Virtual screening for high affinity guests for synthetic supramolecular receptors

The protein/ligand docking software GOLD, which was originally developed for drug discovery, has been used in a virtual screen to identify small molecules that bind with extremely high affinities (K ≈ 107 M-1) in the cavity of a cubic coordination cage in water. A scoring function was developed using known guests as a training set and modified by introducing an additional term to take account of loss of guest flexibility on binding. This scoring function was then used in GOLD to successfully identify 15 new guests and accurately predict the binding constants. This approach provides a powerful predictive tool for virtual screening of large compound libraries to identify new guests for synthetic hosts, thereby greatly simplifying and accelerating the process of identifying guests by removing the reliance on experimental trial-and-error

Bod1, a novel kinetochore protein required for chromosome biorientation

We have combined the proteomic analysis of Xenopus laevis in vitro–assembled chromosomes with RNA interference and live cell imaging in HeLa cells to identify novel factors required for proper chromosome segregation. The first of these is Bod1, a protein conserved throughout metazoans that associates with a large macromolecular complex and localizes with kinetochores and spindle poles during mitosis. Small interfering RNA depletion of Bod1 in HeLa cells produces elongated mitotic spindles with severe biorientation defects. Bod1-depleted cells form syntelic attachments that can oscillate and generate enough force to separate sister kinetochores, suggesting that microtubule–kinetochore interactions were intact. Releasing Bod1-depleted cells from a monastrol block increases the frequency of syntelic attachments and the number of cells displaying biorientation defects. Bod1 depletion does not affect the activity or localization of Aurora B but does cause mislocalization of the microtubule depolymerase mitotic centromere- associated kinesin and prevents its efficient phosphorylation by Aurora B. Therefore, Bod1 is a novel kinetochore protein that is required for the detection or resolution of syntelic attachments in mitotic spindles

Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells.

Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Lévy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Lévy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets

Spitzer observations of the Massive star forming complex S254-S258: structure and evolution

We present Spitzer-IRAC, NOAO 2.1meter-Flamingos, Keck-NIRC, and FCRAO-SEQUOIA observations of the massive star forming complex S254-S258, covering an area of 25x20 arc-minutes. Using a combination of the IRAC and NIR data, we identify and classify the young stellar objects (YSO) in the complex. We detect 510 sources with near or mid IR-excess, and we classify 87 Class I, and 165 Class II sources. The YSO are found in clusters surrounded by isolated YSO in a low-density distributed population. The ratio of clustered to total YSO is 0.8. We identify six new clusters in the complex. One of them, G192.63-00, is located around the ionizing star of the HII region S255. We hypothesize that the ionizing star of S255 was formed in this cluster. We also detect a southern component of the cluster in HII region S256. The cluster G192.54-0.15, located inside HII region S254 has a VLSR of 17 km/s with respect to the main cloud, and we conclude that it is located in the background of the complex. The structure of the molecular cloud is examined using 12CO and 13CO, as well as a near-IR extinction map. The main body of the molecular cloud has VLSR between 5 and 9 km/s. The arc-shaped structure of the molecular cloud, following the border of the HII regions, and the high column density in the border of the HII regions support the idea that the material has been swept up by the expansion of the HII regions.Comment: Accepted for publication in The Astrophysical Journa

Direct observations of the kinetics of migrating T-cells suggest active retention by endothelial cells with continual bidirectional migration.

The kinetics and regulatory mechanisms of T-cell migration through endothelium have not been fully defined. In experimental filter-based assays in vitro, transmigration of lymphocytes takes hours, compared to minutes in vivo. We cultured endothelial cell (EC) monolayers on filters, solid substrates or collagen gels, and treated them with tumour necrosis factor-α (TNF), interferon-γ (IFN), or both, prior to analysis of lymphocyte migration in the presence or absence of flow. Peripheral blood lymphocytes (PBL), CD4+ cells or CD8+ cells, took many hours to migrate through EC-filter constructs for all cytokine treatments. However, direct microscopic observations of EC-filters which had been mounted in a flow chamber showed that PBL crossed the endothelial monolayer in minutes and were highly motile in the subendothelial space. Migration through EC was also observed on clear plastic, with or without flow. After brief settling without flow, PBL and isolated CD3+ or CD4+ cells all crossed EC in minutes, but the numbers of migrated cells varied little with time. Close observation revealed that lymphocytes continuously migrated back and forth across endothelium. Under flow, migration kinetics and the proportions migrating back and forth were little altered. On collagen gels, PBL again crossed EC in minutes and migrated back and forth, but showed little penetration of the gel over hours.In contrast, neutrophils migrated efficiently through EC and into gels. These observations suggest a novel model for lymphoid migration, in which endothelial cells support migration but retain lymphocytes (as opposed to neutrophils), and additional signal(s) are required for onward migration

Detection of Potential Transit Signals in Sixteen Quarters of Kepler Mission Data

We present the results of a search for potential transit signals in four years of photometry data acquired by the Kepler Mission. The targets of the search include 111,800 stars which were observed for the entire interval and 85,522 stars which were observed for a subset of the interval. We found that 9,743 targets contained at least one signal consistent with the signature of a transiting or eclipsing object, where the criteria for detection are periodicity of the detected transits, adequate signal-to-noise ratio, and acceptance by a number of tests which reject false positive detections. When targets that had produced a signal were searched repeatedly, an additional 6,542 signals were detected on 3,223 target stars, for a total of 16,285 potential detections. Comparison of the set of detected signals with a set of known and vetted transit events in the Kepler field of view shows that the recovery rate for these signals is 96.9%. The ensemble properties of the detected signals are reviewed.Comment: Accepted by ApJ Supplemen

Auditory sequence processing reveals evolutionarily conserved regions of frontal cortex in macaques and humans.

An evolutionary account of human language as a neurobiological system must distinguish between human-unique neurocognitive processes supporting language and evolutionarily conserved, domain-general processes that can be traced back to our primate ancestors. Neuroimaging studies across species may determine whether candidate neural processes are supported by homologous, functionally conserved brain areas or by different neurobiological substrates. Here we use functional magnetic resonance imaging in Rhesus macaques and humans to examine the brain regions involved in processing the ordering relationships between auditory nonsense words in rule-based sequences. We find that key regions in the human ventral frontal and opercular cortex have functional counterparts in the monkey brain. These regions are also known to be associated with initial stages of human syntactic processing. This study raises the possibility that certain ventral frontal neural systems, which play a significant role in language function in modern humans, originally evolved to support domain-general abilities involved in sequence processing

Religious Identity, Religious Attendance, and Parental Control

Using a national sample of adolescents aged 10–18 years and their parents (N = 5,117), this article examines whether parental religious identity and religious participation are associated with the ways in which parents control their children. We hypothesize that both religious orthodoxy and weekly religious attendance are related to heightened levels of three elements of parental control: monitoring activities, normative regulations, and network closure. Results indicate that an orthodox religious identity for Catholic and Protestant parents and higher levels of religious attendance for parents as a whole are associated with increases in monitoring activities and normative regulations of American adolescents

A super-Earth-sized planet orbiting in or near the habitable zone around Sun-like star

We present the discovery of a super-earth-sized planet in or near the habitable zone of a sun-like star. The host is Kepler-69, a 13.7 mag G4V-type star. We detect two periodic sets of transit signals in the three-year flux time series of Kepler-69, obtained with the Kepler spacecraft. Using the very high precision Kepler photometry, and follow-up observations, our confidence that these signals represent planetary transits is >99.1%. The inner planet, Kepler-69b, has a radius of 2.24+/-0.4 Rearth and orbits the host star every 13.7 days. The outer planet, Kepler-69c, is a super-Earth-size object with a radius of 1.7+/-0.3 Rearth and an orbital period of 242.5 days. Assuming an Earth-like Bond albedo, Kepler-69c has an equilibrium temperature of 299 +/- 19 K, which places the planet close to the habitable zone around the host star. This is the smallest planet found by Kepler to be orbiting in or near habitable zone of a Sun-like star and represents an important step on the path to finding the first true Earth analog.Comment: Accepted for publication in the Astrophysical Journa

Planetary Candidates Observed by Kepler V: Planet Sample from Q1-Q12 (36 Months)

The Kepler mission discovered 2842 exoplanet candidates with 2 years of data. We provide updates to the Kepler planet candidate sample based upon 3 years (Q1-Q12) of data. Through a series of tests to exclude false-positives, primarily caused by eclipsing binary stars and instrumental systematics, 855 additional planetary candidates have been discovered, bringing the total number known to 3697. We provide revised transit parameters and accompanying posterior distributions based on a Markov Chain Monte Carlo algorithm for the cumulative catalogue of Kepler Objects of Interest. There are now 130 candidates in the cumulative catalogue that receive less than twice the flux the Earth receives and more than 1100 have a radius less than 1.5 Rearth. There are now a dozen candidates meeting both criteria, roughly doubling the number of candidate Earth analogs. A majority of planetary candidates have a high probability of being bonafide planets, however, there are populations of likely false-positives. We discuss and suggest additional cuts that can be easily applied to the catalogue to produce a set of planetary candidates with good fidelity. The full catalogue is publicly available at the NASA Exoplanet Archive.Comment: Accepted for publication, ApJ