potentially sampling different lower mantle components through time.

07 ISOTOPE AND RADIATION SOURCES↗

Comparing multiple statistical methods for inverse prediction in nuclear forensics applications

Forensic science seeks to predict source characteristics using measured observables. Statistically, this objective can be thought of as an inverse problem where interest is in the unknown source characteristics or factors ( X ) of some underlying causal model producing the observables or responses (Y = g ( X ) + error ). Here, this paper reviews several statistical methods for use in inverse problems and demonstrates that comparing results from multiple methods can be used to assess predictive capability. Motivation for assessing inverse predictions comes from the desired application to historical and future experiments involving nuclear material production for forensics research in which inverse predictions, along with an assessment of predictive capability, are desired.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗

The effect of variable fuel staging transients on self-excited instabilities in a multiple-nozzle combustor

Combustion instability in gas turbine engines is often mitigated using fuel staging. Fuel staging, sometimes referred to as fuel splitting, is a strategy by which fuel is unevenly distributed between different nozzles of a multiple-nozzle combustor. These fuel splits are conducted in a transient manner in real engines, and the effects of these transients on instability are not well characterized. This work fills this gap by systematically studying the effects of transient fuel staging on self-excited combustion instability by varying the amount of staging fuel (staging amplitude), timescale in which the fuel is added (transient duration), and whether staging fuel is added or subtracted (transient direction). In this work, three staging amplitudes, five transient durations, and both transient directions are considered. The transient timescales are broadly divided into “short” duration transients, which have fuel delivery timescales shorter than the characteristic instability decay or onset timescales, and “long” duration transients, which have fuel delivery timescales longer than the characteristic instability decay or onset timescales. For short duration transients, we find the instability decay timescale depends on staging amplitude but does not depend on transient duration. For long duration transients, we find the instability decay timescale does not strongly depend on staging amplitude. The instability onset timescale is found to be longer and more variable between runs than the instability decay timescale for a given fuel delivery timescale. The onset timescale is also longer in duration and more variable than the decay timescale at a given fuel delivery timescale, implying that the instability rise process is overall more variable and slower than the instability decay process. Analysis of combustor damping rates show a strong dependence of damping rate on staging amplitude but no strong dependence on transient duration or direction. Instantaneous phase difference images between p' and are used to differentiate regions in the combustor that have constructive versus destructive interference between heat release rate oscillations and pressure fluctuations. Furthermore, the phase images show that p' and q . ' become in-phase early in the transient for the onset transients.

20 FOSSIL-FUELED POWER PLANTS↗

GPU acceleration of the Locally Selfconsistent Multiple Scattering code for first principles calculation of the ground state and statistical physics of materials

The Locally Self-consistent Multiple Scattering (LSMS) code solves the first principles Density Functional theory Kohn–Sham equation for a wide range of materials with a special focus on metals, alloys and metallic nano-structures. It has traditionally exhibited near perfect scalability on massively parallel high performance computer architectures. In this paper, we present our efforts to exploit GPUs to accelerate the LSMS code to enable first principles calculations of O(100,000) atoms and statistical physics sampling of finite temperature properties. We reimplement the scattering matrix calculation for GPUs with a block matrix inversion algorithm that only uses accelerator memory. Finally, using the Cray XK7 system Titan at the Oak Ridge Leadership Computing Facility we achieve a sustained performance of 14.5PFlop/s and a speedup of 8.6 compared to the CPU only code.

36 MATERIALS SCIENCE↗

Multiple charging and chemical stability of tripodal catholyte redoxmers

Macromolecular catholyte materials store multiple positive charges in all-organic redox flow cells. Presently, little is known about the electronic structure and chemical stability of these macromolecules in different states of charge. Here we demonstrate that in propeller-like catholyte trimers (tripods), chemical stability increases when they become fully charged.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Approximating a linear multiplicative objective in watershed management optimization

Implementing management practices in a cost-efficient manner is critical for regional efforts to reduce the amount of pollutants entering the Chesapeake Bay. We study the problem of selecting a subset of practices that minimizes pollutant load—subject to budgetary and environmental constraints—as simulated in a widely used regulatory watershed model. Mimicking the computation of pollutant load in the regulatory model, we formulate this problem as a continuous optimization model with a linear multiplicative objective function and linear constraints. To lay the groundwork for incorporating additional stakeholder requirements in the future, especially those that would require integer variables, we present and study a continuous linear optimization model that approximates the nonlinear model. The linear model, which requires an exponential number of variables, arises naturally as an alternative model for the same underlying physical process. We examine the theoretical behavior of these optimization models and investigate restrictions of the linear model to handle its large number of variables. Through extensive computational tests on real and randomly generated instances, we demonstrate that the linear model and its restrictions provide optimal solutions close to those of the nonlinear model in practice, despite poor approximation properties in the worst case. We conclude that the linear model—together with our approach to handling its large number of variables—provides a viable framework from which to extend the optimization model to better meet the needs of the Chesapeake Bay watershed management stakeholders.

54 ENVIRONMENTAL SCIENCES↗

A techno-economic assessment framework for hydrogen energy storage toward multiple energy delivery pathways and grid services

Hydrogen energy storage (HES) transforms and stores electric energy from the grid into hydrogen, and supplements other energy storage and demand response resources in addressing challenges in renewable-intensive power systems. Understanding how to optimally utilize an HES system to maximize its economic benefits from stacked value streams is highly important to its development and deployment. Here, in this paper, we present a techno-economic assessment framework for an HES system considering three common energy delivery pathways and multiple grid and end-user services. Models are developed to capture the operational capability, flexibility, and constraints associated with hydrogen production, compression, storage, and utilization as well as different grid services in an economic assessment. To define the technically achievable benefits, an optimal dispatch formulation is proposed to maximize the economic benefits over a representative year with an hourly time step considering the trade-offs among different value streams. Representative case studies are designed and carried out to show how system configuration, energy delivery pathways, and grid services may affect economic benefits. It was found that value streams from bundling grid services account for up to 76% of the total benefits and are critical for an HES project to be financially viable.

25 ENERGY STORAGE↗

Urban residential greenspace and mental health in youth: Different approaches to testing multiple pathways yield different conclusions

Highlights: • We compared single and parallel mediation models to serial mediation models. • Single mediation models suggested mediation through neighborhood restorative quality. • Parallel mediation models did not find any mediation through restorative quality. • There was serial mediation through restorative quality, physical activity and social cohesion. • Testing mediators alone or in parallel may lead to incorrect inferences. Urban greenspace can benefit mental health through multiple mechanisms. They may work together, but previous studies have treated them as independent.

54 ENVIRONMENTAL SCIENCES↗

Ozone, NO2 and PM10 are associated with the occurrence of multiple sclerosis relapses. Evidence from seasonal multi-pollutant analyses

Highlights: • Season-dependent associations between short term exposure to NO{sub 2} and O{sub 3} and risk of MS relapses were observed. • Confirmation of PM10-associated risk of MS relapses. • A multi-pollutant approach should be systematically intended, especially when assessing level of PM{sub 10} and NO{sub 2.} • Individual characteristics should be considered alongside other MS relapses risk factors. Triggers of multiple sclerosis (MS) relapses are essentially unknown. PM{sub 10} exposure has recently been associated with an increased risk of relapses.

54 ENVIRONMENTAL SCIENCES↗