Improving Surface Mass Balance Over Ice Sheets and Snow Depth on Sea Ice

Surface mass balance (SMB) over ice sheets and snow on sea ice (SOSI) are important components of the cryosphere. Large knowledge gaps remain in scientists' abilities to monitor SMB and SOSI, including insufficient measurements and difficulties with satellite retrievals. On ice sheets, snow accumulation is the sole mass gain to SMB, and meltwater runoff can be the dominant single loss factor in extremely warm years such as 2012. SOSI affects the growth and melt cycle of the Earth's polar sea ice cover. The summer of 2012 saw the largest satellite-recorded melt area over the Greenland ice sheet and the smallest satellite-recorded Arctic sea ice extent, making this meeting both timely and relevant

Pleiades or Not? Resolving the Status of the Lithium-rich M Dwarfs HHJ 339 and HHJ 430

Oppenheimer et al. discovered two M5 dwarfs in the Pleiades with nearly primordial lithium. These stars are not low enough in mass to represent the leading edge of the lithium depletion boundary at Pleiades age (~125 Myr). A possible explanation for the enhanced lithium in these stars is that they are actually not members of the Pleiades but instead are members of a younger moving group seen in projection toward the Pleiades. We have used data from Gaia DR2 to confirm that these two stars, HHJ 339 and HHJ 430, are indeed not members of the Pleiades. Based on their space motions, parallaxes, and positions in a Gaia-based color–magnitude diagram, it is probable that these two stars are about 40 parsecs foreground to the Pleiades and have ages of ~25 Myr. Kinematically they are best matched to the 32 Ori moving group

Revisiting K2-233 spectroscopic time-series with multidimensional Gaussian Processes

Detecting planetary signatures in radial velocity time-series of young stars is challenging due to their inherently strong stellar activity. However, it is possible to learn information about the properties of the stellar signal by using activity indicators measured from the same stellar spectra used to extract radial velocities. In this manuscript, we present a reanalysis of spectroscopic HARPS data of the young star K2-233, which hosts three transiting planets. We perform a multidimensional Gaussian Process regression on the radial velocity and the activity indicators to characterise the planetary Doppler signals. We demonstrate, for the first time on a real dataset, that the use of a multidimensional Gaussian Process can boost the precision with which we measure the planetary signals compared to a one-dimensional Gaussian Process applied to the radial velocities alone. We measure the semi-amplitudes of K2-233 b, c, and d as 1.31(-0.74)(+0.81), 1.81(-0.67)(+0.71), and 2.72(-0.70)(+0.66) m/s, which translates into planetary masses of 2.4(-1.3)(+1.5), 4.6(-1.7)(+1.8), and 10.3(-2.6)(+2.4), respectively. These new mass measurements make K2-233 d a valuable target for transmission spectroscopy observations with JWST. K2-233 is the only young system with two detected inner planets below the radius valley and a third outer planet above it. This makes it an excellent target to perform comparative studies, to inform our theories of planet evolution, formation, migration, and atmospheric evolution.Comment: Accepted for publication in MNRA

Glacier dynamics at Helheim and Kangerdlugssuaq glaciers, southeast Greenland, since the Little Ice Age

Observations over the past decade show significant ice loss associated with the speed-up of glaciers in southeast Greenland from 2003, followed by a deceleration from 2006. These short-term, episodic, dynamic perturbations have a major impact on the mass balance on the decadal scale. To improve the projection of future sea level rise, a long-term data record that reveals the mass balance beyond such episodic events is required. Here, we extend the observational record of marginal thinning of Helheim and Kangerdlugssuaq glaciers from 10 to more than 80 years. We show that, although the frontal portion of Helheim Glacier thinned by more than 100m between 2003 and 2006, it thickened by more than 50m during the previous two decades. In contrast, Kangerdlugssuaq Glacier underwent minor thinning of 40-50m from 1981 to 1998 and major thinning of more than 100m after 2003. Extending the record back to the end of the Little Ice Age (prior to 1930) shows no thinning of Helheim Glacier from its maximum extent during the Little Ice Age to 1981, while Kangerdlugssuaq Glacier underwent substantial thinning of 230 to 265 m. Comparison of sub-surface water temperature anomalies and variations in air temperature to records of thickness and velocity change suggest that both glaciers are highly sensitive to short-term atmospheric and ocean forcing, and respond very quickly to small fluctuations. On century timescales, however, multiple external parameters (e. g. outlet glacier shape) may dominate the mass change. These findings suggest that special care must be taken in the projection of future dynamic ice loss

Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.

PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. Mol Cancer Ther; 15(6); 1412-24. ©2016 AACR.The Institute of Cancer ResearchThis is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/1535-7163.MCT-15-081

It Takes Two

Theories of conflict emphasize dyadic interaction, yet existing empirical studies of civil war focus largely on state attributes and pay little attention to nonstate antagonists. We recast civil war in a dyadic perspective, and consider how nonstate actor attributes and their relationship to the state influence conflict dynamics. We argue that strong rebels, who pose a military challenge to the government, are likely to lead to short wars and concessions. Conflicts where rebels seem weak can become prolonged if rebels can operate in the periphery so as to defy a government victory yet are not strong enough to extract concessions. Conflicts should be shorter when potential insurgents can rely on alternative political means to violence. We examine these hypotheses in a dyadic analysis of civil war duration and outcomes, using new data on nonstate actors and conflict attributes, finding support for many of our conjectures. </jats:p

One-year delayed effect of fog on malaria transmission: a time-series analysis in the rain forest area of Mengla County, south-west China

Background: Malaria is a major public health burden in the tropics with the potential to significantly increase in response to climate change. Analyses of data from the recent past can elucidate how short-term variations in weather factors affect malaria transmission. This study explored the impact of climate variability on the transmission of malaria in the tropical rain forest area of Mengla County, south-west China. Methods: Ecological time-series analysis was performed on data collected between 1971 and 1999. Auto-regressive integrated moving average (ARIMA) models were used to evaluate the relationship between weather factors and malaria incidence. Results: At the time scale of months, the predictors for malaria incidence included: minimum temperature, maximum temperature, and fog day frequency. The effect of minimum temperature on malaria incidence was greater in the cool months than in the hot months. The fog day frequency in October had a positive effect on malaria incidence in May of the following year. At the time scale of years, the annual fog day frequency was the only weather predictor of the annual incidence of malaria. Conclusion: Fog day frequency was for the first time found to be a predictor of malaria incidence in a rain forest area. The one-year delayed effect of fog on malaria transmission may involve providing water input and maintaining aquatic breeding sites for mosquitoes in vulnerable times when there is little rainfall in the 6-month dry seasons. These findings should be considered in the prediction of future patterns of malaria for similar tropical rain forest areas worldwide

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice