Necrotic cell death: A novel outcome of BHPI-hyperactivation of the anticipatory unfolded protein response

Of the roughly 1 in 8 women that develop breast cancer in their lifetimes, 70% will have estrogen receptor a positive (ERa+) cancer. The standard of care for these cancers is endocrine therapy, including aromatase inhibitors and selective estrogen receptor modulators and degraders (SERMs and SERDs), that either block the production of estrogen or competitively inhibit the binding of estrogen to ERa. These small molecule antiestrogens work by inhibiting the proproliferative actions of estrogen but after years of treatment, many cancers recur as resistant tumors. Recently, we discovered a non-competitive modulator of ERa that works in a strikingly different way. BHPI acts through ERa to hyperactivate a lethal anticipatory unfolded protein response (UPR), hijacking a normally protective and pro-proliferative action of estrogen and ERa. We have found that BHPI effectively inhibits proliferation of and kills breast cancer cells expressing constitutive and antiestrogen resistant mutations, ERaY537S and ERaD538G, that are common in metastatic breast cancer and upregulate the UPR. Surprisingly, BHPI does not kill cancer cells through classical UPR activated, CHOP-mediated, caspase-dependent apoptosis, but rather through necrosis initiated by ATP depletion. This death pathway includes rapid swelling of ERa+ cancer cells and release of arachidonic acid, and is downstream of calcium release from the endoplasmic reticulum (EnR). Interestingly, preliminary data suggests that necrotic products released from cells treated with BHPI may act as markers of inflammation that activate immune cells. Strong and sustained activation of the anticipatory UPR leading to necrotic cell death and inflammation may represent a new strategy to target ERa+ cancers

Eurasian Arctic greening reveals teleconnections and the potential for novel ecosystems

Arctic warming has been linked to observed increases in tundra shrub cover and growth in recent decades on the basis of significant relationships between deciduous shrub growth/biomass and temperature. These vegetation trends have been linked to Arctic sea ice decline and thus to the sea ice/albedo feedback known as Arctic amplification. However, the interactions between climate, sea ice and tundra vegetation remain poorly understood. Here we reveal a 50- year growth response over a >100,000 km2 area to a rise in summer temperature for alder (Alnus) and willow (Salix), the most abundant shrub genera respectively at and north of the continental treeline. We demonstrate that whereas plant productivity is related to sea ice in late spring, the growing season peak responds to persistent synoptic-scale air masses over West Siberia associated with Fennoscandian weather systems through the Rossby wave train. Substrate is important for biomass accumulation, yet a strong correlation between growth and temperature encompasses all observed soil types. Vegetation is especially responsive to temperature in early summer. These results have significant implications for modelling present and future Low Arctic vegetation responses to climate change, and emphasize the potential for structurally novel ecosystems to emerge fromwithin the tundra zone.Vertaisarviointia edeltävä käsikirjoitu

Retarding field energy analyser ion current calibration and transmission

International audienceAccurate measurement of ion current density and ion energy distributions (IED) is often critical for plasma processes in both industrial and research settings. Retarding field energy analyzers (RFEA) have been used to measure IEDs because they are considered accurate, relatively simple and cost effective. However, their usage for critical measurement of ion current density is less common due to difficulties in estimating the proportion of incident ion current reaching the current collector through the RFEA retarding grids. In this paper an RFEA has been calibrated to measure ion current density from an ion beam at pressures ranging from 0.5 to 50.0 mTorr. A unique method is presented where the currents generated at each of the retarding grids and the RFEA upper face are measured separately, allowing the reduction in ion current to be monitored and accounted for at each stage of ion transit to the collector. From these I-V measurements a physical model is described. Subsequently, a mathematical description is extracted which includes parameters to account for grid transmissions, upper face secondary electron emission and collisionality. Pressure-dependant calibration factors can be calculated from least mean square best fits of the collector current to the model allowing quantitative measurement of ion current density

Micronuclei formation in liver fibrosis samples from patients infected by hepatitis C virus

Genetic research on fibrosis outset and its progression in chronic hepatitis (CH) by hepatitis C virus (HCV) are limited. The lack of cytogenetic data led us to investigate the presence of micronuclei (MNi), as a sign of genomic damage. Hepatocytes of hepatic parenchyma from 62 cases diagnosed with CH associated with HCV and displaying different degrees of fibrosis (F1-F4) were analyzed. These data were compared to 15 cases without fibrosis (F0). Twelve healthy liver parenchyma samples were included as control. All samples were obtained from paraffin-embedded archival material. Micronucleated hepatocytes (MN-Heps) were analyzed through Feulgen/Fast-green staining. Results showed that the rates of MN-Heps in the F4 group were statistically significant (p < 0.05) and higher than those in the control group. Like results were also obtained on comparing F4 with F0, F1, F2 and F3 cases. Conversely, differences were not significant (p > 0.05) on comparing F0, F1, F2, F3, one against the other, as well as individual versus control. Although chromosomal losses in CH were detected, it was shown that liver parenchyma with fibrosis in the initial stages (F1-F3) cannot be considered cytogenetically abnormal

