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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.12.054 Byline: Maya Capelson (1), Yun Liang (1), Roberta Schulte (1), William Mair (1), Ulrich Wagner (2), Martin W. Hetzer (1) Keywords: CELLBIO; RNA; DEVBIO Abstract: Nuclear pore complexes have recently been shown to play roles in gene activation; however their potential involvement in metazoan transcription remains unclear. Here we show that the nucleoporins Sec13, Nup98, and Nup88, as well as a group of FG-repeat nucleoporins, bind to the Drosophila genome at functionally distinct loci that often do not represent nuclear envelope contact sites. Whereas Nup88 localizes to silent loci, Sec13, Nup98, and a subset of FG-repeat nucleoporins bind to developmentally regulated genes undergoing transcription induction. Strikingly, RNAi-mediated knockdown of intranuclear Sec13 and Nup98 specifically inhibits transcription of their target genes and prevents efficient reactivation of transcription after heat shock, suggesting an essential role of NPC components in regulating complex gene expression programs of multicellular organisms. Author Affiliation: (1) Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA (2) Ludwig Institute for Cancer Research, University of California School of Medicine, 9500 Gilman Drive, La Jolla, CA 92037, USA Article History: Received 18 May 2009; Revised 6 October 2009; Accepted 29 December 2009 Article Note: (miscellaneous) Published: February 4, 2010

Next-generation sequencing (NGS) enables parallel analysis of multiple genomic targets. The increasing demand for NGS-based multiplexed molecular diagnostics requires standardized protocols and recommendations to ensure reproducibility and accuracy of test results for routine clinical decision making. However, the lack of clinical NGS data from multi-laboratory tests and the absence of inter-laboratory comparisons have hampered the establishment of instructive clinical NGS standards. To fill the gap, we set up Proficiency Testing (PT) for inter-laboratory comparison, in which formalin-fixed paraffin-embedded specimens from eight lung and eight colon cancers were analyzed by 15 European molecular diagnostic laboratories on three different platforms using multiple target enrichment systems. We first performed platform, test, and informatics pipeline validation and conducted sensitivity and specificity analysis by random in silico down-sampling. We then implemented a multi-level filtering strategy based on performance tests of base substitution, replicate runs, and Sanger sequencing verified variants. We finally applied the filter criteria to the NGS data from the respective PT participants and obtained high inter-laboratory agreement. We demonstrated accuracy, scalability, and robustness of NGS by means of PT, serving as a benchmark for detecting clinically actionable molecular alterations in research and diagnostic laboratories. In conclusion, this study strongly highlights the importance of establishing standards for NGS-based testing, particularly when the test results impact on clinical decisions, and systematically provides data sets from multiple different labs to infer such standards. [ABSTRACT FROM AUTHOR]

Purpose Edge illumination (EI) X-ray phase-contrast imaging (XPCI) has been under development at University College London in recent years, and has shown great potential for both laboratory and synchrotron applications. In this work, we propose a new acquisition and processing scheme. Contrary to existing retrieval methods for EI, which require as input two images acquired in different setup configurations, the proposed approach can retrieve an approximate map of the X-ray phase from a single image, thus significantly simplifying the acquisition procedure and reducing data collection times. Methods The retrieval method is analytically derived, based on the assumption of a quasi-homogeneous object, i.e. an object featuring a constant ratio between refractive index and absorption coefficient. The noise properties of the input and retrieved images are also theoretically analyzed under the developed formalism. The method is applied to experimental synchrotron images of a biological object. Results The experimental results show that the method can provide high-quality images, where the “edge” signal typical of XPCI images is transformed to an “area” contrast that enables an easier interpretation of the sample geometry. Moreover, the retrieved images confirm that the method is highly stable against noise. Conclusions We anticipate that the developed approach will become the method of choice for a variety of applications of EI XPCI, thanks to its ability to simplify the acquisition procedure and reduce acquisitions time and dose to the sample. Future work will focus on the adaptation of the method to computed tomography and to polychromatic radiation from X-ray tubes. [ABSTRACT FROM AUTHOR]

Abstract: Recent advances in intergroup contact theory and research are reviewed. A meta-analysis with 515 studies and more than 250,000 subjects demonstrates that intergroup contact typically reduces prejudice (mean r =−.21). Allport''s original conditions for optimal contact – equal status, common goals, no intergroup competition, and authority sanction – facilitate the effect but are not necessary conditions. There are other positive outcomes of intergroup contact, such as greater trust and forgiveness for past transgressions. These contact effects occur not only for ethnic groups but also for such other groups as homosexuals, the disabled and the mentally ill. Intergroup friendship is especially important. Moreover, these effects typically generalize beyond the immediate outgroup members in the situation to the whole outgroup, other situations, and even to other outgroups not involved in the contact. They also appear to be universal – across nations, genders, and age groups. The major mediators of the effect are basically affective: reduced anxiety and empathy. And even indirect contact reduces prejudice – vicarious contact through the mass media and having a friend who has an outgroup friend. Of course, negative contact occurs – especially when it is non-voluntary and threatening. Criticisms of the theory and policy implications are also discussed. [Copyright &y& Elsevier]

Abstract: According to Allport''s (1954) model of socialization of prejudice the level of prejudice of parents and their offspring should co-vary due to the offspring''s adaptation to the parents’ attitudes. Available empirical studies and literature reviews support Allport''s assumption. Modern models of socialization give reason to extend Allport''s unidirectional influence model to a bidirectional perspective which assumes that parents influence their offspring''s attitudes and are simultaneously influenced by them. In a cross-sectional study, 408 parent–offspring dyads (64% female parents, 55% female offspring, mean age of children=16.47 years, SD 1.87, parents=42.08 years, SD 7.08) from the ethnic majority population in Costa Rica were asked about their prejudice towards immigrants and ethnic minorities in Costa Rica. Using structural equation modelling, unidirectional and bidirectional models of prejudice determination were tested. The data clearly support the unidirectional model of prejudice transmission from parents to offspring, even if moderator effects of sex, age, and importance of contact are taken into account. [Copyright &y& Elsevier]

Abstract: Intergroup contact theory and research have advanced rapidly in recent years. Among the advances is the surprising finding that indirect contact (having an ingroup friend who has an outgroup friend) reduces prejudice at levels comparable to those of direct contact (having an outgroup friend yourself). Using a large, probability survey of German adults, we explore the relationship between direct and indirect contact. We find they are highly interrelated, and both are negatively related to prejudices against foreigners and Muslims living in Germany. Direct and indirect contact together enhance the prediction of prejudice. Moreover, the two contact types are shaped by similar social and personality variables. Opportunity for contact is important, while authoritarians avoid contact. Their effects are mediated by threat, but here we find the one difference between the two types. Direct contact is negatively related to both individual and collective threat. Indirect contact is also negatively related to collective threat but only slightly related to individual threat. We interpret these relationships within a normative perspective. [Copyright &y& Elsevier]

Abstract: In the current research, we examined whether promoting an inclusive national ingroup that includes both immigrants and nonimmigrants would improve attitudes toward immigrants and immigration among members of receiving societies. We also determined whether one''s nation of citizenship and individual differences in social dominance orientation would moderate the effects. Participants were 126 Canadian students and 282 German students, who completed a measure of social dominance orientation and were then asked to respond to a series of questions designed to heighten the salience of national identity (national identity), promote a national ingroup that includes immigrants (common national ingroup), or irrelevant questions (control). The dependent measures included attitudes toward immigrants and immigration, and subtle prejudice toward immigrants. Results revealed that the manipulation of a common national ingroup successfully promoted more positive attitudes toward immigrants and immigration among higher social dominance oriented Canadian participants, but tended to have detrimental effects on the attitudes of higher social dominance oriented German participants. Results are discussed in terms of the importance of considering the context in which groups are situated, as well as implications for developing strategies to promote harmony between immigrants and members of receiving societies. [Copyright &y& Elsevier]

Because company cars add to corporate CO 2 footprints, companies are beginning to replace cars with mobility budgets that employees can use for leisure and commuting trips. This study examines whether nudges can encourage sustainable travel in such a subsidized setting. We conduct a field experiment with 341 employees of a large German company. Observing expenditure items charged to the mobility budget, we test if social comparisons and a climate-related moral appeal induce a shift towards low-emissions transport modes. We find that simultaneous application of both nudges causes a reduction in car use, particularly taxi and ride sharing, as well as substitution towards micromobility, but not public transport. The social comparison alone is not effective, and the treatment effects of the combined nudge vanish in the second half of the treatment period. Survey evidence suggests that these results are driven by a minority that complies with the communicated social norm. [ABSTRACT FROM AUTHOR]

Highlights • A market model for energy trading and energy management of Microgrids is described. • Device-oriented bidding strategies are presented for each device type in buildings. • PV probabilistic forecast is integrated to demonstrate market dynamics on different type days. • The utility and prosumers benefit, in addition to the added value of the ICT infrastructure are quantified. Abstract Energy trading markets are one of the most viable solutions to incentivize prosumers in Microgrids. They offer the utility a versatile access for flexible loads coordination without violating the consumer privacy. In the literature, several models and designs were presented to address different aspects of energy trading markets, yet there is a gap between these models and their application in real-life. This paper describes a novel discrete-timely double-sided auction model that facilitates energy trading between prosumers in near real-time and forward markets. Since the practical realization of the model represents a crucial criterion for this model, the market is designed with fast clearing mechanism and simple bidding rules that guarantee the benefits of the prosumers, their privacy, and consider their personal preferences. Additionally, a decentralized home energy management approach is followed at the prosumer level to maximize the system reliability and enable an easy integration of multiple devices from different manufacturers. Hence, a device-oriented bidding strategy is demonstrated that considers the physical characteristics and technical limitations of each device type such as electric vehicles (EV), micro-combined heat and power systems (micro-CHP) or heat pumps. Furthermore, an open-source day-ahead probabilistic forecast for the photovoltaic systems (PV) is integrated with a bidding scheme that maximizes the prosumers commitment in the forward market. In the results, field measurements and testbeds data are used to quantify the benefits of the market model to the utility and the prosumers based on different metrics such as self-sufficiency, self-consumption, peak load and CO 2 emission reduction, and total costs. The results indicate that the market model can increase self-sufficiency and self-consumption of a microgrid while reducing the prosumer costs on average by 23%. [ABSTRACT FROM AUTHOR]

Highlights • A probabilistic PV forecast model tailored for EMS applications is presented. • The model showed its capability to forecast using only the commonly available data in buildings. • Different evaluation metrics were used to validate the reliability and accuracy of the model. Abstract The photovoltaic (PV) generation forecast is a key element to an efficient building energy management system (EMS) operation. The forecast’s uncertainties and generation variabilities expose the loads to misplanning, and hence decrease building autonomy, self-sufficiency, and potential costs savings. In this paper, a novel approach for a day-ahead PV power generation probabilistic forecast is proposed that is especially optimized for building EMS applications. The model consists of several modules to develop the probabilistic forecast. Initially, a clear sky model is tuned to incorporate the system and temperature losses and partial shading. The deviation of the PV power from the clear sky power is used to train a bagging regression tree, which produces a deterministic point forecast. The probabilistic forecast is developed based on the probabilistic analysis of the point forecast and regenerating it based on the given weather conditions. The model is developed based on the available data in buildings such as the historic PV measurements acquired from the inverter and the weather forecasts. The probabilistic forecast was validated over a complete-year data set of a rooftop PV system in Munich, Germany, where the results showed its capability to provide an accurate and reliable forecast for EMS applications. [ABSTRACT FROM AUTHOR]

: ObjectiveThe number of scientific publications is often used to measure scientific achievement. This practice can motivate unethical conduct, such as redundant or duplicate publications, defined as publication of the same scientific contents in more than 1 journal. The aim of this study was to estimate the amount of redundant publications in ophthalmologic journals.: DesignRetrospective analysis of published literature.: MethodsWe developed an electronic search engine for redundancies to estimate the amount of duplicate publications in scientific journals. When redundancies reached a given degree (matching score), the articles were screened manually based on authors, titles, and abstracts. We applied this method to the 22 433 articles that were published between 1997 and 2000 in 70 ophthalmologic journals indexed by MEDLINE.: Main outcome measuresThe number of duplicate publications with a matching score of 0.6 or more, the number of involved journals, and the number of authors.: ResultsRedundancies reached a matching score of 0.6 or more in 13 967 pairs of articles. Out of them, a sample of 2210 was reviewed manually. We found 60 redundant articles and estimated that 1.39% of the publications were redundant. Thirty-two journals and an estimate of 1092 authors were involved. In 5% of cases, the scientific conclusions were modified.: ConclusionsBecause of the restrictive selection process, the impracticability of detecting all redundant publications, and the estimated amount of duplicates increases with lower matching scores, we regard our estimate to be the tip of the iceberg. Duplicate publications have several negative impacts, but neither peer reviewers nor editors can protect their journal from them completely. Several deterrents for duplicate publications are possible, but as long as publications remain the central requirement for academic advancement, a solution seems unlikely. Nevertheless, it is the responsibility of all those who care about objective research and evidence-based medicine to address this problem—not only in ophthalmology. [Copyright &y& Elsevier]

