Advances in next-generation sequencing (NGS) promise to facilitate diagnosis of inherited disorders. Although in research settings NGS has pinpointed causal alleles using segregation in large ...families, the key challenge for clinical diagnosis is application to single individuals. To explore its diagnostic use, we performed targeted NGS in 42 unrelated infants with clinical and biochemical evidence of mitochondrial oxidative phosphorylation disease. These devastating mitochondrial disorders are characterized by phenotypic and genetic heterogeneity, with more than 100 causal genes identified to date. We performed "MitoExome" sequencing of the mitochondrial DNA (mtDNA) and exons of ~1000 nuclear genes encoding mitochondrial proteins and prioritized rare mutations predicted to disrupt function. Because patients and healthy control individuals harbored a comparable number of such heterozygous alleles, we could not prioritize dominant-acting genes. However, patients showed a fivefold enrichment of genes with two such mutations that could underlie recessive disease. In total, 23 of 42 (55%) patients harbored such recessive genes or pathogenic mtDNA variants. Firm diagnoses were enabled in 10 patients (24%) who had mutations in genes previously linked to disease. Thirteen patients (31%) had mutations in nuclear genes not previously linked to disease. The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings.
Background
Cancer patients treated in community hospitals receive less guideline-recommended care and experience poorer outcomes than those treated in academic medical centers or National Cancer ...Institute-Designated Cancer Centers. The Markey Cancer Center Affiliate Network (MCCAN) was designed to address this issue in Kentucky, the state with the highest cancer incidence and mortality rates in the U.S.
Methods
Using data obtained from the Kentucky Cancer Registry, the study evaluated the impact of patients treated in MCCAN hospitals on four evidence-based Commission on Cancer (CoC) quality measures using a before-and-after matched-cohort study design. Each group included 13 hospitals matched for bed size, cancer patient volume, community population, and region (Appalachian vs. non-Appalachian). Compliance with quality measures was assessed for the 3 years before the hospital joined MCCAN (T1) and the 3 years afterward (T2).
Results
In T1, the control hospitals demonstrated greater compliance with two quality measures than the MCCAN hospitals. In T2, the MCCAN hospitals achieved greater compliance in three measures than the control hospitals. From T1 to T2, the MCCAN hospitals significantly increased compliance on three measures (vs. 1 measure for the control hospitals). Although most of the hospitals were not accredited by the CoC in T1, 92% of the MCCAN hospitals had achieved accreditation by the end of T2 compared with 23% of the control hospitals.
Conclusion
After the MCCAN hospitals joined the Network, their compliance with quality measures and achievement of CoC accreditation increased significantly compared with the control hospitals. The unique academic/community-collaboration model provided by MCCAN was able to make a significant impact on improvement of cancer care. Future research is needed to adapt and evaluate similar interventions in other states and regions.
The infection of potato tubers (Solanum tuberosum) by Erwinia carotovora ssp carotovora in aerobic and anaerobic conditions was studied using chemical analysis and Fourier-transform infrared (FT-IR) ...microscopy and diffuse reflectance spectroscopy. Analysis of the uninfected and infected residues following sequential extraction with diethyl ether, water (40 degrees C), 90% dimethyl sulphoxide (DMSO) and digestion with amyloglucosidase showed that the principal effect of infection, particularly in anaerobic conditions, is starch degradation. This was substantiated by gel filtration chromatography of the 90% DMSO extracts. Extensive lignification was not found to be intimately associated with either infective condition. FT-IR microscopical analysis of tissue sections showed that infection in both aerobic and anaerobic conditions caused starch and cell wall degradation, whilst extensive membrane degradation was only evident with anaerobic infection.
Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have ...been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.
From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set.
LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018).
This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.
Platelets have long been recognized to be of central importance in haemostasis, but their participation in pathological conditions such as thrombosis, atherosclerosis and inflammation is now also ...well established. The platelet has therefore become a key target in therapies to combat cardiovascular disease. Anti‐platelet therapies are used widely, but current approaches lack efficacy in a proportion of patients, and are associated with side effects including problem bleeding. In the last decade, substantial progress has been made in understanding the regulation of platelet function, including the characterization of new ligands, platelet‐specific receptors and cell signalling pathways. It is anticipated this progress will impact positively on the future innovations towards more effective and safer anti‐platelet agents. In this review, the mechanisms of platelet regulation and current anti‐platelet therapies are introduced, and strong, and some more speculative, potential candidate target molecules for future anti‐platelet drug development are discussed.
British Journal of Pharmacology (2008) 154, 918–939; doi:10.1038/bjp.2008.151; published online 21 April 2008
We use the first-year Dark Energy Survey (DES) data down to previously unprobed photometric depths to search for stellar systems in the Galactic halo, therefore complementing the previous analysis of ...the same data carried out by our group earlier this year. Our search is based on a matched filter algorithm that produces stellar density maps consistent with stellar population models of various ages, metallicities, and distances over the survey area. The most conspicuous density peaks in these maps have been identified automatically and ranked according to their significance and recurrence for different input models. We report the discovery of one additional stellar system besides those previously found by several authors using the same first-year DES data. The object is compact, and consistent with being dominated by an old and metal-poor population. DES 1 is found at high significance and appears in the DES images as a compact concentration of faint blue point sources. Assuming different spatial profile parameterizations, the best-fitting heliocentric distance and total absolute magnitude in the range of 77.6–87.1 kpc and −3.00 ≲ M
V
≲ −2.21, respectively. The half-light radius of this object, r
h ∼ 10 pc and total luminosity are consistent with it being a low-mass halo cluster. It is also found to have a very elongated shape (ϵ ∼ 0.57). In addition, our deeper probe of DES first-year data confirms the recently reported satellite galaxy candidate Horologium II as a significant stellar overdensity. We also infer its structural properties and compare them to those reported in the literature.
The relation between satellite measurements of the normalized difference vegetation index (NDVI), cumulated over the growing season, and inventory estimates of forest woody biomass carbon is ...estimated statistically with data from 167 provinces and states in six countries (Canada, Finland, Norway, Russia and the USA for a single time period and Sweden for two periods). Statistical tests indicate that the regression model can be used to represent the relation between forest biomass and NDVI across spatial, temporal and ecological scales for relatively long time scales. For the 1.42 billion ha of boreal and temperate forests in the Northern Hemisphere, the woody biomass carbon pools and sinks are estimated at a relatively high spatial resolution (8×8 km). We estimate the carbon pool to be 61±20 gigatons (10
9) carbon (Gt C) during the late 1990s and the biomass sink to be 0.68±0.34 Gt C/year between the 1982 and 1999. The geographic detail of carbon sinks provided here can contribute to a potential monitoring program for greenhouse gas emission reduction commitments under the Kyoto Protocol.
Abstract The inability of the adult mammalian retina to regenerate can be partly attributed to the expression of injury-induced inhibitory extracellular matrix (ECM) and cell adhesion molecules. In ...particular, photoreceptor degeneration stimulates deposition of the inhibitory ECM proteins neurocan and CD44 at the outer limits of the dystrophic retina, where they act as a barrier against cellular migration and axonal extension. We have previously shown that degradation of these molecules, via induction of MMP2, promotes host–donor integration and retinal repopulation following transplantation. Here we present a biodegradable/biocompatible polymer scaffold that has the ability to deliver MMP2, in conjunction with retinal progenitor cells, directly to the site of retinal injury in an attempt to enhance cellular integration and promote retinal repopulation. Pre-activated MMP2, loaded into a PLGA polymer, maintained its activity throughout polymer fabrication and hydrolysis. Following delivery, significant degradation of CD44 and neurocan from the outer limits of the dystrophic retina, without further disruption of retinal architecture, was observed. As a result, the number of retinal progenitor cells that migrated beyond the glial barrier into the degenerating host increased significantly. These cells took up residence in the retinal outer nuclear layer, adopted appropriate photoreceptor morphology and expressed the mature photoreceptor markers recoverin and rhodopsin. Thus, we have created a cell delivery platform that upon transplantation provides controlled release of active-MMP2 directly to the site of retinal injury, stimulating inhibitory ECM barrier removal and enhancement of stem cell integration and retinal repopulation.
We present time-delay measurements for the new quadruple imaged quasar DES J0408−5354, the first quadruple imaged quasar found in the Dark Energy Survey (DES). Our result is made possible by ...implementing a new observational strategy using almost daily observations with the MPIA 2.2 m telescope at La Silla observatory and deep exposures reaching a signal-to-noise ratio of about 1000 per quasar image. This data qualityallows us to catch small photometric variations (a few mmag rms) of the quasar, acting on temporal scales much shorter than microlensing, and hence making the time delay measurement very robust against microlensing. In only seven months we very accurately measured one of the time delays in DES J0408−5354: Δ
t
(AB) = −112.1 ± 2.1 days (1.8%) using only the MPIA 2.2 m data. In combination with data taken with the 1.2 m
Euler
Swiss telescope, we also measured two delays involving the D component of the system Δ
t
(AD) = −155.5 ± 12.8 days (8.2%) and Δ
t
(BD) = −42.4 ± 17.6 days (41%), where all the error bars include systematics. Turning these time delays into cosmological constraints will require deep
Hubble
Space Telescope (HST) imaging or ground-based adaptive optics (AO), and information on the velocity field of the lensing galaxy.
We present DES13S2cmm, the first spectroscopically-confirmed superluminous supernova (SLSN) from the Dark Energy Survey (DES). We briefly discuss the data and search algorithm used to find this event ...in the first year of DES operations, and outline the spectroscopic data obtained from the European Southern Observatory (ESO) Very Large Telescope to confirm its redshift (z = 0.663 ± 0.001 based on the host-galaxy emission lines) and likely spectral type (Type I). Using this redshift, we find
$M^{\rm peak}_U=-21.05^{+0.10}_{-0.09}$
for the peak, rest-frame U-band absolute magnitude, and find DES13S2cmm to be located in a faint, low-metallicity (sub-solar), low stellar-mass host galaxy (log (M/M⊙) = 9.3 ± 0.3), consistent with what is seen for other SLSNe-I. We compare the bolometric light curve of DES13S2cmm to 14 similarly well-observed SLSNe-I in the literature and find that it possesses one of the slowest declining tails (beyond +30 d rest-frame past peak), and is the faintest at peak. Moreover, we find the bolometric light curves of all SLSNe-I studied herein possess a dispersion of only 0.2–0.3 mag between +25 and +30 d after peak (rest frame) depending on redshift range studied; this could be important for ‘standardizing’ such supernovae, as is done with the more common Type Ia. We fit the bolometric light curve of DES13S2cmm with two competing models for SLSNe-I – the radioactive decay of 56Ni, and a magnetar – and find that while the magnetar is formally a better fit, neither model provides a compelling match to the data. Although we are unable to conclusively differentiate between these two physical models for this particular SLSN-I, further DES observations of more SLSNe-I should break this degeneracy, especially if the light curves of SLSNe-I can be observed beyond 100 d in the rest frame of the supernova.
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