Wolf Trap continuation study Final report

Critical evaluation of light and X ray scatter, conductivity, and fluorescence as part of Wolf Trap extraterrestrial life detector developmen

SIRT6 stabilizes DNA-dependent Protein Kinase at chromatin for DNA double-strand break repair

The Sir2 chromatin regulatory factor links maintenance of genomic stability to life span extension in yeast. The mammalian Sir2 family member SIRT6 has been proposed to have analogous functions, because SIRT6-deficiency leads to shortened life span and an aging-like degenerative phenotype in mice, and SIRT6 knockout cells exhibit genomic instability and DNA damage hypersensitivity. However, the molecular mechanisms underlying these defects are not fully understood. Here, we show that SIRT6 forms a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-PK (DNA-dependent protein kinase) and promotes DNA DSB repair. In response to DSBs, SIRT6 associates dynamically with chromatin and is necessary for an acute decrease in global cellular acetylation levels on histone H3 Lysine 9. Moreover, SIRT6 is required for mobilization of the DNA-PK catalytic subunit (DNA-PKcs) to chromatin in response to DNA damage and stabilizes DNA-PKcs at chromatin adjacent to an induced site-specific DSB. Abrogation of these SIRT6 activities leads to impaired resolution of DSBs. Together, these findings elucidate a mechanism whereby regulation of dynamic interaction of a DNA repair factor with chromatin impacts on the efficiency of repair, and establish a link between chromatin regulation, DNA repair, and a mammalian Sir2 factor

Lunar Outgassing, Transient Phenomena and The Return to The Moon, I: Existing Data

Herein the transient lunar phenomena (TLP) report database is subjected to a discriminating statistical filter robust against sites of spurious reports, and produces a restricted sample that may be largely reliable. This subset is highly correlated geographically with the catalog of outgassing events seen by the Apollo 15, 16 and Lunar Prospector alpha-particle spectrometers for episodic Rn-222 gas release. Both this robust TLP sample and even the larger, unfiltered sample are highly correlated with the boundary between mare and highlands, as are both deep and shallow moonquakes, as well as Po-210, a long-lived product of Rn-222 decay and a further tracer of outgassing. This offers another significant correlation relating TLPs and outgassing, and may tie some of this activity to sagging mare basalt plains (perhaps mascons). Additionally, low-level but likely significant TLP activity is connected to recent, major impact craters (while moonquakes are not), which may indicate the effects of cracks caused by the impacts, or perhaps avalanches, allowing release of gas. The majority of TLP (and Rn-222) activity, however, is confined to one site that produced much of the basalt in the Procellarum Terrane, and it seems plausible that this TLP activity may be tied to residual outgassing from the formerly largest volcanic ffusion sites from the deep lunar interior. With the coming in the next few years of robotic spacecraft followed by human exploration, the study of TLPs and outgassing is both promising and imperiled. We will have an unprecedented pportunity to study lunar outgassing, but will also deal with a greater burden of anthropogenic lunar gas than ever produced. There is a pressing need to study lunar atmosphere and its sources while still pristine. [Abstract abridged.]Comment: 35 pages, 3 figures, submitted to Icarus. Other papers in series found at http://www.astro.columbia.edu/~arlin/TLP

Nonlinear Dynamics and Interpersonal Correlates of Verbal Turn-Taking Patterns in a Group Therapy Session

Interpersonal processes and dynamics are ubiquitous topics in psychotherapy, yet they are difficult to study and are theoretically fragmented across therapeutic subdisciplines. The current study tests an integrative model of interpersonal dynamics in small groups using nonlinear dynamical systems theory. The conversation of one group therapy session (with six adolescent sex offenders) is analyzed using orbital decomposition, which allows for the identification of patterns in categorical time series data. The results show evidence of selforganizing social patterns, based on formal measures of turbulence (Lyapunov dimension), information novelty (Shannon\u27s entropy), and complexity (fractal dimension). The degree of patterning in turn taking is significantly correlated with measurements of control, closeness, and conflict among group members. Clinical implications and directions for future research are discussed

Plasmatic and urinary glycosaminoglycans characterization in mucopolysaccharidosis II Patient treated with enzyme-replacement therapy with Idursulfase

We report the structural characterization of plasmatic and urinary GAGs in a Patient affected by MPS II (Hunter syndrome) before and during the first ten months of enzyme-replacement therapy (ERT). Plasmatic GAGs before ERT were rich in pathological DS consisting of iduronic acid (IdoA) and composed of ~90% \uf044Di4s and trace amounts of disulfated disaccharides. DS was also characterized as the main (~90%) urinary GAG mainly composed of ~90% \uf044Di4s with minor percentages of monosulfated and disulfated disaccharides, in particular \u394Di2,4dis. After 300 days of ERT, plasmatic DS strongly decreased but ~14% of IdoA-rich \uf044Di4s was still detected. Similarly, urinary galactosaminoglycans were mainly composed of 78% \uf044Di4s, ~11% \uf044Di6s and ~4% \uf044Di0s with the persistence of \u394Di2,4dis (~4%). About 40% of IdoA-formed \uf044Di4s were also calculated thus confirming that pathological DS is still present in excreted urinary GAGs during ERT. By considering the % of IdoA, we observed rather similar kinetics of excretion in fluids from the beginning of the treatment. Immediately after the first enzyme infusion, a large amount of abnormal DS is removed from tissues reaching the blood compartment and eliminated via the urine, and this process lasts for about two weeks. After this, the percentage of IdoA-rich material present in biological fluids remains fairly constant over the following nine months of treatment. To date, these are the first data regarding plasmatic and urinary kinetics directly measured on products released by the activity of the recombinant enzyme Idursulfase, iduronate-2-sulfatase, evaluated using specific and sensitive analytical procedures

Human antibodies targeting cell surface antigens overexpressed by the hormone refractory metastatic prostate cancer cells: ICAM-1 is a tumor antigen that mediates prostate cancer cell invasion

Transition from hormone-sensitive to hormone-refractory metastatic tumor types poses a major challenge for prostate cancer treatment. Tumor antigens that are differentially expressed during this transition are likely to play important roles in imparting prostate cancer cells with the ability to grow in a hormone-deprived environment and to metastasize to distal sites such as the bone and thus, are likely targets for therapeutic intervention. To identify those molecules and particularly cell surface antigens that accompany this transition, we studied the changes in cell surface antigenic profiles between a hormone-sensitive prostate cancer line LNCaP and its hormone-refractory derivative C4-2B, using an antibody library-based affinity proteomic approach. We selected a naïve phage antibody display library to identify human single-chain antibodies that bind specifically to C4-2B but not LNCaP. Using mass spectrometry, we identified one of the antibody-targeted antigens as the ICAM-1/CD54/human rhinovirus receptor. Recombinant IgG1 derived from this single-chain antibody binds to a neutralizing epitope of ICAM-1 and blocks C4-2B cell invasion through extracellular matrix in vitro. ICAM-1 is thus differentially expressed during the transition of the hormone-sensitive prostate cancer cell line LNCaP to its hormone-refractory derivative C4-2B, plays an important role in imparting the C4-2B line with the ability to invade, and may therefore be a target for therapeutic intervention

Strategies Outside the Formal Classroom: Nonprofit Management Education in Transparency and Accountability

A demand for nonprofit management training and organizational capacity building exists in Latin America. However, few nonprofit management education (NME) programs in Latin America exist, and there is limited content related to ethics, transparency, and accountability. Using the case of Ecuador, we identify three strategies implemented by nonprofit leaders to cope with limited NME. We find that first, organizations engage in a process of collectivity that seeks to explore and give meaning to civil society in Ecuador. Second, this process leads to the production of knowledge about civil society in Ecuador. And third, based on both the process of collectivity and knowledge production, nonprofit leaders in Ecuador take ownership in the training of nonprofit leaders through several pilot courses related to transparency and accountability. The case of Ecuador reminds public affairs educators that organizations themselves can be successful producers of knowledge that can and should create and inform curricular content

Promiscuous Aggregate-Based Inhibitors Promote Enzyme Unfolding

One of the leading sources of false positives in early drug discovery is the formation of organic small molecule aggregates, which inhibit enzymes nonspecifically at micromolar concentrations in aqueous solution. The molecular basis for this widespread problem remains hazy. To investigate the mechanism of inhibition at a molecular level, we determined changes in solvent accessibility that occur when an enzyme binds to an aggregate using hydrogen-deuterium exchange mass spectrometry. For AmpC beta-lactamase, binding to aggregates of the small molecule rottlerin increased the deuterium exchange of all 10 reproducibly detectable peptides, which covered 41% of the sequence of beta-lactamase. This suggested a global increase in proton accessibility upon aggregate binding, consistent with denaturation. We then investigated whether enzyme-aggregate complexes were more susceptible to proteolysis than uninhibited enzyme. For five aggregators, trypsin degradation of beta-lactamase increased substantially when beta-lactamase was inhibited by aggregates, whereas uninhibited enzyme was generally stable to digestion. Combined, these results suggest that the mechanism of action of aggregate-based inhibitors proceeds via partial protein unfolding when bound to an aggregate particle

Orientation dependent molecular electrostatics drives efficient charge generation in homojunction organic solar cells

Organic solar cells usually utilise a heterojunction between electron-donating (D) and electron-accepting (A) materials to split excitons into charges. However, the use of D-A blends intrinsically limits the photovoltage and introduces morphological instability. Here, we demonstrate that polycrystalline films of chemically identical molecules offer a promising alternative and show that photoexcitation of α-sexithiophene (α-6T) films results in efficient charge generation. This leads to α-6T based homojunction organic solar cells with an external quantum efficiency reaching up to 44% and an open-circuit voltage of 1.61 V. Morphological, photoemission, and modelling studies show that boundaries between α-6T crystalline domains with different orientations generate an electrostatic landscape with an interfacial energy offset of 0.4 eV, which promotes the formation of hybridised exciton/charge-transfer states at the interface, dissociating efficiently into free charges. Our findings open new avenues for organic solar cell design where material energetics are tuned through molecular electrostatic engineering and mesoscale structural control