Automated Formula Generation and Performance Learning for the FFT

A single signal processing algorithm can be represented by many different but mathematically equivalent formulas. When these formulas are implemented in actual code, they often have very different running times. Thus, an important problem is finding a formula that implements the signal processing algorithm as efficiently as possible. In this paper we present three major results toward this goal: (1) Different but mathematically equivalent formulas can be generated automatically in a principled way, (2) Simple features describing formulas can be used to distinguish formulas with significantly different running times, and (3) A function approximator can learn to accurately predict the running time of a formula given a limited set of training data

Discrimination against Mixed-Status Families and its Health Impact on Latino Children

Background and Objective: Restrictive immigration policies and discrimination are associated with negative health outcomes for immigrant and Latino families. Mixed-status families represent a unique subpopulation of Latinos affected by restrictive immigration policies. This qualitative study explored discrimination against mixed-status families and its potential health impact on Latino children from the perspective of Latina mothers. Methods: In 2017, twenty in-depth interviews with Latina mothers of mixed-status families living in northwestern North Carolina were conducted, transcribed, and analyzed. Constant comparison, an approach to grounded theory development, was used. Results: Nine themes emerged that reflected experiences with discrimination and its negative impact on children. Themes included more frequent and severe discrimination during and after the 2016 US presidential election, determination to stay together and remain in the US, experiences of discrimination in multiple settings, the impact of discrimination on child health and well-being, the impact of fear and stress on meeting the needs of children, the burden on children serving as liaisons between families and services, the inability of citizenship to protect against the effects of discrimination, positive and hopeful responses to discrimination, and the potential role of education in building a foundation for reducing discrimination (and thus promoting the health and well-being of Latino children) in the future. Conclusions: Discrimination against mixed-status Latino families constitutes a critical threat to the health and well-being of Latino children. Further research should inform immigration policies that support (rather than threaten) the health, well-being, and health care practices that mitigate the stresses experienced by Latino children

Association of lung clearance index with survival in individuals with cystic fibrosis.

BACKGROUND The lung clearance index (LCI) assesses global ventilation inhomogeneity and is a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease. OBJECTIVES We examined the association of LCI with the risk of death or lung transplantation (LTX) in individuals with CF. METHODS We performed a retrospective analysis in a cohort of individuals with CF aged≥5 years with LCI and FEV1 measurements performed between 1980 and 2006. The outcome was time until death or LTX. We used the earliest available LCI and FEV1 values in a Cox proportional hazard regression adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV1 measurements, stratified the cohort based on age, and investigated individuals with normal FEV1. RESULTS In total, 237 individuals with CF with a mean (range) age of 13.9 (5.6-41.0) years were included. The time-to-event analysis accrued 3813 person-years and 94 (40%) individuals died or received LTX. Crude hazard ratios [95% CI] were 1.04 [1.01-1.06] per one z-score increase in LCI and 1.25 [1.11-1.41] per one z-score decrease in FEV1. After adjusting LCI and FEV1 mutually in addition to sex, age, BMI and the number of hospitalisations, hazard ratios were 1.04 [1.01-1.07] for LCI, and 1.12 [0.95-1.33] for FEV1. Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations. CONCLUSIONS Increased ventilation inhomogeneity is associated with greater risk of death or LTX. Our data support LCI as novel surrogate of survival in individuals with CF

Actin Cytoskeleton Regulation by the Yeast NADPH Oxidase Yno1p Impacts Processes Controlled by MAPK Pathways

Reactive oxygen species (ROS) that exceed the antioxidative capacity of the cell can be harmful and are termed oxidative stress. Increasing evidence suggests that ROS are not exclusively detrimental, but can fulfill important signaling functions. Recently, we have been able to demonstrate that a NADPH oxidase-like enzyme (termed Yno1p) exists in the single-celled organism Saccharomyces cerevisiae. This enzyme resides in the peripheral and perinuclear endoplasmic reticulum and functions in close proximity to the plasma membrane. Its product, hydrogen peroxide, which is also produced by the action of the superoxide dismutase, Sod1p, influences signaling of key regulatory proteins Ras2p and Yck1p/2p. In the present work, we demonstrate that Yno1p-derived H2O2 regulates outputs controlled by three MAP kinase pathways that can share components: the filamentous growth (filamentous growth MAPK (fMAPK)), pheromone response, and osmotic stress response (hyperosmolarity glycerol response, HOG) pathways. A key structural component and regulator in this process is the actin cytoskeleton. The nucleation and stabilization of actin are regulated by Yno1p. Cells lacking YNO1 showed reduced invasive growth, which could be reversed by stimulation of actin nucleation. Additionally, under osmotic stress, the vacuoles of a ∆yno1 strain show an enhanced fragmentation. During pheromone response induced by the addition of alpha-factor, Yno1p is responsible for a burst of ROS. Collectively, these results broaden the roles of ROS to encompass microbial differentiation responses and stress responses controlled by MAPK pathway

