Organotypic Brain Cultures for Metastasis Research

We thank members of Brain Metastasis Group for critical discussion. Research in the Brain Metastasis Group is supported by MINECO-Retos SAF2017-89643-R (M.V.), Cancer Research Institute CLIP Award 2018 (M.V.), AECC (GCTRA16015SEOA) (M.V.), Bristol-Myers Squibb Melanoma Research Alliance Young Investigator Award 2017 (M.V.), Beug Foundation’s Prize for Metastasis Research 2017 (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Fundación Ramón Areces (CIVP19S8163), and La Caixa-Severo Ochoa International PhD Program Fellowship (L.Z.). M.V. is a Ramón y Cajal Investigator (RYC-2013-13365) and an EMBO YIP investigator.N

Bithiazole: An Intriguing Electron-Deficient Building for Plastic Electronic Applications.

The heterocyclic thiazole unit has been extensively used as electron-deficient building block in π-conjugated materials over the last decade. Its incorporation into organic semiconducting materials is particularly interesting due to its structural resemblance to the more commonly used thiophene building block, thus allowing the optoelectronic properties of a material to be tuned without significantly perturbing its molecular structure. Here, we discuss the structural differences between thiazole- and thiophene-based organic semiconductors, and the effects on the physical properties of the materials. An overview of thiazole-based polymers is provided, which have emerged over the past decade for organic electronic applications and it is discussed how the incorporation of thiazole has affected the device performance of organic solar cells and organic field-effect transistors. Finally, in conclusion, an outlook is presented on how thiazole-based polymers can be incorporated into all-electron deficient polymers in order to obtain high-performance acceptor polymers for use in bulk-heterojunction solar cells and as organic field-effect transistors. Computational methods are used to discuss some newly designed acceptor building blocks that have the potential to be polymerized with a fused bithiazole moiety, hence propelling the advancement of air-stable n-type organic semiconductors

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries

Serial search for targets defined by divergence or deformation of optic flow.

The optic flow field can be described in terms of the local differential measures, divergence, deformation, and rotation, which are informative about observer motion and the 3-D structure of the environment. Does an explicit representation of these measures exist in human visual processing in the form of a feature map? Triesman's criteria were used to investigate this; ie is there 'pop-out' for a target defined as different in local divergence or deformation from surrounding elements, or is a serial search necessary? The stimulus arrays contained 3, 5, or 9 square or rectangular elements, which each underwent repeated cycles of expansion, contraction, or deformation. The time required to detect a target undergoing the opposite transformation increased steeply with the number of elements, implying very slow serial search. (The mean time was 210 ms per element for divergence targets and 542 ms per element for deformation). The process was clearly still serial when the density and number of elements was increased up to 48 in an array 2.16 deg x 2.16 deg. In contrast, a single line element undergoing the opposite direction of translation motion to the rest of the display did show pop-out. It is concluded that no parallel processes seem to exist which are sensitive to the spatial uniformity of divergence and of deformation of optic flow. These differential properties may be derived as conjunctions of signals from a primary process which extracts local velocity. This result contrasts with our findings for targets defined by stereo disparity gradient, which show parallel processing in analogous experiments

Pre-attentive detection of a target defined by stereoscopic slant.

Does the visual system represent stereoscopic depth purely as a map of local disparities, or does it explicitly represent local relationships of disparity, such as disparity gradients? Experiments are reported in which visual search for a target containing the same disparity range as other elements in the display, but differing in the relationship of the disparities (stereo slant), was used to determine whether the target showed 'pop-out' like a unitary feature, or the serial search characteristic of feature conjunctions. Each stereo pair of elements was selected randomly from a range of outline parallelograms leaning to the right or to the left, so that the target could not be identified using any monocular shape cue. Response times for detection of the target (present on 50% of the trials) were independent of the number of elements in the display. This result was confirmed by varying element size and spacing, and by using oblique crosses rather than parallelograms as stimuli. It is concluded that stereoscopically defined slant, or disparity gradient, can be processed and compared in parallel across the display, and acts in this respect as an explicit unitary visual property. This contrasts with findings in analogous experiments on movement, which show that targets defined by divergence or deformation of optic flow can only be identified by serial search

Stimuli of varying spatial scale induce gamma activity with distinct temporal characteristics in human visual cortex.

Gamma activity to stationary grating stimuli was studied non-invasively using MEG recordings in humans. Using a spatial filtering technique, we localized gamma activity to primary visual cortex. We tested the hypothesis that spatial frequency properties of visual stimuli may be related to the temporal frequency characteristics of the associated cortical responses. We devised a method to assess temporal frequency differences between stimulus-related responses that typically exhibit complex spectral shapes. We applied this methodology to either single-trial (induced) or time-averaged (evoked) responses in four frequency ranges (0-40, 20-60, 40-80 and 60-100 Hz) and two time windows (either the entire duration of stimulus presentation or the first second following stimulus onset). Our results suggest that stimuli of varying spatial frequency induce responses that exhibit significantly different temporal frequency characteristics. These effects were particularly accentuated for induced responses in the classical gamma frequency band (20-60 Hz) analyzed over the entire duration of stimulus presentation. Strikingly, examining the first second of the responses following stimulus onset resulted in significant loss in stimulus specificity, suggesting that late signal components contain functionally relevant information. These findings advocate a functional role of gamma activity in sensory representation. We suggest that stimulus specific frequency characteristics of MEG signals can be mapped to processes of neuronal synchronization within the framework of coupled dynamical systems