Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4

Hereditary cancers derive from gene defects that often compromise DNA repair. Thus, BRCA-associated cancers are sensitive to DNA-damaging agents such as cisplatin. The efficacy of cisplatin is limited, however, by the development of resistance. One cisplatin resistance mechanism is restoration of homologous recombination (HR), which can result from BRCA reversion mutations. However, in BRCA2 mutant cancers, cisplatin resistance can occur independently of restored HR by a mechanism that remains unknown. Here we performed a genome-wide shRNA screen and found that loss of the nucleosome remodeling factor CHD4 confers cisplatin resistance. Restoration of cisplatin resistance is independent of HR but correlates with restored cell cycle progression, reduced chromosomal aberrations, and enhanced DNA damage tolerance. Suggesting clinical relevance, cisplatin-resistant clones lacking genetic reversion of BRCA2 show de novo loss of CHD4 expression in vitro. Moreover, BRCA2 mutant ovarian cancers with reduced CHD4 expression significantly correlate with shorter progression-free survival and shorter overall survival. Collectively, our findings indicate that CHD4 modulates therapeutic response in BRCA2 mutant cancer cells

3+1 Approach to the Long Wavelength Iteration Scheme

Large-scale inhomogeneities and anisotropies are modeled using the Long Wavelength Iteration Scheme. In this scheme solutions are obtained as expansions in spatial gradients, which are taken to be small. It is shown that the choice of foliation for spacetime can make the iteration scheme more effective in two respects: (i) the shift vector can be chosen so as to dilute the effect of anisotropy on the late-time value of the extrinsic curvature of the spacelike hypersurfaces of the foliation; and (ii) pure gauge solutions present in a similar calculation using the synchronous gauge vanish when the spacelike hypersurfaces have extrinsic curvature with constant trace. We furthermore verify the main conclusion of the synchronous gauge calculation which is large-scale inhomogeneity decays if the matter--considered to be that of a perfect-fluid with a barotropic equation of state--violates the strong-energy condition. Finally, we obtain the solution for the lapse function and discuss its late-time behaviour. It is found that the lapse function is well-behaved when the matter violates the strong energy condition.Comment: 21 pages, TeX file, already publishe

Infectious Complications of Ventricular Assist Device Use in Children in the US: Data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs)

Background Infections are frequent in pediatric ventricular assist device (VAD) patients. In this study we aimed to describe infections in durable VAD patients reported to Pedimacs. Methods Durable VAD data from the Pedimacs registry (September 19, 2012 to December 31, 2015) were analyzed. Infections were described with standard descriptive statistics, Kaplan–Meier analysis and competing outcomes analysis. Results There were 248 implants in 222 patients, with a mean age and a median follow-up of 11 ± 6.4 years and 2.4 patient-months (<1 day to 2.6 years), respectively. Device types were pulsatile flow (PF) in 91 (41%) patients and continuous flow (CF) in 131 (59%) patients. PF patients were younger (4 ± 4 vs 14 ± 4 years; p < 0.0001) and were more likely to have congenital heart disease (25% vs 12%; p = 0.03), prior surgery (53% vs 26%; p < 0.0001) and prior extracorporeal membrane oxygenation (24% vs 7%; p = 0.0003). Infection accounted for 17% (96 of 564) of the reported adverse events (AEs). A non-device infection was most common (51%), followed by sepsis (24%), external pump component infection (20%) and internal pump component infection (5%). Most infections were bacterial (73%) and required intravenous therapy only (77%). The risk of infection in the constant phase was higher in patients with a history of prior infection and in patients with a history of a non-infectious major AEs. Survival was lower after infection only in CF patients (p = 0.008). Conclusions Infection was the most common AE after pediatric VAD implantation. Non-device infections were most common. The best predictor of a future infection was a past infection. CF patients have higher risk of death after an infection

A weighted de Rham operator acting on arbitrary tensor fields and their local potentials

We introduce a weighted de Rham operator which acts on arbitrary tensor fields by considering their structure as r-fold forms. We can thereby define associated superpotentials for all tensor fields in all dimensions and, from any of these superpotentials, we deduce in a straightforward and natural manner the existence of 2r potentials for any tensor field, where r is its form-structure number. By specialising this result to symmetric double forms, we are able to obtain a pair of potentials for the Riemann tensor, and a single (2,3)-form potential for the Weyl tensor due to its tracelessness. This latter potential is the n-dimensional version of the double dual of the classical four dimensional (2,1)-form Lanczos potential. We also introduce a new concept of harmonic tensor fields, demonstrate that the new weighted de Rham operator has many other desirable properties and, in particular, it is the natural operator to use in the Laplace-like equation for the Riemann tensor.Comment: 33 pages: corrected typos and minor additions; reference [39] adde

Integration of electrostatic and fluid dynamics within a dust devil

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94610/1/jgre2050.pd

Immune Amplification of Murine CD8+ Suppressor T Cells Induced via An Immune-Privileged Site: Quantifying Suppressor T Cells Functionally

BACKGROUND: CD8(+) suppressor T cells exert antigen-specific suppression of the expression of hypersensitivity by activated T cells. Therefore, CD8(+) suppressor T cells serve a major regulatory role for the control of active immunity. Accordingly, the number and/or activity of CD8(+) suppressor T cells should be influenced by an immune response to the antigen. To test this hypothesis we used an adoptive transfer assay that measures the suppression of the expression of delayed-type hypersensitivity (DTH) by CD8(+) suppressor T cells to quantify the antigen-specific suppression of DTH by these suppressor T cells. METHODS: Suppressor T cells were induced in the spleens of mice by the injection of antigen into the anterior chamber of an eye. Following this injection, the mice were immunized by the same antigen injected into the anterior chamber. Spleen cells recovered from these mice (AC-SPL cells) were titrated in an adoptive transfer assay to determine the number of AC-SPL cells required to effect a 50% reduction of antigen-induced swelling (Sw50) in the footpad of immunized mice challenged by antigen. RESULTS: Suppression of the expression of DTH is proportional to the number of AC-SPL cells injected into the site challenged by antigen. The number of AC-SPL cells required for a 50% reduction in DTH-induced swelling is reduced by injecting a cell population enriched for CD8(+) AC-SPL cells. Immunizing the mice receiving intracameral antigen to the same antigen decreases the RSw50 of AC-SPL cells required to inhibit the expression of DTH. CONCLUSIONS: The results provide the first quantitative demonstration that the numbers of antigen-specific splenic CD8(+) suppressor T cells are specifically amplified by antigen during an immune response

Dust Devil Tracks

Dust devils that leave dark- or light-toned tracks are common on Mars and they can also be found on the Earth’s surface. Dust devil tracks (hereinafter DDTs) are ephemeral surface features with mostly sub-annual lifetimes. Regarding their size, DDT widths can range between ∼1 m and ∼1 km, depending on the diameter of dust devil that created the track, and DDT lengths range from a few tens of meters to several kilometers, limited by the duration and horizontal ground speed of dust devils. DDTs can be classified into three main types based on their morphology and albedo in contrast to their surroundings; all are found on both planets: (a) dark continuous DDTs, (b) dark cycloidal DDTs, and (c) bright DDTs. Dark continuous DDTs are the most common type on Mars. They are characterized by their relatively homogenous and continuous low albedo surface tracks. Based on terrestrial and martian in situ studies, these DDTs most likely form when surficial dust layers are removed to expose larger-grained substrate material (coarse sands of ≥500 μm in diameter). The exposure of larger-grained materials changes the photometric properties of the surface; hence leading to lower albedo tracks because grain size is photometrically inversely proportional to the surface reflectance. However, although not observed so far, compositional differences (i.e., color differences) might also lead to albedo contrasts when dust is removed to expose substrate materials with mineralogical differences. For dark continuous DDTs, albedo drop measurements are around 2.5 % in the wavelength range of 550–850 nm on Mars and around 0.5 % in the wavelength range from 300–1100 nm on Earth. The removal of an equivalent layer thickness around 1 μm is sufficient for the formation of visible dark continuous DDTs on Mars and Earth. The next type of DDTs, dark cycloidal DDTs, are characterized by their low albedo pattern of overlapping scallops. Terrestrial in situ studies imply that they are formed when sand-sized material that is eroded from the outer vortex area of a dust devil is redeposited in annular patterns in the central vortex region. This type of DDT can also be found in on Mars in orbital image data, and although in situ studies are lacking, terrestrial analog studies, laboratory work, and numerical modeling suggest they have the same formation mechanism as those on Earth. Finally, bright DDTs are characterized by their continuous track pattern and high albedo compared to their undisturbed surroundings. They are found on both planets, but to date they have only been analyzed in situ on Earth. Here, the destruction of aggregates of dust, silt and sand by dust devils leads to smooth surfaces in contrast to the undisturbed rough surfaces surrounding the track. The resulting change in photometric properties occurs because the smoother surfaces have a higher reflectance compared to the surrounding rough surface, leading to bright DDTs. On Mars, the destruction of surficial dust-aggregates may also lead to bright DDTs. However, higher reflective surfaces may be produced by other formation mechanisms, such as dust compaction by passing dust devils, as this may also cause changes in photometric properties. On Mars, DDTs in general are found at all elevations and on a global scale, except on the permanent polar caps. DDT maximum areal densities occur during spring and summer in both hemispheres produced by an increase in dust devil activity caused by maximum insolation. Regionally, dust devil densities vary spatially likely controlled by changes in dust cover thicknesses and substrate materials. This variability makes it difficult to infer dust devil activity from DDT frequencies. Furthermore, only a fraction of dust devils leave tracks. However, DDTs can be used as proxies for dust devil lifetimes and wind directions and speeds, and they can also be used to predict lander or rover solar panel clearing events. Overall, the high DDT frequency in many areas on Mars leads to drastic albedo changes that affect large-scale weather patterns

