We present a new compilation of Type Ia supernovae (SNe Ia), a new data set of low-redshift nearby-Hubble-flow SNe, and new analysis procedures to work with these heterogeneous compilations. This ...'Union' compilation of 414 SNe Ia, which reduces to 307 SNe after selection cuts, includes the recent large samples of SNe Ia from the Supernova Legacy Survey and ESSENCE Survey, the older data sets, as well as the recently extended data set of distant supernovae observed with the Hubble Space Telescope (HST). A single, consistent, and blind analysis procedure is used for all the various SN Ia subsamples, and a new procedure is implemented that consistently weights the heterogeneous data sets and rejects outliers. We present the latest results from this Union compilation and discuss the cosmological constraints from this new compilation and its combination with other cosmological measurements (CMB and BAO). The constraint we obtain from supernovae on the dark energy density is image, for a flat, Lambda CDM universe. Assuming a constant equation of state parameter, w, the combined constraints from SNe, BAO, and CMB give image. While our results are consistent with a cosmological constant, we obtain only relatively weak constraints on a w that varies with redshift. In particular, the current SN data do not yet significantly constrain w at image. With the addition of our new nearby Hubble-flow SNe Ia, these resulting cosmological constraints are currently the tightest available.
Atomistic modelling of magnetic materials provides unprecedented detail about the underlying physical processes that govern their macroscopic properties, and allows the simulation of complex effects ...such as surface anisotropy, ultrafast laser-induced spin dynamics, exchange bias, and microstructural effects. Here we present the key methods used in atomistic spin models which are then applied to a range of magnetic problems. We detail the parallelization strategies used which enable the routine simulation of extended systems with full atomistic resolution.
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and ...their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca
1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly ...upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.
•GDH1 predominantly controls intracellular α-KG and subsequent fumarate levels•GDH1 contributes to redox homeostasis by activating GPx1•Fumarate binds to and activates GPx1•GDH1 is a promising anticancer target
Jin et al. show that mitochondrial glutaminolysis contributes to redox homeostasis through glutamate dehydrogenase 1 (GDH1) regulation of α-ketoglutarate, fumarate, and GPx1. GDH1 is upregulated in human cancers, and its inhibition perturbs redox homeostasis and attenuates cancer cell proliferation and tumor growth.
Histones and their post-translational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecular pattern ...molecules when they are released into the extracellular space. Administration of exogenous histones to animals leads to systemic inflammatory and toxic responses through activating Toll-like receptors and inflammasome pathways. Anti-histone treatment (e.g., neutralizing antibodies, activated protein C, recombinant thrombomodulin, and heparin) protect mice against lethal endotoxemia, sepsis, ischemia/reperfusion injury, trauma, pancreatitis, peritonitis, stroke, coagulation, and thrombosis. In addition, elevated serum histone and nucleosome levels have been implicated in multiple pathophysiological processes and progression of diseases including autoimmune diseases, inflammatory diseases, and cancer. Therefore, extracellular histones could serve as biomarkers and novel therapeutic targets in human diseases.
Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of ...270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Meiotic recombination and de novo mutation are the two main contributions toward gamete genome diversity, and many questions remain about how an individual human’s genome is edited by these two ...processes. Here, we describe a high-throughput method for single-cell whole-genome analysis that was used to measure the genomic diversity in one individual’s gamete genomes. A microfluidic system was used for highly parallel sample processing and to minimize nonspecific amplification. High-density genotyping results from 91 single cells were used to create a personal recombination map, which was consistent with population-wide data at low resolution but revealed significant differences from pedigree data at higher resolution. We used the data to test for meiotic drive and found evidence for gene conversion. High-throughput sequencing on 31 single cells was used to measure the frequency of large-scale genome instability, and deeper sequencing of eight single cells revealed de novo mutation rates with distinct characteristics.
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► A microfluidic system for high-throughput single cell whole-genome amplification ► Personal recombination map by single-sperm whole-genome analysis ► Genome-wide meiotic drive and gene conversion tests ► De novo germline mutations with distinct molecular characteristics
A new high-throughput method, based on a microfluidic system, generates a personal recombination map from 91 individual sperm cells. The single-cell sequencing data provide measurements of gene conversion activity and genome instability rates in human sperm.
In this study involving 1655 men who had been treated for localized prostate cancer, differences between prostatectomy and radiotherapy were noted in the first 5 years after treatment, but these ...differences tended to disappear after 15 years of follow-up.
Patients with clinically localized prostate cancer have a favorable long-term overall and cancer-specific rate of survival regardless of treatment choice.
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There are currently no completed prospective, randomized trials that evaluate differences in survival outcomes between radical prostatectomy and external-beam radiation therapy. Consequently, predicted functional outcomes have become essential components of treatment decision making.
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Although studies with short-term follow-up (1 to 3 years) and intermediate-term follow-up (4 to 5 years) have identified incremental differences in functional outcomes between patients undergoing prostatectomy and those undergoing radiotherapy, longer-term outcomes remain largely unknown. Since the median life expectancy after treatment for prostate . . .
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