MONITORING AND UNDERSTANDING CHANGES IN EXTREMES Vose, Russell S.; Applequist, Scott; Bourassa, Mark A. ...
Bulletin of the American Meteorological Society,
03/2014, Volume:
95, Issue:
3
Journal Article
Peer reviewed
Open access
This scientific assessment examines changes in three climate extremes—extratropical storms, winds, and waves—with an emphasis on U.S. coastal regions during the cold season. There is moderate ...evidence of an increase in both extratropical storm frequency and intensity during the cold season in the Northern Hemisphere since 1950, with suggestive evidence of geographic shifts resulting in slight upward trends in offshore/coastal regions. There is also suggestive evidence of an increase in extreme winds (at least annually) over parts of the ocean since the early to mid-1980s, but the evidence over the U.S. land surface is inconclusive. Finally, there is moderate evidence of an increase in extreme waves in winter along the Pacific coast since the 1950s, but along other U.S. shorelines any tendencies are of modest magnitude compared with historical variability. The data for extratropical cyclones are considered to be of relatively high quality for trend detection, whereas the data for extreme winds and waves are judged to be of intermediate quality. In terms of physical causes leading to multidecadal changes, the level of understanding for both extratropical storms and extreme winds is considered to be relatively low, while that for extreme waves is judged to be intermediate. Since the ability to measure these changes with some confidence is relatively recent, understanding is expected to improve in the future for a variety of reasons, including increased periods of record and the development of “climate reanalysis” projects.
Approximately 30 % of breast cancer patients receive chemotherapy, yet little is known about influences of current regimens on circulating lymphocyte levels and phenotypes. Similarly, ...clinico-pathological factors that modify these influences, and implications for future immune health remain mainly unexplored.
We used flow-cytometry to assess circulating lymphocyte levels and phenotypes in 88 primary breast cancer patients before chemotherapy and at time-points from 2 weeks to 9 months after chemotherapy completion. We examined circulating titres of antibodies against pneumococcal and tetanus antigens using ELISAs.
Levels of B, T and NK cells were significantly reduced 2 weeks after chemotherapy (p < 0.001). B cells demonstrated particularly dramatic depletion, falling to 5.4 % of pre-chemotherapy levels. Levels of all cells recovered to some extent, although B and CD4(+) T cells remained significantly depleted even 9 months post-chemotherapy (p < 0.001). Phenotypes of repopulating B and CD4(+) T cells were significantly different from, and showed no sign of returning to pre-chemotherapy profiles. Repopulating B cells were highly depleted in memory cells, with proportions of memory cells falling from 38 % to 10 % (p < 0.001). Conversely, repopulating CD4(+) T cells were enriched in memory cells, which increased from 63 % to 75 % (p < 0.001). Differences in chemotherapy regimen and patient smoking were associated with significant differences in depletion extent or repopulation dynamics. Titres of anti-pneumococcal and anti-tetanus antibodies were both significantly reduced post-chemotherapy and did not recover during the study (p < 0.001).
Breast cancer chemotherapy is associated with long-term changes in immune parameters that should be considered during clinical management.
Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also ...be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations.
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•AAV can be endowed with robust retrograde functionality through directed evolution•Up to two orders of magnitude increase in retrograde transport over existing variants•Efficiency comparable to synthetic tracers•Sufficient payload expression for circuit interrogation and gene manipulation
Projection neurons are a critical component of large-scale networks distributing the results of local circuit computations between distant brain regions, but their specific contribution is often hard to pinpoint because of the difficulty of gaining selective genetic access. Tervo et al. introduce a designer variant of adeno-associated virus, rAAV2-retro, that allows for efficient mapping, monitoring, and manipulation of projection neurons.
Here we present an optimized workflow for global proteome and phosphoproteome analysis of tissues or cell lines that uses isobaric tags (TMT (tandem mass tags)-10) for multiplexed analysis and ...relative quantification, and provides 3× higher throughput than iTRAQ (isobaric tags for absolute and relative quantification)-4-based methods with high intra- and inter-laboratory reproducibility. The workflow was systematically characterized and benchmarked across three independent laboratories using two distinct breast cancer subtypes from patient-derived xenograft models to enable assessment of proteome and phosphoproteome depth and quantitative reproducibility. Each plex consisted of ten samples, each being 300 μg of peptide derived from <50 mg of wet-weight tissue. Of the 10,000 proteins quantified per sample, we could distinguish 7,700 human proteins derived from tumor cells and 3100 mouse proteins derived from the surrounding stroma and blood. The maximum deviation across replicates and laboratories was <7%, and the inter-laboratory correlation for TMT ratio-based comparison of the two breast cancer subtypes was r > 0.88. The maximum deviation for the phosphoproteome coverage was <24% across laboratories, with an average of >37,000 quantified phosphosites per sample and differential quantification correlations of r > 0.72. The full procedure, including sample processing and data generation, can be completed within 10 d for ten tissue samples, and 100 samples can be analyzed in ~4 months using a single LC-MS/MS instrument. The high quality, depth, and reproducibility of the data obtained both within and across laboratories should enable new biological insights to be obtained from mass spectrometry-based proteomics analyses of cells and tissues together with proteogenomic data integration.