Ecological opportunity and the adaptive diversification of lineages

The tenet that ecological opportunity drives adaptive diversification has been central to theories of speciation since Darwin, yet no widely accepted definition or mechanistic framework for the concept currently exists. We propose a definition for ecological opportunity that provides an explicit mechanism for its action. In our formulation, ecological opportunity refers to environmental conditions that both permit the persistence of a lineage within a community, as well as generate divergent natural selection within that lineage. Thus, ecological opportunity arises from two fundamental elements: (1) niche availability, the ability of a population with a phenotype previously absent from a community to persist within that community and (2) niche discordance, the diversifying selection generated by the adaptive mismatch between a population's niche-related traits and the newly encountered ecological conditions. Evolutionary response to ecological opportunity is primarily governed by (1) spatiotemporal structure of ecological opportunity, which influences dynamics of selection and development of reproductive isolation and (2) diversification potential, the biological properties of a lineage that determine its capacity to diversify. Diversification under ecological opportunity proceeds as an increase in niche breadth, development of intraspecific ecotypes, speciation, and additional cycles of diversification that may themselves be triggered by speciation. Extensive ecological opportunity may exist in depauperate communities, but it is unclear whether ecological opportunity abates in species-rich communities. Because ecological opportunity should generally increase during times of rapid and multifarious environmental change, human activities may currently be generating elevated ecological opportunity – but so far little work has directly addressed this topic. Our framework highlights the need for greater synthesis of community ecology and evolutionary biology, unifying the four major components of the concept of ecological opportunity.Supported by National Science Foundation grants to GAW (DEB-0716927) and RBL (DEB-0842364). University of Oklahoma Libraries and Biological Station assisted with publication charges.YesEcology and Evolution maintains the highest standards of peer review while increasing the efficiency of the process. All research articles published in the journal will undergo full peer review, key characteristics of which are: • All research articles submitted directly to the Journal are initially evaluated by the Editor-in-Chief; articles found appropriate for the Journal will be reviewed by at least two suitably qualified experts. • All publication decisions are made by the Editor-in-Chief on the basis of the reviews provided. • Members of the editorial board lend insight, advice and guidance to the Editor-in-Chief generally and assist in decision making on specific submissions. • The managing editor and editorial assistant provide administrative support to ensure Ecology and Evolution maintains the integrity of peer review and delivers rapid and efficient publication to authors and reviewers. http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%292045-7758/homepage/ProductInformation.htm

A verification framework for interannual-to-decadal predictions experiments

Decadal predictions have a high profile in the climate science community and beyond, yet very little is known about their skill. Nor is there any agreed protocol for estimating their skill. This paper proposes a sound and coordinated framework for verification of decadal hindcast experiments. The framework is illustrated for decadal hindcasts tailored to meet the requirements and specifications of CMIP5 (Coupled Model Intercomparison Project phase 5). The chosen metrics address key questions about the information content in initialized decadal hindcasts. These questions are: (1) Do the initial conditions in the hindcasts lead to more accurate predictions of the climate, compared to un-initialized climate change projections? and (2) Is the prediction model’s ensemble spread an appropriate representation of forecast uncertainty on average? The first question is addressed through deterministic metrics that compare the initialized and uninitialized hindcasts. The second question is addressed through a probabilistic metric applied to the initialized hindcasts and comparing different ways to ascribe forecast uncertainty. Verification is advocated at smoothed regional scales that can illuminate broad areas of predictability, as well as at the grid scale, since many users of the decadal prediction experiments who feed the climate data into applications or decision models will use the data at grid scale, or downscale it to even higher resolution. An overall statement on skill of CMIP5 decadal hindcasts is not the aim of this paper. The results presented are only illustrative of the framework, which would enable such studies. However, broad conclusions that are beginning to emerge from the CMIP5 results include (1) Most predictability at the interannual-to-decadal scale, relative to climatological averages, comes from external forcing, particularly for temperature; (2) though moderate, additional skill is added by the initial conditions over what is imparted by external forcing alone; however, the impact of initialization may result in overall worse predictions in some regions than provided by uninitialized climate change projections; (3) limited hindcast records and the dearth of climate-quality observational data impede our ability to quantify expected skill as well as model biases; and (4) as is common to seasonal-to-interannual model predictions, the spread of the ensemble members is not necessarily a good representation of forecast uncertainty. The authors recommend that this framework be adopted to serve as a starting point to compare prediction quality across prediction systems. The framework can provide a baseline against which future improvements can be quantified. The framework also provides guidance on the use of these model predictions, which differ in fundamental ways from the climate change projections that much of the community has become familiar with, including adjustment of mean and conditional biases, and consideration of how to best approach forecast uncertainty