Men's preferences for prostate cancer screening: A discrete choice experiment

Background: Screening for prostate cancer (PC) may save lives, but overdiagnosis and overtreatment are serious drawbacks. We aimed to determine men's preferences for PC screening, and to elicit the trade-offs they make. Methods: A discrete choice experiment (DCE) was conducted among a population-based random sample of 1000 elderly men (55-75-years-old). Trade-offs were quantified with a panel latent class model between five PC screening aspects: risk reduction of PC-related death, screening interval, risk of unnecessary biopsies, risk of unnecessary treatments, and out-of-pocket costs. Results: The response rate was 46% (459/1000). Men were willing to trade-off 2.0% (CI: 1.6%-2.4%) or 1.8% (CI: 1.3%-2.3%) risk reduction of PC-related death to decrease their risk of unnecessary treatment or biopsy with 10%, respectively. They were willing to pay \[euro]188 per year (CI: \[euro]141-\[euro]258) to reduce their relative risk of PC-related death with 10%. Preference heterogeneity was substantial, with men with higher educational levels having a lower probability to opt for PC screening than men with lower educational levels. Conclusion: Men were willing to trade-off some risk reduction of PC-related death to be relieved of the burden of biopsies or unnecessary treatments. Increasing knowledge on overdiagnosis and overtreatment, especially for men with lower educational levels, is warranted to prevent unrealistic expectations from PC screening. © 2013 Cancer Research UK. All rights reserved

Friend of GATA (FOG) Interacts with the Nucleosome Remodeling and Deacetylase Complex (NuRD) to Support Primitive Erythropoiesis in Xenopus laevis

Friend of GATA (FOG) plays many diverse roles in adult and embryonic hematopoiesis, however the mechanisms by which it functions and the roles of potential interaction partners are not completely understood. Previous work has shown that overexpression of FOG in Xenopus laevis causes loss of blood suggesting that in contrast to its role in mammals, FOG might normally function to repress erythropoiesis in this species. Using loss-of-function analysis, we demonstrate that FOG is essential to support primitive red blood cell (RBC) development in Xenopus. Moreover, we show that it is specifically required to prevent excess apoptosis of circulating primitive RBCs and that in the absence of FOG, the pro-apoptotic gene Bim-1 is strongly upregulated. To identify domains of FOG that are essential for blood development and, conversely, to begin to understand the mechanism by which overexpressed FOG represses primitive erythropoiesis, we asked whether FOG mutants that are unable to interact with known co-factors retain their ability to rescue blood formation in FOG morphants and whether they repress erythropoiesis when overexpressed in wild type embryos. We find that interaction of FOG with the Nucleosome Remodeling and Deacetylase complex (NuRD), but not with C-terminal Binding Protein, is essential for normal primitive RBC development. In contrast, overexpression of all mutant and wild type constructs causes a comparable repression of primitive erythropoiesis. Together, our data suggest that a requirement for FOG and its interaction with NuRD during primitive erythropoiesis are conserved in Xenopus and that loss of blood upon FOG overexpression is due to a dominant-interfering effect

Psychological and Environmental Correlates of Well-being Among Undergraduate University Students

This study explored whether the university environment provides similar well-being enhancing elements to those that have been found in the workplace and school contexts. Whether psychological inflexibility accounts for well-being over and above personality and environmental influences was also explored. A representative sample of 163 undergraduate university students in an Australian university completed an online survey measuring the key constructs. Environmental influences assessed included financial resources, physical security, opportunity to use new skills, externally generated goals, variety, environmental clarity, interpersonal contact, and valued social position. Hierarchical multiple linear regression analyses were then conducted to test for predictors of three domains of subjective well-being: positive affect, negative affect, and life satisfaction. The results suggested that university context contributes significantly to undergraduate students’ well-being by providing a valued social role, externally generated goals, and variety. Students’ perception of their physical security was also an important influence on their well-being. These results are consistent with the literature on well-being and employment. Neuroticism significantly predicted negative affect, while psychological inflexibility accounted for unique variance in life satisfaction and negative affect even when personality and environmental influences were taken into account. The implications of these findings for enhancing undergraduate university students’ well-being are discussed