Studies of nonvolcanic tremor (NVT) have established the significant impact of small stress perturbations on NVT generation. Here we analyze the influence of the solid earth and ocean tides on a ...catalog of ∼550,000 low frequency earthquakes (LFEs) distributed along a 150 km section of the San Andreas Fault centered at Parkfield. LFE families are identified in the NVT data on the basis of waveform similarity and are thought to represent small, effectively co‐located earthquakes occurring on brittle asperities on an otherwise aseismic fault at depths of 16 to 30 km. We calculate the sensitivity of each of these 88 LFE families to the tidally induced right‐lateral shear stress (RLSS), fault‐normal stress (FNS), and their time derivatives and use the hypocentral locations of each family to map the spatial variability of this sensitivity. LFE occurrence is most strongly modulated by fluctuations in shear stress, with the majority of families demonstrating a correlation with RLSS at the 99% confidence level or above. Producing the observed LFE rate modulation in response to shear stress perturbations requires low effective stress in the LFE source region. There are substantial lateral and vertical variations in tidal shear stress sensitivity, which we interpret to reflect spatial variation in source region properties, such as friction and pore fluid pressure. Additionally, we find that highly episodic, shallow LFE families are generally less correlated with tidal stresses than their deeper, continuously active counterparts. The majority of families have weaker or insignificant correlation with positive (tensile) FNS. Two groups of families demonstrate a stronger correlation with fault‐normal tension to the north and with compression to the south of Parkfield. The families that correlate with fault‐normal clamping coincide with a releasing right bend in the surface fault trace and the LFE locations, suggesting that the San Andreas remains localized and contiguous down to near the base of the crust. The deep families that have high sensitivity to both shear and tensile normal stress perturbations may be indicative of an increase in effective fault contact area with depth. Synthesizing our observations with those of other LFE‐hosting localities will help to develop a comprehensive understanding of transient fault slip below the “seismogenic zone” by providing constraints on parameters in physical models of slow slip and LFEs.
Key Points
LFEs are tidally triggered
LFEs are most sensitive to small amplitude shear stresses
Pore fluid pressures on the deep San Andreas fault are near‐lithostatic
The groundbreaking detection of gravitational waves produced by the inspiralling and coalescence of the black hole (BH) binary GW150914 confirms the existence of ‘heavy’ stellar-mass BHs with masses ...>25 M⊙. Initial characterization of the system by Abbott et al. supposes that the formation of BHs with such large masses from the evolution of single massive stars is only feasible if the wind mass-loss rates of the progenitors were greatly reduced relative to the mass-loss rates of massive stars in the Galaxy, concluding that heavy BHs must form in low-metallicity (Z ≲ 0.25-0.5 Z⊙) environments. However, strong surface magnetic fields also provide a powerful mechanism for modifying mass-loss and rotation of massive stars, independent of environmental metallicity. In this paper, we explore the hypothesis that some heavy BHs, with masses >25 M⊙ such as those inferred to compose GW150914, could be the natural end-point of evolution of magnetic massive stars in a solar-metallicity environment. Using the mesa code, we developed a new grid of single, non-rotating, solar-metallicity evolutionary models for initial zero-age main sequence masses from 40 to 80 M⊙ that include, for the first time, the quenching of the mass-loss due to a realistic dipolar surface magnetic field. The new models predict terminal-age main-sequence (TAMS) masses that are significantly greater than those from equivalent non-magnetic models, reducing the total mass lost by a strongly magnetized 80 M⊙ star during its main-sequence evolution by 20 M⊙. This corresponds approximately to the mass-loss reduction expected from an environment with metallicity Z = 1/30 Z⊙.
The rapid progress that plasma wakefield accelerators are experiencing is now posing the question as to whether they could be included in the design of the next generation of high-energy ...electron-positron colliders. However, the typical structure of the accelerating wakefields presents challenging complications for positron acceleration. Despite seminal proof-of-principle experiments and theoretical proposals, experimental research in plasma-based acceleration of positrons is currently limited by the scarcity of positron beams suitable to seed a plasma accelerator. Here, we report on the first experimental demonstration of a laser-driven source of ultra-relativistic positrons with sufficient spectral and spatial quality to be injected in a plasma accelerator. Our results indicate, in agreement with numerical simulations, selection and transport of positron beamlets containing
positrons in a 5% bandwidth around 600 MeV, with femtosecond-scale duration and micron-scale normalised emittance. Particle-in-cell simulations show that positron beams of this kind can be guided and accelerated in a laser-driven plasma accelerator, with favourable scalings to further increase overall charge and energy using PW-scale lasers. The results presented here demonstrate the possibility of performing experimental studies of positron acceleration in a laser-driven wakefield accelerator.
With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving ...treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease.
Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling.
Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease.
This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.
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