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At least 685 records · Page 38

Structure-function analysis of the FCRL5–IgG1 Fc complex reveals an unappreciated pathway for B cell modulation by Fc-attenuated IgG

The Fc region of therapeutic IgG antibodies is often engineered to remove or “silence” Fc effector functions, but it remains unclear whether these mutations eliminate all Fc-mediated effector activity. Human Fc receptor-like 5 (FCRL5/FcRH5) is a low-affinity IgG Fc receptor expressed on B cells and is an actively pursued antibody target in multiple myeloma. Here, we show that common Fc function-silencing mutations do not impair FCRL5-mediated activity and therefore attenuate, rather than eliminate, Fc effector function. The crystal structure of the FCRL5-IgG1 Fc complex, solved at 3.4 Å resolution, revealed that FCRL5 binds IgG1 Fc in a 1:1 complex through a binding mode distinct from that of classical Fcγ receptors, explaining why mutations that attenuate Fc effector function spare FCRL5 binding. Fc-engineered antibodies that selectively engage FCRL5 inhibited B cell receptor-induced Ca 2+ flux in FCRL5-expressing B cells. These findings demonstrate that Fc-attenuated therapeutic IgG retains the ability to engage FCRL5, identifying an unappreciated pathway for B cell modulation.

Herpers, Bart M. [Department of Biomedical Enginee↗

A quasi-linear control theory analysis of timesharing skills

The compliance of the human ankle joint is measured by applying 0 to 50 Hz band-limited gaussian random torques to the foot of a seated human subject. These torques rotate the foot in a plantar-dorsal direction about a horizontal axis at a medial moleolus of the ankle. The applied torques and the resulting angular rotation of the foot are measured, digitized and recorded for off-line processing. Using such a best-fit, second-order model, the effective moment of inertia of the ankle joint, the angular viscosity and the stiffness are calculated. The ankle joint stiffness is shown to be a linear function of the level of tonic muscle contraction, increasing at a rate of 20 to 40 Nm/rad/Kg.m. of active torque. In terms of the muscle physiology, the more muscle fibers that are active, the greater the muscle stiffness. Joint viscosity also increases with activation. Joint stiffness is also a linear function of the joint angle, increasing at a rate of about 0.7 to 1.1 Nm/rad/deg from plantar flexion to dorsiflexion rotation.

Agarwal, G. C.↗

Energetics and structural properties of twist grain boundaries in Cu

Structural and energetics properties of atoms near a grain boundary are of great importance from theoretical and experimental standpoints. From various experimental work it is concluded that diffusion at low temperatures at polycrystalline materials take place near grain boundary. Experimental and theoretical results also indicate changes of up to 70 percent in physical properties near a grain boundary. The Embedded Atom Method (EAM) calculations on structural properties of Au twist grain boundaries are in quite good agreement with their experimental counterparts. The EAM is believed to predict reliable values for the single vacancy formation energy as well as migration energy. However, it is not clear whether the EAM functions which are fitted to the bulk properties of a perfect crystalline solid can produce reliable results on grain boundaries. One of the objectives of this work is to construct the EAM functions for Cu and use them in conjunction with the molecular static simulation to study structures and energetics of atoms near twist grain boundaries in Cu. This provides tests of the EAM functions near a grain boundary. In particular, we determine structure, single vacancy formation energy, migration energy, single vacancy activation energy, and interlayer spacing as a function of distance from grain boundary. Our results are compared with the available experimental and theoretical results from grain boundaries and bulk.

Karimi, Majid↗

Protecting Neural Structures and Cognitive Function During Prolonged Space Flight by Targeting the Brain Derived Neurotrophic Factor Molecular Network