Inflammatory myofibroblastic tumors are rare tumors with an ALK (anaplastic lymphoma kinase) gene rearrangement in up to 65% of all cases. In our patient, the tumor was not primary resectable due to its extension. Under neoadjuvant treatment with the first generation ALK inhibitor crizotinib no tumor response was seen, but the following therapy with the next generation ALK inhibitor lorlatinib led to a rapid and deep response, enabling a complete tumor resection by partial cystectomy. Our case indicates that ALK positive inflammatory myofibroblastic tumors which do not respond to ALK inhibition with crizotinib can be successfully treated with newer agents. [ABSTRACT FROM AUTHOR]

Demand-side Management (DSM) algorithms are exposed to several uncertainties due to their dependency on renewable energy generation forecasts. On the large scale, generation and load forecasts can be relatively accurate, yet on the residential scale, forecasting errors increase due to higher uncertainties. One potential solution is to incorporate a probabilistic PV forecast into an optimal DSM algorithm instead of the existing deterministic PV forecasting algorithms. Hence, in this contribution, a numerical analysis that compares the potential of using a probabilistic PV forecast instead of the conventional deterministic algorithms in a DSM algorithm, is presented. Results show that under different household energy system configurations, the DSM algorithm with the probabilistic PV generation forecast leads to an increase in self-sufficiency and self-consumption by 24.2% and 17.7%, respectively, compared to the conventional deterministic algorithms. These results indicate that probabilistic PV forecasting algorithms may indeed have a higher potential compared to the conventional deterministic ones. [ABSTRACT FROM AUTHOR]

Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non- ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK , EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology. [ABSTRACT FROM AUTHOR]

Increasing distributed energy resource penetration requires additional methods to tackle grid congestion and enhance reliability. In addition, advancements in demand-side management can help strengthen distribution network stability. A viable approach is to develop local flexibility markets (LFMs) to aggregate prosumer flexibility potentials and offer grid ancillary services. To facilitate such prosumer–market interactions, an open-source model, named OpenTUMFlex is developed in this study to quantify and price prosumer flexibility. The core of this model is an energy management system that optimizes prosumer data to obtain a cost-optimal operation schedule. Flexibility potential is defined as all possible deviations from this optimal operation without violating device constraints. Flexibility services are characterized as positive and negative flexibility based on the energy exchanged with the grid. Also, a predictive pricing mechanism is introduced to identify the minimum price the prosumer needs to be compensated for their flexibility service. The outcome of this model is a flexibility offer table using which the prosumer can bid in the LFMs. An iterative interaction between the OpenTUMFlex model and LFM is possible as the model integrates the flexibility service requirements from the selected bid into its operational schedule and generates a new optimal operation schedule with renewed flexibility offers. The model is analyzed using two case studies where a sample flexibility service implementation for different prosumer devices is discussed. In addition, a unique flexibility representation technique is introduced to illustrate the flexibility offers graphically. Future research will focus on identifying the impact of forecast uncertainty on flexibility quantification. [Display omitted] • OpenTUMFlex performs prosumer flexibility quantification using a Home Energy Management System. • A predictive pricing mechanism is introduced to identify the minimum price for the prosumer flexibility service. • A flexibility representation technique is used to graphically illustrate the flexibility bids. • Case studies on implementation of prosumer flexibility service using the OpenTUMFlex model are discussed. [ABSTRACT FROM AUTHOR]

Summary Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients. [ABSTRACT FROM AUTHOR]

