A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude ...lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P<5 × 10(-8) approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P=1.83 × 10(-7)) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL. Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4, a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.
We demonstrated a unique approach that combines a layer‐by‐layer (LbL) self‐assembly method with dendrimer chemistry to functionalize Fe3O4 nanoparticles (NPs) for specific targeting and imaging of ...cancer cells. In this approach, positively charged Fe3O4 NPs (8.4 nm in diameter) synthesized by controlled co‐precipitation of FeII and FeIII ions were modified with a bilayer composed of polystyrene sulfonate sodium salt and folic acid (FA)‐ and fluorescein isothiocyanate (FI)‐functionalized poly(amidoamine) dendrimers of generation 5 (G5.NH2‐FI‐FA) through electrostatic LbL assembly, followed by an acetylation reaction to neutralize the remaining surface amine groups of G5 dendrimers. Combined flow cytometry, confocal microscopy, transmission electron microscopy, and magnetic resonance imaging studies show that Fe3O4/PSS/G5.NHAc‐FI‐FA NPs can specifically target cancer cells overexpressing FA receptors. The present approach to functionalizing Fe3O4 NPs opens a new avenue to fabricating various NPs for numerous biological sensing and therapeutic applications.
Dendrimer‐functionalized iron oxide nanoparticles are fabricated by a unique approach that combines a layer‐by‐layer self‐assembly technique with dendrimer chemistry. In vitro flow cytometry, confocal microscopy, transmission electron microscopy, and magnetic resonance imaging (see figure) results show that these multifunctional nanoparticles can specifically target cancer cells overexpressing folate receptors.
Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of ...clinicians to select antiplatelet therapy based on CYP2C19 loss‐of‐function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio HR in poor metabolizers 8.1, 95% confidence interval CI 5.4, 12.2 and HR 5.0, 95% CI 4.0, 6.3 in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision‐making.
Summary
Acoustic radiation force impulse (ARFI) imaging is a novel ultrasound‐based elastography method that is integrated in a conventional ultrasound machine. It might provide an alternative method ...to transient elastography for the noninvasive assessment of liver fibrosis. While previous studies have shown comparable diagnostic accuracy of ARFI to transient elastography in chronic hepatitis C, the aim of the present prospective multicenter study was to evaluate ARFI for the assessment of liver fibrosis in chronic hepatitis B. ARFI imaging involves the mechanical excitation of tissue using short‐duration acoustic pulses to generate localized displacements in tissue. The displacements result in shear‐wave propagation which is tracked using ultrasonic, correlation‐based methods and recorded in m/s. In the present international prospective study, patients infected with chronic hepatitis B received ARFI imaging, blood tests and if available transient elastography. The results were compared to liver biopsy as reference method analysed by a central pathologist. In 92 of 114 patients, a comparison of ARFI with transient elastography was possible. ARFI imaging and transient elastography correlated significantly with histological fibrosis stage. The diagnostic accuracy expressed as areas under ROC curves for ARFI imaging and transient elastography was 0.75 and 0.83 for the diagnosis of significant fibrosis (F ≥ 2), 0.93 and 0.94 for the diagnosis of severe fibrosis (F ≥ 3), and 0.97 and 0.93 for the diagnosis of liver cirrhosis, respectively. No significant difference was found between ARFI and transient elastography. ARFI imaging is a reliable ultrasound‐based method for the assessment of advanced stages of liver fibrosis in chronic hepatitis B.
To examine the potential utility of conventional MRI signs in differentiating pseudoprogression (PsP) from early progression (EP).
This retrospective study reviewed initial postradiotherapy MRI scans ...of 321 patients with glioblastoma undergoing chemotherapy and radiotherapy. A total of 93 patients were found to have new or increased enhancing mass lesions, raising the possibility of PsP. Final diagnosis of PsP or EP was established upon review of surgical specimens from a second resection or by clinical and radiologic follow-up. A total of 11 MRI signs potentially helpful in the differentiation between PsP and EP were examined on the initial post-RT MRI and were correlated with the final diagnosis through χ(2) or Fisher exact test.
Sixty-three (67.7%) of the 93 patients had EP, of which 22 (34.9%) were diagnosed by pathology. Thirty patients (32.3%) had PsP; 6 (16.7% of the 30) were diagnosed by pathology. Subependymal enhancement was predictive for EP (p = 0.001) with 38.1% sensitivity, 93.3% specificity, and 41.8% negative predictive value. The other 10 signs had no predictive value (p = 0.06-1.0).
Conventional MRI signs have limited utility in diagnosing PsP in patients with recently treated glioblastomas and worsening enhancing lesions. We did not find a sign with a high negative predictive value for PsP that would have been the most useful for the clinical physician. When present, subependymal spread of the enhancing lesion is a useful MRI marker in identifying EP rather than PsP.
In humans and many other mammals, the cortex (the outer layer of the brain) folds during development. The mechanics of folding are not well understood; leading explanations are either incomplete or ...at odds with physical measurements. We propose a mathematical model in which (i) folding is driven by tangential expansion of the cortex and (ii) deeper layers grow in response to the resulting stress. In this model the wavelength of cortical folds depends predictably on the rate of cortical growth relative to the rate of stress-induced growth. We show analytically and in simulations that faster cortical expansion leads to shorter gyral wavelengths; slower cortical expansion leads to long wavelengths or even smooth (lissencephalic) surfaces. No inner or outer (skull) constraint is needed to produce folding, but initial shape and mechanical heterogeneity influence the final shape. The proposed model predicts patterns of stress in the tissue that are consistent with experimental observations.
