Customized antisense oligonucleotide-based therapy for neurofilament-associated Charcot-Marie-Tooth disease.

DNA-based therapeutics have emerged as a revolutionary approach for addressing the treatment gap in rare inherited conditions by targeting the fundamental genetic causes of disease. Charcot-Marie-Tooth (CMT) disease, a group of inherited neuropathies, represents one of the most prevalent Mendelian disease groups in neurology and is characterized by diverse genetic etiology. Axonal forms of CMT, known as CMT2, are caused by dominant mutations in over 30 different genes which lead to degeneration of lower motor neuron axons. Recent advances in antisense oligonucleotide (ASO) therapeutics have shown promise in targeting neurodegenerative disorders. Here we elucidate pathomechanistic changes contributing to variant specific molecular phenotypes in CMT2E, caused by a single nucleotide substitution (p.N98S) in the neurofilament light chain gene (NEFL). We used a patient-derived pluripotent stem cell (iPSC)-induced motor neuron model, which recapitulates several cellular and biomarker phenotypes associated with CMT2E. Using an ASO treatment strategy targeting a heterozygous gain-of-function variant, we aimed to resolve molecular phenotypic changes observed in the CMT2E p.N98S subtype. To determine ASO therapeutic potential, we employed our treatment strategy in iPSC-derived motor neurons and used established as well as novel biomarkers of peripheral nervous system axonal degeneration. Our findings have demonstrated a significant decrease in clinically relevant biomarkers of axonal degeneration, presenting the first clinically viable genetic therapeutic for CMT2E. Similar strategies could be used to develop precision medicine approaches for otherwise untreatable gain of function inherited disorders.

Making the Unseen Seen: The Role of Signaling and Novelty in Rating Metaphors.

Comprehension of metaphorical expressions differs with their degree of novelty. Conventional metaphors are typically comprehended as easily as literal sentences, while novel metaphors are responded to less quickly than their conventional counterparts. However, the influence of metaphor signals on the interpretability and acceptability of sentences with metaphors, especially their potential interaction with novelty, remains an open question. We conducted six online experiments among 1,694 native speakers of American English to examine how interpretability and acceptability ratings of individually presented sentences were affected by metaphor novelty and different types of metaphor signals. Across all six experiments, we consistently found that novel metaphors decreased the interpretability and acceptability of sentences compared to both conventional metaphors and literal controls. Signals, on the contrary, did not impact the interpretability or acceptability of the sentences. Moreover, only in experiment 3b did we find an interaction between metaphor type and signals. Specifically, when a metaphor was marked by double signals (i.e., both lexical signals and a typographical signal were added around the metaphorical keywords) vs. no signals, acceptability of novel metaphors increased, but acceptability of conventional metaphors decreased. We hypothesize that the double signaling of novel metaphors marks their novelty, making them more acceptable. By contrast, the double signaling of conventional metaphors may have been perceived as redundant, leading to a lower acceptability.

Neologisms are epidemic: Modeling the life cycle of neologisms in China 2008-2016.

This paper adopts models from epidemiology to account for the development and decline of neologisms based on internet usage. The research design focuses on the issue of whether a host-driven epidemic model is well-suited to explain human behavior regarding neologisms. We extracted the search frequency data from Google Trends that covers the ninety most influential Chinese neologisms from 2008-2016 and found that the majority of them possess a similar rapidly rising-decaying pattern. The epidemic model is utilized to fit the evolution of these internet-based neologisms. The epidemic model not only has good fitting performance to model the pattern of rapid growth, but also is able to predict the peak point in the neologism's life cycle. This result underlines the role of human agents in the life cycle of neologisms and supports the macro-theory that the evolution of human languages mirrors the biological evolution of human beings.

Ambiguity advantage revisited: two meanings are better than one when accessing Chinese nouns.

This paper revisits the effect of lexical ambiguity in word recognition, which has been controversial as previous research reported advantage, disadvantage, and null effects. We discuss factors that were not consistently treated in previous research (e.g., the level of lexical ambiguity investigated, parts of speech of the experimental stimuli, and the choice of non-words) and report on a lexical decision experiment with Chinese nouns in which ambiguous nouns with homonymic and/or metaphorical meanings were contrasted with unambiguous nouns. An ambiguity advantage effect was obtained-Chinese nouns with multiple meanings were recognized faster than those with only one meaning. The results suggested that both homonymic and metaphorical meanings are psychologically salient semantic levels actively represented in the mental lexicon. The results supported a probability-based model of random lexical access with multiple meanings represented by separate semantic nodes. We further discuss these results in terms of lexical semantic representation and how different experimental paradigms result in different ambiguity effects in lexical access.

Functional MRI of conventional and anomalous metaphors in Mandarin Chinese.

This study looks at whether conventional and anomalous metaphors are processed in different locations in the brain while being read when compared with a literal condition in Mandarin Chinese. We find that conventional metaphors differ from the literal condition with a slight amount of increased activation in the right inferior temporal gyrus. In addition, when the anomalous metaphor condition is compared with the literal condition, increased activation occurs bilaterally in the frontal and temporal gyri. Lastly, the comparison between the anomalous and conventional metaphor conditions shows bilateral activation in the middle frontal gyrus and the precentral gyrus, and right-hemisphere activation in the superior frontal gyrus. Left hemisphere activation is found in the inferior frontal gyrus and fusiform gyrus. The left hemisphere activation in the frontal and temporal gyri point to the recruitment of traditional language-based areas for anomalous metaphor sentences, while the right-hemisphere activation found suggests that remote associations are being formed. In short, our study supports the idea that metaphors are not a homogenous type of figurative language and that distinguishing between different types of metaphors will advance theories of language comprehension.

Verbal integration: the interaction of participant roles and sentential argument structure.

This paper explores the interaction between sentence level syntactic information and the semantic information that is carried with the verb during sentence comprehension. A cross-modal integration task was employed to examine whether the number of participant roles (thematic roles associated with the central meaning of the verb) causes an increase in processing load during integration of the verb into on-going sentence comprehension. The effect of preceding sentential structural information (varied with respect to the number of argument and/or adjunct NPs preceding the verb) was also manipulated. Independent of the structural information preceding the verb, verbs with two participant roles were integrated into the sentence faster than verbs with three participant roles. This finding suggests that participant roles are stored with the representation of the verb and made immediately available during integration and comprehension. In addition, the syntactic distinction between arguments and adjuncts is also shown to play an immediate role in parsing and integration of language on-line.