Thirdhand Tobacco Smoke: Emerging Evidence and Arguments for a Multidisciplinary Research Agenda

There is broad consensus regarding the health impact of tobacco use and secondhand smoke exposure, yet considerable ambiguity exists about the nature and consequences of thirdhand smoke (THS). We introduce definitions of THS and THS exposure and review recent findings about constituents, indoor sorption-desorption dynamics, and transformations of THS; distribution and persistence of THS in residential settings; implications for pathways of exposure; potential clinical significance and health effects; and behavioral and policy issues that affect and are affected by THS. Physical and chemical transformations of tobacco smoke pollutants take place over time scales ranging from seconds to months and include the creation of secondary pollutants that in some cases are more toxic (e.g., tobacco-specific nitrosamines). THS persists in real-world residential settings in the air, dust, and surfaces and is associated with elevated levels of nicotine on hands and cotinine in urine of nonsmokers residing in homes previously occupied by smokers. Much still needs to be learned about the chemistry, exposure, toxicology, health risks, and policy implications of THS. The existing evidence on THS provides strong support for pursuing a programmatic research agenda to close gaps in our current understanding of the chemistry, exposure, toxicology, and health effects of THS, as well as its behavioral, economic, and sociocultural considerations and consequences. Such a research agenda is necessary to illuminate the role of THS in existing and future tobacco control efforts to decrease smoking initiation and smoking levels, to increase cessation attempts and sustained cessation, and to reduce the cumulative effects of tobacco use on morbidity and mortality

Methyl-binding domain protein-based DNA isolation from human blood serum combines DNA analyses and serum-autoantibody testing

<p>Abstract</p> <p>Background</p> <p>Circulating cell free DNA in serum as well as serum-autoantibodies and the serum proteome have great potential to contribute to early cancer diagnostics via non invasive blood tests. However, most DNA preparation protocols destroy the protein fraction and therefore do not allow subsequent protein analyses. In this study a novel approach based on methyl binding domain protein (MBD) is described to overcome the technical difficulties of combining DNA and protein analysis out of one single serum sample.</p> <p>Methods</p> <p>Serum or plasma samples from 98 control individuals and 54 breast cancer patients were evaluated upon silica membrane- or MBD affinity-based DNA isolation via qPCR targeting potential DNA methylation markers as well as by protein-microarrays for tumor-autoantibody testing.</p> <p>Results</p> <p>In control individuals, an average DNA level of 22.8 ± 25.7 ng/ml was detected applying the silica membrane based protocol and 8.5 ± 7.5 ng/ml using the MBD-approach, both values strongly dependent on the serum sample preparation methods used. In contrast to malignant and benign tumor serum samples, cell free DNA concentrations were significantly elevated in sera of metastasizing breast cancer patients. Technical evaluation revealed that serum upon MBD-based DNA isolation is suitable for protein-array analyses when data are consistent to untreated serum samples.</p> <p>Conclusion</p> <p>MBD affinity purification allows DNA isolations under native conditions retaining the protein function, thus for example enabling combined analyses of DNA methylation and autoantigene-profiles from the same serum sample and thereby improving minimal invasive diagnostics.</p

The Cost of Male Aggression and Polygyny in California Sea Lions (Zalophus californianus)

In polygynous mating systems, males often increase their fecundity via aggressive defense of mates and/or resources necessary for successful mating. Here we show that both male and female reproductive behavior during the breeding season (June–August) affect female fecundity, a vital rate that is an important determinant of population growth rate and viability. By using 4 years of data on behavior and demography of California sea lions (Zalophus californianus), we found that male behavior and spatial dynamics—aggression and territory size—are significantly related to female fecundity. Higher rates of male aggression and larger territory sizes were associated with lower estimates of female fecundity within the same year. Female aggression was significantly and positively related to fecundity both within the same year as the behavior was measured and in the following year. These results indicate that while male aggression and defense of territories may increase male fecundity, such interactions may cause a reduction in the overall population growth rate by lowering female fecundity. Females may attempt to offset male-related reductions in female fecundity by increasing their own aggression—perhaps to defend pups from incidental injury or mortality. Thus in polygynous mating systems, male aggression may increase male fitness at the cost of female fitness and overall population viability

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors