The Spectroscopically Determined Substellar Mass Function of the Orion Nebula Cluster

We present a spectroscopic study of candidate brown dwarf members of the Orion Nebula Cluster (ONC). We obtained new J- and/or K-band spectra of ~100 objects within the ONC which are expected to be substellar based on their K,(H-K) magnitudes and colors. Spectral classification in the near-infrared of young low mass objects is described, including the effects of surface gravity, veiling due to circumstellar material, and reddening. From our derived spectral types and existing near-infrared photometry we construct an HR diagram for the cluster. Masses are inferred for each object and used to derive the brown dwarf fraction and assess the mass function for the inner 5.'1 x 5.'1 of the ONC, down to ~0.02 solar masses. The derived logarithmic mass function rises to a peak at ~0.2 solar masses, similar to previous IMF determinations derived from purely photometric methods, but falls off more sharply at the hydrogen-burning limit before leveling through the substellar regime. We compare the mass function derived here for the inner ONC to those presented in recent literature for the sparsely populated Taurus cloud members and the rich cluster IC 348. We find good agreement between the shapes and peak values of the ONC and IC 348 mass distributions, but little similarity between the ONC and Taurus results.Comment: Accepted for Publication in Apj. Added Erratu

Purine biosynthesis in archaea: variations on a theme

<p>Abstract</p> <p>Background</p> <p>The ability to perform <it>de novo </it>biosynthesis of purines is present in organisms in all three domains of life, reflecting the essentiality of these molecules to life. Although the pathway is quite similar in eukaryotes and bacteria, the archaeal pathway is more variable. A careful manual curation of genes in this pathway demonstrates the value of manual curation in archaea, even in pathways that have been well-studied in other domains.</p> <p>Results</p> <p>We searched the Integrated Microbial Genome system (IMG) for the 17 distinct genes involved in the 11 steps of <it>de novo </it>purine biosynthesis in 65 sequenced archaea, finding 738 predicted proteins with sequence similarity to known purine biosynthesis enzymes. Each sequence was manually inspected for the presence of active site residues and other residues known or suspected to be required for function.</p> <p>Many apparently purine-biosynthesizing archaea lack evidence for a single enzyme, either glycinamide ribonucleotide formyltransferase or inosine monophosphate cyclohydrolase, suggesting that there are at least two more gene variants in the purine biosynthetic pathway to discover. Variations in domain arrangement of formylglycinamidine ribonucleotide synthetase and substantial problems in aminoimidazole carboxamide ribonucleotide formyltransferase and inosine monophosphate cyclohydrolase assignments were also identified.</p> <p>Manual curation revealed some overly specific annotations in the IMG gene product name, with predicted proteins without essential active site residues assigned product names implying enzymatic activity (21 proteins, 2.8% of proteins inspected) or Enzyme Commission (E. C.) numbers (57 proteins, 7.7%). There were also 57 proteins (7.7%) assigned overly generic names and 78 proteins (10.6%) without E.C. numbers as part of the assigned name when a specific enzyme name and E. C. number were well-justified.</p> <p>Conclusions</p> <p>The patchy distribution of purine biosynthetic genes in archaea is consistent with a pathway that has been shaped by horizontal gene transfer, duplication, and gene loss. Our results indicate that manual curation can improve upon automated annotation for a small number of automatically-annotated proteins and can reveal a need to identify further pathway components even in well-studied pathways.</p> <p>Reviewers</p> <p>This article was reviewed by Dr. Céline Brochier-Armanet, Dr Kira S Makarova (nominated by Dr. Eugene Koonin), and Dr. Michael Galperin.</p

Reference-free removal of EEG-fMRI ballistocardiogram artifacts with harmonic regression

Combining electroencephalogram (EEG) recording and functional magnetic resonance imaging (fMRI) offers the potential for imaging brain activity with high spatial and temporal resolution. This potential remains limited by the significant ballistocardiogram (BCG) artifacts induced in the EEG by cardiac pulsation-related head movement within the magnetic field. We model the BCG artifact using a harmonic basis, pose the artifact removal problem as a local harmonic regression analysis, and develop an efficient maximum likelihood algorithm to estimate and remove BCG artifacts. Our analysis paradigm accounts for time-frequency overlap between the BCG artifacts and neurophysiologic EEG signals, and tracks the spatiotemporal variations in both the artifact and the signal. We evaluate performance on: simulated oscillatory and evoked responses constructed with realistic artifacts; actual anesthesia-induced oscillatory recordings; and actual visual evoked potential recordings. In each case, the local harmonic regression analysis effectively removes the BCG artifacts, and recovers the neurophysiologic EEG signals. We further show that our algorithm outperforms commonly used reference-based and component analysis techniques, particularly in low SNR conditions, the presence of significant time-frequency overlap between the artifact and the signal, and/or large spatiotemporal variations in the BCG. Because our algorithm does not require reference signals and has low computational complexity, it offers a practical tool for removing BCG artifacts from EEG data recorded in combination with fMRI.National Institutes of Health (U.S.) (Award DP1-OD003646)National Institutes of Health (U.S.) (Award TR01-GM104948)National Institutes of Health (U.S.) (Grant R44NS071988)National Institute of Neurological Diseases and Stroke (U.S.) (Grant Grant R44NS071988

Comparing alternating pressure mattresses and high-specification foam mattresses to prevent pressure ulcers in high-risk patients: the PRESSURE 2 RCT

Background: Pressure ulcers (PUs) are a burden to patients, carers and health-care providers. Specialist mattresses minimise the intensity and duration of pressure on vulnerable skin sites in at-risk patients. Primary objective: Time to developing a new PU of category ≥ 2 in patients using an alternating pressure mattress (APM) compared with a high-specification foam mattress (HSFM). Design: A multicentre, Phase III, open, prospective, planned as an adaptive double-triangular group sequential, parallel-group, randomised controlled trial with an a priori sample size of 2954 participants. Randomisation used minimisation (incorporating a random element). Setting: The trial was set in 42 secondary and community inpatient facilities in the UK. Participants: Adult inpatients with evidence of acute illness and at a high risk of PU development. Interventions and follow-up: APM or HSFM – the treatment phase lasted a maximum of 60 days; the final 30 days were post-treatment follow-up. Main outcome measures: Time to event. Results: From August 2013 to November 2016, 2029 participants were randomised to receive either APM (n = 1016) or HSFM (n = 1013). Primary end point – 30-day final follow-up: of the 2029 participants in the intention-to-treat population, 160 (7.9%) developed a new PU of category ≥ 2. There was insufficient evidence of a difference between groups for time to new PU of category ≥ 2 [Fine and Gray model HR 0.76, 95% confidence interval (CI) 0.56 to 1.04; exact p-value of 0.0890 and 2% absolute difference]. Treatment phase sensitivity analysis: 132 (6.5%) participants developed a new PU of category ≥ 2 between randomisation and end of treatment phase. There was a statistically significant difference in the treatment phase time-to-event sensitivity analysis (Fine and Gray model HR 0.66, 95% CI 0.46 to 0.93; p = 0.0176 and 2.6% absolute difference). Secondary end points – 30-day final follow-up: new PUs of category ≥ 1 developed in 350 (17.2%) participants, with no evidence of a difference between mattress groups in time to PU development, (Fine and Gray model HR 0.83, 95% CI 0.67 to 1.02; p-value = 0.0733 and absolute difference 3.1%). New PUs of category ≥ 3 developed in 32 (1.6%) participants with insufficient evidence of a difference between mattress groups in time to PU development (Fine and Gray model HR 0.81, 95% CI 0.40 to 1.62; p = 0.5530 and absolute difference 0.4%). Of the 145 pre-existing PUs of category 2, 89 (61.4%) healed – there was insufficient evidence of a difference in time to healing (Fine and Gray model HR 1.12, 95% CI 0.74 to 1.68; p = 0.6122 and absolute difference 2.9%). Health economics – the within-trial and long-term analysis showed APM to be cost-effective compared with HSFM; however, the difference in costs models are small and the quality-adjusted life-year gains are very small. There were no safety concerns. Blinded photography substudy – the reliability of central blinded review compared with clinical assessment for PUs of category ≥ 2 was ‘very good’ (kappa statistic 0.82, prevalence- and bias-adjusted kappa 0.82). Quality-of-life substudy – the Pressure Ulcer Quality of Life – Prevention (PU-QoL-P) instrument meets the established criteria for reliability, construct validity and responsiveness. Limitations: A lower than anticipated event rate. Conclusions: In acutely ill inpatients who are bedfast/chairfast and/or have a category 1 PU and/or localised skin pain, APMs confer a small treatment phase benefit that is diminished over time. Overall, the APM patient compliance, very low PU incidence rate observed and small differences between mattresses indicate the need for improved indicators for targeting of APMs and individualised decision-making. Decisions should take into account skin status, patient preferences (movement ability and rehabilitation needs) and the presence of factors that may be potentially modifiable through APM allocation, including being completely immobile, having nutritional deficits, lacking capacity and/or having altered skin/category 1 PU. Future work: Explore the relationship between mental capacity, levels of independent movement, repositioning and PU development. Explore ‘what works for whom and in what circumstances’. Trial registration: Current Controlled Trials ISRCTN01151335. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 52. See the NIHR Journals Library website for further project information