Brain derived neurotrophic factor (BDNF) is the main activity-dependent neurotrophin in the human nervous system. BDNF is implicated in production of new neurons from dentate gyrus stem cells (hippocampal neurogenesis), synapse formation, sprouting of new axons, growth of new axons, sprouting of new dendrites, and neuron survival. Alterations in the amount or activity of BDNF can produce significant detrimental changes to cortical function and synaptic transmission in the human brain. This can result in glial and neuronal dysfunction, which may contribute to a range of clinical conditions, spanning a number of learning, behavioral, and neurological disorders. There is an extensive body of work surrounding the BDNF molecular network, including BDNF gene polymorphisms, methylated BDNF gene promoters, multiple gene transcripts, varied BDNF functional proteins, and different BDNF receptors (whose activation differentially drive the neuron to neurogenesis or apoptosis). BDNF is also closely linked to mitochondrial biogenesis through PGC-1alpha, which can influence brain and muscle metabolic efficiency. BDNF AS A HUMAN SPACE FLIGHT COUNTERMEASURE TARGET Earth-based studies reveal that BDNF is negatively impacted by many of the conditions encountered in the space environment, including oxidative stress, radiation, psychological stressors, sleep deprivation, and many others. A growing body of work suggests that the BDNF network is responsive to a range of diet, nutrition, exercise, drug, and other types of influences. This section explores the BDNF network in the context of 1) protecting the brain and nervous system in the space environment, 2) optimizing neurobehavioral performance in space, and 3) reducing the residual effects of space flight on the nervous system on return to Earth

Schmidt, M. A.↗

Enhanced spectral purity of WSe 2 quantum emitters via conformal organic adlayers

Quantum emitters in solid-state materials are typically embedded in the bulk of their hosts, making their electronic transitions inaccessible to surface modification. In contrast, two-dimensional materials, with their all-surface nature, offer a platform for tuning quantum emitters via chemical functionalization. Because of its semiconducting properties that enable electrical addressability, monolayer WSe 2 is a promising candidate for quantum emission, although the complex interplay between point defects and the localized strain needed to activate quantum emission leads to poor spectral purity. Here, we demonstrate that functionalizing monolayer WSe 2 with conformal adlayers of 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA) improves quantum emission spectral purity. Optical spectroscopy reveals that PTCDA functionalization lowers defect activation energies by 10 meV and induces a 30 nm redshift in quantum emission wavelength, while preserving the bright and dark exciton energies of monolayer WSe 2 . First-principles calculations corroborate these findings, thus providing molecular-level insight into the underlying mechanism of enhanced spectral purity.

Ananth, Riddhi [Northwestern Univ., Evanston, IL (↗

Effects of gravity on the circadian period in rats

The effect of increased gravity force on the circadian period of body temperature and activity of rats was investigated using rats implanted with a small radio telemetry device and, after a 2-week recovery and a 3-week control period at 1G, rotated at for 4 weeks at a constant 2G field in a 18-ft-diam centrifuge. Measurements of the mean freerunning period of the temperature and activity rhythms after 10 days showed that the exposure to 2G led to a functional separation of the pacemakers that regulate the activity and the temperature in the animals. Each pacemaker reacted differently: the activity period increased and the temperature period decreased. By the third or the fourth week, the activity and the temperature periods have returned to 1G control levels.

Murakami, Dean M.↗

Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at p< 0.5. RESULTS Among the redox homeostasis genes examined, metallothionein showed a significant down regulation in the radiation treated group (-3.85 fold) and a trend toward down regulation in the high Fe + rad group. Metallothionein is involved in the regulation of physiological metals and also has antioxidant activities. Among the drug metabolism genes examined, ATP binding cassette subfamily B (Abcb1b) gene expression increased more than 10-fold in both groups that received radiation treatments. This increased expression was also seen at the protein level. This ABC transporter carries many different compounds across cell membranes, including administered medications. The cytochrome P450 2E1 enzyme, a mixed-function oxidase that deactivates some medications and activates others, showed about a 2-fold increase in gene expression in both radiation-treated groups, with a trend toward increased expression at the protein level. Expression of epoxide hydrolase, which detoxifies polycyclic aromatic hydrocarbons, showed similar 2-fold increases. Among the DNA repair genes examined, expression of RAD51 was significantly down regulated (1.5 fold) in the radiation treated group. RAD51 is involved in repair of double-stranded DNA breaks. CONCLUSION This experiment used 2 different sources of physiological oxidative stress, administered separately and together, and examined their impacts on liver gene and protein expression. It is clear that significant changes occurred in expression of several genes and proteins in the radiation-treated animals. If the results from this ground analog of portions of the spaceflight environment hold true for the spaceflight environment itself, the physiological roles of the affected enzymes (drug transport and metabolism, redox homeostasis) could mean consequences in redox homeostasis or the pharmacokinetics of administered medications

Faust, K. M.↗

Bringing Inorganic Carbon to Life: Developing Model Metalloenzymes for C1 Conversion Reactions

