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Recent breakthroughs in generative modelling have led to a number of works proposing molecular generation models for drug discovery. While these models perform well at capturing drug-like motifs, they are known to often produce synthetically inaccessible molecules. This is because they are trained to compose atoms or fragments in a way that approximates the training distribution, but they are not explicitly aware of the synthesis constraints that come with making molecules in the lab. To address this issue, we introduce SynFlowNet, a GFlowNet model whose action space uses chemically validated reactions and reactants to sequentially build new molecules. We evaluate our approach using synthetic accessibility scores and an independent retrosynthesis tool. SynFlowNet consistently samples synthetically feasible molecules, while still being able to find diverse and high-utility candidates. Furthermore, we compare molecules designed with SynFlowNet to experimentally validated actives, and find that they show comparable properties of interest, such as molecular weight, SA score and predicted protein binding affinity., Comment: Presented at ICLR 2024 GEM Workshop

Computational RNA design tasks are often posed as inverse problems, where sequences are designed based on adopting a single desired secondary structure without considering 3D geometry and conformational diversity. We introduce gRNAde, a geometric RNA design pipeline operating on 3D RNA backbones to design sequences that explicitly account for structure and dynamics. Under the hood, gRNAde is a multi-state Graph Neural Network that generates candidate RNA sequences conditioned on one or more 3D backbone structures where the identities of the bases are unknown. On a single-state fixed backbone re-design benchmark of 14 RNA structures from the PDB identified by Das et al. [2010], gRNAde obtains higher native sequence recovery rates (56% on average) compared to Rosetta (45% on average), taking under a second to produce designs compared to the reported hours for Rosetta. We further demonstrate the utility of gRNAde on a new benchmark of multi-state design for structurally flexible RNAs, as well as zero-shot ranking of mutational fitness landscapes in a retrospective analysis of a recent RNA polymerase ribozyme structure. Open source code: https://github.com/chaitjo/geometric-rna-design, Comment: Previously titled 'Multi-State RNA Design with Geometric Multi-Graph Neural Networks', presented at ICML 2023 Computational Biology Workshop

Structure-based drug design (SBDD) aims to design small-molecule ligands that bind with high affinity and specificity to pre-determined protein targets. In this paper, we formulate SBDD as a 3D-conditional generation problem and present DiffSBDD, an SE(3)-equivariant 3D-conditional diffusion model that generates novel ligands conditioned on protein pockets. Comprehensive in silico experiments demonstrate the efficiency and effectiveness of DiffSBDD in generating novel and diverse drug-like ligands with competitive docking scores. We further explore the flexibility of the diffusion framework for a broader range of tasks in drug design campaigns, such as off-the-shelf property optimization and partial molecular design with inpainting.

Discusses recent commission reports that call tenure into question and call for reformation and clarification of the concept of shared governance. Asserts that what is required is a general reenvisioning of educators' professional selves, not just as scholars and teachers, but as citizens of the larger academic world. (CR)

Describes an integrated problem-based learning experience for first-year medical students and assesses the effectiveness of the process in identifying basic science issues relevant to biochemical principles. (DDR)

The outline lists 14 career education activities that middle school teachers (grades 6-8) can relate to subject areas of: science, mathematics, English, social studies, foreign language, art, home economics, music, and industrial arts. Educational requirements are described for various occupations; occupations also are listed under appropriate subject areas. Activities include: role playing, field trips, audiovisual aids, interviewing, panel discussions, job applications, career notebooks, and hobby displays. (EA)

Array programming provides a powerful, compact, expressive syntax for accessing, manipulating, and operating on data in vectors, matrices, and higher-dimensional arrays. NumPy is the primary array programming library for the Python language. It plays an essential role in research analysis pipelines in fields as diverse as physics, chemistry, astronomy, geoscience, biology, psychology, material science, engineering, finance, and economics. For example, in astronomy, NumPy was an important part of the software stack used in the discovery of gravitational waves and the first imaging of a black hole. Here we show how a few fundamental array concepts lead to a simple and powerful programming paradigm for organizing, exploring, and analyzing scientific data. NumPy is the foundation upon which the entire scientific Python universe is constructed. It is so pervasive that several projects, targeting audiences with specialized needs, have developed their own NumPy-like interfaces and array objects. Because of its central position in the ecosystem, NumPy increasingly plays the role of an interoperability layer between these new array computation libraries.

