243 research outputs found
MicroRNA Regulation of Cell Lineages in Mouse and Human Embryonic Stem Cells
SummaryCell fate decisions of pluripotent embryonic stem (ES) cells are dictated by activation and repression of lineage-specific genes. Numerous signaling and transcriptional networks progressively narrow and specify the potential of ES cells. Whether specific microRNAs help refine and limit gene expression and, thereby, could be used to manipulate ES cell differentiation has largely been unexplored. Here, we show that two serum response factor (SRF)-dependent muscle-specific microRNAs, miR-1 and miR-133, promote mesoderm formation from ES cells but have opposing functions during further differentiation into cardiac muscle progenitors. Furthermore, miR-1 and miR-133 were potent repressors of nonmuscle gene expression and cell fate during mouse and human ES cell differentiation. miR-1's effects were in part mediated by translational repression of the Notch ligand Delta-like 1 (Dll-1). Our findings indicate that muscle-specific miRNAs reinforce the silencing of nonmuscle genes during cell lineage commitment and suggest that miRNAs may have general utility in regulating cell-fate decisions from pluripotent ES cells
L-Edge Spectroscopy of Dilute, Radiation-Sensitive Systems Using a Transition-Edge-Sensor Array
We present X-ray absorption spectroscopy and resonant inelastic X-ray
scattering (RIXS) measurements on the iron L-edge of 0.5 mM aqueous
ferricyanide. These measurements demonstrate the ability of high-throughput
transition-edge-sensor (TES) spectrometers to access the rich soft X-ray
(100-2000eV) spectroscopy regime for dilute and radiation-sensitive samples.
Our low-concentration data are in agreement with high-concentration
measurements recorded by conventional grating-based spectrometers. These
results show that soft X-ray RIXS spectroscopy acquired by high-throughput TES
spectrometers can be used to study the local electronic structure of dilute
metal-centered complexes relevant to biology, chemistry and catalysis. In
particular, TES spectrometers have a unique ability to characterize frozen
solutions of radiation- and temperature-sensitive samples.Comment: 19 pages, 4 figure
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Genetic Surveillance Detects Both Clonal and Epidemic Transmission of Malaria following Enhanced Intervention in Senegal
Using parasite genotyping tools, we screened patients with mild uncomplicated malaria seeking treatment at a clinic in Thiès, Senegal, from 2006 to 2011. We identified a growing frequency of infections caused by genetically identical parasite strains, coincident with increased deployment of malaria control interventions and decreased malaria deaths. Parasite genotypes in some cases persisted clonally across dry seasons. The increase in frequency of genetically identical parasite strains corresponded with decrease in the probability of multiple infections. Further, these observations support evidence of both clonal and epidemic population structures. These data provide the first evidence of a temporal correlation between the appearance of identical parasite types and increased malaria control efforts in Africa, which here included distribution of insecticide treated nets (ITNs), use of rapid diagnostic tests (RDTs) for malaria detection, and deployment of artemisinin combination therapy (ACT). Our results imply that genetic surveillance can be used to evaluate the effectiveness of disease control strategies and assist a rational global malaria eradication campaign.Human Evolutionary BiologyOrganismic and Evolutionary Biolog
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Sequence-Based Association and Selection Scans Identify Drug Resistance Loci in the Plasmodium Falciparum Malaria Parasite
Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite—the deadliest of those that cause malaria—is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites’ in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.Molecular and Cellular BiologyOrganismic and Evolutionary Biolog
The Atacama Cosmology Telescope: Two-Season ACTPol Spectra and Parameters
We present the temperature and polarization angular power spectra measured by
the Atacama Cosmology Telescope Polarimeter (ACTPol). We analyze night-time
data collected during 2013-14 using two detector arrays at 149 GHz, from 548
deg of sky on the celestial equator. We use these spectra, and the spectra
measured with the MBAC camera on ACT from 2008-10, in combination with Planck
and WMAP data to estimate cosmological parameters from the temperature,
polarization, and temperature-polarization cross-correlations. We find the new
ACTPol data to be consistent with the LCDM model. The ACTPol
temperature-polarization cross-spectrum now provides stronger constraints on
multiple parameters than the ACTPol temperature spectrum, including the baryon
density, the acoustic peak angular scale, and the derived Hubble constant.
Adding the new data to planck temperature data tightens the limits on damping
tail parameters, for example reducing the joint uncertainty on the number of
neutrino species and the primordial helium fraction by 20%.Comment: 23 pages, 25 figure
Patient-reported outcomes in the aging population of adults with congenital heart disease: results from APPROACH-IS.
The congenital heart disease (CHD) population now comprises an increasing number of older persons in their 6th decade of life and beyond. We cross-sectionally evaluated patient-reported outcomes (PROs) in persons with CHD aged 60 years or older, and contrasted these with PROs of younger patients aged 40-59 years and 18-39 years. Adjusted for demographic and medical characteristics, patients ≥60 years had a lower Physical Component Summary, higher Mental Component Summary, and lower anxiety (Hospital Anxiety and Depression Scale-Anxiety) scores than patients in the two younger categories. For satisfaction with life, older persons had a higher score than patients aged 40-59 years. Registration: ClinicalTrials.gov NCT02150603
Engineering GPCR signaling pathways with RASSLs
We are creating families of designer G-protein-coupled receptors (GPCRs) to allow for precise spatiotemporal control of GPCR signaling in vivo. These engineered GPCRs, called receptors activated solely by synthetic ligands (RASSLs), are unresponsive to endogenous ligands but can be activated by nanomolar concentrations of pharmacologically inert, drug-like small molecules. Currently, RASSLs exist for the three major GPCR signaling pathways (Gs, Gi, Gq). These new advances are reviewed here to help facilitate the use of these powerful and diverse tools
Fibrodysplasia Ossificans Progressiva: what have we achieved and where are we now? follow-up to the 2015 Lorentz Workshop
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics
Modifying Ligand-Induced and Constitutive Signaling of the Human 5-HT4 Receptor
G protein–coupled receptors (GPCRs) signal through a limited number of G-protein pathways and play crucial roles in many biological processes. Studies of their in vivo functions have been hampered by the molecular and functional diversity of GPCRs and the paucity of ligands with specific signaling effects. To better compare the effects of activating different G-protein signaling pathways through ligand-induced or constitutive signaling, we developed a new series of RASSLs (receptors activated solely by synthetic ligands) that activate different G-protein signaling pathways. These RASSLs are based on the human 5-HT4b receptor, a GPCR with high constitutive Gs signaling and strong ligand-induced G-protein activation of the Gs and Gs/q pathways. The first receptor in this series, 5-HT4-D100A or Rs1 (RASSL serotonin 1), is not activated by its endogenous agonist, serotonin, but is selectively activated by the small synthetic molecules GR113808, GR125487, and RO110-0235. All agonists potently induced Gs signaling, but only a few (e.g., zacopride) also induced signaling via the Gq pathway. Zacopride-induced Gq signaling was enhanced by replacing the C-terminus of Rs1 with the C-terminus of the human 5-HT2C receptor. Additional point mutations (D66A and D66N) blocked constitutive Gs signaling and lowered ligand-induced Gq signaling. Replacing the third intracellular loop of Rs1 with that of human 5-HT1A conferred ligand-mediated Gi signaling. This Gi-coupled RASSL, Rs1.3, exhibited no measurable signaling to the Gs or Gq pathway. These findings show that the signaling repertoire of Rs1 can be expanded and controlled by receptor engineering and drug selection
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