The global carbon cycle is carefully balanced through the use of specialized enzymes in plants, algae, bacteria, and archaea. A primordial metabolic pathway for the conversion of inorganic carbon into cellular biomass uses a large, nickel-containing enzyme called carbon monoxide dehydrogenase (CODH)/acetyl coenzyme A synthase (ACS). This system fixes carbon dioxide (CO 2 ) into carbon monoxide (CO) at the CODH site. The carbon monoxide is then used to generate acetyl coenzyme A, a biological building block, through a key carbon-carbon bond forming step at the nickel site in ACS. Despite the significance of these processes in the context of energy conversion, the fundamental chemistry underlying these transformations has remained elusive, in part due to the complexity of the natural enzyme. To better understand the principles governing these biological processes, which represent one-carbon (C 1 ) activation reactions, this project will develop functional models of CODH and ACS based on modifications to a small metalloprotein scaffold. Comprehensive characterization of these systems using advanced spectroscopic and biophysical techniques will reveal key elements responsible for conferring high levels of activity to the model systems, with implications for gaining insight into the mechanisms of the natural enzymes. Moreover, the principles learned from this research can be used to guide design of robust catalysts for efficient conversion of CO 2 and CO into liquid fuels.

10 SYNTHETIC FUELS↗

The O II /7320-7330 A/ airglow - A morphological study

A statistical study of the 7320-30 A airglow arising from the metastable transition between aP and aD states of atomic oxygen ions was conducted by analyzing the data taken from the visible airglow experiment on the Atmosphere Explorer satellites C and E during the time periods between 1974 and 1979. Averaged column emission rate profiles as a function of solar zenith angle and solar activity variation are presented. The galactic background has been carefully subtracted. The result shows that the rate of decreasing emission as a function of solar zenith angle agrees with the theoretical calculation based upon a neutral atmosphere model and the solar spectrum as measured by the EUV spectrometer on the Atmosphere Explorer satellite. Furthermore, an expected increase with solar activity also appeared in a plot of emission brightness versus solar 10.7-cm flux.

Yee, J. H.↗

Multi-catalytic active site biochar-based catalysts for glucose isomerized to fructose: Experiments and density functional theory study

In this study, this work provides an innovative method for preparing different isomerization catalysts by impregnating different proportions of MgCl 2 and AlCl 3 and combining different K compounds on cellulose-derived biochar, followed by pyrolysis. Results show MgO and Al(OH) 3 existing in 4 Mg- 1 Al-C catalyst can obtain better catalytic effect on glucose isomerization than the singe of Al presenting in 0 Mg- 1 Al-C catalyst. Moreover, the synergism effects of the multi-catalytic active sites such as β-, γ -Al(OH) 3 , KCl, MgO, and K 4 H 2 (CO 3 ) 3 in Mg-Al-KHCO 3 -C catalyst can further lead to an increase in glucose isomerization, compared to the 4 Mg- 1 Al-C catalyst. The X-ray diffraction results present that the value of O/Al in Mg-Al-KHCO 3 -C catalyst is as high as 13.38, which provides many unsaturated acidic catalysis sites and benefits the glucose isomerization. Simultaneously, the TPD results reveal that the main active sites (MgO, Al(OH) 3 , and K 4 H 2 (CO 3 ) 3 ) in Mg-Al-KHCO 3 -C catalyst can provide weakly acidic and basic sites and avoid strongly acidic and basic sites to excessively attack the glucose. Based on the DFT analysis, the results indicate that the MgO has a great effect on the ring-opening reaction to form acyclic glucose, while Al(OH) 3+ has a great effect on promoting acyclic glucose hydrogen transfer isomerized to form fructose. Compared to other carbon-based metal catalysts, the prepared Mg-Al-KHCO 3 -C has excellent catalytic performance, which gives a higher fructose yield (38.7%) and selectivity (87.72%) and glucose conversion (44.12%) at 100 °C in 30 min. In this study, we develop a highly efficient Mg-Al-K-biochar catalyst for glucose isomerization and provide an efficient method for cellulose valorization.

