Asymmetric discrimination of non-speech tonal analogues of vowels

Published in final edited form as: J Exp Psychol Hum Percept Perform. 2019 February ; 45(2): 285–300. doi:10.1037/xhp0000603.Directional asymmetries reveal a universal bias in vowel perception favoring extreme vocalic articulations, which lead to acoustic vowel signals with dynamic formant trajectories and well-defined spectral prominences due to the convergence of adjacent formants. The present experiments investigated whether this bias reflects speech-specific processes or general properties of spectral processing in the auditory system. Toward this end, we examined whether analogous asymmetries in perception arise with non-speech tonal analogues that approximate some of the dynamic and static spectral characteristics of naturally-produced /u/ vowels executed with more versus less extreme lip gestures. We found a qualitatively similar but weaker directional effect with two-component tones varying in both the dynamic changes and proximity of their spectral energies. In subsequent experiments, we pinned down the phenomenon using tones that varied in one or both of these two acoustic characteristics. We found comparable asymmetries with tones that differed exclusively in their spectral dynamics, and no asymmetries with tones that differed exclusively in their spectral proximity or both spectral features. We interpret these findings as evidence that dynamic spectral changes are a critical cue for eliciting asymmetries in non-speech tone perception, but that the potential contribution of general auditory processes to asymmetries in vowel perception is limited.Accepted manuscrip

Retrieving the global distribution of the threshold of wind erosion from satellite data and implementing it into the Geophysical Fluid Dynamics Laboratory land–atmosphere model (GFDL AM4.0/LM4.0)

Dust emission is initiated when surface wind velocities exceed the threshold of wind erosion. Many dust models used constant threshold values globally. Here we use satellite products to characterize the frequency of dust events and land surface properties. By matching this frequency derived from Moderate Resolution Imaging Spectroradiometer (MODIS) Deep Blue aerosol products with surface winds, we are able to retrieve a climatological monthly global distribution of the wind erosion threshold (Vthreshold) over dry and sparsely vegetated surfaces. This monthly two-dimensional threshold velocity is then implemented into the Geophysical Fluid Dynamics Laboratory coupled land–atmosphere model (AM4.0/LM4.0). It is found that the climatology of dust optical depth (DOD) and total aerosol optical depth, surface PM10 dust concentrations, and the seasonal cycle of DOD are better captured over the “dust belt” (i.e., northern Africa and the Middle East) by simulations with the new wind erosion threshold than those using the default globally constant threshold. The most significant improvement is the frequency distribution of dust events, which is generally ignored in model evaluation. By using monthly rather than annual mean Vthreshold, all comparisons with observations are further improved. The monthly global threshold of wind erosion can be retrieved under different spatial resolutions to match the resolution of dust models and thus can help improve the simulations of dust climatology and seasonal cycles as well as dust forecasting

Determining Frequent Patterns of Copy Number Alterations in Cancer

Cancer progression is often driven by an accumulation of genetic changes but also accompanied by increasing genomic instability. These processes lead to a complicated landscape of copy number alterations (CNAs) within individual tumors and great diversity across tumor samples. High resolution array-based comparative genomic hybridization (aCGH) is being used to profile CNAs of ever larger tumor collections, and better computational methods for processing these data sets and identifying potential driver CNAs are needed. Typical studies of aCGH data sets take a pipeline approach, starting with segmentation of profiles, calls of gains and losses, and finally determination of frequent CNAs across samples. A drawback of pipelines is that choices at each step may produce different results, and biases are propagated forward. We present a mathematically robust new method that exploits probe-level correlations in aCGH data to discover subsets of samples that display common CNAs. Our algorithm is related to recent work on maximum-margin clustering. It does not require pre-segmentation of the data and also provides grouping of recurrent CNAs into clusters. We tested our approach on a large cohort of glioblastoma aCGH samples from The Cancer Genome Atlas and recovered almost all CNAs reported in the initial study. We also found additional significant CNAs missed by the original analysis but supported by earlier studies, and we identified significant correlations between CNAs

NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches

Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies

A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma

AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cells. This phase 2 study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory MM