98 research outputs found
Externally heated protostellar cores in the Ophiuchus star-forming region
We present APEX 218 GHz observations of molecular emission in a complete
sample of embedded protostars in the Ophiuchus star-forming region. To study
the physical properties of the cores, we calculate HCO and c-CH
rotational temperatures, both of which are good tracers of the kinetic
temperature of the molecular gas. We find that the HCO temperatures range
between 16 K and 124 K, with the highest HCO temperatures toward the hot
corino source IRAS 16293-2422 (69-124 K) and the sources in the Oph A
cloud (23-49 K) located close to the luminous Herbig Be star S 1, which
externally irradiates the Oph A cores. On the other hand, the
c-CH rotational temperature is consistently low (7-17 K) in all
sources. Our results indicate that the c-CH emission is primarily
tracing more shielded parts of the envelope whereas the HCO emission (at
the angular scale of the APEX beam; 3600 au in Ophiuchus) mainly traces the
outer irradiated envelopes, apart from in IRAS 16293-2422, where the hot corino
emission dominates. In some sources, a secondary velocity component is also
seen, possibly tracing the molecular outflow.Comment: 19 pages, 9 figures, accepted for publication in Ap
Warm gas towards young stellar objects in Corona Australis - Herschel/PACS observations from the DIGIT key programme
The effects of external irradiation on the chemistry and physics in the
protostellar envelope around low-mass young stellar objects are poorly
understood. The Corona Australis star-forming region contains the R CrA dark
cloud, comprising several low-mass protostellar cores irradiated by an
intermediate-mass young star. We study the effects on the warm gas and dust in
a group of low-mass young stellar objects from the irradiation by the young
luminous Herbig Be star R CrA. Herschel/PACS far-infrared datacubes of two
low-mass star-forming regions in the R CrA dark cloud are presented. The
distribution of CO, OH, H2O, [C II], [O I], and continuum emission is
investigated. We have developed a deconvolution algorithm which we use to
deconvolve the maps, separating the point-source emission from the extended
emission. We also construct rotational diagrams of the molecular species. By
deconvolution of the Herschel data, we find large-scale (several thousand AU)
dust continuum and spectral line emission not associated with the point
sources. Similar rotational temperatures are found for the warm CO (
K), hot CO ( K), OH ( K), and H2O ( K) emission,
respectively, in the point sources and the extended emission. The rotational
temperatures are also similar to what is found in other more isolated cores.
The extended dust continuum emission is found in two ridges similar in extent
and temperature to molecular mm emission, indicative of external heating from
the Herbig Be star R CrA. Our results show that a nearby luminous star does not
increase the molecular excitation temperatures in the warm gas around a young
stellar object (YSO). However, the emission from photodissociation products of
H2O, such as OH and O, is enhanced in the warm gas associated with these
protostars and their surroundings compared to similar objects not suffering
from external irradiation.Comment: 37 pages, accepted for publication in A&
A recent accretion burst in the low-mass protostar IRAS 15398-3359: ALMA imaging of its related chemistry
Low-mass protostars have been suggested to show highly variable accretion
rates through-out their evolution. Such changes in accretion, and related
heating of their ambient envelopes, may trigger significant chemical variations
on different spatial scales and from source-to-source. We present images of
emission from C17O, H13CO+, CH3OH, C34S and C2H toward the low-mass protostar
IRAS 15398-3359 on 0.5" (75 AU diameter) scales with the Atacama Large
Millimeter/submillimeter Array (ALMA) at 340 GHz. The resolved images show that
the emission from H13CO+ is only present in a ring-like structure with a radius
of about 1-1.5" (150-200 AU) whereas the CO and other high dipole moment
molecules are centrally condensed toward the location of the central protostar.
We propose that HCO+ is destroyed by water vapor present on small scales. The
origin of this water vapor is likely an accretion burst during the last
100-1000 years increasing the luminosity of IRAS 15398-3359 by a factor of 100
above its current luminosity. Such a burst in luminosity can also explain the
centrally condensed CH3OH and extended warm carbon-chain chemistry observed in
this source and furthermore be reflected in the relative faintness of its
compact continuum emission compared to other protostars.Comment: Accepted for publication in ApJ Letters; 14 pages, 5 figure
Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose
BACKGROUND: Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure.
OBJECTIVES: To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial.
METHODS: The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis.
RESULTS: A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min.
CONCLUSIONS: The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily
Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence
Background
Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
Methods
We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling.
Results
Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones.
Conclusions
Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)National Human Genome Research Institute (U.S.) (Grant U54 HG003067)National Human Genome Research Institute (U.S.) (Grant R01 HG006855)Stanley Center for Psychiatric ResearchAlexander and Margaret Stewart TrustNational Institute of Mental Health (U.S.) (Grant R01 MH 077139)National Institute of Mental Health (U.S.) (Grant RC2 MH089905)Sylvan C. Herman Foundatio
Transmission of Stress-Induced Learning Impairment and Associated Brain Gene Expression from Parents to Offspring in Chickens
BACKGROUND: Stress influences many aspects of animal behaviour and is a major factor driving populations to adapt to changing living conditions, such as during domestication. Stress can affect offspring through non-genetic mechanisms, but recent research indicates that inherited epigenetic modifications of the genome could possibly also be involved. METHODOLOGY/PRINCIPAL FINDINGS: Red junglefowl (RJF, ancestors of modern chickens) and domesticated White Leghorn (WL) chickens were raised in a stressful environment (unpredictable light-dark rhythm) and control animals in similar pens, but on a 12/12 h light-dark rhythm. WL in both treatments had poorer spatial learning ability than RJF, and in both populations, stress caused a reduced ability to solve a spatial learning task. Offspring of stressed WL, but not RJF, raised without parental contact, had a reduced spatial learning ability compared to offspring of non-stressed animals in a similar test as that used for their parents. Offspring of stressed WL were also more competitive and grew faster than offspring of non-stressed parents. Using a whole-genome cDNA microarray, we found that in WL, the same changes in hypothalamic gene expression profile caused by stress in the parents were also found in the offspring. In offspring of stressed WL, at least 31 genes were up- or down-regulated in the hypothalamus and pituitary compared to offspring of non-stressed parents. CONCLUSIONS/SIGNIFICANCE: Our results suggest that, in WL the gene expression response to stress, as well as some behavioural stress responses, were transmitted across generations. The ability to transmit epigenetic information and behaviour modifications between generations may therefore have been favoured by domestication. The mechanisms involved remain to be investigated; epigenetic modifications could either have been inherited or acquired de novo in the specific egg environment. In both cases, this would offer a novel explanation to rapid evolutionary adaptation of a population
TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer
Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).
Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of Cell Search-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models.
Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001).
Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.
See related commentary by Rebello et al., p. 169
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