Expression and cellular localization of the transcription factor NeuroD1 in the developing and adult rat pineal gland

Circadian rhythms govern many aspects of mammalian physiology. The daily pattern of melatonin synthesis and secretion is one of the classic examples of circadian oscillations. It is mediated by a class of neuroendocrine cells known as pinealocytes which are not yet fully defined. An established method to evaluate functional and cytological characters is through the expression of lineage‐specific transcriptional regulators. NeuroD1 is a basic helix‐loop‐helix transcription factor involved in the specification and maintenance of both endocrine and neuronal phenotypes. We have previously described developmental and adult regulation of NeuroD1 mRNA in the rodent pineal gland. However, the transcript levels were not influenced by the elimination of sympathetic input, suggesting that any rhythmicity of NeuroD1 might be found downstream of transcription. Here, we describe NeuroD1 protein expression and cellular localization in the rat pineal gland during development and the daily cycle. In embryonic and perinatal stages, protein expression follows the mRNA pattern and is predominantly nuclear. Thereafter, NeuroD1 is mostly found in pinealocyte nuclei in the early part of the night and in cytoplasm during the day, a rhythm maintained into adulthood. Additionally, nocturnal nuclear NeuroD1 levels are reduced after sympathetic disruption, an effect mimicked by the in vivo administration of α‐ and β‐adrenoceptor blockers. NeuroD1 phosphorylation at two sites, Ser274 and Ser336, associates with nuclear localization in pinealocytes. These data suggest that NeuroD1 influences pineal phenotype both during development and adulthood, in an autonomic and phosphorylation‐dependent manner.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111177/1/jpi12228.pd

Detection of volcanic ash clouds from Nimbus 7/total ozone mapping spectrometer

Measured radiances from the Version 7 reprocessing of the Nimbus 7/total ozone mapping spectrometer (TOMS) 340- and 380-nm channels are used to detect absorbing particulates injected into the atmosphere after the El Chichon eruption on April 4, 1982. It is shown that while the single-channel reflectivity determined from the 380-nm channel is able to detect clouds and haze composed of nonabsorbing aerosols, the spectral contrast between the 340- and 380-nm channels is sensitive to absorbing particulates such as volcanic ash, desert dust, or smoke from biomass burning. In this paper the spectral contrast between these two channels is used to detect the volcanic ash injection into the atmosphere and to track its evolution for several days. The movement of the ash clouds is shown to be consistent with the motions expected from the National Centers for Environmental Prediction (NCEP)-derived balanced wind fields in the troposphere and lower stratosphere. The movement of the volcanic SO2 cloud detected from TOMS data was also in agreement with the NCEP wind at higher altitudes of up to 100–10 mbar. The vertical wind shear in the neighborhood of the eruption site resulted in a clear separation of the ash and SO2 clouds. The location and movement of the ash cloud are consistent with information obtained by the advanced very high resolution radiometer (AVHRR) instrument on board the NOAA 7 satellite and to ground reports of ash fall

Statistical properties of hybrid estimators proposed for GEDI – NASA’s Global Ecosystem Dynamics Investigation

NASA’s Global Ecosystem Dynamics Investigation (GEDI) mission will collect waveform lidar data at a dense sample of ∼25 m footprints along ground tracks paralleling the orbit of the International Space Station (ISS). GEDI’s primary science deliverable will be a 1 km grid of estimated mean aboveground biomass density (Mg ha ^−1 ), covering the latitudes overflown by ISS (51.6 °S to 51.6 °N). One option for using the sample of waveforms contained within an individual grid cell to produce an estimate for that cell is hybrid inference, which explicitly incorporates both sampling design and model parameter covariance into estimates of variance around the population mean. We explored statistical properties of hybrid estimators applied in the context of GEDI, using simulations calibrated with lidar and field data from six diverse sites across the United States. We found hybrid estimators of mean biomass to be unbiased and the corresponding estimators of variance appeared to be asymptotically unbiased, with under-estimation of variance by approximately 20% when data from only two clusters (footprint tracks) were available. In our study areas, sampling error contributed more to overall estimates of variance than variability due to the model, and it was the design-based component of the variance that was the source of the variance estimator bias at small sample sizes. These results highlight the importance of maximizing GEDI’s sample size in making precise biomass estimates. Given a set of assumptions discussed here, hybrid inference provides a viable framework for estimating biomass at the scale of a 1 km grid cell while formally accounting for both variability due to the model and sampling error

Epitaxial Growth and Processing of Compound Semiconductors

Contains an introduction and reports on six research projects.Defense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research University Research Initiative Subcontract N00014-92-J-1893Joint Services Electronics Program Grant DAAH04-95-1-0038National Center for Integrated Photonics Technology Contract 542-381National Science Foundation Grant DMR 92-02957MIT Lincoln Laboratory Contract BX-6085National Center for Integrated Photonics Technology Subcontract 542-383U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0126U.S. Navy - Office of Naval Research Grant N00014-91-J-1956National Science Foundation Grant DMR 94-0033

Vocal Accuracy and Neural Plasticity Following Micromelody-Discrimination Training

Recent behavioral studies report correlational evidence to suggest that non-musicians with good pitch discrimination sing more accurately than those with poorer auditory skills. However, other studies have reported a dissociation between perceptual and vocal production skills. In order to elucidate the relationship between auditory discrimination skills and vocal accuracy, we administered an auditory-discrimination training paradigm to a group of non-musicians to determine whether training-enhanced auditory discrimination would specifically result in improved vocal accuracy.We utilized micromelodies (i.e., melodies with seven different interval scales, each smaller than a semitone) as the main stimuli for auditory discrimination training and testing, and we used single-note and melodic singing tasks to assess vocal accuracy in two groups of non-musicians (experimental and control). To determine if any training-induced improvements in vocal accuracy would be accompanied by related modulations in cortical activity during singing, the experimental group of non-musicians also performed the singing tasks while undergoing functional magnetic resonance imaging (fMRI). Following training, the experimental group exhibited significant enhancements in micromelody discrimination compared to controls. However, we did not observe a correlated improvement in vocal accuracy during single-note or melodic singing, nor did we detect any training-induced changes in activity within brain regions associated with singing.Given the observations from our auditory training regimen, we therefore conclude that perceptual discrimination training alone is not sufficient to improve vocal accuracy in non-musicians, supporting the suggested dissociation between auditory perception and vocal production

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe

Measurement of prompt open-charm production cross sections in proton-proton collisions at root s=13 TeV

The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13TeV are reported. The measurement is performed using a data sample collected by the CMS experiment corresponding to an integrated luminosity of 29 nb(-1). The differential production cross sections of the D*(+/-), D-+/-, and D-0 ((D) over bar (0)) mesons are presented in ranges of transverse momentum and pseudorapidity 4 < p(T) < 100 GeV and vertical bar eta vertical bar < 2.1, respectively. The results are compared to several theoretical calculations and to previous measurements.Peer reviewe