THz and IR spectroscopy of endofullerene H₂O@C₆₀

Terahertz time-domain and infrared Fourier-transform spectroscopy techniques are used to investigate the properties of H2O@C60 endofullerene in 6 K – 300 K temperature interval. A number of absorption lines associated with rotational transitions of water molecule entrapped inside C60 cages are observed and assigned. Fitting the resonances with Lorenzian lineshapes allowed us to obtain temperature dependencies of absorption lines parameters – frequency, strength and damping

Rotational coherence of encapsulated ortho and para water in fullerene-C₆₀ revealed by time-domain terahertz spectroscopy

We resolve the real-time coherent rotational motion of isolated water molecules encapsulated in fullerene-C60 cages by time-domain terahertz (THz) spectroscopy. We employ single-cycle THz pulses to excite the low-frequency rotational motion of water and measure the subsequent coherent emission of electromagnetic waves by water molecules. At temperatures below ~ 100 K, C60 lattice vibrational damping is mitigated and the quantum dynamics of confined water are resolved with a markedly long rotational coherence, extended beyond 10 ps. The observed rotational transitions agree well with low-frequency rotational dynamics of single water molecules in the gas phase. However, some additional spectral features with their major contribution at ~2.26 THz are also observed which may indicate interaction between water rotation and the C60 lattice phonons. We also resolve the real-time change of the emission pattern of water after a sudden cooling to 4 K, signifying the conversion of ortho-water to para-water over the course of 10s hours. The observed long coherent rotational dynamics of isolated water molecules confined in C60 makes this system an attractive candidate for future quantum technology

CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance

The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies

Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing

How informative is a negative finding in a small pharmacogenetic study?

Many pharmacogenetic studies fail to yield any statistically significant associations. Such negative findings may be due to the absence of, or inadequate statistical power to test for, an effect at the genetic variants tested. In many instances, sample sizes are small, making it unclear how to interpret the absence of statistically significant findings. We demonstrate that the amount of information that can be drawn from a negative study is improved by incorporating statistical power and the added context of well-validated pharmacogenetic effects into the interpretation process. This approach permits clearer inferences to be made about the possible range of genetic effects that may be present in, or are likely absent from, small drug studies

A note on the use of the generalized odds ratio in meta-analysis of association studies involving bi- and tri-allelic polymorphisms

<p>Abstract</p> <p>Background</p> <p>The generalized odds ratio (GOR) was recently suggested as a genetic model-free measure for association studies. However, its properties were not extensively investigated. We used Monte Carlo simulations to investigate type-I error rates, power and bias in both effect size and between-study variance estimates of meta-analyses using the GOR as a summary effect, and compared these results to those obtained by usual approaches of model specification. We further applied the GOR in a real meta-analysis of three genome-wide association studies in Alzheimer's disease.</p> <p>Findings</p> <p>For bi-allelic polymorphisms, the GOR performs virtually identical to a standard multiplicative model of analysis (e.g. per-allele odds ratio) for variants acting multiplicatively, but augments slightly the power to detect variants with a dominant mode of action, while reducing the probability to detect recessive variants. Although there were differences among the GOR and usual approaches in terms of bias and type-I error rates, both simulation- and real data-based results provided little indication that these differences will be substantial in practice for meta-analyses involving bi-allelic polymorphisms. However, the use of the GOR may be slightly more powerful for the synthesis of data from tri-allelic variants, particularly when susceptibility alleles are less common in the populations (≤10%). This gain in power may depend on knowledge of the direction of the effects.</p> <p>Conclusions</p> <p>For the synthesis of data from bi-allelic variants, the GOR may be regarded as a multiplicative-like model of analysis. The use of the GOR may be slightly more powerful in the tri-allelic case, particularly when susceptibility alleles are less common in the populations.</p

Association between Type 2 Diabetes Loci and Measures of Fatness

Background: Type 2 diabetes (T2D) is a metabolic disorder characterized by disturbances of carbohydrate, fat and protein metabolism and insulin resistance. The majority of T2D patients are obese and obesity by itself may be a cause of insulin resistance. Our aim was to evaluate whether the recently identified T2D risk alleles are associated with human measures of fatness as characterized with Dual Energy X-ray Absorptiometry (DEXA). Methodology/Principal Findings: Genotypes and phenotypes of approximately 3,000 participants from cross-sectional ERF study were analyzed. Nine single nucleotide polymorphisms (SNPs) in CDKN2AB, CDKAL1, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8 and TCF7L2 were genotyped. We used linear regression to study association between individual SNPs and the combined allelic risk score with body mass index (BMI), fat mass index (FMI), fat percentage (FAT), waist circumference (WC) and waist to hip ratio (WHR). Significant association was observed between rs8050136 (FTO) and BMI (p = 0.003), FMI (p = 0.007) and WC (p = 0.03); fat percentage was borderline significant (p = 0.053). No other SNPs alone or combined in a risk score demonstrated significant association to the measures of fatness. Conclusions/Significance: From the recently identified T2D risk variants only the risk variant of the FTO gene (rs8050136) showed statistically significant association with BMI, FMI, and WC

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers

Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

Hair cortisol concentration (HCC) is a promising measure of long-Term hypothalamus-pituitary-Adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables