Connecting Subseasonal Movements of the Winter Mean Ridge in Western North America to Inversion Climatology in Cache Valley, Utah

A 10-yr record of PM2.5 (particulate matter of aerodynamic diameter ≤ 2.5 μm), collected in Cache Valley near downtown Logan, Utah, reveals a strong peak in the PM2.5 concentration climatology that is tightly localized in mid-January. The cause of this subseasonal variation in the PM2.5 climatology is investigated through dynamical downscaling and large-scale diagnostics. Climatological analysis of the U.S. winter mean ridge reveals a mid-January subseasonal shift in the zonal direction, likely in response to variations in the Rossby wave source over the central North Pacific Ocean. This displacement of the winter mean ridge, in turn, has an impact on regional-scale atmospheric conditions—specifically, subsidence with local leeside enhancements and midlevel warming over Cache Valley. The analyses of this study indicate that the subseasonal peak of long-term mean PM2.5 concentrations in Cache Valley is linked to the large-scale circulations’ subseasonal evolution, which involves remote forcing in the circumpolar circulations as well as possible tropical–midlatitude interactions. This subseasonal evolution of the winter mean circulation also affects precipitation along the West Coast

A Chemical Proteomics Approach to Phosphatidylinositol 3-Kinase Signaling in Macrophages

Prior work using lipid-based affinity matrices has been done to investigate distinct sets of lipid-binding proteins, and one series of experiments has proven successful in mammalian cells for the proteome-wide identification of lipid-binding proteins. However, most lipid-based proteomics screens require scaled up sample preparation, are often composed of multiple cell types, and are not adapted for simultaneous signal transduction studies. Herein we provide a chemical proteomics strategy that uses cleavable lipid "baits" with broad applicability to diverse biological samples. The novel baits were designed to avoid preparative steps to allow functional proteomics studies when the biological source is a limiting factor. Validation of the chemical baits was first confirmed by the selective isolation of several known endogenous phosphatidylinositol 3-kinase signaling proteins using primary bone marrow-derived macrophages. The use of this technique for cellular proteomics and MS/MS analysis was then demonstrated by the identification of known and potential novel lipid-binding proteins that was confirmed in vitro for several proteins by direct lipid-protein interactions. Further to the identification, the method is also compatible with subsequent signal transduction studies, notably for protein kinase profiling of the isolated lipid-bound protein complexes. Taken together, this integration of minimal scale proteomics, lipid chemistry, and activity-based readouts provides a significant advancement in the ability to identify and study the lipid proteome of single, relevant cell types

The breakthrough listen search for intelligent life: a wideband data recorder system for the Robert C. Byrd green bank telescope

The Breakthrough Listen Initiative is undertaking a comprehensive search for radio and optical signatures from extraterrestrial civilizations. An integral component of the project is the design and implementation of wide-bandwidth data recorder and signal processing systems. The capabilities of these systems, particularly at radio frequencies, directly determine survey speed; further, given a fixed observing time and spectral coverage, they determine sensitivity as well. Here, we detail the Breakthrough Listen wide-bandwidth data recording system deployed at the 100-m aperture Robert C. Byrd Green Bank Telescope. The system digitizes up to 6 GHz of bandwidth at 8 bits for both polarizations, storing the resultant 24 GB/s of data to disk. This system is among the highest data rate baseband recording systems in use in radio astronomy. A future system expansion will double recording capacity, to achieve a total Nyquist bandwidth of 12 GHz in two polarizations. In this paper, we present details of the system architecture, along with salient configuration and disk-write optimizations used to achieve high-throughput data capture on commodity compute servers and consumer-class hard disk drives

Modeling and forecasting riverine dissolved inorganic nitrogen export using anthropogenic nitrogen inputs, hydroclimate, and land-use change

A quantitative understanding of riverine nitrogen (N) export in response to human activities and climate change is critical for developing effective watershed N pollution control measures. This study quantified net anthropogenic N inputs (NANI) and riverine dissolved inorganic N (DIN=NO3-N+NH4-N+NO2-N) export for the upper Jiaojiang River catchment in eastern China over the 1980-2010 time period and examined how NANI, hydroclimate, and land-use practices influenced riverine DIN export. Over the 31-yr study period, riverine DIN yield increased by 1.6-fold, which mainly results from a ~77% increase in NANI and increasing fractional delivery of NANI due to a ~55% increase in developed land area. An empirical model that utilizes an exponential function of NANI and a power function of combining annual water discharge and developed land area percentage could account for 89% of the variation in annual riverine DIN yields in 1980-2010. Applying this model, annual NANI, catchment storage, and natural background sources were estimated to contribute 57%, 22%, and 21%, respectively, of annual riverine DIN exports on average. Forecasting based on a likely future climate change scenario predicted a 19.6% increase in riverine DIN yield by 2030 due to a 4% increase in annual discharge with no changes in NANI and land-use compared to the 2000-2010 baseline condition. Anthropogenic activities have increased both the N inputs available for export and the fractional export of N inputs, while climate change can further enhance riverine N export. An integrated N management strategy that considers the influence of anthropogenic N inputs, land-use and climate change is required to effectively control N inputs to coastal areas

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

PhD

dissertationThe PI3K/Akt signaling pathway is critical for normal growth and development of a cell. The activation of Akt, while playing an important role in cell survival, has also been linked to cancer and diabetes. A specific Akt inhibitor is predicted to be of immense value in cancer treatment. Akt activation requires recruitment to the plasma membrane through interaction of its N-terminal pleckstrin homology (PH) domain with the phosphoinositide products of phosphatidylinositol-3-kinase (PI3K); phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) and (PI(3,4,5)P). Two synthe tic peptide libraries were screened for binding to the Akt PH domain using competitive displacement of PI(3,4)P2. One library consisted of random octamers and the second library was biased with alternate racemic glutamate or aspartate amino acids. Twenty-seven sequences were obtained and analyzed for Akt PH binding and the three sequences with highest affinity were chosen for further study. Each peptide demonstrated low micromolar in vitr