Abstract
We collect observational evidence that supports the scheme of mass transfer on the nucleus of comet 67P/Churyumov–Gerasimenko. The obliquity of the rotation axis of 67P causes strong ...seasonal variations. During perihelion the southern hemisphere is four times more active than the north. Northern territories are widely covered by granular material that indicates back fall originating from the active south. Decimetre sized chunks contain water ice and their trajectories are influenced by an antisolar force instigated by sublimation. OSIRIS observations suggest that up to 20 per cent of the particles directly return to the nucleus surface taking several hours of traveltime. The back fall covered northern areas are active if illuminated but produce mainly water vapour. The decimetre chunks from the nucleus surface are too small to contain more volatile compounds such as CO2 or CO. This causes a north–south dichotomy of the composition measurements in the coma. Active particles are trapped in the gravitational minimum of Hapi during northern winter. They are ‘shock frozen’ and only re-activated when the comet approaches the sun after its aphelion passage. The insolation of the big cavity is enhanced by self-heating, i.e. reflection and IR radiation from the walls. This, together with the pristinity of the active back fall, explains the early observed activity of the Hapi region. Sobek may be a role model for the consolidated bottom of Hapi. Mass transfer in the case of 67P strongly influences the evolution of the nucleus and the interpretation of coma measurements.
Context. Two distinct halo populations were found in the solar neighborhood by a series of works. They can be clearly separated by α/Fe and several other elemental abundance ratios including Cu/Fe. ...Very recently, a non-local thermodynamic equilibrium (non-LTE) study revealed that relatively large departures exist between LTE and non-LTE results in copper abundance analysis. The study also showed that non-LTE effects of neutral copper vary with stellar parameters and thus affect the Cu/Fe trend. Aims. We aim to derive the copper abundances for the stars from the sample of Nissen & Schuster (2010) with both LTE and non-LTE calculations. Based on our results, we study the non-LTE effects of copper and investigate whether the high-α population can still be distinguished from the low-α population in the non-LTE Cu/Fe results. Methods. Our differential abundance ratios are derived from the high-resolution spectra collected from VLT/UVES and NOT/FIES spectrographs. Applying the MAFAGS opacity sampling atmospheric models and spectrum synthesis method, we derive the non-LTE copper abundances based on the new atomic model with current atomic data obtained from both laboratory and theoretical calculations. Results. The copper abundances determined from non-LTE calculations are increased by 0.01 to 0.2 dex depending on the stellar parameters compared with the LTE results. The non-LTE Cu/Fe trend is much flatter than the LTE one in the metallicity range −1.6 < Fe / H < −0.8. Taking non-LTE effects into consideration, the high- and low-α stars still show distinguishable copper abundances, which appear even more clear in a diagram of non-LTE Cu/Fe versus Fe/H. Conclusions. The non-LTE effects are strong for copper, especially in metal-poor stars. Our results confirmed that there are two distinct halo populations in the solar neighborhood. The dichotomy in copper abundance is a peculiar feature of each population, suggesting that they formed in different environments and evolved obeying diverse scenarios.
To monitor changes in α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor distribution in living neurons, the AMPA receptor subunit GluR1 was tagged with green fluorescent protein ...(GFP). This protein (GluR1-GFP) was functional and was transiently expressed in hippocampal CA1 neurons. In dendrites visualized with two-photon laser scanning microscopy or electron microscopy, most of the GluR1-GFP was intracellular, mimicking endogenous GluR1 distribution. Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines as well as clusters in dendrites. These postsynaptic trafficking events required synaptic N-methyl-D-aspartate (NMDA) receptor activation and may contribute to the enhanced AMPA receptor-mediated transmission observed during long-term potentiation and activity-dependent synaptic maturation.
The impact of central Asian aridification on the low latitude North Pacific Ocean since the late Miocene remains unclear. To address this question, we systematically studied an abyssal manganese ...nodule from the northwestern Pacific Ocean, which is expected to be sensitive to eolian dust sourced from central Asia. Geochemical variations and the fossilized remains of magnetotactic bacteria within the studied nodule manifest two prominent Asian aridification events at ∼8–7 Ma and 3.6–0 Ma. These results suggest that central Asian aridification impacted both primary productivity and abyssal microbial activity in the NW Pacific Ocean via eolian dust inputs. In contrast to the Pliocene aridification event, the late Miocene event was associated with a primary productivity bloom that is not evident in coeval global primary productivity records, which indicates that the ∼8–7 Asian aridification event was likely due to NE Tibetan Plateau uplift rather than to global cooling.
Plain Language Summary
Central Asian aridification since the late Miocene has had a significant influence on climate, temperature, and North Pacific Ocean productivity through eolian dust inputs transported by westerlies. However, it is unclear whether the low latitude of NW Pacific Ocean responded to this aridification. We systematically analyzed the geochemistry and magnetism of a NW Pacific manganese nodule, and find that Asian aridification since, the late Miocene impacted biogeochemical cycling and abyssal microbial activity in the NW Pacific Ocean via eolian dust input. Our results imply that these two prominent Asian aridification events at around 8–7 Ma and ca. 3.6 Ma can be attributed to the NE Tibetan Plateau uplift and global cooling, respectively.
Key Points
A manganese nodule from the NW Pacific carries a paleoclimatic record of Asian aridification since the Late Miocene
Asian aridification impacted biogeochemical cycling and abyssal microbial activity in the NW Pacific Ocean
Major Asian aridification events at ∼8–7 Ma and ∼3.6–0 Ma may be attributed to NE Tibetan Plateau uplift and global cooling, respectively
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