Extending Phenomenological Crystal-Field Methods to C_{1} Point-Group Symmetry: Characterization of the Optically Excited Hyperfine Structure of

We show that crystal-field calculations for C_{1} point-group symmetry are possible, and that such calculations can be performed with sufficient accuracy to have substantial utility for rare-earth based quantum information applications. In particular, we perform crystal-field fitting for a C_{1}-symmetry site in ^{167}Er^{3+}:Y_{2}SiO_{5}. The calculation simultaneously includes site-selective spectroscopic data up to 20 000 cm^{-1}, rotational Zeeman data, and ground- and excited-state hyperfine structure determined from high-resolution Raman-heterodyne spectroscopy on the 1.5 µm telecom transition. We achieve an agreement of better than 50 MHz for assigned hyperfine transitions. The success of this analysis opens the possibility of systematically evaluating the coherence properties, as well as transition energies and intensities, of any rare-earth ion doped into Y_{2}SiO_{5}.

An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Generating an image that affords slant perception from stereo, without pictorial cues.

This paper describes an algorithm for generating a planar image that when tilted provides stereo cues to slant, without contamination from pictorial gradients. As the stimuli derived from this image are ultimately intended for use in studies of slant perception under magnification, a further requirement is that the generated image be suitable for high-definition printing or display on a monitor. A first stage generates an image consisting of overlapping edges with sufficient density that when zoomed, edges that nearly span the original scale are replaced with newly emergent content that leaves the visible edge statistics unchanged. A second stage reduces intensity clumping while preserving edges by enforcing a broad dynamic range across the image. Spectral analyses demonstrate that the low-frequency content of the resulting image, which would correspond to the pictorial cue of texture gradient changes under slant, (a) has a power fall-off deviating from 1/f noise (to which the visual system is particularly sensitive), and (b) does not offer systematic cues under changes in scale or slant. Two behavioral experiments tested whether the algorithm generates stimuli that offer cues to slant under stereo viewing only, and not when disparities are eliminated. With a particular adjustment of dynamic range (and nearly so with the other version that was tested), participants viewing without stereo cues were essentially unable to discriminate slanted from flat (frontal) stimuli, and when slant was reported, they failed to discriminate its direction. In contrast, non-stereo viewing of a control stimulus with pictorial cues, as well as stereoscopic observation, consistently allowed participants to perceive slant correctly. Experiment 2 further showed that these results generalized across a population of different stimuli from the same generation process and demonstrated that the process did not substitute biased slant cues.

Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.

Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.

Genomic profiles and predictors of early allograft dysfunction after human liver transplantation.

Early hepatic allograft dysfunction (EAD) manifests posttransplantation with high serum transaminases, persistent cholestasis, and coagulopathy. The biological mechanisms are poorly understood. This study investigates the molecular mechanisms involved in EAD and defines a gene expression signature revealing different biological pathways in subjects with EAD from those without EAD, a potential first step in developing a molecular classifier as a potential clinical diagnostic. Global gene expression profiles of 30 liver transplant recipients of deceased donor grafts with EAD and 26 recipients without graft dysfunction were investigated using microarrays of liver biopsies performed at the end of cold storage and after graft reperfusion prior to closure. Results reveal a shift in inflammatory and metabolic responses between the two time points and differences between EAD and non-EAD. We identified relevant pathways (PPARα and NF-κB) and targets (such as CXCL1, IL1, TRAF6, TIPARP, and TNFRSF1B) associated with the phenotype of EAD. Preliminary proof of concept gene expression classifiers that distinguish EAD from non-EAD patients, with Area Under the Curve (AUC) >0.80 were also identified. This data may have mechanistic and diagnostic implications for EAD.

Modulation of behavioral networks by selective interneuronal inactivation.

Gamma-aminobutyric acid (GABA)-ergic disturbances are hallmark features of schizophrenia and other neuropsychiatric disorders and encompass multiple interneuronal cell types. Using bacterial artificial chromosome-driven, miRNA silencing technology we generated transgenic mouse lines that suppress glutamic acid decarboxylase 1 (GAD1) in either cholecystokinin (CCK)- or neuropeptide Y (NPY)-expressing interneurons. In situ lipidomic and proteomic analyses on brain tissue sections revealed distinct, brain region-specific profiles in each transgenic line. Behavioral analyses revealed that suppression of GAD1 in CCK+ interneurons resulted in locomotor and olfactory sensory changes, whereas suppression in NPY+ interneurons affected anxiety-related behaviors and social interaction. Both transgenic mouse lines had altered sensitivity to amphetamine albeit in opposite directions. Together, these data argue that reduced GAD1 expression leads to altered molecular and behavioral profiles in a cell type-dependent manner, and that these subpopulations of interneurons are strong and opposing modulators of dopamine system function. Furthermore, our findings also support the hypothesis that neuronal networks are differentially controlled by diverse inhibitory subnetworks.

Molecular classifiers for acute kidney transplant rejection in peripheral blood by whole genome gene expression profiling.

There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection (ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi-array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one-by-one analysis strategy to model the real clinical application of this test. Multiple three-way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction.

The CALERIE™ Genomic Data Resource.

Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from CALERIE-2™ - the first ever randomized, controlled trial of long-term CR in healthy, non-obese humans - broadly supports a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n=218 participants during the trial. These data constitute the first publicly-accessible genomic data resource for a randomized controlled trial of an intervention targeting the biology of aging. Datasets include whole-genome SNP genotypes, and three-timepoint-longitudinal DNA methylation, mRNA, and small RNA datasets generated from blood, skeletal muscle, and adipose tissue samples (total sample n=2327). The CALERIE Genomic Data Resource described in this article is available from the Aging Research Biobank. This mult-itissue, multi-omic, longitudinal data resource has great potential to advance translational geroscience.

Alpha-2 macroglobulin is genetically associated with Alzheimer disease.

Alpha-2-macroglobulin (alpha-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon4 allele in the same sample, but in contrast to APOE-epsilon4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

Clinical and plasma proteomic markers correlating with chronic kidney disease after liver transplantation.

Chronic kidney disease (CKD) occurs frequently after liver transplantation (LT) and is associated with significant morbidity and mortality. Thus, there is a pressing need to identify characteristics and biomarkers diagnostic of CKD to enable early diagnosis allowing preemptive interventions, as well as mechanistic insights into the progression from kidney injury to irreversible kidney failure. We analyzed 342 patients who had baseline glomerular filteration rate (GFR) >60 at the time of LT and are now >3 years post-LT. Risk factors for post-LT CKD were compared between three different groups defined by current GFR: >90 (n = 40), 60-90 (n = 146) and <60 (n = 156) mL/min. Age, cyclosporine use and pre-LT GFR were independently associated with new onset CKD. A subset (n = 64) without viral/immune disease or graft dysfunction underwent multianalyte plasma proteomic evaluations for correlation with CKD. Plasma proteomic analysis of two independent cohorts, test (n = 22) and validation (n = 42), identified 10 proteins highly associated with new onset CKD. In conclusion, we have identified clinical characteristics and a unique plasma proteomic signature correlating with new onset CKD after LT. These preliminary results are currently being validated in a prospective, multicenter study to determine if this signature precedes the onset of CKD and resolves with early interventions aimed at preserving kidney function.