The Influence of Orthographic Consistency on Eye Movement Behaviour in Word and Sentence Processing

In reading science, studies carried out with English-speaking participants reading in their native language have traditionally formed the basis for most theories and models. From the 1990s, however, there was a continuously growing conviction that this English-based research agenda alone would not lead to a universal science of reading. A major reason why English is not a good basis for developing univerally applicable theories and models on reading and reading acquisition is that the English orthography is exceptionally inconsistent with regards to the relationship of letters and sounds (low grapheme-phoneme consistency). One consequence of this inconsistency is that for reading English linguistic processing rather relies on small lingusitic units, whereas for more consistent languages (such as German) large linguistic units are rather relied upon. (Psycholinguistic grain size theory (Ziegler & Goswami, 2005)) – for example ultimately leading to a relative delay regarding reading acquisition skills for children learning English. The research project presented here set out to deepen and broaden the understanding of this phenomenon. In three studies, both word processing and sentence processing in the consistent German and the inconsistent English orthography were investigated. Methodologically, I studied eye movement behaviour in both developing readers and adult readers. The studies reported here support the central claim of grain size theory. Study one investigated the transition in predominant reading strategy from serial sublexical decoding to more parallel lexical processing as a function of word frequency in the consistent German orthography. The least experienced readers of grade 2 were found to apply serial sublexical decoding as a default reading strategy to most items, largely independent of word frequency, whereas more experienced readers of grades 3 and 4, and adults, were increasingly relying on direct lexical access. Studies two and three investigated the influence of orthographic consistency on the time-course of word and sentence processing; now focusing on a cross-linguistic comparison. The two studies found evidence for more small-unit bottom-up processing on the part of the German, and more large-unit top-down processing on the part of the English readers, for both the local word level, and the global sentence level. The overall processing pattern differed between orthographies: while German readers showed a plodder-like reading style with more diligent first-pass reading and less re-reading, English readers showed an explorer-like reading style with more word skippings and more regressive eye movements. In sum, orthographic consistency impacts upon both local word recognition and global sentence processing, in both developing and skilled readers

Individuals at increased risk for development of bipolar disorder display structural alterations similar to people with manifest disease

In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder

Discovery of a Highly Selective Tankyrase Inhibitor Displaying Growth Inhibition Effects against a Diverse Range of Tumor Derived Cell Lines

The availability of high quality probes for specific protein targets is fundamental to the investigation of their function and their validation as therapeutic targets. We report the utilization of a dedicated chemoproteomic assay platform combining affinity enrichment technology with high-resolution protein mass spectrometry to the discovery of a novel nicotinamide isoster, the tetrazoloquinoxaline <b>41</b>, a highly potent and selective tankyrase inhibitor. We also describe the use of <b>41</b> to investigate the biology of tankyrase, revealing the compound induced growth inhibition of a number of tumor derived cell lines, demonstrating the potential of tankyrase inhibitors in oncology

Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis

Background and Objectives To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis. Methods We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes. Results We identified 2 independent risk loci harboring genome-wide significant variants (p = 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes. Discussion This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism