De novo design of bioactive protein switches.

Allosteric regulation of protein function is widespread in biology, but is challenging for de novo protein design as it requires the explicit design of multiple states with comparable free energies. Here we explore the possibility of designing switchable protein systems de novo, through the modulation of competing inter- and intramolecular interactions. We design a static, five-helix 'cage' with a single interface that can interact either intramolecularly with a terminal 'latch' helix or intermolecularly with a peptide 'key'. Encoded on the latch are functional motifs for binding, degradation or nuclear export that function only when the key displaces the latch from the cage. We describe orthogonal cage-key systems that function in vitro, in yeast and in mammalian cells with up to 40-fold activation of function by key. The ability to design switchable protein functions that are controlled by induced conformational change is a milestone for de novo protein design, and opens up new avenues for synthetic biology and cell engineering

G28.17+0.05: An unusual giant HI cloud in the inner Galaxy

New 21 cm HI observations have revealed a giant HI cloud in the Galactic plane that has unusual properties. It is quite well defined, about 150 pc in diameter at a distance of 5 kpc, and contains as much as 100,000 Solar Masses of atomic hydrogen. The outer parts of the cloud appear in HI emission above the HI background, while the central regions show HI self-absorption. Models which reproduce the observations have a core with a temperature <40 K and an outer envelope as much as an order of magnitude hotter. The cold core is elongated along the Galactic plane, whereas the overall outline of the cloud is approximately spherical. The warm and cold parts of the HI cloud have a similar, and relatively large, line width of approximately 7 km/s. The cloud core is a source of weak, anomalously-excited 1720 MHz OH emission, also with a relatively large line width, which delineates the region of HI self-absorption but is slightly blue-shifted in velocity. The intensity of the 1720 MHz OH emission is correlated with N(H) derived from models of the cold core. There is 12CO emission associated with the cloud core. Most of the cloud mass is in molecules, and the total mass is > 200,000 Solar Masses. In the cold core the HI mass fraction may be 10 percent. The cloud has only a few sites of current star formation. There may be about 100 more objects like this in the inner Galaxy; every line of sight through the Galactic plane within 50 degrees of the Galactic center probably intersects at least one. We suggest that G28.17+0.05 is a cloud being observed as it enters a spiral arm and that it is in the transition from the atomic to the molecular state.Comment: 35 pages, inludes 12 figure

Reducing in-stent restenosis therapeutic manipulation of miRNA in vascular remodeling and inflammation

Background: Drug-eluting stents reduce the incidence of in-stent restenosis, but they result in delayed arterial healing and are associated with a chronic inflammatory response and hypersensitivity reactions. Identifying novel interventions to enhance wound healing and reduce the inflammatory response may improve long-term clinical outcomes. Micro–ribonucleic acids (miRNAs) are noncoding small ribonucleic acids that play a prominent role in the initiation and resolution of inflammation after vascular injury.&lt;p&gt;&lt;/p&gt; Objectives: This study sought to identify miRNA regulation and function after implantation of bare-metal and drug-eluting stents.&lt;p&gt;&lt;/p&gt; Methods: Pig, mouse, and in vitro models were used to investigate the role of miRNA in in-stent restenosis.&lt;p&gt;&lt;/p&gt; Results: We documented a subset of inflammatory miRNAs activated after stenting in pigs, including the miR-21 stem loop miRNAs. Genetic ablation of the miR-21 stem loop attenuated neointimal formation in mice post-stenting. This occurred via enhanced levels of anti-inflammatory M2 macrophages coupled with an impaired sensitivity of smooth muscle cells to respond to vascular activation.&lt;p&gt;&lt;/p&gt; Conclusions: MiR-21 plays a prominent role in promoting vascular inflammation and remodeling after stent injury. MiRNA-mediated modulation of the inflammatory response post-stenting may have therapeutic potential to accelerate wound healing and enhance the clinical efficacy of stenting

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis

The evolution of quantitative sensitivity

This work was supported by the National Science Foundation Graduate Research Fellowship Programme grant no. DGE-1419118 to S.E.K., and NSF 2000759 from the Division of Research on Learning in Formal and Informal Settings (DRL) to S.T.P., the Austrian Science Fund (FWF project no. P33928_B) to F.R., the Alfred P. Sloan Foundation Fellowship grant no. 220020300 to J.F.C., National Institutes of Health grant no. R01 HD085996 to J.F.C. and S.T.P. and the James S. McDonnell Foundation.The ability to represent approximate quantities appears to be phylogenetically widespread, but the selective pressures and proximate mechanisms favouring this ability remain unknown. We analysed quantity discrimination data from 672 subjects across 33 bird and mammal species, using a novel Bayesian model that combined phylogenetic regression with a model of number psychophysics and random effect components. This allowed us to combine data from 49 studies and calculate the Weber fraction (a measure of quantity representation precision) for each species. We then examined which cognitive, socioecological and biological factors were related to variance in Weber fraction. We found contributions of phylogeny to quantity discrimination performance across taxa. Of the neural, socioecological and general cognitive factors we tested, cortical neuron density and domain-general cognition were the strongest predictors of Weber fraction, controlling for phylogeny. Our study is a new demonstration of evolutionary constraints on cognition, as well as of a relation between species-specific neuron density and a particular cognitive ability. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.Publisher PDFPeer reviewe

Evaluating Lossy Data Compression on Climate Simulation Data within a Large Ensemble

High-resolution Earth system model simulations generate enormous data volumes, and retaining the data from these simulations often strains institutional storage resources. Further, these exceedingly large storage requirements negatively impact science objectives, for example, by forcing reductions in data output frequency, simulation length, or ensemble size. To lessen data volumes from the Community Earth System Model (CESM), we advocate the use of lossy data compression techniques. While lossy data compression does not exactly preserve the original data (as lossless compression does), lossy techniques have an advantage in terms of smaller storage requirements. To preserve the integrity of the scientific simulation data, the effects of lossy data compression on the original data should, at a minimum, not be statistically distinguishable from the natural variability of the climate system, and previous preliminary work with data from CESM has shown this goal to be attainable. However, to ultimately convince climate scientists that it is acceptable to use lossy data compression, we provide climate scientists with access to publicly available climate data that have undergone lossy data compression. In particular, we report on the results of a lossy data compression experiment with output from the CESM Large Ensemble (CESM-LE) Community Project, in which we challenge climate scientists to examine features of the data relevant to their interests, and attempt to identify which of the ensemble members have been compressed and reconstructed. We find that while detecting distinguishing features is certainly possible, the compression effects noticeable in these features are often unimportant or disappear in post-processing analyses. In addition, we perform several analyses that directly compare the original data to the reconstructed data to investigate the preservation, or lack thereof, of specific features critical to climate science. Overall, we conclude that applying lossy data compression to climate simulation data is both advantageous in terms of data reduction and generally acceptable in terms of effects on scientific results

High pT hadron spectra at RHIC: an overview

Recent results on high transverse momentum (pT) hadron production in p+p, d+Au and Au+Au collisions at the Relativistic Heavy Ion Collider (RHIC) are reviewed. Comparison of the nuclear modification factors, $R_{dAu}(pT)$ and $R_{AA}(pT)$, demonstrates that the large suppression in central Au+Au collisions is due to strong final-state effects. Theoretical models which incorporate jet quenching via gluon Bremsstrahlung in the dense partonic medium that is expected in central Au+Au collisions at ultra-relativistic energies are shown to reproduce the shape and magnitude of the observed suppression over the range of collision energies so far studied at RHIC.Comment: 12 pages, 10 figures, Talk given at Hot Quarks 2004: Workshop for Young Scientists on the Physics of Ultrarelativistic Nucleus-Nucleus Collisions (HQ'04), Taos Valley, New Mexico, 18-24 Jul 2004, to be published in J. Phys.

Eliciting the child's voice in adverse event reporting in oncology trials: Cognitive interview findings from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events initiative: Reeve et al.

Adverse event (AE) reporting in oncology trials is required, but current practice does not directly integrate the child’s voice. The Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is being developed to assess symptomatic AEs via child/adolescent self-report or proxy-report. This qualitative study evaluates the child’s/adolescent’s understanding and ability to provide valid responses to the PRO-CTCAE to inform questionnaire refinements and confirm content validity

Testing gravitational-wave searches with numerical relativity waveforms: Results from the first Numerical INJection Analysis (NINJA) project

The Numerical INJection Analysis (NINJA) project is a collaborative effort between members of the numerical relativity and gravitational-wave data analysis communities. The purpose of NINJA is to study the sensitivity of existing gravitational-wave search algorithms using numerically generated waveforms and to foster closer collaboration between the numerical relativity and data analysis communities. We describe the results of the first NINJA analysis which focused on gravitational waveforms from binary black hole coalescence. Ten numerical relativity groups contributed numerical data which were used to generate a set of gravitational-wave signals. These signals were injected into a simulated data set, designed to mimic the response of the Initial LIGO and Virgo gravitational-wave detectors. Nine groups analysed this data using search and parameter-estimation pipelines. Matched filter algorithms, un-modelled-burst searches and Bayesian parameter-estimation and model-selection algorithms were applied to the data. We report the efficiency of these search methods in detecting the numerical waveforms and measuring their parameters. We describe preliminary comparisons between the different search methods and suggest improvements for future NINJA analyses.Comment: 56 pages, 25 figures; various clarifications; accepted to CQ