Herschel/PACS far-infrared photometry of two z>4 quasars

We present Herschel far-infrared (FIR) observations of two sub-mm bright quasars at high redshift: SDSS J1148+5251 (z=6.42) and BR 1202-0725 (z=4.69) obtained with the PACS instrument. Both objects are detected in the PACS photometric bands. The Herschel measurements provide additional data points that constrain the FIR spectral energy distributions (SEDs) of both sources, and they emphasise a broad range of dust temperatures in these objects. For lambda_rest ~< 20mu, the two SEDs are very similar to the average SEDs of quasars at low redshift. In the FIR, however, both quasars show excess emission compared to low-z QSO templates, most likely from cold dust powered by vigorous star formation in the QSO host galaxies. For SDSS J1148+5251 we detect another object at 160mu with a distance of ~10 arcseconds from the QSO. Although no physical connection between the quasar and this object can be shown with the available data, it could potentially confuse low-resolution measurements, thus resulting in an overestimate of the FIR luminosity of the z=6.42 quasar.Comment: 4 pages, 3 figures, accepted for publication in the A&A special issue on Hersche

Short-term Building Energy Model Recommendation System: A Meta-learning Approach

High-fidelity and computationally efficient energy forecasting models for building systems are needed to ensure optimal automatic operation, reduce energy consumption, and improve the building’s resilience capability to power disturbances. Various models have been developed to forecast building energy consumption. However, given buildings have different characteristics and operating conditions, model performance varies. Existing research has mainly taken a trial-and-error approach by developing multiple models and identifying the best performer for a specific building, or presumed one universal model form which is applied on different building cases. To the best of our knowledge, there does not exist a generalized system framework which can recommend appropriate models to forecast the building energy profiles based on building characteristics. To bridge this research gap, we propose a meta-learning based framework, termed Building Energy Model Recommendation System (BEMR). Based on the building’s physical features as well as statistical and time series meta-features extracted from the operational data and energy consumption data, BEMR is able to identify the most appropriate load forecasting model for each unique building. Three sets of experiments on 48 test buildings and one real building were conducted. The first experiment was to test the accuracy of BEMR when the training data and testing data cover the same condition. BEMR correctly identified the best model on 90% of the buildings. The second experiment was to test the robustness of the BEMR when the testing data is only partially covered by the training data. BEMR correctly identified the best model on 83% of the buildings. The third experiment uses a real building case to validate the proposed framework and the result shows promising applicability and extensibility. The experimental results show that BEMR is capable of adapting to a wide variety of building types ranging from a restaurant to a large office, and gives excellent performance in terms of both modeling accuracy and computational efficiency

Do student perceptions of teaching predict the development of representational competence and biological knowledge?

Dealing with representations is a crucial skill for students and such representational competence is essential for learning science. This study analysed the relationship between representational competence and content knowledge, student perceptions of teaching practices concerning the use of different representations, and their impact on students’ outcome over a teaching unit. Participants were 931 students in 51 secondary school classes. Representational competence and content knowledge were interactively related. Representational aspects were only moderately included in teaching and students did not develop rich representational competence although content knowledge increased significantly. Multilevel regression showed that student perceptions of interpreting and constructing visual-graphical representations and active social construction of knowledge predicted students’ outcome at class level, whereas the individually perceived amount of terms and use of symbolic representations influenced the students’ achievement at individual level. Methodological and practical implications of these findings are discussed in relation to the development of representational competence in classrooms

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria

Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients

Elemental and isotopic carbon and nitrogen records of organic matter accumulation in a Holocene permafrost peat sequence in the East European Russian Arctic

A peat deposit from the East European Russian Arctic, spanning nearly 10 000 years, was investigated to study soil organic matter degradation using analyses of bulk elemental and stable isotopic compositions and plant macrofossil remains. The peat accumulated initially in a wet fen that was transformed into a peat plateau bog following aggradation of permafrost in the late Holocene (∼2500 cal a BP). Total organic carbon and total nitrogen (N) concentrations are higher in the fen peat than in the moss‐dominated bog peat layers. Layers in the sequence that have lower concentrations of total hydrogen (H) are associated with degraded vascular plant residues. C/N and H/C atomic ratios indicate better preservation of organic matter in peat material dominated by bryophytes as opposed to vascular plants. The presence of permafrost in the peat plateau stage and water‐saturated conditions at the bottom of the fen stage appear to lead to better preservation of organic plant material. δ 15 N values suggest N isotopic fractionation was driven primarily by microbial decomposition whereas differences in δ 13 C values appear to reflect mainly changes in plant assemblages. Positive shifts in both δ 15 N and δ 13 C values coincide with a local change to drier conditions as a result of the onset of permafrost and frost heave of the peat surface. This pattern suggests that permafrost aggradation not only resulted in changes in vegetation but also aerated the underlying fen peat, which enhanced microbial denitrification, causing the observed 15 N‐enrichment. Copyright © 2012 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93575/1/2541_ftp.pd

Model-guided therapy for hepatocellular carcinoma: A role for information technology in predictive, preventive and personalized medicine

Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different disciplines including hepatologists, gastroenterologists, medical and surgical oncologists, liver transplant teams, interventional radiologists and radiation oncologists. The article concludes with a review providing an outlook and recommendations for the application of MGT to enhance the medical management of HCC through PPPM

MMP-28 as a regulator of myelination

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinase-28 (MMP-28) is a poorly understood member of the matrix metalloproteinase family. Metalloproteinases are important mediators in the development of the nervous system and can contribute to the maturation of the neural micro-environment.</p> <p>Results</p> <p>MMP-28 added to myelinating rat dorsal root ganglion (DRG) co-cultures reduces myelination and two antibodies targeted to MMP-28 (pAb180 and pAb183) are capable of binding MMP-28 and inhibiting its activity in a dose-dependent manner. Addition of 30 nM pAb180 or pAb183 to rat DRG cultures resulted in the 2.6 and 4.8 fold enhancement of myelination respectively while addition of MMP-28 to DRG co-cultures resulted in enhanced MAPK, ErbB2 and ErbB3 phosphorylation. MMP-28 protein expression was increased within demyelinated lesions of mouse experimental autoimmune encephalitis (EAE) and human multiple sclerosis lesions compared to surrounding normal tissue.</p> <p>Conclusion</p> <p>MMP-28 is upregulated in conditions of demyelination in vivo, induces signaling in vitro consistent with myelination inhibition and, neutralization of MMP-28 activity can enhance myelination in vitro. These results suggest inhibition of MMP-28 may be beneficial under conditions of dysmyelination.</p