Fasting induces a biphasic adaptive metabolic response in murine small intestine

BACKGROUND: The gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting. RESULTS: Intestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gut's structural components, so that the microarrays' tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine, and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed. CONCLUSION: The changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnove

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Purpose Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. Methods We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. Results We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. Conclusion Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping

Everything is not equal in adult and child Dutch

An investigation into the production of universal quantifiers with negation in the CHILDES database of Dutch shows several scopal properties that have not been discussed before. First, it shows a crucial distinction between child and adult Dutch. A universal quantifier with scope over negation has an isomorphic interpretation in adult Dutch, but an inverse scope interpretation in child Dutch. This raises the question why children do not adopt the surface scope interpretation. Second, it indicates a possible answer to the puzzle why languages often avoid a universal quantifier under the scope of negation. I will discuss the idea that the explanation may lie in the type of reading of a quantifier, collective/distributive and specific/non-specific. It might also explain why no language has a lexicalized negated universal pronoun *neverything

A perspective on doubling constructions in Dutch

Scope-bearing elements for negations and questions may appear in Dutch child language as “doubling” constructions. The doublings are not part of the adult system. They arise spontaneously in early and later child language. The early doublings have a -element or a -element in sentence-initial position and double it by means of a sentence adverb in a sentence-final position. These doublings disappear in child Dutch after the acquisition of V-second. A later temporary doubling appears in negative constructions that contain a quantifier. The analysis below will consider the temporary doublings in child Dutch as attempts to maintain an earlier, more simplified construction. Temporary options in child language may result from a learnability hierarchy

Dit is Laura-se (trui). The spreading of the possessive se construction in Dutch

Dutch children temporarily use a possessor se construction with proper/kinship names and pronouns, like dit is Laura-se/opa-se/hem-se jas (‘this is Laura’s/grandpa’s/his coat’). The se possessive is not available in standard Dutch, although examples of it are found on the internet. The se possessive is fully productive with all nouns in Afrikaans. In standard Dutch prenominal possessive constructions show a wide range of variations and restrictions. Dutch children avoid the complexity of the system, but what makes the children apply the se possessive in the first place? I will show that it is due to three properties specific to Dutch. Nevertheless, the se possessive does not persist in standard Dutch as it did in Afrikaans. The Dutch Achilles’ heel might be the early use of weak possessive pronouns

The Non-Biological Evolution of Grammar: Wh-Question Formation in Germanic

The wh-marking of questions in child English is as early as the appearance of the wh-questions themselves. The wh-marking of questions in child Dutch (and the other Germanic languages) is delayed until the acquisition of articles and free anaphoric pronouns. An acquisition procedure is proposed that succeeds to set first a typological difference, V2 for Dutch and SVfinO for English. The different setting of the typological parameters determines the wh-development in subsequent acquisition steps. The learnability approach relativizes Chomsky’s poverty of the stimulus, but affirms his position that language is ‘perfect’ in the sense of being learnable as a cultural construct without the assumption of innate grammar-specific a prioris

Towards a Theory of Language Acquisition

"We have seen at the workshop a diversity of measurements and a no less diverse amount of different phenomena. Shared areas were acquisition phenomena in Romance languages and more general: the beginnings for a true theory of language acquisition. I will not attempt to evaluate the various contributions here. All of this must get its time to sink in. Yet, the general point of our endeavors, - the theory of language acquisition -, may be underlined to gain a further outlook

The Learnability of Syntactic Categories

"It is a common position in generative acquisition studies to accept Chomsky's view that first language acquisition is determined by a set of innate grammatical a priories. The development of the child would be more a matter of biological maturation than a matter of input-control. Because language universals are innate in the human mind, they cause grammar to grow into the mind almost automatically under the slightest provocations. Early child language would already show the relevance the grammatical a priories. Generative grammarians guided by this view have often drawn far-reaching conclusions about the structure of early child language. The present paper will present an alternative view, the derivation of UG principles from structural acquisition steps. It acknowledges that it is indeed a sentence-generating system that is acquired, but contends that generative systems are learned from the language-specific input material. The basic argument for this approach is that all eventual ‘UG’ properties are identified due to local relations with language specific shapes. One might see the language specific shapes as an entrance to the UG distinctions. Unless a grammar offers a way to identify UG properties, it will not be learnable. This suggests that UG properties may be seen as the outcome of an acquisition procedure rather than being its source