CRAF R391W is a melanoma driver oncogene.

Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma. CRAF R391W was homozygous and over expressed. These melanoma cells were highly sensitive to CRAF, but not BRAF knockdown. In reconstitution experiments, CRAF R391W, but not CRAF WT, transformed NIH3T3 cells in soft-agar colony formation assays, increased kinase activity in vitro, induced MAP kinase signaling and conferred vemurafenib resistance. MAP kinase inducing activity was dependent on CRAF dimerization. Thus, CRAF is a bona fide alternative oncogene for BRAF/NRAS/GNAQ/GNA11 wild type melanomas

Helping or Hurting?: Understanding Women’s Perceptions of Male Allies

In the past decade, organizational scholars have begun to explore the role of allies in mitigating workplace discrimination toward women and members of minority groups. However, this nascent literature has, to this point, failed to consider the perspective of targets of ally behavior. That is, we do not yet know how targets of discrimination experience others’ intervention or advocacy. To begin to understand these issues, we examine target perceptions of allyship through a qualitative critical incident approach, asking women to describe experiences in which a man has effectively and ineffectively acted as an ally to them in the workplace. Our findings from surveying 100 women provide new insights regarding who engages in ally behaviors, what behaviors these allies enact, when and where the behaviors take place, and why participants believed their male ally engaged in this behavior

Regulation of thyroid hormone-induced development \u3cem\u3ein vivo\u3c/em\u3e by thyroid hormone transporters and cytosolic binding proteins

Differential tissue sensitivity/responsivity to hormones can explain developmental asynchrony among hormone-dependent events despite equivalent exposure of each tissue to circulating hormone levels. A dramatic vertebrate example is during frog metamorphosis, where transformation of the hind limb, brain, intestine, liver, and tail are completely dependent on thyroid hormone (TH) but occurs asynchronously during development. TH transporters (THTs) and cytosolic TH binding proteins (CTHBPs) have been proposed to affect the timing of tissue transformation based on expression profiles and in vitro studies, but they have not been previously tested in vivo. We used a combination of expression pattern, relative expression level, and in vivo functional analysis to evaluate the potential for THTs (LAT1, OATP1c1, and MCT8) and CTHBPs (PKM2, CRYM, and ALDH1) to control the timing of TH-dependent development. Quantitative PCR analysis revealed complex expression profiles of THTs and CTHBPs with respect to developmental stage, tissue, and TH receptor β (TRβ) expression. For some tissues, the timing of tissue transformation was associated with a peak in the expression of some THTs or CTHBPs. An in vivo overexpression assay by tail muscle injection showed LAT1, PKM2, and CRYM increased TH-dependent tail muscle cell disappearance. Co-overexpression of MCT8 and CRYM had a synergistic effect on cell disappearance. Our data show that each tissue examined has a unique developmental expression profile of THTs and CTHBPs and provide direct in vivo evidence that the ones tested are capable of affecting the timing of developmental responses to TH

Draft Genome Sequences of 1,183 Salmonella Strains from the 100K Pathogen Genome Project.

Salmonella is a common food-associated bacterium that has substantial impact on worldwide human health and the global economy. This is the public release of 1,183 Salmonella draft genome sequences as part of the 100K Pathogen Genome Project. These isolates represent global genomic diversity in the Salmonella genus

Coherent deglacial changes in western Atlantic Ocean circulation

Abrupt climate changes in the past have been attributed to variations in Atlantic Meridional Overturning Circulation (AMOC) strength. However, the exact timing and magnitude of past AMOC shifts remain elusive, which continues to limit our understanding of the driving mechanisms of such climate variability. Here we show a consistent signal of the 231Pa/230Th proxy that reveals a spatially coherent picture of western Atlantic circulation changes over the last deglaciation, during abrupt millennial-scale climate transitions. At the onset of deglaciation, we observe an early slowdown of circulation in the western Atlantic from around 19 to 16.5 thousand years ago (ka), consistent with the timing of accelerated Eurasian ice melting. The subsequent weakened AMOC state persists for over a millennium (~16.5–15 ka), during which time there is substantial ice rafting from the Laurentide ice sheet. This timing indicates a role for melting ice in driving a two-step AMOC slowdown, with a positive feedback sustaining continued iceberg calving and climate change during Heinrich Stadial 1NERC | Ref. NE/K008536/

Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats

Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filovirus host range in nature

Wave dissipation by muddy seafloors

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 35 (2008): L07611, doi:10.1029/2008GL033245.Muddy seafloors cause tremendous dissipation of ocean waves. Here, observations and numerical simulations of waves propagating between 5- and 2-m water depths across the muddy Louisiana continental shelf are used to estimate a frequency- and depth-dependent dissipation rate function. Short-period sea (4 s) and swell (7 s) waves are shown to transfer energy to long-period (14 s) infragravity waves, where, in contrast with theories for fluid mud, the observed dissipation rates are highest. The nonlinear energy transfers are most rapid in shallow water, consistent with the unexpected strong increase of the dissipation rate with decreasing depth. These new results may explain why the southwest coast of India offers protection for fishing (and for the 15th century Portuguese fleet) only after large waves and strong currents at the start of the monsoon move nearshore mud banks from about 5- to 2-m water depth. When used with a numerical nonlinear wave model, the new dissipation rate function accurately simulates the large reduction in wave energy observed in the Gulf of Mexico.The Office of Naval Research provided support

New Limits on the Ultra-high Energy Cosmic Neutrino Flux from the ANITA Experiment

We report initial results of the first flight of the Antarctic Impulsive Transient Antenna (ANITA-1) 2006-2007 Long Duration Balloon flight, which searched for evidence of a diffuse flux of cosmic neutrinos above energies of 3 EeV. ANITA-1 flew for 35 days looking for radio impulses due to the Askaryan effect in neutrino-induced electromagnetic showers within the Antarctic ice sheets. We report here on our initial analysis, which was performed as a blind search of the data. No neutrino candidates are seen, with no detected physics background. We set model-independent limits based on this result. Upper limits derived from our analysis rule out the highest cosmogenic neutrino models. In a background horizontal-polarization channel, we also detect six events consistent with radio impulses from ultra-high energy extensive air showers.Comment: 4 pages, 2 table

Race and place differences in patients hospitalized with an acute coronary syndrome: Is there double jeopardy? Findings from TRACE-CORE

The objectives of this longitudinal study were to examine differences between whites and blacks, and across two geographical regions, in the socio-demographic, clinical, and psychosocial characteristics, hospital treatment practices, and post-discharge mortality for hospital survivors of an acute coronary syndrome (ACS). In this prospective cohort study, we performed in-person interviews and medical record abstractions for patients discharged from the hospital after an ACS at participating sites in Central Massachusetts and Central Georgia during 2011-2013. Among the 1143 whites in Central Massachusetts, 514 whites in Central Georgia, and 277 blacks in Central Georgia, we observed a gradient of socioeconomic position with whites in Central Massachusetts being the most privileged, followed by whites and then blacks from Central Georgia; similar gradients pertained to psychosocial vulnerability (e.g., 10.7%, 25.1%, and 49.1% had cognitive impairment, respectively) and to the hospital receipt of all 4 evidence-based cardiac medications (35.5%, 18.1%, and 14.4%, respectively) used in the acute management of patients hospitalized with an ACS. Multivariable adjusted odds ratios (95% confidence intervals) for the receipt of a percutaneous coronary intervention for whites and blacks in Georgia vs. whites in Massachusetts were 0.57 (0.46-0.71) and 0.40(0.30-0.52), respectively. Thirty-day and one-year mortality risks exhibited a similar gradient. The results of this contemporary clinical/epidemiologic study in a diverse patient cohort suggest that racial and geographic disparities continue to exist for patients hospitalized with an ACS