SciPy is an open source scientific computing library for the Python programming language. SciPy 1.0 was released in late 2017, about 16 years after the original version 0.1 release. SciPy has become a de facto standard for leveraging scientific algorithms in the Python programming language, with more than 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repositories, and millions of downloads per year. This includes usage of SciPy in almost half of all machine learning projects on GitHub, and usage by high profile projects including LIGO gravitational wave analysis and creation of the first-ever image of a black hole (M87). The library includes functionality spanning clustering, Fourier transforms, integration, interpolation, file I/O, linear algebra, image processing, orthogonal distance regression, minimization algorithms, signal processing, sparse matrix handling, computational geometry, and statistics. In this work, we provide an overview of the capabilities and development practices of the SciPy library and highlight some recent technical developments., Comment: Article source data is available here: https://github.com/scipy/scipy-articles

Glucocorticoids are steroid hormones that play a key role in metabolic adaptations during stress, such as fasting and starvation, in order to maintain plasma glucose levels. Excess and chronic glucocorticoid exposure, however, causes metabolic syndrome including insulin resistance, dyslipidemia, and hyperglycemia. Studies in animal models of metabolic disorders frequently demonstrate that suppressing glucocorticoid signaling improves insulin sensitivity and metabolic profiles. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator. The adipocyte is one cell type that contributes to whole body metabolic homeostasis under the influence of GR. Glucocorticoids' functions on adipose tissues are complex. Depending on various physiological or pathophysiological states as well as distinct fat depots, glucocorticoids can either increase or decrease lipid storage in adipose tissues. In rodents, glucocorticoids have been shown to reduce the thermogenic activity of brown adipocytes. However, in human acute glucocorticoid exposure, glucocorticoids act to promote thermogenesis. In this article, we will review the recent studies on the mechanisms underlying the complex metabolic functions of GR in adipocytes. These include studies of the metabolic outcomes of adipocyte specific GR knockout mice and identification of novel GR primary target genes that mediate glucocorticoid action in adipocytes.

The rise of inorganic-biological hybrid organisms for solar-to-chemical production has spurred mechanistic investigations into the dynamics of the biotic-abiotic interface to drive the development of next-generation systems. The model system, Moorella thermoacetica-cadmium sulfide (CdS), combines an inorganic semiconductor nanoparticle light harvester with an acetogenic bacterium to drive the photosynthetic reduction of CO2 to acetic acid with high efficiency. In this work, we report insights into this unique electrotrophic behavior and propose a charge-transfer mechanism from CdS to M. thermoacetica Transient absorption (TA) spectroscopy revealed that photoexcited electron transfer rates increase with increasing hydrogenase (H2ase) enzyme activity. On the same time scale as the TA spectroscopy, time-resolved infrared (TRIR) spectroscopy showed spectral changes in the 1,700-1,900-cm-1 spectral region. The quantum efficiency of this system for photosynthetic acetic acid generation also increased with increasing H2ase activity and shorter carrier lifetimes when averaged over the first 24 h of photosynthesis. However, within the initial 3 h of photosynthesis, the rate followed an opposite trend: The bacteria with the lowest H2ase activity photosynthesized acetic acid the fastest. These results suggest a two-pathway mechanism: a high quantum efficiency charge-transfer pathway to H2ase generating H2 as a molecular intermediate that dominates at long time scales (24 h), and a direct energy-transducing enzymatic pathway responsible for acetic acid production at short time scales (3 h). This work represents a promising platform to utilize conventional spectroscopic methodology to extract insights from more complex biotic-abiotic hybrid systems.

The mechanism of water oxidation to molecular oxygen at the surface of strontiumtitanate, a representative transition-metal oxide photocatalyst, was investigatedusing ultrafast pump-probe spectroscopy and accompanying characterization methods.The dependence of the rate of initial charge transfer on applied potential was investigatedwith transient absorption spectroscopy, revealing a phenomenological transfer coefficientfor this single step of the multi-step water oxidation reaction. Time resolvedinfrared spectroscopy provided the first direct evidence of the molecular character of thefirst intermediate to be a titanium-bound oxyl radical, and revealed interfacial Fano couplingbetween the electrolyte, surface species, and catalyst electronic continuum. Furtherwork combining both transient absorption and time-resolved mid-infrared spectroscopyexposed a minimum of three distinct surface states at the strontium titanate surface,providing insight into the rich chemistry mediated at the catalyst surface. These resultshighlight the intricacies of charge transfer at the surface of these promising materials,provide insight into an important but difficult reaction necessary for any artificialphotosynthetic system, and offer a generalizable paradigm for considering heterogeneousphotochemistry. Finally, preliminary groundwork was done to uncover the mechanismof the carbon dioxide reduction half reaction in a novel inorganic-biological bacterialsystem with potential to produce green chemicals such as carbon-neutral liquid fuels.

The properties of interfacial electronic states in device-relevant materials are investigatedusing time- and angle-resolved two photon photoemission (TPPE) spectroscopy.Angle- and time-resolved TPPE is used to investigate electronic states in the buffer layerof 4H-SiC(0001). An image potential state (IPS) series is observed on this strongly surface-bound buffer layer, and dispersion measurements indicated free-electron-like behavior for all states in this series. These results are compared with TPPE taken on bilayer graphene, which also shows the existence of a free-electron-like IPS series. Lifetimes for the n = 2, and n = 3 states are obtained from time-resolved TPPE; slightly increased lifetimes are observed in the bilayer graphene sample for the n = 2 the n = 3 states. Despite the large band gap of graphene at the center of the Brillouin zone, the lifetime results demonstrate that the graphene layers do not behave as a simple tunneling barrier, suggesting that the buffer layer and graphene overlayers play a direct role in the decay of IPS electrons. Ultrafast response of the room temperature ionic liquid (RTIL) 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([Bmpyr][NTf2]) to a photoinjected electron is investigated in few-monolayer films using time- and angle-resolved two-photon photoemission spectroscopy. A delocalized precursor state and a localized solvated state are resolved at early times, but after 200 fs only a single solvated state is observed. The dynamics of film response to this solvated state are shown to depend significantly on film temperature and thickness. Population lifetime measurements demonstrate that the RTIL film can significantly affect the coupling between solvated state and metal substrate, as the solvated state’s average lifetime increases from 90 ± 20 fs in 1 ML films to 195 ± 83 ps in 3 ML films. Additionally, a temperature dependence of the time-dependent binding energy shift of the solvated state after c.a. 500 fs

Angle- and time-resolved two-photon photoemission is used to study the ultrafast electron dynamics at alkali halide-metal interfaces under ultrahigh vacuum conditions. The initial excited states and electron localization at trap states are characterized on the ultrafast timescales.For NaCl on Ag(100), the well characterized island growth of NaCl on low Miller indices noble metal substrates in the ultrathin coverage limit is studied. The initial excited states observed correspond to the n = 1, n = 2, and n = 3 image potential state (IPS) progression of the NaCl-metal interface. The delocalized n = 1 IPS electrons, evidenced by their light effective mass, m* = 0.7me, are found to localize via population transfer to two localized states on the hundreds of femtosecond timescale. The first localized state, indicated by its flat band dispersion, is located at the bottom of the free state band with a decay lifetime comparable to the free n = 1 electrons of < 100 fs. The second, discrete, localized state observed leads to a binding energy gain of hundreds of meVs and results in a substantial lifetime increase of 0.5-1 ps versus the ca. 100 fs of the initial delocalized n = 1 IPS. The long-lived localized state's lifetime shows an exponential dependence with increasing coverage, indicating the NaCl film acts as a tunneling barrier and that the localized state is located at the surface-vacuum interface, versus inside the film. The long lived localized state is assigned to low coordinated defect sites on the NaCl surface such as step edges, corners, and NaCl pair vacancies. The binding energy and decay lifetime of electron trapping at low coordinated defects shows strong temperature dependence but qualitatively similar behavior for temperatures of 125-350 K. A new emerging trap state is observed at the NaCl/Ag(100) upon cooling to temperatures << 125 K. This state is only observed after long time delays (> 500 fs) and at increased binding energies of 380 meV. Addit

Pulmonary hyalinizing granuloma (PHG) is a rare benign pulmonary nodular lesion of unknown etiology. We present a case of a 5-year-old boy who was found to have a chest mass while being evaluated for abdominal pain. He underwent a CXR and CT scan that showed popcorn calcifications in the right posterior mediastinum and within the hilum of right lung. These lesions were suspicious for benign calcified lymph nodes and follow-up chest CT after 3.5 months showed no interval changes in the calcified mediastinal masses. Extensive testing ruled out infectious diseases and malignancies. Given the unknown etiology of the lesions, he underwent VATS biopsy that demonstrated a nodular lesion characterized by a peripheral rim of fibrous tissue and central zone of necrosis and calcification, findings consistent with hyalinizing granuloma. PHG is extremely rare in pediatric age group. Although diagnosis of this condition is made by radiological and histopathological findings, it is important to rule out other causes of chest masses. Most of the patients usually have good prognosis with this rare disorder.

Ultrafast angle-resolved two-photon photoemission (TPPE) is used to probe the electronic structure of highly ordered monolayers of organic materials deposited on the Ag(111) and Ag(100) surfaces. Studies focus on how the electronic states intrinsic to the silver surface are perturbed by the presence of the organic adlayer. These studies show that the strength of the interaction between the surface states and the organic adlayer depends on the nature of the surface state being investigated. For states localized at or near the organic adlayer, substantial changes in the surface state band structure were discovered, whereas for states residing farther in the vacuum the surface state band structure was perturbed surprisingly little. The results presented here give detailed insight into the interaction between the electronic states of organic adlayers and the silver surface.

Vibrational spectroscopy is a powerful tool for structural characterization. Modern spectroscopy has been used ultrashort laser pulses in infrared region to monitor the structure evolution of species involving in chemical reaction. This spectroscopic technique can give dynamics of chemical reaction in ultrafast timescale, helping us understand the reaction mechanism in great detail. In this thesis, a wide range of ultrafast dynamics in solution triggered via photochemical reactions has been investigated: the photoisomerization mechanism of solar storage molecules (Fulvalene)tetracarbonyldiruthenium, the photo-inactive of analog molecules (Fulvalene)tetracarbonyldiiron, the spin state and reactivity of 14-electron species Fe(CO)3 and the heat transfer from various photochemical reaction to solvent. Finally, the dynamics of molecular rotational diffusion was also investigated to measure the effect of molecular mass on rotational motion of small solute in solution. The trends discovered from these prototypical complexes are expected to be applicable to other organometallics complexes. These results will have a great contribution to the ultrafast spectroscopy as well as the synthesis research community.

Ultrafast time-resolved infrared spectroscopy provides a powerful tool for studying the photochemistry of organometallic complexes. The studies described herein focus on the mechanisms of photochemically initiated organometallic reactions with a particular emphasis on two topics: the role of spin states and spin state changes in organometallic reactions, and the primary photochemical dynamics of complexes containing metal-metal bonds (e.g. transition metal dimers and clusters). Many of these studies seek to uncover trends in reactivity based on the spin states of organometallic reaction intermediates, with the goal of being able to offer some level of predictive insight into the reactivity of complexes as classified by their spin multiplicity. The reactivity of various coordinatively unsaturated reaction intermediates are studied with respect to bond activation, electron transfer, excited state photoisomerization, and other classes of reactions important to organometallic catalysis. A second focus, which shares some degree of overlap with the topic of spin state changes, is the primary photochemistry of complexes containing metal-metal bonds. Several of the studies reported herein use time-resolved infrared spectroscopy to examine the primary photochemical processes occurring upon excitation of transition metal dimers and clusters, and often spin state changes also found to play an important role. Results of computational chemistry calculations are frequently used to facilitate interpretation of the experimental results by computation of structures, relative energies, infrared spectra, and spin-orbit coupling for the complexes studied experimentally. Additional studies outside these two primary areas of focus also investigated the ring-slippage of cyclopentadienyl ligands and the CO-delivery properties of a popular CO-Releasing Molecule.

Liver steatosis is a common health problem associated with hepatitis C virus (HCV) and an important risk factor for the development of liver fibrosis and cancer. Steatosis is caused by triglycerides (TG) accumulating in lipid droplets (LDs), cellular organelles composed of neutral lipids surrounded by a monolayer of phospholipids. The HCV nucleocapsid core localizes to the surface of LDs and induces steatosis in cultured cells and mouse livers by decreasing intracellular TG degradation (lipolysis). Here we report that core at the surface of LDs interferes with the activity of adipose triglyceride lipase (ATGL), the key lipolytic enzyme in the first step of TG breakdown. Expressing core in livers or mouse embryonic fibroblasts of ATGL(-/-) mice no longer decreases TG degradation as observed in LDs from wild-type mice, supporting the model that core reduces lipolysis by engaging ATGL. Core must localize at LDs to inhibit lipolysis, as ex vivo TG hydrolysis is impaired in purified LDs coated with core but not when free core is added to LDs. Coimmunoprecipitation experiments revealed that core does not directly interact with the ATGL complex but, unexpectedly, increased the interaction between ATGL and its activator CGI-58 as well as the recruitment of both proteins to LDs. These data link the anti-lipolytic activity of the HCV core protein with altered ATGL binding to CGI-58 and the enhanced association of both proteins with LDs.

Glucocorticoids (GCs) exert key metabolic influences on skeletal muscle. GCs increase protein degradation and decrease protein synthesis. The released amino acids are mobilized from skeletal muscle to liver, where they serve as substrates for hepatic gluconeogenesis. This metabolic response is critical for mammals' survival under stressful conditions, such as fasting and starvation. GCs suppress insulin-stimulated glucose uptake and utilization and glycogen synthesis, and play a permissive role for catecholamine-induced glycogenolysis, thus preserving the level of circulating glucose, the major energy source for the brain. However, chronic or excess exposure of GCs can induce muscle atrophy and insulin resistance. GCs convey their signal mainly through the intracellular glucocorticoid receptor (GR). While GR can act through different mechanisms, one of its major actions is to regulate the transcription of its primary target genes through genomic glucocorticoid response elements (GREs) by directly binding to DNA or tethering onto other DNA-binding transcription factors. These GR primary targets trigger physiological and pathological responses of GCs. Much progress has been made to understand how GCs regulate protein and glucose metabolism. In this review, we will discuss how GR primary target genes confer metabolic functions of GCs, and the mechanisms governing the transcriptional regulation of these targets. Comprehending these processes not only contributes to the fundamental understanding of mammalian physiology, but also will provide invaluable insight for improved GC therapeutics.

Two systems were studied using either a pump-probe spectroscopic technique or a density functional theory computational method. Ultrafast time-resolved infrared spectroscopy has been used to investigate the reactivity of V(CO)5, a doublet species, with silicon-hydrogen and carbon-hydrogen bonds. Using a ultraviolet pump pulse, a carbonyl was dissociated from V(CO)6 while dissolved in triethylsilane; subsequently, a broad bandwidth infrared pulse interrogated the system. On timescales less than 1 ns, vanadium pentacarbonyl does not appear to react. The second study used the Growing String Method incorporating density functional theory to examine the possible reaction mechanisms for the fluxional rearrangement of Fe3(CO)12 and Ru3(CO)12. Fluxional mechanisms have structurally identical reactants and products; the atoms swap positions with other atoms of the same element. The concerted bridge-opening, bridge-closing mechanism for the Fe3(CO)12 was calculated to have the lowest barrier of those tested at 0.777 kcal/mol; in this mechanism, all twelve carbonyl change position and the final structure is equivalent to the initial structure. At 4.285 kcal/mol, the next lowest energy barrier was calculated for the Cotton's Merry-Go-Round mechanism.

Femtosecond, angle resolved two photon photoemission spectroscopy is used as a probe of the metal-molecule interface. In four related investigations, monolayer or submonolayer coverages of a molecule are adsorbed onto an Ag(111) surface under ultrahigh vacuum conditions. Studies use a an optically excited electronic probe to investigate to probe the energetic landscape experienced and the response of a molecular adsorbate to an excess charge. Energy levels, electronic population, and band structure reveal molecular structure and mechanisms of dynamic response to an injected charge.Room temperature ionic liquids (RTIL), consisting of charge separated anions and cations, represent a new and poorly understood class of electrochemical solvents. The mechanism of electron solvation has been proposed to be vastly different at the electrode interface than has been observed in bulk studies. Optical excitation into the RTIL conduction band results in a localized excess charge, as measured by band dispersions. Electron solvation is measured directly as the photoemitted kinetic energy. Solvation by 200-540 meV is found to occur rapidly on the timescale of 350 fs, supporting previous predictions of fast charge solvation at the interface. Further, a previously proposed phase transition is observed between a low temperature ordered phase and high temperature disordered phase. This phase transition, which occurs at 250 K, is quantified by both the change in workfunction and a change in the energy of solvation between the two phases.The image state is often used as a sensitive probe of molecular films, however, the electronic potential experienced by the image state electron is poorly understood. Theoretical predictions of image state energy in molecular films with a positive electron affinity are often wrong by 1-3 eV, and descriptions of the band structure typically remain limited to a measurement of effective mass. An image state is investigated within a film of metallated phthal

Vibrational spectroscopy is one of the most powerful techniques in chemistry due to its ability to report direct information on the geometries and nuclear motions of complex molecules. At thermal equilibrium, rearrangements between different, or equivalent, molecular structures help to define the reactivity of the system. On the ultrafast timescale, these chemical exchange reactions may cause features in the vibrational spectrum to become averaged. The Bloch equations have been used previously to quantitatively predict the rates of such reactions. This approach has been quite successful in NMR spectroscopy where exchange on the microsecond timescale is often sufficient to cause peak coalescence. The application of the Bloch equations to IR spectroscopy has been debated due to the presence of other contributions to the vibrational lineshape that may prevent an accurate description of the relevant dynamics. Two dimensional infrared spectroscopy (2D-IR) is a time resolved ultrafast technique that is capable of directly measuring the kinetics of chemical exchange at thermal equilibrium where there is no net change in the populations of reactants and products. This work examines two model systems that display dynamic IR peak coalescence. A group of mixed valence dimers of trinuclear ruthenium clusters have exhibited a wide range of IR coalescence that is sensitive to solvent, temperature, and ligand substitution. No electron exchange was observed by 2D-IR during the timescale required for peak coalescence. The two isomers of a square pyramidal ruthenium dithiolene compound also result in highly coalesced spectra. The equilibrium populations, as well as the extent of peak coalescence, are strongly dependent on temperature and solvent. The experimental results of this second project were largely inconconclusive; however, future work with density functional theory calculations looks promising for revealing more information on these dynamics. Ultimately, the application of t

Glucocorticoids are steroid hormones that play critical and complex roles in the regulation of triglyceride (TG) homeostasis. Depending on physiological states, glucocorticoids can modulate both TG synthesis and hydrolysis. More intriguingly, glucocorticoids can concurrently affect these two processes in adipocytes. The metabolic effects of glucocorticoids are conferred by intracellular glucocorticoid receptors (GR). GR is a transcription factor that, upon binding to glucocorticoids, regulates the transcriptional rate of specific genes. These GR primary target genes further initiate the physiological and pathological responses of glucocorticoids. In this article, we overview glucocorticoid-regulated genes, especially those potential GR primary target genes, involved in glucocorticoid-regulated TG metabolism. We also discuss transcriptional regulators that could act with GR to participate in these processes. This knowledge is not only important for the fundamental understanding of steroid hormone actions, but also are essential for future therapeutic interventions against metabolic diseases associated with aberrant glucocorticoid signaling, such as insulin resistance, dyslipidemia, central obesity and hepatic steatosis.

Presented at the 22nd Systems and Software Technology Conference (SSTC), 26-29 April 2010, Salt Lake City, UT. Sponsored in part by the USAF. U.S. Government or Federal Rights License

Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.

Ultrafast angle-resolved two photon photoemission was used to study the dynamics and interfacial band structure of ultrathin films adsorbed onto Ag(111). Studies focused on the image potential state (IPS) in each system as a probe for measuring changes in electronic behavior in differing environments. The energetics and dynamics of the IPS at the toluene/Ag(111) interface are strongly dependent upon coverage. For a single monolayer, the first IPS is bound by 0.81 eV below the vacuum level and has a lifetime of 50 femtoseconds (fs). Further adsorption of toluene creates islands of toluene with an exposed wetting layer underneath. The IPS is then split into two peaks, one corresponding to the islands and one corresponding to the monolayer. The wetting layer IPS shows the same dynamics as the monolayer, while the lifetime of the islands increases exponentially with increasing thickness. Furthermore, the island IPS transitions from delocalized to localized within 500 fs, and electrons with larger parallel momenta decay much faster. Attempts were made using a stochastic model to extract the rates of localization and intraband cooling at differing momenta. In sexithiophene (6T) and dihexyl-sexithiophene (DH6T), the IPS was used as a probe to see if the nuclear motion of spectating side chains can interfere with molecular conduction. The energy and band mass of the IPS was measured for 6T and two geometries of DH6T on Ag(111). Electrons injected into the thicker coverages of DH6T grew exponentially heavier until they were completely localized by 230 fs, while those injected into 6T remained nearly free electron like. Based off of lifetime arguments and the density of defects, the most likely cause for the mass enhancement of the IPS in this system is small polaron formation caused by coupling of the electron to vibrations of the alkyl substituents. The energetic relaxation of the molecular adsorbate was also measured to be 20 meV/100 fs for the DH6T, and 0 meV/100 fs for t

Hepatitis C virus (HCV) infection is closely tied to the lipid metabolism of liver cells. Here we identify the triglyceride-synthesizing enzyme diacylglycerol acyltransferase-1 (DGAT1) as a key host factor for HCV infection. DGAT1 interacts with the viral nucleocapsid core and is required for the trafficking of core to lipid droplets. Inhibition of DGAT1 activity or RNAi-mediated knockdown of DGAT1 severely impairs infectious virion production, implicating DGAT1 as a new target for antiviral therapy.