Contaminants in commercial preparations of ‘purified’ small leucine-rich proteoglycans may distort mechanistic studies

The authors are grateful to Genodisc (EC’s 7th Framework Programme (FP7, 2007-2013) under grant agreement no. HEALTH-F2-2008-201626) and the Orthopaedic Institute Ltd for funding.This paper reports the perplexing results that came about because of seriously impure commercially available reagents. Commercial reagents and chemicals are routinely ordered by scientists and are expected to have been rigorously assessed for their purity. Unfortunately, we found this assumption to be risky. Extensive work was carried out within our laboratory using commercially-sourced preparations of the small leucine-rich proteoglycans, decorin and biglycan, to investigate their influence on nerve cell growth. Unusual results compelled us to analyse the composition and purity of both preparations of these proteoglycans using both mass spectrometry and Western blotting, with and without various enzymatic deglycosylations. Commercial ‘decorin’ and ‘biglycan’ were found to contain a mixture of proteoglycans including not only both decorin and biglycan but also fibromodulin and aggrecan. The unexpected effects of ‘decorin’ and ‘biglycan’ on nerve cell growth could be explained by these impurities. Decorin and biglycan contain either chondroitin or dermatan sulphate glycosaminoglycan chains whilst fibromodulin only contains keratan sulphate and the large (>2,500 kDa), highly glycosylated aggrecan, contains both keratan and chondroitin sulphate. The different structure, molecular weights and composition of these impurities significantly affected our work and any conclusions that could be made. These findings beg the question as to whether scientists need to verify the purity of each commercially obtained reagent used in their experiments. The implications of these findings are vast, since the effects of these impurities may already have led to inaccurate conclusions and reports in the literature with concomitant loss of researchers’ funds and time.Publisher PDFPeer reviewe

Circulating microRNAs miR-331 and miR-195 differentiate local luminal a from metastatic breast cancer

BACKGROUND: Breast cancer is the leading cause of cancer related death in women, with metastasis the principle cause of mortality. New non-invasive prognostic markers are needed for the early detection of metastasis, facilitating treatment decision optimisation. MicroRNA (miRNA) are small, non-coding RNAs regulating gene expression and involved in many cellular processes, including metastasis. As biomarkers, circulating miRNAs (in blood) hold great promise for informing diagnosis or monitoring treatment responses. METHODS: Plasma extracted RNA from age matched local Luminal A (n = 4) or metastatic disease (n = 4) were profiled using Next Generation Sequencing. Selected differentially expressed miRNA were validated on a whole blood extracted miRNA cohort [distant metastatic disease (n = 22), local disease (n = 31), healthy controls (n = 21)]. Area Under the Curve (AUC) in Receiver Operating Characteristic (ROC) analyses was performed. RESULTS: Of 4 miRNA targets tested (miR-181a, miR-329, miR-331, miR-195), mir-331 was significantly over-expressed in patients with metastatic disease, compared to patients with local disease (p \u3c 0.001) or healthy controls (p \u3c 0.001). miR-195 was significantly under-expressed in patients with metastatic disease, compared to patients with local disease (p \u3c 0.001) or healthy controls (p = 0.043). In combination, miR-331 and miR-195 produced an AUC of 0.902, distinguishing metastatic from local breast cancer. CONCLUSIONS: We identified and validated two circulating miRNAs differentiating local Luminal A breast cancers from metastatic breast cancers. Further investigation will reveal the molecular role of these miRNAs in metastasis, and determine if they are subtype specific. This work demonstrates the ability of circulating miRNA to identify metastatic disease, and potentially inform diagnosis or treatment effectiveness

