We provide the whole set of Lick indices from CN1 to TiO2 in the wavelength range 4000 ≲≲λ≲ 6500 Å of simple stellar population models with, for the first time, variable element abundance ratios, ...α/Fe = 0.0, 0.3, 0.5, α/Ca =−0.1, 0.0, 0.2, 0.5 and α/N=−0.5, 0.0. The models cover ages between 1 and 15 Gyr, metallicities between 1/200 and 3.5 solar. The impact from the element abundance changes on the absorption-line indices is taken from Tripicco & Bell, using an extension of the method introduced by Trager et al. Our models are free from the intrinsic α/Fe bias that was imposed by the Milky Way template stars up to now, hence they reflect well-defined α/Fe ratios at all metallicities. The models are calibrated with Milky Way globular clusters for which metallicities and α/Fe ratios are known from independent spectroscopy of individual stars. The metallicities that we derive from the Lick indices Mg b and Fe5270 are in excellent agreement with the metallicity scale by Zinn & West, and we show that the latter provides total metallicity rather than iron abundance. We can reproduce the relatively strong CN-absorption features CN1 and CN2 of galactic globular clusters with models in which nitrogen is enhanced by a factor of 3. An enhancement of carbon, instead, would lead to serious inconsistencies with the indices Mg1 and C24668. The calcium sensitive index Ca4227 of globular clusters is well matched by our models with Ca/Fe= 0.3, including the metal-rich bulge clusters NGC 6528 and 6553. From our α/Fe-enhanced models we infer that the index MgFe defined by González is quite independent of α/Fe but still slightly decreases with increasing α/Fe. We find that the index , instead, is completely independent of α/Fe and serves best as a tracer of total metallicity. Searching for blue indices that give similar information as Mg b and 〈Fe〉, we find that CN1 and Fe4383 may be best suited to estimating α/Fe ratios of objects at redshifts z∼ 1.
We examined relationships between regional brain shrinkage and changes in cognitive performance, while taking into account the influence of chronological age, vascular risk, Apolipoprotein E variant ...and socioeconomic status. Regional brain volumes and cognitive performance were assessed in 167 healthy adults (age 19–79 at baseline), 90 of whom returned for the follow-up after two years. Brain volumes were measured in six regions of interest (ROIs): lateral prefrontal cortex (LPFC), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), cerebellar hemispheres (CbH), and primary visual cortex (VC), and cognitive performance was evaluated in three domains: episodic memory (EM), fluid intelligence (Gf), and vocabulary (V). Average volume loss was observed in Hc, PhG and CbH, but reliable individual differences were noted in all examined ROIs. Average positive change was observed in EM and V performance but not in Gf scores, yet only the last evidenced individual differences in change. We observed reciprocal influences among neuroanatomical and cognitive variables. Larger brain volumes at baseline predicted greater individual gains in Gf, but differences in LPFC volume change were in part explained by baseline level of cognitive performance. In one region (PFw), individual change in volume was coupled with change in Gf. Larger initial brain volumes did not predict slower shrinkage. The results underscore the complex role of brain maintenance and cognitive reserve in adult development.
•Volume change and individual differences in change across brain regions.•Average change: memory & vocabulary; individual differences: fluid intelligence.•Larger baseline brain volumes predicted greater gains in Gf.•Prefrontal gray shrinkage was related to poorer baseline cognitive performance.•Shrinkage of prefrontal white matter correlated with negative change in Gf.