The advancing energy transition is leading to a constantly increasing number of prosumers and active participants in the energy system. Local energy markets are considered a promising approach to coordinate those active participants efficiently, increase acceptance among the population, and decrease grid expansion costs. However, energy models and markets do not consider heterogeneous user preferences which are considered crucial for the progressing energy transition. Therefore, this paper proposes new auction-based local energy market models that consider user preferences and users' willingness to pay a premium for heterogeneous energy qualities. In order to account for the unknown and stochastic user behavior in such a new market setting, we simulate and compare existing and newly developed auction-based clearing algorithms with an unbiased Monte Carlo method and evaluate whether they fulfill pre-defined key characteristics. Based on the results, we conclude and identify a clearing algorithm that verifiably satisfies user preferences, considers willingness to pay a premium, increases local coverage of electricity, maintains individual rationality, and computational tractability. The presented clearing algorithms enable new market designs that can help to increase acceptance and accelerate the expansion of renewable energies. All market models and simulations are publicly available in the open-source repository lemlab. Future research will validate the presented results in a field trial in Germany with 20 households. • New auction-based clearing algorithms for community-based local energy markets. • New bidding format for local energy markets. • Verifiable satisfaction of user preferences. • Incorporation of willingness-to-pay a premium for heterogeneous energy qualities. • Increasing local coverage of electricity supply and demand. [ABSTRACT FROM AUTHOR]

Abstract: Adaptations in the anterior cingulate cortex (ACC) have been implicated in alcohol and drug addiction. To identify genes that may contribute to excessive drinking, here we performed microarray analyses in laser microdissected rat ACC after a single or repeated administration of an intoxicating dose of alcohol (3g/kg). Expression of the small G protein K-ras was differentially regulated following both single and repeated alcohol administration. We also observed that voluntary alcohol intake in K-ras heterozygous null mice (K-ras+/ −) did not increase after withdrawal from repeated cycles of intermittent ethanol vapor exposure, unlike in their wild-type littermates. To identify K-ras regulated pathways, we then profiled gene expression in the ACC of K-ras+/−, heterozygous null mice for the K-ras negative regulator Nf1 (Nf1+/−) and wild-type mice following repeated administration of an intoxicating dose of alcohol. Pathway analysis showed that alcohol differentially affected various pathways in a K-ras dependent manner – some of which previously shown to be regulated by alcohol – including the insulin/PI3K pathway, the NF-κB, the phosphodiesterases (PDEs) pathway, the Jak/Stat and the adipokine signaling pathways. Altogether, the data implicate K-ras-regulated pathways in the regulation of excessive alcohol drinking after a history of dependence. [Copyright &y& Elsevier]

Summary: Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) α and β and their receptor (LTβR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTαβ expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6+ oval cells, depends on lymphocytes and IKappa B kinase β expressed by hepatocytes but is independent of TNFR1. In vivo LTβR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTβR inhibition in LTαβ-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC. [Copyright &y& Elsevier]

Abstract: Cysteinyl-leukotriene-1 receptor antagonists are important tools in the therapy of asthma. Although many studies have been performed concerning their effects on airway smooth muscle tone, there are no basic data on their effects on airway secretions. Therefore, we assessed the effects of zafirlukast and montelukast on rat tracheal secretion by quantification of secreted 35S04 labelled mucus macromolecules, and determined the influence of the arachidonic acid pathway using the modified Ussing chamber technique. Zafirlukast (432±89.99%) and montelukast (167±16.74%) stimulated rat tracheal secretion. This was abolished by application of eicosatetraenoic acid, an inhibitor of the arachidonic acid metabolism. Whereas inhibition of cyclooxygenase did not show any significant effect on zafirlukast induced secretion, blockade of the 5-lipoxygenase pathway markedly reduced the secretagogue effects. Furthermore, inhibition of phosphatidylinositol-3-kinase completely inhibited the effects elicited by zafirlukast. Additional experiments revealed secretagogue effects of zafirlukast also in human bronchial tissue. In conclusion, zafirlukast is a potent inducer of tracheal secretion. Obviously, these effects are induced by involvement of a phosphatidylinositol-3-kinase dependent pathway mediated by products of the arachidonic acid metabolism. [Copyright &y& Elsevier]