Transportation is the key to this nation's strength. Within this industry, the movement of freight is critical-an aspect made even more significant in a global economy. Effective management of freight movement requires a robust infrastructure and the implementation of an integrated, intermodal approach to transportation. The government must address the immediate needs of upgrading and expanding the infrastructure associated with all modes of transportation from both a requirements and financial perspective. Effectively addressing freight movement also requires the Department of Transportation to develop a strategy to implement an intermodal vision to overseeing the transportation industry.

Ducted fan VTOL UAVs are currently being designed for use by the Army for surveillance and reconnaissance in the battlefield. The vehicle tested in this research is part of the Honeywell MAV program. Able to be carried in a backpack by a single soldier, it has a duct diameter of 11.5-in. and weighs approximately 20-lbs at takeoff. It is designed for flight up to 50-knots with fan speeds varying between 5000 and 8500 RPM. Reynolds numbers, based on the duct diameter, were on the order of Re = 0.96 x 106 to 4.6 x 106. Various control effectors were mounted to the vehicle and tested for maximum control authority to reduce the nose-up pitch moment created during forward flight or with crosswinds present. Static and wind tunnel tests were conducted to measure each control effector's performance. Box vanes, mounted downstream of the duct, utilized four assemblies, each with three vanes and one flap. This configuration showed adequate results in generating a nose-down pitch moment. Duct deflectors, mounted on the windward strut upstream of the duct, reduced the windward lift produced by both the fan and duct, resulting in a nose-down pitch moment. Opposed vanes, utilizing two vanes and flaps for each of the four assemblies, were designed with the same surface area as the box vanes. With each pair capable of independent vane movement, the opposed vanes were tested with the vanes rotating in tandem for a basic elevator deflection and with the leading edges touching, disrupting the flow at the duct exit. Opposed vanes combined the capabilities of the box vanes and duct deflector. Results show that the opposed vanes were the most practical control effector, offering the most control authority for maximum nose-down pitch moment (up to 80% better) with minimal loss in thrust.

This paper presents a summary and analysis of data gathered from thirteen domain engineering projects, participant surveys, and demographic information. Taking a failure modes approach, project data is compared to an ideal model of the DARE methodology, revealing valuable insights into points of failure in the domain engineering process. This study suggests that success is a function of the domain analyst’s command of a specific set of domain engineering concepts and skills, the time invested in the process, and persistence in difficult areas. We conclude by presenting strategies to avoid points of failure in future domain engineering projects.

The ligand rearrangement reaction of Cr(CO)6 is studied in a series of alcohol solutions using ultafast, infrared spectroscopy and Brownian dynamics simulations.

The photochemistry of the trimetal cluster,Ru(3)(CO)12, was investigated on the ultrafast timescale using UV-vis pump, infrared probe spectroscopy in order to study the transient intermediates formed upon photoexcitation.

Odd electron species are important intermediates in organometallic chemistry.

The thickness-dependent interfacial band structure was determined for thin films of Co(6) on Ag(111) by angle-resolved two-photon photoemission spectroscopy.

In high latitudes, recent research has demonstrated that both thermo-erosion and temperature dependence influence sediment release into fluvial systems. An analysis of proglacial suspended sediment concentration (SSC) dynamics is presented for three glacierized basins: cold-based Austre Brøggerbreen (Svalbard), polythermal Midre Lovénbreen (Svalbard) and polythermal Glacier B28 (Bylot Island). The temporal variation in processes dominating SSC patterns is assessed using stepwise multivariate regression following the subdivision of the time series. Partitioning of the time series is achieved through principal components and change point analyses. The regression models use discharge and surrogate predictor variables to model SSC, while improvements are made by using air temperature and radiation terms as independent variables. Comparisons are drawn between two sets of models with contrasting subseasonal division. By interpretation of the regression model characteristics, temporal changes in physical processes are implied over the course of the time periods. Numerical analyses suggest there is a trend for changes between fluvial, glacial and periglacial factors forcing responses in SSC. Therefore, it is conjectured that glaciofluvial sediment transfer at high latitudes is influenced by periglacial processes and conditions. This has implications for the predictions of fluvial sediment loads in a changing environment, and the use of sedimentary records for environmental reconstruction.

Massachusetts Institute of Technology. Dept. of Chemistry. Thesis. 1966. Ph.D., Includes bibliographies., Ph.D.

Due to the destructive nature of flutter, flutter testing is a mandatory requirement for certification of both civilian and military aircraft. However, along with the complexity of newer aircraft, the time and cost associated with flutter testing has increased dramatically. Considering that many of the test techniques and analysis methods used to perform flutter testing date back to the 1950s and 1960's it may be time to take a fresh look at how flutter testing can best be accomplished. This thesis revisits flutter testing techniques and proposes an alternative to traditional flutter testing. The alternative uses flight test data from an aircraft that is performing an acceleration to clear the flutter envelope of the aircraft. Four academic issues arise from this new test approach. 1) Are frequencies and damping affected by the acceleration of the aircraft? 2) Can parameter identification algorithms extract frequency and damping values from the time varying data? 3) Can the vibration response at airspeeds (or Mach numbers) beyond which the aircraft has accelerated be anticipated? 4) What formal criteria can be used to determine when the aircraft needs to end the acceleration and terminate the test point? The academic contribution of this thesis is to address these issues. It is shown that although the frequencies and damping values do change the change is so small that it is irrelevant. It is also shown that by taking small windows of data, within which the change in parameters is small, it is possible to accurately identify parameters from the time varying data. Finally it is shown that at least in principal parameters can be predicted using data from sub-critical airspeeds, and that testing can be discontinued before an unstable flight condition is reached.

Analysis methodologies for predicting fatigue-crack growth from rivet holes in panels subjected to cyclic loads and for predicting the residual strength of aluminum fuselage structures with cracks and subjected to combined internal pressure and mechanical loads are described. The fatigue-crack growth analysis methodology is based on small-crack theory and a plasticity induced crack-closure model, and the effect of a corrosive environment on crack-growth rate is included. The residual strength analysis methodology is based on the critical crack-tip-opening-angle fracture criterion that characterizes the fracture behavior of a material of interest, and a geometric and material nonlinear finite element shell analysis code that performs the structural analysis of the fuselage structure of interest., The original document contains color images. Presented at the RTO Applied Vehicle Technology Panel (AVT) Specialists' Meeting, 8-11 Oct 2001, Manchester, United Kingdom, p(SM)27-1-(SM)27-16. This article is from ADA415672 Ageing Mechanisms and Control. Specialists' Meeting on Life Management Techniques for Ageing Air Vehicles (Les mecanismes vieillissants et le controle) (Reunions des specialistes des techniques de gestion du cycle de vie pour vehicules aeriens vieillissants)

In epithelial ovarian cancer, tumor grade is an independent prognosticator whose molecular determinants remain unknown. We investigated patterns of gene expression in well- and poorly differentiated serous papillary ovarian and peritoneal carcinomas with cDNA microarrays. A 6500-feature cDNA microarray was used for comparison of the molecular profiles of eight grade III and four grade I stage III serous papillary adenocarcinomas. With a modified F-test in conjunction with random permutations, 99 genes whose expression was significantly different between grade I and grade III tumors were identified (P < 0.01). A disproportionate number of these differentially expressed genes were located on the chromosomal regions 20q13 and all exhibited higher expression in grade III tumors. Interphase fluorescent in situ hybridization demonstrated 20q13 amplification in two of the four grade III and none of the three grade I tumors available for evaluation. Several centrosome-related genes also showed higher expression in grade III tumors. We propose a model in which tumor differentiation is inversely correlated with the overexpression of several oncogenes located on 20q13, a common amplicon in ovarian and numerous other cancers. Dysregulation of centrosome function is one potential mechanistic link between genetic/epigenetic changes and the poorly differentiated phenotype in ovarian cancer., Journal Article, info:eu-repo/semantics/published

The purpose of the Conference was to bring together world leaders in aviation safety research, aircraft design and manufacturing, fleet operation and aviation maintenance to disseminate information on current practices and advanced technologies that will assure the continued airworthiness of the aging aircraft in the military and commercial fleets. The Conference included reviews of current industry practices, assessments of future technology requirements, and status of aviation safety research. The Conference provided an opportunity for interactions among the key personnel in the research and technology development community, the original equipment manufacturers, commercial airline operators, military fleet operators, aviation maintenance, and aircraft certification and regulatory authorities. Conference participation was unrestricted and open to the international aviation community. Appendix B contains the name and addresses of the 623 participants in the Conference.

Idaho Dept. of Fish and Game, Div. of Wildlife report W-176-R-4. Period covered: July 1,1997-June 30,1998. Nongame Data Collection and Coordination.