High-throughput profiling of sequence recognition by phosphotyrosine signaling proteins

Protein tyrosine kinase and phosphatase domains have binding specificities that depend on the amino acid sequence surrounding the target (phospho)tyrosine residue on their substrates. Although the preferred recognition motifs of many kinase and phosphatase domains have been characterized, we lack a quantitative description of sequence specificity that could guide predictions about signaling pathways or be used to design sequences for biomedical applications. Here, we present a platform that combines genetically-encoded peptide libraries and deep sequencing to profile sequence recognition by tyrosine kinases. We screened several tyrosine kinases against a million-peptide random library and used the resulting profiles to design high-activity sequences and predict phosphorylation efficiencies of substrates. We then screened several kinases against a library containing thousands of human proteome-derived peptides and their naturally-occurring variants. These screens recapitulated independently measured phosphorylation rates and revealed hundreds of phosphosite-proximal mutations that impact phosphosite recognition by tyrosine kinases. Finally, we have made progress towards extending this platform to the analysis of tyrosine phosphatase domains, by optimizing methods to produce tyrosine-phosphorylated bacterial display libraries and implementing methods to detect peptide dephosphorylation on the cell surface. Collectively, these experiments demonstrate the utility of our platform for rapid profiling of sequence specificity by tyrosine kinases and will shed new light on phosphotyrosine signaling

Feasibility Study of Electric Bicycle Sharing in the Xiasha District of Hangzhou, China

Traffic and pollution are persistently growing problems in Hangzhou, one of the oldest and most modern cities in China. To offset this, Hangzhou Omnipay Co., Ltd. sponsored this project to determine if an electric bike sharing system would be feasible in the Xiasha District of Hangzhou. If the system proves effective, Omnipay can implement it in the rest of the city. Electric bikes produce no direct emissions and occupy less road space than automobiles, circumventing the common issues of cars. This project used various onsite research techniques including a survey, focus group, and interviews to discern if there is adequate demand for this system and what its environmental influence may be. This report concludes that an electric bike sharing system would be feasible

Disk Heating, Galactoseismology, and the Formation of Stellar Halos

Deep photometric surveys of the Milky Way have revealed diffuse structures encircling our Galaxy far beyond the "classical" limits of the stellar disk. This paper reviews results from our own and other observational programs, which together suggest that, despite their extreme positions, the stars in these structures were formed in our Galactic disk. Mounting evidence from recent observations and simulations implies kinematic connections between several of these distinct structures. This suggests the existence of collective disk oscillations that can plausibly be traced all the way to asymmetries seen in the stellar velocity distribution around the Sun. There are multiple interesting implications of these findings: they promise new perspectives on the process of disk heating, they provide direct evidence for a stellar halo formation mechanism in addition to the accretion and disruption of satellite galaxies, and, they motivate searches of current and near-future surveys to trace these oscillations across the Galaxy. Such maps could be used as dynamical diagnostics in the emerging field of "Galactoseismology", which promises to model the history of interactions between the Milky Way and its entourage of satellites, as well examine the density of our dark matter halo. As sensitivity to very low surface brightness features around external galaxies increases, many more examples of such disk oscillations will likely be identified. Statistical samples of such features not only encode detailed information about interaction rates and mergers, but also about long sought-after dark matter halo densities and shapes. Models for the Milky Way's own Galactoseismic history will therefore serve as a critical foundation for studying the weak dynamical interactions of galaxies across the universe.Comment: 20 pages, 5 figures, accepted in for publication in a special edition of the journal "Galaxies", reporting the proceedings of the conference "On the Origin (and Evolution) of Baryonic Galaxy Halos", Puerto Ayora, Ecuador, March 13-17 2017, Eds. Duncan A. Forbes and Ericson D. Lope

Exploring Halo Substructure with Giant Stars. XV. Discovery of a Connection between the Monoceros Ring and the Triangulum-Andromeda Overdensity?

Thanks to modern sky surveys, over twenty stellar streams and overdensity structures have been discovered in the halo of the Milky Way. In this paper, we present an analysis of spectroscopic observations of individual stars from one such structure, "A13", first identified as an overdensity using the M giant catalog from the Two Micron All-Sky Survey. Our spectroscopic observations show that stars identified with A13 have a velocity dispersion of $\lesssim$ 40 $\mathrm{km~s^{-1}}$, implying that it is a genuine coherent structure rather than a chance super-position of random halo stars. From its position on the sky, distance ($\sim$15~kpc heliocentric), and kinematical properties, A13 is likely to be an extension of another low Galactic latitude substructure -- the Galactic Anticenter Stellar Structure (also known as the Monoceros Ring) -- towards smaller Galactic longitude and farther distance. Furthermore, the kinematics of A13 also connect it with another structure in the southern Galactic hemisphere -- the Triangulum-Andromeda overdensity. We discuss these three connected structures within the context of a previously proposed scenario that one or all of these features originate from the disk of the Milky Way.Comment: 12 pages, 9 figures. Accepted for publication in Ap

Health Justice Strategies to Eradicate Lead Poisoning: An Urgent Call to Safeguard Future Generations

Despite over a century of evidence that lead is a neurotoxin that causes irreparable harm, today, lead continues to pervade children\u27s environments and remains a constant threat to health and wellbeing. One in three homes across the United States housing children under the age of six has significant lead-based paint hazards that place occupants at risk of permanent neurological harm and lifelong poor health risks. Federal, state, and local governments must use a range of primary prevention strategies in order to fully eradicate the risks and protect children from lead poisoning. This Article provides a comprehensive examination of best practices for addressing lead poisoning and proposes urgent reform measures at the local and state levels. Successful interventions ultimately prioritize health justice strategies and rely on community ownership and cross-sector participation; dedicate significant resources and funding to completely eliminate lead in the environment; and prioritize primary prevention practices that identify lead-based paint hazards before children are exposed

Duty to Protect: Enhancing the Federal Framework to Prevent Childhood Lead Poisoning and Exposure to Environmental Harm

Scientific evidence indisputably demonstrates that lead poisoning causes permanent neurological damage and numerous co-morbidities for children and adults. Exposure to lead hazards irreversibly harms individuals and, left unchecked, can devastate communities into the future. In recognition of these threats, the President\u27s Task Force on Environmental Health Risks and Safety Risks to Children (Task Force) was established by Executive Order in 1997. The original Task Force created the first coordinated federal response to eliminate childhood lead poisoning in the United States and set an ambitious ten-year timeline to achieve its goals of prevention, treatment, research, and progress management

Duty to Protect: Enhancing the Federal Framework to Prevent Childhood Lead Poisoning and Exposure to Environmental Harm

Scientific evidence indisputably demonstrates that lead poisoning causes permanent neurological damage and numerous co-morbidities for children and adults. Exposure to lead hazards irreversibly harms individuals and, left unchecked, can devastate communities into the future. In recognition of these threats, the President\u27s Task Force on Environmental Health Risks and Safety Risks to Children (Task Force) was established by Executive Order in 1997. The original Task Force created the first coordinated federal response to eliminate childhood lead poisoning in the United States and set an ambitious ten-year timeline to achieve its goals of prevention, treatment, research, and progress management. However, the most recent Task Force retreated from these bold goals. Rather than eliminating lead poisoning, in 2018 the Task Force sought merely to reduce it. This Article provides a comprehensive overview of the dangers of lead exposure, details the federal government\u27s evolving response to lead poisoning, and, for the first time, disseminates previously unpublished comments on Drafting a New Federal Strategy to Reduce Childhood Lead Exposures and Impacts, submitted to the Task Force in 2017, ahead of its most recent report. By providing these comments publicly, this Article creates a record of critical recommendations to the Task Force, provides best practices for the federal government\u27s response to lead poisoning, and encourages federal policymakers to take the necessary steps to meet the original goal of eradicating lead hazards and protecting children from lead poisoning

Evidence in support of the call to ban the tackle and harmful contact in school rugby: a response to World Rugby

In a paper published in BJSM (June 2016), World Rugby employees Ross Tucker and Martin Raftery and a third coauthor Evert Verhagen took issue with the recent call to ban tackling in school rugby in the UK and Ireland. That call (to ban tackling) was supported by a systematic review published in BJSM. Tucker et al claim that: (1) the mechanisms and risk factors for injury along with the incidence and severity of injury in youth rugby union have not been thoroughly identified or understood; (2) rugby players are at no greater risk of injury than other sports people, (3) this is particularly the case for children under 15 years and (4) removing the opportunity to learn the tackle from school pupils might increase rates of injuries. They conclude that a ban ‘may be unnecessary and may also lead to unintended consequences such as an increase in the risk of injury later in participation.’ Here we aim to rebut the case by Tucker et al. We share new research that extends the findings of our original systematic review and meta-analysis. A cautionary approach requires the removal of the tackle from school rugby as the quickest and most effective method of reducing high injury rates in youth rugby, a public health priority

Discovery and Validation of Kepler-452b: A 1.6-Re Super Earth Exoplanet in the Habitable Zone of a G2 Star

We report on the discovery and validation of Kepler-452b, a transiting planet identified by a search through the 4 years of data collected by NASA's Kepler Mission. This possibly rocky 1.63$^{+0.23}_{-0.20}$ R$_\oplus$ planet orbits its G2 host star every 384.843$^{+0.007}_{0.012}$ days, the longest orbital period for a small (R$_p$ < 2 R$_\oplus$) transiting exoplanet to date. The likelihood that this planet has a rocky composition lies between 49% and 62%. The star has an effective temperature of 5757$\pm$85 K and a log g of 4.32$\pm$0.09. At a mean orbital separation of 1.046$^{+0.019}_{-0.015}$ AU, this small planet is well within the optimistic habitable zone of its star (recent Venus/early Mars), experiencing only 10% more flux than Earth receives from the Sun today, and slightly outside the conservative habitable zone (runaway greenhouse/maximum greenhouse). The star is slightly larger and older than the Sun, with a present radius of 1.11$^{+0.15}_{-0.09}$ R$_\odot$ and an estimated age of 6 Gyr. Thus, Kepler-452b has likely always been in the habitable zone and should remain there for another 3 Gyr.Comment: 19 pages, 16 figure