Design and evaluation of an osteogenesis-on-a-chip microfluidic device incorporating 3D cell culture

Microfluidic-based tissue-on-a-chip devices have generated significant research interest for biomedical applications, such as pharmaceutical development, as they can be used for small volume, high throughput studies on the effects of therapeutics on tissue-mimics. Tissue-on-a-chip devices are evolving from basic 2D cell cultures incorporated into microfluidic devices to complex 3D approaches, with modern designs aimed at recapitulating the dynamic and mechanical environment of the native tissue. Thus far, most tissue-on-a-chip research has concentrated on organs involved with drug uptake, metabolism and removal (e.g., lung, skin, liver, and kidney); however, models of the drug metabolite target organs will be essential to provide information on therapeutic efficacy. Here, we develop an osteogenesis-on-a-chip device that comprises a 3D environment and fluid shear stresses, both important features of bone. This inexpensive, easy-to-fabricate system based on a polymerized High Internal Phase Emulsion (polyHIPE) supports proliferation, differentiation and extracellular matrix production of human embryonic stem cell-derived mesenchymal progenitor cells (hES-MPs) over extended time periods (up to 21 days). Cells respond positively to both chemical and mechanical stimulation of osteogenesis, with an intermittent flow profile containing rest periods strongly promoting differentiation and matrix formation in comparison to static and continuous flow. Flow and shear stresses were modeled using computational fluid dynamics. Primary cilia were detectable on cells within the device channels demonstrating that this mechanosensory organelle is present in the complex 3D culture environment. In summary, this device aids the development of ‘next-generation’ tools for investigating novel therapeutics for bone in comparison with standard laboratory and animal testing

A geometric approach to the precession of compact binaries

We discuss a geometrical method to define a preferred reference frame for precessing binary systems and the gravitational waves they emit. This minimal-rotation frame is aligned with the angular-momentum axis and fixes the rotation about that axis up to a constant angle, resulting in an essentially invariant frame. Gravitational waveforms decomposed in this frame are similarly invariant under rotations of the inertial frame and exhibit relatively smoothly varying phase. By contrast, earlier prescriptions for radiation-aligned frames induce extraneous features in the gravitational-wave phase which depend on the orientation of the inertial frame, leading to fluctuations in the frequency that may compound to many gravitational-wave cycles. We explore a simplified description of post-Newtonian approximations for precessing systems using the minimal-rotation frame, and describe the construction of analytical/numerical hybrid waveforms for such systems.Comment: Minor clarifications and journal referenc

The Cochrane Skin Group: a vanguard for developing and promoting evidence-based dermatology

Aim The Cochrane Skin Group (CSG) is part of the international Cochrane Collaboration (http://www.cochrane.org/). The CSG prepares, maintains and disseminates high quality evidence-based summaries on the prevention, diagnosis and treatment of skin diseases. We present a synopsis of the history, scope and priorities of the CSG. In addition, we report outcomes of CSG reviews and critically assess clinical value. Methods Descriptive analysis of systematic reviews published by the CSG since its inception including output, impact factor, associated methodological studies, and influence in clinical guidelines, promoting patient and public engagement and in triggering new primary research. Results The CSG started in 1997, and has published 61 reviews, 34 protocols and 31 registered titles by August 2013. The CSG scope includes 1000 skin diseases; 80% of reviews cover the top ten diagnoses and 40% of reviews provide clear guidance for clinical practice. CSG reviews had an impact factor of 6.1 in 2011 which places it alongside top dermatology journals. CSG reviews are typically broad in focus and have been shown to be of better quality than non-Cochrane reviews. They are highly cited in clinical guidelines. Several reviews have identified evidence gaps that have led to better primary research. Conclusions The CSG has emerged as a vanguard of evidence-based dermatology by growing a community interested in applying best external evidence to the care of skin patients and by identifying topics for research. CSG reviews are high impact, clinically relevant and have tangibly influenced international dermatology clinical practice guidelines and new research

The spectrum and clinical impact of epigenetic modifier mutations in myeloma

Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike in other B cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been previously reported. We sought to address this using results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison.Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences. We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease.In diagnostic myeloma patient samples we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers.Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available

Citizen science can improve conservation science, natural resource management, and environmental protection

Citizen science has advanced science for hundreds of years, contributed to many peer-reviewed articles, and informed land management decisions and policies across the United States. Over the last 10 years, citizen science has grown immensely in the United States and many other countries. Here, we show how citizen science is a powerful tool for tackling many of the challenges faced in the field of conservation biology. We describe the two interwoven paths bywhich citizen science can improve conservation efforts, natural resource management, and environmental protection. The first path includes building scientific knowledge, while the other path involves informing policy and encouraging public action. We explore how citizen science is currently used and describe the investments needed to create a citizen science program. We find that: 1. Citizen science already contributes substantially to many domains of science, including conservation, natural resource, and environmental science. Citizen science informs natural resource management, environmental protection, and policymaking and fosters public input and engagement. 2. Many types of projects can benefit fromcitizen science, but one must be careful tomatch the needs for science and public involvement with the right type of citizen science project and the right method of public participation. 3. Citizen science is a rigorous process of scientific discovery, indistinguishable from conventional science apart from the participation of volunteers.When properly designed, carried out, and evaluated, citizen science can provide sound science, efficiently generate high-quality data, and help solve problems

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

PMCID: PMC3710212This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Colors of 2625 Quasars at 0<z<5 Measured in the Sloan Digital Sky Survey Photometric System

We present an empirical investigation of the colors of quasars in the Sloan Digital Sky Survey (SDSS) photometric system. The sample studied includes 2625 quasars with SDSS photometry. The quasars are distributed in a 2.5 degree wide stripe centered on the Celestial Equator covering $\sim529$ square degrees. Positions and SDSS magnitudes are given for the 898 quasars known prior to SDSS spectroscopic commissioning. New SDSS quasars represent an increase of over 200% in the number of known quasars in this area of the sky. The ensemble average of the observed colors of quasars in the SDSS passbands are well represented by a power-law continuum with $\alpha_{\nu} = -0.5$ ($f_{\nu} \propto \nu^{\alpha}$). However, the contributions of the $3000 {\rm \AA}$ bump and other strong emission lines have a significant effect upon the colors. The color-redshift relation exhibits considerable structure, which may be of use in determining photometric redshifts for quasars. The range of colors can be accounted for by a range in the optical spectral index with a distribution $\alpha_{\nu}=-0.5\pm0.65$ (95% confidence), but there is a red tail in the distribution. This tail may be a sign of internal reddening. Finally, we show that there is a continuum of properties between quasars and Seyfert galaxies and we test the validity of the traditional division between the two classes of AGN.Comment: 66 pages, 15 figures (3 color), accepted by A

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1,905 trial patients

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10−7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10−14) and 1.68 (P=2.18 × 10−14), respectively. Patients with ‘double-hit’ defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10−27) for all patients and 3.19 (P=1.23 × 10−18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10−15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10 -7 ), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10 -14 ) and 1.68 (P=2.18 × 10 -14 ), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10 -27 ) for all patients and 3.19 (P=1.23 × 10 -18 ) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10 -15 ), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment