Spatial analysis of IRAS observations of nearby spirals

The unbiased survey of the infrared sky carried out by the Infrared Astronomy Satellite (IRAS) satellite has greatly accelerated advances in understanding the dust component of our own and external galaxies. However, most extragalactic studies to date have been based on the IRAS Point Source Catalog (PSC), which has two serious limitations. First, in sources where a significant fraction of the flux is extended, significant errors may result from using PSC fluxes in comparative studies, and these errors could be systematic if the tendency to be non-pointlike depends on physical properties of the galaxy. Additionally, use of PSC fluxes rules out any direct investigation of the spatial distribution of the IRAS emission from disks in external galaxies. Since work on the Galactic IRAS results has shown that very different physical processes can make varying contributions to the observed flux, it is important to look at a wide sample of galaxies with some spatial resolution to study the relative dominance of these processes under a variety of conditions. Here, researchers report on work they are doing to carry out this program for many nearby spirals, using an analysis package that was developed for this purpose. Researchers carried out analysis for a sample of 121 nearby spirals. The fraction of the flux contained in a point source varies from 0 to 1 across the sample, all of which are well resolved at their nominal optical diameters. There is no evidence that the galaxies of smaller angular size are less likely to be resolved by IRAS at this level. The program gives results which are quite repeatable from scan to scan; the fraction f (point source flux over total flux) at 60 microns has typical errors of 0.03 when different scans are combined. Approximately two-thirds of the sample have more flux in the extended than in the nuclear component. There is a tendency for earlier-type spirals to be less centrally concentrated, but this effect is slight and the degree of variation is large for all types. Barred spirals are also found across the spectrum of f, but are much more likely to have little or no nuclear emission

The Productive Status of Laurentian French Liaison: Variation across Words and Grammar

There are competing views in contemporary phonological theory about how to best represent processes that are pervasive, frequent, and phonologically motivated, yet still lexically sensitive. To what extent can – or should – a process that applies idiosyncratically to different morphemes, words, and even phrases, be represented in a way that allows it to generalize to novel forms? We examine this question by looking at prenominal liaison as it is used in contemporary Laurentian French, spoken in Canada. We present the results of an online production study that compares application of liaison in real vs. nonce nouns, and that considers the effect of nonce nouns’ phonological properties and morphosyntactic context on the process. We interpret our results as evidence that liaison behaviour is driven jointly by lexical representations and an abstract grammar, with properties of the real-word lexicon affecting liaison rates in nonce words. We further show that there is considerable variation in the population in the extent to which speakers produce liaison with real h-aspiré words, but that all speakers nonetheless share an understanding of what types of words are more vs. less likely to undergo liaison

An Observational Study of Engineering Online Education During the COVID-19 Pandemic

Although online education has become a viable and major component of higher education in many fields, its employment in engineering disciplines has been limited. COVID-19 pandemic compelled the global and abrupt conversion of conventional face-to-face instruction to the online format. The negative impact of such sudden change is undeniable. Urgent and careful planning is needed to mitigate pandemic negative effects on engineering education, especially for vulnerable, disadvantaged, and underrepresented students who have to deal with additional challenges (e.g. digital equity gap). To enhance engineering online instruction during the pandemic era, we conducted an observational study at California State University, Long Beach (a minority-serving institution). 110 faculty and 627 students from six engineering departments participated in our surveys and answered quantitative and qualitative questions to highlight the challenges they experienced during the online instruction in Spring 2020. In this work, we present the results of these surveys in detail and propose solutions to address the identified issues including logistical, technical, learning/teaching challenges, assessment methods, and hands-on training. As the pandemic continues, sharing these results with other educators can help with more effective planning and choice of best practices to improve the online engineering education during COVID-19 and beyond.Comment: 10 pages, 3 figures, 2 table

Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death.

The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis

Financing drug discovery for orphan diseases

Recently proposed ‘megafund’ financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10–20 projects in the portfolio.MIT Laboratory for Financial Engineerin

Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma.

