Order through Disorder: Hyper-Mobile C-Terminal Residues Stabilize the Folded State of a Helical Peptide. A Molecular Dynamics Study

Conventional wisdom has it that the presence of disordered regions in the three-dimensional structures of polypeptides not only does not contribute significantly to the thermodynamic stability of their folded state, but, on the contrary, that the presence of disorder leads to a decrease of the corresponding proteins' stability. We have performed extensive 3.4 µs long folding simulations (in explicit solvent and with full electrostatics) of an undecamer peptide of experimentally known helical structure, both with and without its disordered (four residue long) C-terminal tail. Our simulations clearly indicate that the presence of the apparently disordered (in structural terms) C-terminal tail, increases the thermodynamic stability of the peptide's folded (helical) state. These results show that at least for the case of relatively short peptides, the interplay between thermodynamic stability and the apparent structural stability can be rather subtle, with even disordered regions contributing significantly to the stability of the folded state. Our results have clear implications for the understanding of peptide energetics and the design of foldable peptides

Right hemisphere has the last laugh: neural dynamics of joke appreciation

Understanding a joke relies on semantic, mnemonic, inferential, and emotional contributions from multiple brain areas. Anatomically constrained magnetoencephalography (aMEG) combining high-density whole-head MEG with anatomical magnetic resonance imaging allowed us to estimate where the humor-specific brain activations occur and to understand their temporal sequence. Punch lines provided either funny, not funny (semantically congruent), or nonsensical (incongruent) replies to joke questions. Healthy subjects rated them as being funny or not funny. As expected, incongruous endings evoke the largest N400m in left-dominant temporo-prefrontal areas, due to integration difficulty. In contrast, funny punch lines evoke the smallest N400m during this initial lexical–semantic stage, consistent with their primed “surface congruity” with the setup question. In line with its sensitivity to ambiguity, the anteromedial prefrontal cortex may contribute to the subsequent “second take” processing, which, for jokes, presumably reflects detection of a clever “twist” contained in the funny punch lines. Joke-selective activity simultaneously emerges in the right prefrontal cortex, which may lead an extended bilateral temporo-frontal network in establishing the distant unexpected creative coherence between the punch line and the setup. This progression from an initially promising but misleading integration from left frontotemporal associations, to medial prefrontal ambiguity evaluation and right prefrontal reprocessing, may reflect the essential tension and resolution underlying humor

Representation of the verb's argument-structure in the human brain

<p>Abstract</p> <p>Background</p> <p>A verb's argument structure defines the number and relationships of participants needed for a complete event. One-argument (intransitive) verbs require only a subject to make a complete sentence, while two- and three-argument verbs (transitives and ditransitives) normally take direct and indirect objects. Cortical responses to verbs embedded into sentences (correct or with syntactic violations) indicate the processing of the verb's argument structure in the human brain. The two experiments of the present study examined whether and how this processing is reflected in distinct spatio-temporal cortical response patterns to isolated verbs and/or verbs presented in minimal context.</p> <p>Results</p> <p>The magnetoencephalogram was recorded while 22 native German-speaking adults saw 130 German verbs, presented one at a time for 150 ms each in experiment 1. Verb-evoked electromagnetic responses at 250 – 300 ms after stimulus onset, analyzed in source space, were higher in the left middle temporal gyrus for verbs that take only one argument, relative to two- and three-argument verbs. In experiment 2, the same verbs (presented in different order) were preceded by a proper name specifying the subject of the verb. This produced additional activation between 350 and 450 ms in or near the left inferior frontal gyrus, activity being larger and peaking earlier for one-argument verbs that required no further arguments to form a complete sentence.</p> <p>Conclusion</p> <p>Localization of sources of activity suggests that the activation in temporal and frontal regions varies with the degree by which representations of an event as a part of the verbs' semantics are completed during parsing.</p

Association between Protective and Deleterious HLA Alleles with Multiple Sclerosis in Central East Sardinia

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS). The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS. We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS. The main stage of our study involved an analysis of the ancestral haplotypes A2Cw7B58DR2DQ1 and A30Cw5B18DR3DQ2. On the basis of a multiplicative model, the effect of the first haplotype is protective with an odds ratio (OR) = 0.27 (95% confidence interval CI 0.13–0.57), while that of the second is deleterious, OR 1.78 (95% CI 1.26–2.50). We found both class I (A, Cw, B) and class II (DR, DQ) loci to have an effect on MS susceptibility, but we saw that they act independently from each other. We also performed an exploratory analysis on a set of 796 SNPs in the same HLA region. Our study supports the claim that Class I and Class II loci act independently on MS susceptibility and this has a biological explanation. Also, the analysis of SNPs suggests that there are other HLA genes involved in MS, but replication is needed. This opens up new perspective on the study of MS

A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions

Vowel reduction in word-final position by early and late Spanish-English bilinguals

Vowel reduction is a prominent feature of American English, as well as other stress-timed languages. As a phonological process, vowel reduction neutralizes multiple vowel quality contrasts in unstressed syllables. For bilinguals whose native language is not characterized by large spectral and durational differences between tonic and atonic vowels, systematically reducing unstressed vowels to the central vowel space can be problematic. Failure to maintain this pattern of stressed-unstressed syllables in American English is one key element that contributes to a ?foreign accent? in second language speakers. Reduced vowels, or ?schwas,? have also been identified as particularly vulnerable to the co-articulatory effects of adjacent consonants. The current study examined the effects of adjacent sounds on the spectral and temporal qualities of schwa in word-final position. Three groups of English-speaking adults were tested: Miami-based monolingual English speakers, early Spanish-English bilinguals, and late Spanish-English bilinguals. Subjects performed a reading task to examine their schwa productions in fluent speech when schwas were preceded by consonants from various points of articulation. Results indicated that monolingual English and late Spanish-English bilingual groups produced targeted vowel qualities for schwa, whereas early Spanish-English bilinguals lacked homogeneity in their vowel productions. This extends prior claims that schwa is targetless for F2 position for native speakers to highly-proficient bilingual speakers. Though spectral qualities lacked homogeneity for early Spanish-English bilinguals, early bilinguals produced schwas with near native-like vowel duration. In contrast, late bilinguals produced schwas with significantly longer durations than English monolinguals or early Spanish-English bilinguals. Our results suggest that the temporal properties of a language are better integrated into second language phonologies than spectral qualities. Finally, we examined the role of nonstructural variables (e.g. linguistic history measures) in predicting native-like vowel duration. These factors included: Age of L2 learning, amount of L1 use, and self-reported bilingual dominance. Our results suggested that different sociolinguistic factors predicted native-like reduced vowel duration than predicted native-like vowel qualities across multiple phonetic environments