36 MATERIALS SCIENCE↗

A Synthesis of Solar Cycle Prediction Techniques

A number of techniques currently in use for predicting solar activity on a solar cycle timescale are tested with historical data. Some techniques, e.g., regression and curve fitting, work well as solar activity approaches maximum and provide a month-by-month description of future activity, while others, e.g., geomagnetic precursors, work well near solar minimum but only provide an estimate of the amplitude of the cycle. A synthesis of different techniques is shown to provide a more accurate and useful forecast of solar cycle activity levels. A combination of two uncorrelated geomagnetic precursor techniques provides a more accurate prediction for the amplitude of a solar activity cycle at a time well before activity minimum. This combined precursor method gives a smoothed sunspot number maximum of 154 plus or minus 21 at the 95% level of confidence for the next cycle maximum. A mathematical function dependent on the time of cycle initiation and the cycle amplitude is used to describe the level of solar activity month by month for the next cycle. As the time of cycle maximum approaches a better estimate of the cycle activity is obtained by including the fit between previous activity levels and this function. This Combined Solar Cycle Activity Forecast gives, as of January 1999, a smoothed sunspot maximum of 146 plus or minus 20 at the 95% level of confidence for the next cycle maximum.

Hathaway, David H.↗

Results of the study of the vestibular apparatus and the functions of the perception of space in cosmonauts (pre- and post-flight observations)

The effect of the set of space flight factors caused a change in the activity of the vestibular apparatus and the spatial perception function. More significant and longer shifts were observed during expeditions of great duration. The detected disorders (increase in reactivity of the otolithic apparatus, decrease in sensitivity of the cupula receptor, deterioration in the perception accuracy, etc.) had a definite tendency to be restored. The primary damage to the otolithic reflex (changes were found in practically all the subjects) is probably caused by the specific effect of zero gravitation, and apparently, may be one of the trigger mechanisms for discrepancy in the activity of the sensory systems, disorders in the correcting function of the cerebellum, and central vestibular formations.

Yakovleva, I. Y.↗

A complete X-ray sample of the high-latitude /absolute value of b greater than 20 deg/ sky from HEAO 1 A-2 - Log N-log S and luminosity functions

An all-sky survey of X-ray sources was performed, complete to a limiting sensitivity of 3.1 x 10 to the -11 ergs/sq cm/s in the 2-10 keV band. The complete sample has allowed construction of luminosity functions based on a flux-limited sample for clusters of galaxies and active galactic nuclei. Integration of the best-fit luminosity functions indicates that clusters of galaxies contribute about 4% of the 2-10 keV DXRB, and active galactic nuclei about 20%. It is predicted that many of the objects seen in the deep survey should be local, relatively low luminosity active galactic nuclei and clusters of galaxies.

Piccinotti, G.↗

Down-Selection of Four Common Habitat Variants

The Common Habitat is a large habitat that uses the Space Launch System core stage liquid oxygen tank as its primary structure. It has a gravity-independent internal architecture, such that identical units can be used on the lunar surface, Mars surface, and in microgravity. In developing the habitat, two key architectural questions emerged. Should the internal layout use a vertical or horizontal orientation of the tank? Should the crew size be four or eight? This led to the design of four variants: a four-crew horizontal, four-crew vertical, eight-crew horizontal, and eight-crew vertical. The primary consideration applied for down-selection was the crew experience living and working in the habitat, inclusive of crew productivity, well-being, and survivability. Based on this consideration, a series of seven assessments was performed to compare the four variants. A stowage assessment developed a standard logistics module and then considered the amounts of water to be stored in each variant. It then estimated how much stowage could be carried onboard each Common Habitat and how many logistics modules are required by each variant for a given mission duration. A functional analysis identified and compared the living and working functions across the four habitat, ranking them relative to each other. A crew time assessment first estimated the total crew time, building a weekly crew timeline for both four and eight-person crews. It then allocated time to activities linked to living and working functions, comparing how much time was available for each function in each variant. A science productivity assessment developed a relative metric using crew time, science stowage, and assumed rates of experiment consumables use to analytically compare the four variants. It also comparatively ranked the habitats with respect to a number of subjective parameters and a workstation acceptability rating. A maintenance capacity assessment identified and compared eleven generic maintenance capabilities across the four variants and also ranked the variants for their predicted ability to complete twelve fabrication, maintenance, and repair scenarios. A contingency responsiveness analysis examined twelve serious in-flight contingencies. For each scenario, the number of crew needed to respond was predicted and acceptability of various aspects of contingency response was evaluated, comparing the four variants against each other. Finally, in a habitability assessment, 120 habitability characteristics reflecting 13 major categories were evaluated for each habitat. These results were compared to identify the most acceptable habitat in each category. Ultimately, the data was shown to favor the horizontal orientation over the vertical and an eight-person crew over four. Implications of selecting this variant are discussed, including specific architectural challenges that result from the use of the full SLS liquid oxygen tank.

