Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent–child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case–control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive–compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes

Thermal Perceptual Thresholds are typical in Autism Spectrum Disorder but Strongly Related to Intra-individual Response Variability

Individuals with autism spectrum disorder (ASD) are often reported to exhibit an apparent indifference to pain or temperature. Leading models suggest that this behavior is the result of elevated perceptual thresholds for thermal stimuli, but data to support these assertions are inconclusive. An alternative proposal suggests that the sensory features of ASD arise from increased intra-individual perceptual variability. In this study, we measured method-of-limits warm and cool detection thresholds in 142 individuals (83 with ASD, 59 with typical development [TD], aged 7–54 years), testing relationships with diagnostic group, demographics, and clinical measures. We also investigated the relationship between detection thresholds and a novel measure of intra-individual (trial-to-trial) threshold variability, a putative index of “perceptual noise.” This investigation found no differences in thermal detection thresholds between individuals with ASD and typical controls, despite large differences between groups in sensory reactivity questionnaires and modest group differences in intra-individual variability. Lower performance IQ, male sex, and higher intra-individual variability in threshold estimates were the most significant predictors of elevated detection thresholds. Although no psychophysical measure was significantly correlated with questionnaire measures of sensory hyporeactivity, large intra-individual variability may partially explain the elevated psychophysical thresholds seen in a subset of the ASD population

Class I ß-1,3-glucanase in the endosperm of tobacco during germination

Rupture of the seed coat and rupture of the endosperm are separate events in the germination of Nicotiana tabacum L. cv Havana 425 seeds. Treatment with 10-5 M abscisic acid (ABA) did not appreciably affect seed-coat rupture but greatly delayed subsequent endosperm rupture by more than 100 h and resulted in the formation of a novel structure consisting of the enlarging radicle with a sheath of greatly elongated endosperm tissue. Therefore, ABA appears to act primarily by delaying endosperm rupture and radicle emergence. Measurements of [beta]-1,3-glucanase activity, antigen content, and mRNA accumulation together with reporter gene experiments showed that induction of class I [beta]-1,3-glucanase genes begins just prior to the onset of endosperm rupture but after the completion of seed-coat rupture. This induction was localized exclusively in the micropylar region of the endosperm, where the radicle will penetrate. ABA treatment markedly inhibited the rate of [beta]-1,3-glucanase accumulation but did not delay the onset of induction. Independent of the ABA concentration used, onset of endosperm rupture was correlated with the same [beta]-1,3-glucanase content/seed. These results suggest that ABA-sensitive class I [beta]-1,3-glucanases promote radicle penetration of the endosperm, which is a key limiting step in tobacco seed germination

Physical oceanography during the cruise POS432 in the Madeira basin in May 2012

This set provides 19 CTD profiles of temperature, salinity, dissolved oxygen, fluorescence, turbidity and sound velocity measured on board of the German R/V Poseidon in May 2012, in the Madeira basin region, Northeast Atlantic. We aimed to study the physical and biogeochemical conditions of the water column along the 22°W meridian, north and south of the Azores Front. The biogeochemical data associated to this dataset can be found in doi:10.1594/PANGAEA.94662

Biological and chemical water properties measured in water bottle samples during the cruise POS432 in Madeira basin in May 2012

During the cruise POS432 on board the German R/V Poseidon, we collected water with a CTD SBE 11plus equipped with 14 Hydrobios free flow bottles of 10 L each in 15 stations (resulting in almost 100 samples) in the Madeira basin region, Northeast Atlantic. We aimed to study the physical and biogeochemical conditions of the water column along the 22°W meridian, north and south of the Azores Front, in May 2012. We measured concentrations of chlorophyll a, phaeopigments, suspended particulate material (SPM), and nutrients such as nitrate, nitrite, phosphate, and silicate

Acoustic Tomography in the Canary Basin: Meddies and Tides

An acoustic propagation experiment over 308-km range conducted in the Canary Basin in 1997–1998 was used to assess the ability of ocean acoustic tomography to measure the flux of Mediterranean water and Meddies. Instruments on a mooring adjacent to the acoustic path measured the southwestward passage of a strong Meddy in temperature, salinity, and current. Over nine months of transmissions, the acoustic arrival pattern was an initial broad stochastic pulse varying in duration by 250 to 500 ms, followed eight stable, identified ray arrivals. Small-scale sound speed fluctuations from Mediterranean water parcels littered around the sound channel axis caused acoustic scattering. Internal waves contributed more modest acoustic scattering. Based on simulations, the main effect of a Meddy passing across the acoustic path is the formation of many early-arriving, near-axis rays, but these rays are thoroughly scattered by the small-scale Mediterranean water fluctuations. A Meddy decreases the deep-turning ray travel times by 10–30 ms. The dominant acoustic signature of a Meddy is therefore the expansion of the width of the initial stochastic pulse. While this signature appears inseparable from the other effects of Mediterranean water in this region, the acoustic time series indicates the steady passage of Mediterranean water across the acoustic path. Tidal variations caused by the mode-1 internal tides were measured by the acoustic travel times. The observed internal tides were partly predicted using a recent global model for such tides derived from satellite altimetry

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

BACKGROUND Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). Prognostic biomarkers are an unmet need. METHODS Patients with HCC put on PD-(L)1-based immunotherapy in 6 European centers (training set; n=190) and in 8 European centers (validation set; n=102) were included. We investigated the prognostic value of baseline variables on overall survival by using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n=204). RESULTS Baseline serum alpha-fetoprotein ≥100 ng/ml (HR, 1.7; p=0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p=0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95%CI, 19.5-35.8) months), followed by those fulfilling one criterion (1 point; CRAFITY-intermediate; 11.3 (95%CI, 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95%CI, 4.8-8.1) months; p<0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low:9%/20%/52%/20% vs. CRAFITY-intermediate:3%/25%/36%/36% vs. CRAFITY-high:2%/15%/22%/61%; p=0.003). These results were confirmed in the independent validation set as well as in different subgroups including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS The CRAFITY score is associated with survival and radiological response. The score may help with patient counseling, but requires prospective validation. LAY SUMMARY The immunotherapy based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers