A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East.

Background: Nephropathic Cystinosis, the most common cause of renal Fanconi syndrome, is a lysosomal transport disorder with an autosomal recessive inheritance pattern. A large number of mutations in CTNS have been identified as causative to date. A 57 kb deletion encompassing parts of CTNS is most commonly identified in Caucasians but this allele has not been identified in individuals of Eastern Mediterranean, Middle Eastern, Persian, or Arab origin to date. Methods and Results: Implementing whole exome sequencing (WES) in a consanguineous Iranian family, we identified this large deletion affecting CTNS in a patient initially presenting with hypokalemic metabolic alkalosis symptoms and considerable proteinuria. Conclusion: We show WES is a cost and time efficient genetic diagnostics modality to identify the underlying molecular pathology in Cystinosis individuals and provide a summary of all previously reported CTNS alleles in the Middle east population. Our work also highlights the importance to consider the 57-kb deletion as underlying genetic cause in non-European populations, including the Middle East. Limited diagnostic modalities for Cystinosis in developing countries could account for the lack of previously reported cases in these populations carrying this allele. Further, our findings emphasize the utility of WES to define genetic causes in clinically poorly defined phenotypes and demonstrate the requirement of Copy number variation (CNV) analysis of WES data

Primary rat LSECs preserve their characteristic phenotype after cryopreservation

Liver disease is a leading cause of morbidity and mortality worldwide. Recently, the liver non-parenchymal cells have gained increasing attention for their potential role in the development of liver disease. Liver sinusoidal endothelial cells (LSECs), a specialized type of endothelial cells that have unique morphology and function, play a fundamental role in maintaining liver homeostasis. Current protocols for LSEC isolation and cultivation rely on freshly isolated cells which can only be maintained differentiated in culture for a few days. This creates a limitation in the use of LSECs for research and a need for a consistent and reliable source of these cells. To date, no LSEC cryopreservation protocols have been reported that enable LSECs to retain their functional and morphological characteristics upon thawing and culturing. Here, we report a protocol to cryopreserve rat LSECs that, upon thawing, maintain full LSEC-signature features: fenestrations, scavenger receptor expression and endocytic function on par with freshly isolated cells. We have confirmed these features by a combination of biochemical and functional techniques, and super-resolution microscopy. Our findings offer a means to standardize research using LSECs, opening the prospects for designing pharmacological strategies for various liver diseases, and considering LSECs as a therapeutic target

Primary rat LSECs preserve their characteristic phenotype after cryopreservation

Mönkemöller V, Mao H, Hübner W, et al. Primary rat LSECs preserve their characteristic phenotype after cryopreservation. Scientific Reports. 2018;8(1): 14657.Liver disease is a leading cause of morbidity and mortality worldwide. Recently, the liver nonparenchymal cells have gained increasing attention for their potential role in the development of liver disease. Liver sinusoidal endothelial cells (LSECs), a specialized type of endothelial cells that have unique morphology and function, play a fundamental role in maintaining liver homeostasis. Current protocols for LSEC isolation and cultivation rely on freshly isolated cells which can only be maintained differentiated in culture for a few days. This creates a limitation in the use of LSECs for research and a need for a consistent and reliable source of these cells. To date, no LSEC cryopreservation protocols have been reported that enable LSECs to retain their functional and morphological characteristics upon thawing and culturing. Here, we report a protocol to cryopreserve rat LSECs that, upon thawing, maintain full LSEC-signature features: fenestrations, scavenger receptor expression and endocytic function on par with freshly isolated cells. We have confirmed these features by a combination of biochemical and functional techniques, and super-resolution microscopy. Our findings offer a means to standardize research using LSECs, opening the prospects for designing pharmacological strategies for various liver diseases, and considering LSECs as a therapeutic target

Words cluster phonetically beyond phonotactic regularities

Recent evidence suggests that cognitive pressures associated with language acquisition and use could affect the organization of the lexicon. On one hand, consistent with noisy channel models of language (e.g., Levy, 2008), the phonological distance between wordforms should be maximized to avoid perceptual confusability (a pressure for dispersion). On the other hand, a lexicon with high phonological regularity would be simpler to learn, remember and produce (e.g., Monaghan et al., 2011) (a pressure for clumpiness). Here we investigate wordform similarity in the lexicon, using measures of word distance (e.g., phonological neighborhood density) to ask whether there is evidence for dispersion or clumpiness of wordforms in the lexicon. We develop a novel method to compare lexicons to phonotactically-controlled baselines that provide a null hypothesis for how clumpy or sparse wordforms would be as the result of only phonotactics. Results for four languages, Dutch, English, German and French, show that the space of monomorphemic wordforms is clumpier than what would be expected by the best chance model according to a wide variety of measures: minimal pairs, average Levenshtein distance and several network properties. This suggests a fundamental drive for regularity in the lexicon that conflicts with the pressure for words to be as phonologically distinct as possible. Keywords: Linguistics; Lexical design; Communication; Phonotactic

Word forms are structured for efficient use

Zipf famously stated that, if natural language lexicons are structured for efficient communication, the words that are used the most frequently should require the least effort. This observation explains the famous finding that the most frequent words in a language tend to be short. A related prediction is that, even within words of the same length, the most frequent word forms should be the ones that are easiest to produce and understand. Using orthographics as a proxy for phonetics, we test this hypothesis using corpora of 96 languages from Wikipedia. We find that, across a variety of languages and language families and controlling for length, the most frequent forms in a language tend to be more orthographically well‐formed and have more orthographic neighbors than less frequent forms. We interpret this result as evidence that lexicons are structured by language usage pressures to facilitate efficient communication. Keywords: Lexicon; Word frequency; Phonology; Communication; EfficiencyNational Science Foundation (Grant ES/N0174041/1

Syntactic probabilities affect pronunciation variation in spontaneous speech

Speakers frequently have a choice among multiple ways of expressing one and the same thought. When choosing between syntactic constructions for expressing a given meaning, speakers are sensitive to probabilistic tenden-cies for syntactic, semantic or contextual properties of an utterance to favor one construction or another. Taken together, such tendencies may align to make one construction overwhelmingly more probable, marginally more probable, or no more probable than another. Here, we present evidence that acoustic features of spontaneous speech reflect these probabilities: when speakers choose a less probable construction, they are more likely to be disfluent, and their fluent words are likely to have a relatively longer du-ration. Conversely, words in more probable constructions are shorter and spoken more fluently. Our findings suggest that the di¤ering probabilities of a syntactic construction in context are not epiphenomenal, but reflect a part of a speakers ’ knowledge of their language