We present results for a galaxy-galaxy lensing study based on imaging data from the Canada-France-Hawaii Telescope Legacy Survey Wide. From a 12 million object multicolour catalogue for 124 deg2 of ...photometric data in the u*g
′
r
′
i
′
z
′ filters, we compute photometric redshifts (with a scatter of σΔz/(1 + z) = 0.033 and an outlier rate of η = 2.0 per cent for i
′ ≤ 22.5) and extract galaxy shapes down to i
′ = 24.0. We select a sample of lenses and sources with 0.05 < z
d ≤ 1 and 0.05 < z
s ≤ 2. We fit three different galaxy halo profiles to the lensing signal, a singular isothermal sphere (SIS), a truncated isothermal sphere (BBS) and a universal density profile (NFW). We derive velocity dispersions by fitting an SIS out to 100 h
−1 kpc to the excess surface mass density ΔΣ and perform maximum likelihood analyses out to a maximum scale of 2 h
−1 Mpc to obtain halo parameters and scaling relations. We find luminosity scaling relations of σred ∝ L
0.24 ± 0.03 for the red lens sample, σblue ∝ L
0.23 ± 0.03 for blue lenses and σ ∝ L
0.29 ± 0.02 for the combined lens sample with zero-points of
,
and σ* = 135 ± 2 km s−1 at a chosen reference luminosity
. The steeper slope for the combined sample is due to the different zero-points of the blue and red lenses and the fact that blue lenses dominate at low luminosities and red lenses at high luminosities. The mean effective redshifts for the lens samples are 〈z
red〉 = 0.28 for red lenses, 〈z
blue〉 = 0.35 for blue lenses and 〈z〉 = 0.34 for the combined lens sample. The BBS maximum likelihood analysis yields for the combined sample a velocity dispersion of
km s− 1 and a truncation radius of
kpc, corresponding to a total mass of
and a mass-to-light (M/L) ratio of
at
. At a given luminosity, both velocity dispersion σ and truncation radius s are larger for red galaxies than for blue galaxies. For an NFW profile, we measure at
a virial radius of
kpc and a concentration parameter of
, implying a virial mass of
. At L* for blue galaxies the concentration parameter is slightly higher than for red galaxies and r
200 is significantly lower. For the combined sample, if described as a single power law, the M/L ratio scales as
, the concentration parameter scales as
. Analysing the M/L scaling for red and blue galaxies separately, we find that a broken power law (with a flat slope at high luminosities) provides a more appropriate description for red and possibly also for blue galaxies. We measure M
200/M
star for red galaxies over 2.5 decades in stellar mass. We find a minimum for this ratio at M
star ∼ 3-4 × 1010 h
− 2 M with a strong increase for lower stellar masses.
Receptor-targeted lentiviral vectors (LVs) can be an effective tool for selective transfer of genes into distinct cell types of choice. Moreover, they can be used to determine the molecular ...properties that cell surface proteins must fulfill to act as receptors for viral glycoproteins. Here we show that LVs pseudotyped with receptor-targeted Nipah virus (NiV) glycoproteins effectively enter into cells when they use cell surface proteins as receptors that bring them closely enough to the cell membrane (less than 100 Å distance). Then, they were flexible in receptor usage as demonstrated by successful targeting of EpCAM, CD20, and CD8, and as selective as LVs pseudotyped with receptor-targeted measles virus (MV) glycoproteins, the current standard for cell-type specific gene delivery. Remarkably, NiV-LVs could be produced at up to two orders of magnitude higher titers compared to their MV-based counterparts and were at least 10,000-fold less effectively neutralized than MV glycoprotein pseudotyped LVs by pooled human intravenous immunoglobulin. An important finding for NiV-LVs targeted to Her2/neu was an about 100-fold higher gene transfer activity when particles were targeted to membrane-proximal regions as compared to particles binding to a more membrane-distal epitope. Likewise, the low gene transfer activity mediated by NiV-LV particles bound to the membrane distal domains of CD117 or the glutamate receptor subunit 4 (GluA4) was substantially enhanced by reducing receptor size to below 100 Å. Overall, the data suggest that the NiV glycoproteins are optimally suited for cell-type specific gene delivery with LVs and, in addition, for the first time define which parts of a cell surface protein should be targeted to achieve optimal gene transfer rates with receptor-targeted LVs.
Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biomarkers in cell-free DNA in blood and may ultimately replace invasive tissue biopsies. However, a ...better understanding of the performance of blood-based NGS assays is needed prior to routine clinical use. As part of an IRB-approved molecular profiling registry trial of pancreatic ductal adenocarcinoma (PDA) patients, we facilitated blood-based NGS testing of 34 patients from multiple community-based and high-volume academic oncology practices. 23 of these patients also underwent traditional tumor tissue-based NGS testing. cfDNA was not detected in 9/34 (26%) patients. Overall concordance between blood and tumor tissue NGS assays was low, with only 25% sensitivity of blood-based NGS for tumor tissue NGS. Mutations in KRAS, the major PDA oncogene, were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies. The presence of mutations in circulating DNA was associated with reduced overall survival (54% in mutation-positive versus 90% in mutation-negative). Our results suggest that in the setting of previously treated, advanced PDA, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test.
The Pan-Planets survey observed an area of 42 sq deg. in the galactic disk for about 165 h. The main scientific goal of the project is the detection of transiting planets around M dwarfs. We ...establish an efficient procedure for determining the stellar parameters Teff and log g of all sources using a method based on SED fitting, utilizing a three-dimensional dust map and proper motion information. In this way we identify more than 60 000 M dwarfs, which is by far the largest sample of low-mass stars observed in a transit survey to date. We present several planet candidates around M dwarfs and hotter stars that are currently being followed up. Using Monte Carlo simulations we calculate the detection efficiency of the Pan-Planets survey for different stellar and planetary populations. We expect to find 3.0+3.3-1.6 hot Jupiters around F, G, and K dwarfs with periods lower than 10 days based on the planet occurrence rates derived in previous surveys. For M dwarfs, the percentage of stars with a hot Jupiter is under debate. Theoretical models expect a lower occurrence rate than for larger main sequence stars. However, radial velocity surveys find upper limits of about 1% due to their small sample, while the Kepler survey finds a occurrence rate that we estimate to be at least 0.17b(+0.67-0.04) %, making it even higher than the determined fraction from OGLE-III for F, G and K stellar types, 0.14 (+0.15-0.076) %. With the large sample size of Pan-Planets, we are able to determine an occurrence rate of 0.11 (+0.37-0.02) % in case one of our candidates turns out to be a real detection. If, however, none of our candidates turn out to be true planets, we are able to put an upper limit of 0.34% with a 95% confidence on the hot Jupiter occurrence rate of M dwarfs. This limit is a significant improvement over previous estimates where the lowest limit published so far is 1.1% found in the WFCAM Transit Survey. Therefore we cannot yet confirm the theoretical prediction of a lower occurrence rate for cool stars.
The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the ...family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing.
To apply whole-genome sequencing to a patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANT: Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer (negative for BRCA1 and BRCA2 mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping.
Structural variants, copy number alterations, single-nucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. RESULTS; Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome.
Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.
We examined regional changes in brain volume in healthy adults (N=167, age 19–79years at baseline; N=90 at follow-up) over approximately two years. With latent change score models, we evaluated mean ...change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the Hc, CbH, In, OF, and PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants modified shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1β C-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFR C677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC, thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan.
•In healthy adults, 10 brain ROI volumes measured manually twice 2years apart•Average shrinkage was observed in the medial temporal and orbitofrontal cortices.•No mean change noted in lateral prefrontal cortex and prefrontal white matter•Heterogeneity in change was noted in all regions, except the orbitofrontal cortex.•Pro-inflammatory SNPs were linked to parahippocampal and cerebellar shrinkage.
Advanced age and vascular risk negatively affect episodic memory. The hippocampus (HC) is a complex structure, and little is known about the roles of different HC regions in age-related memory ...declines. Using data from an ongoing longitudinal study, we investigated whether memory functions are related to volumes of specific HC subregions (CA1-2, CA3-4/dentate gyrus, and subiculum). Furthermore, we inquired if arterial hypertension, a common age-related vascular risk factor, modifies age-related differences in HC regional volumes, concurrent memory performance, and improvement in memory over multiple administrations. Healthy adults (
= 49, 52–82 years old) completed associative recognition and free recall tasks. In grouped path models, covariance structures differed between hypertensive and normotensive participants. Whereas larger CA3-4/dentate gyrus volumes predicted greater improvement in associative memory over repeated tests regardless of vascular risk, CA1-2 volumes were associated with improvement in noun recall only in hypertensive participants. Only among hypertensive participants, CA1-2 volumes negatively related to age and CA3-4/dentate gyrus and CA1-2 volumes were associated with performance at the last measurement occasion. These findings suggest that relatively small regions of the HC may play a role in age-related memory declines and that vascular risk factors associated with advanced age may modify that relationship.
Advanced age is associated with decrements in episodic memory, which are more pronounced in memory for associations than for individual items. The associative deficit hypothesis (ADH) states that age ...differences in recognition memory reflect difficulty in binding components of a memory episode and retrieving bound units. To date, ADH has received support only in studies of extreme age groups, and the influence of sex, education, and health on age-related associative deficit is unknown. We address those issues using a verbal paired-associate yes-no recognition paradigm on a lifespan sample of 278 healthy, well-educated adults. In accord with the ADH, greater age was associated with lower hit and greater false alarm rates and more liberal response bias on associative recognition tests. Women outperformed men on recognition of items and associations, but among normotensive participants, women outperformed men only on memory for associations and not on item recognition. Thus, although supporting ADH in a large lifespan sample of healthy adults, the findings indicate that the effect may be partially driven by an age-related increase in liberal bias in recognition of associations. Sex differences and health factors may modify the associative deficit regardless of age.
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