BackgroundIn melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma.MethodsThe 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined.ResultsSensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis.ConclusionsCombining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors

Shrinking VOD Traffic via Rényi-Entropic Optimal Transport

In response to the exponential surge in Internet Video on Demand (VOD) traffic, numerous research endeavors have concentrated on optimizing and enhancing infrastructure efficiency. In contrast, this paper explores whether users’ demand patterns can be shaped to reduce the pressure on infrastructure. Our main idea is to design a mechanism that alters the distribution of user requests to another distribution which is much more cache-efficient, but still remains ‘close enough’ (in the sense of cost) to fulfil each individual user’s preference. To quantify the cache footprint of VOD traffic, we propose a novel application of Rényi entropy as its proxy, capturing the ‘richness’ (the number of distinct videos or cache size) and the ‘evenness’ (the relative popularity of video accesses) of the on-demand video distribution. We then demonstrate how to decrease this metric by formulating a problem drawing on the mathematical theory of optimal transport (OT). Additionally, we establish a key equivalence theorem: minimizing Rényi entropy corresponds to maximizing soft cache hit ratio (SCHR) — a variant of cache hit ratio allowing similarity-based video substitutions. Evaluation on a real-world, city-scale video viewing dataset reveals a remarkable 83% reduction in cache size (associated with VOD caching traffic). Crucially, in alignment with the above-mentioned equivalence theorem, our approach yields a significant uplift to SCHR, achieving close to 100%

Community Priority Index: utility, applicability and validation for priority setting in community-based participatory research

Background. Providing practitioners with an intuitive measure for priority setting that can be combined with diverse data collection methods is a necessary step to foster accountability of the decision-making process in community settings. Yet, there is a lack of easy-to-use, but methodologically robust measures, that can be feasibly implemented for reliable decision-making in community settings. To address this important gap in community based participatory research (CBPR), the purpose of this study was to demonstrate the utility, applicability, and validation of a community priority index in a community-based participatory research setting. Design and Methods. Mixed-method study that combined focus groups findings, nominal group technique with six key informants, and the generation of a Community Priority Index (CPI) that integrated community importance, changeability, and target populations. Bootstrapping and simulation were performed for validation. Results. For pregnant mothers, the top three highly important and highly changeable priorities were: stress (CPI=0.85; 95%CI: 0.70, 1.00), lack of affection (CPI=0.87; 95%CI: 0.69, 1.00), and nutritional issues (CPI=0.78; 95%CI: 0.48, 1.00). For non-pregnant women, top priorities were: low health literacy (CPI=0.87; 95%CI: 0.69, 1.00), low educational attainment (CPI=0.78; 95%CI: 0.48, 1.00), and lack of self-esteem (CPI=0.72; 95%CI: 0.44, 1.00). For children and adolescents, the top three priorities were: obesity (CPI=0.88; 95%CI: 0.69, 1.00), low self-esteem (CPI=0.81; 95%CI: 0.69, 0.94), and negative attitudes toward education (CPI=0.75; 95%CI: 0.50, 0.94). Conclusions. This study demonstrates the applicability of the CPI as a simple and intuitive measure for priority setting in CBPR

JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.

A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets

Commercializing Biomedical Research Through Securitization Techniques

Biomedical innovation has become riskier, more expensive and more difficult to finance with traditional sources such as private and public equity. Here we propose a financial structure in which a large number of biomedical programs at various stages of development are funded by a single entity to substantially reduce the portfolio's risk. The portfolio entity can finance its activities by issuing debt, a critical advantage because a much larger pool of capital is available for investment in debt versus equity. By employing financial engineering techniques such as securitization, it can raise even greater amounts of more-patient capital. In a simulation using historical data for new molecular entities in oncology from 1990 to 2011, we find that megafunds of $5–15 billion may yield average investment returns of 8.9–11.4% for equity holders and 5–8% for 'research-backed obligation' holders, which are lower than typical venture-capital hurdle rates but attractive to pension funds, insurance companies and other large institutional investors