Feasibility and Impact of Telemonitor-Based Depression Care Management for Geriatric Homecare Patients

Objective: The objective of this study was to test the feasibility, acceptability, and preliminary clinical outcomes of a method to leverage existing home healthcare telemonitoring technology to deliver depression care management (DCM) to both Spanish- and English-speaking elderly homebound recipients of homecare services. Materials and Methods: Three stand-alone, nonprofit community homecare agencies located in New York, Vermont, and Miami participated in this study. Evidence-based DCM was adapted to the telemonitor platform by programming questions and educational information on depression symptoms, antidepressant adherence, and side effects. Recruited patients participated for a minimum of 3 weeks. Telehealth nurses were trained on DCM and received biweekly supervision. On-site trained research assistants conducted in-home research interviews on depression diagnosis and severity and patient satisfaction with the protocol. Results: An ethnically diverse sample of 48 English- and Spanish-only- speaking patients participated, along with seven telehealth nurses. Both patients and telehealth nurses reported high levels of protocol acceptance. Among 19 patients meeting diagnostic criteria for major depression, the mean depression severity was in the markedly severe range at baseline and in the mild range at follow-up. Conclusions: Results of this pilot support the feasibility of using homecare\u27s existing telemonitoring technology to deliver DCM to their elderly homebound patients. This was true for both English- and Spanish-speaking patients. Preliminary clinical outcomes suggest improvement in depression severity, although these findings require testing in a randomized clinical trial. Implications for the science and service of telehealth-based depression care for elderly patients are discussed

Confirmation of a gapped primordial disk around LkCa 15

Recently, analysis of near-infrared broad-band photometry and Spitzer IRS spectra has led to the identification of a new "pre-transitional disk" class whose members have an inner optically thick disk separated from an outer optically thick disk by an optically thin gap. This is in contrast to the "transitional disks" which have inner disk holes (i.e. large reductions of small dust from the star out to an outer optically thick wall). In LkCa 15, one of these proposed pre-transitional disks, detailed modeling showed that although the near-infrared fluxes could be understood in terms of optically thick material at the dust sublimation radius, an alternative model of emission from optically thin dust over a wide range of radii could explain the observations as well. To unveil the true nature of LkCa 15's inner disk we obtained a medium-resolution near-infrared spectrum spanning the wavelength range 2-5 microns using SpeX at the NASA Infrared Telescope Facility. We report that the excess near-infrared emission above the photosphere of LkCa 15 is a black-body continuum which can only be due to optically thick material in an inner disk around the star. When this confirmation of a primordial inner disk is combined with earlier observations of an inner edge to LkCa 15's outer disk it reveals a gapped structure. Forming planets emerge as the most likely mechanism for clearing the gap we detect in this evolving disk.Comment: accepted ApJ

Copper modulates zinc metalloproteinase-dependent ectodomain shedding of key signaling and adhesion proteins and promotes the invasion of prostate cancer epithelial cells

A disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) are zinc metalloproteinases (ZMPs) that catalyse the 'ectodomain shedding' of a range of cell surface proteins including signalling and adhesion molecules. These 'sheddases' are associated with the invasion and metastasis of a range of cancers. Increased serum and tumour tissue levels of copper are also observed in several cancers although little is known about how the metal might promote disease progression at the molecular level. In the current study, we investigated whether copper might regulate the ectodomain shedding of two key cell surface proteins implicated in the invasion and metastasis of prostate cancer, the Notch ligand Jagged1 and the adhesion molecule E-cadherin, and whether the metal was able to influence the invasion of the prostate cancer epithelial cell line PC3. Physiological copper concentrations stimulated the ZMP-mediated proteolysis of Jagged1 and E-cadherin in cell culture models whilst other divalent metals had no effect. Copper-mediated Jagged1 proteolysis was also observed following the pre-treatment of cells with cycloheximide and in a cell-free membrane system, indicating a post-translational mechanism of sheddase activation. Finally, the concentrations of copper that stimulated ZMP-mediated protein shedding also enhanced PC3 invasion; an effect which could be negated using a sheddase inhibitor or copper chelators. Collectively, these data implicate copper as an important factor in promoting prostate cancer cell invasion and indicate that the selective post-translational activation of ZMP-mediated protein shedding might play a role in this process.