Habitability↗

Data system architecture considerations for a space station

The functions that a space station could serve are outlined and details of the data systems requirements are discussed. The data system design will be guided by an overall space systems plan, and will feature distributed, layered architecture, user friendliness, hierarchical control, technology transparency, standard interfaces, and automated engineering tools. The station would begin with a limited core capability and evolve to serve functions defined thereafter. The automation of the engineering tools will be necessary to permit an optimized, minimized crew to control all functions of the space station, while at the same time freeing the crew from being actively involved in maintaining the nominal life support functions of the equipment. One major criterion is that the software must be error free, while another is adaptibility to changing space station configurations and demands.

Connell, E. B.↗

Semi-Analytic Forecasts for JWST– V. AGN Luminosity Functions and Helium Reionization at z= 2–7

Active galactic nuclei (AGN) forming in the early universe are thought to be the pri-mary source of hard ionizing photons contributing to the reionization of intergalactic helium. However, the number density and spectral properties of high-redshift AGN remain largely unconstrained. In this work, we make use of physically-informed mod-els calibrated with a wide variety of available observations to provide estimates for the role of AGN throughout the Epoch of Reionization. We present AGN luminosity functions in various bands between z= 2 to 7 predicted by the well-established Santa Cruz semi-analytic model, which includes modelling of black hole accretion and AGN feedback. We then combine the predicted AGN populations with a physical spectral model for self-consistent estimates of ionizing photon production rates, which depend on the mass and accretion rate of the accreting supermassive black hole. We then couple the predicted comoving ionizing emissivity with an analytic model to compute the subsequent reionization history of intergalactic helium and hydrogen. This work demonstrates the potential of coupling physically motivated analytic or semi-analytic techniques to capture multi-scale physical processes across a vast range of scales (here, from AGN accretion disks to cosmological scales). Our physical model predicts an in-trinsic ionizing photon budget well above many of the estimates in the literature, meaning that helium reionization can comfortably be accomplished even with a rel-atively low escape fraction. We also make predictions for the AGN populations that are expected to be detected in future James Webb Space Telescope surveys

L Y Aaron Yung↗

Observational evidence of aging processes in comets

Emphasis was on searching for systematic differences among two groups of comets: periodic comets which spend most of their time in the vicinity of the inner Solar System and the new comets which are believed to be passing through the inner Solar System for the first time. Such differences are expected, but have never been observed, in part because there has never been a systematic observational program aimed at addressing this question. Understanding possible physical and compositional differences between these two groups will lead to a better understanding of the cometary formation conditions in the early Solar System. The employed method studies the activity in the comets as a function of distance by obtaining charge coupled device (CCD) observations of the comets at frequent intervals on both the pre- and post-perihelion legs of their orbits in order to ascertain the distances at the onset and turn-off of activity through comparison with sublimation models.

Meech, Karen J.↗

MAP kinase pathways in the yeast Saccharomyces cerevisiae

A cascade of three protein kinases known as a mitogen-activated protein kinase (MAPK) cascade is commonly found as part of the signaling pathways in eukaryotic cells. Almost two decades of genetic and biochemical experimentation plus the recently completed DNA sequence of the Saccharomyces cerevisiae genome have revealed just five functionally distinct MAPK cascades in this yeast. Sexual conjugation, cell growth, and adaptation to stress, for example, all require MAPK-mediated cellular responses. A primary function of these cascades appears to be the regulation of gene expression in response to extracellular signals or as part of specific developmental processes. In addition, the MAPK cascades often appear to regulate the cell cycle and vice versa. Despite the success of the gene hunter era in revealing these pathways, there are still many significant gaps in our knowledge of the molecular mechanisms for activation of these cascades and how the cascades regulate cell function. For example, comparison of different yeast signaling pathways reveals a surprising variety of different types of upstream signaling proteins that function to activate a MAPK cascade, yet how the upstream proteins actually activate the cascade remains unclear. We also know that the yeast MAPK pathways regulate each other and interact with other signaling pathways to produce a coordinated pattern of gene expression, but the molecular mechanisms of this cross talk are poorly understood. This review is therefore an attempt to present the current knowledge of MAPK pathways in yeast and some directions for future research in this area.

Non-NASA Center↗