Sortilin-derived peptides promote pancreatic beta-cell survival through CREB signaling pathway.

Deterioration of insulin secretion and pancreatic beta-cell mass by inflammatory attacks is one of the main pathophysiological features of type 2 diabetes (T2D). Therefore, preserving beta-cell mass and stimulating insulin secretion only in response to glucose for avoiding the hypoglycemia risks, are the most state-of-the-art option for the treatment of T2D. In this study we tested two correlated hypothesis that 1/ the endogenous peptide released from sortilin, known as PE, that stimulates insulin secretion only in response to glucose, protects beta-cells against death induced by cytokines, and 2/ Spadin and Mini-Spadin, two synthetic peptides derived from PE, that mimic the effects of PE in insulin secretion, also provide beneficial effect on beta-cells survival. We show that PE and its derivatives by inducing a rise of intracellular calcium concentration by depolarizing the membrane protect beta-cells against death induced by Interleukin-1ß. Using biochemical, confocal imaging and cell biology techniques, we reveal that the protective effects of PE and its derivatives rely on the activation of the CaM-Kinase pathway, and on the phosphorylation and activation of the transcription factor CREB. In addition, Mini-Spadin promotes beta-cell proliferation, suggesting its possible regenerative effect. This study highlights new possible roles of PE in pancreatic beta-cell survival and its derivatives as pharmacological tools against diabetes.

How deaf are French speakers to stress?

This event-related potential study examined whether French listeners use stress at a phonological level when discriminating between stressed and unstressed words in their language. Participants heard five words and made same/different decisions about the final word (male voice) with respect to the four preceding words (different female voices). Compared to the first four context words, the target word was (i) phonemically and prosodically identical (/ʃu/-/ʃu/; control condition), (ii) phonemically identical but differing in the presence of a primary stress (/ʃu'/-/ʃu/), (iii) prosodically identical but phonemically different (/ʃo/-/ʃu/), or (iv) both phonemically and prosodically different (/ʃo'/-/ʃu/). Crucially, differences on the P200 and the following N200 components were observed for the /ʃu'/-/ʃu/ and the /ʃo/-/ʃu/ conditions compared to the /ʃu/-/ʃu/ control condition. Moreover, on the N200 component more negativity was observed for the /ʃo/-/ʃu/ condition compared to the /ʃu'/-/ʃu/ conditions, while no difference emerged between these two conditions on the earlier P200 component. Crucially, the results suggest that French listeners are capable of creating an abstract representation of stress. However, as they receive more input, participants react more strongly to phonemic than to stress information.

Does orthographic training on a phonemic contrast absent in the listener's dialect influence word recognition?

This study examined whether the ability of southern French speakers to discriminate between standard French word forms such as /pike/ and /pikε/ can be improved by a training procedure in which participants were exposed to the orthographic representations of words forming /e/-/ε/ minimal pairs. The results of the training procedure showed that southern French speakers were able to perceive the /e/-/ε/ contrast in word final position when they associated words containing these vowels with their correct spelled form. Further, participants in a priming experiment, which was run immediately after training, no longer showed the priming effect on the trained minimal pairs that they had shown in the pre-test. However, a priming effect on the untrained minimal pairs was still observed immediately after training, showing that this training failed to transfer to untrained items. Finally, the benefits of the training procedure were no longer observed the day after training, since southern French speakers once again showed a priming effect on the trained minimal pair of words in a one day post-test. Implications of these findings for the locus of the difficulties of the southern French speakers with the word-final /e/-/ε/ contrast are discussed.

Acute Physical Exercise Affects Cognitive Functioning in Children With Cerebral Palsy.

Little is known about the effects of acute exercise on the cognitive functioning of children with cerebral palsy (CP). Selected cognitive functions were thus measured using a pediatric version of the Stroop test before and after maximal, locomotor based aerobic exercise in 16 independently ambulatory children (8 children with CP), 6-15 years old. Intense exercise had: 1) a significant, large, positive effect on reaction time (RT) for the CP group (preexercise: 892 ± 56.5 ms vs. postexercise: 798 ± 45.6 ms, p < .002, d = 1.87) with a trend for a similar but smaller response for the typically developing (TD) group (preexercise: 855 ± 56.5 ms vs. postexercise: 822 ± 45.6 ms, p < .08, d = 0.59), and 2) a significant, medium, negative effect on the interference effect for the CP group (preexercise: 4.5 ± 2.5%RT vs. postexercise: 13 ± 2.9%RT, p < .04, d = 0.77) with no significant effect for the TD group (preexercise: 7.2 ± 2.5%RT vs. postexercise: 6.9 ± 2.9%RT, p > .4, d = 0.03). Response accuracy was high in both groups pre- and postexercise (>96%). In conclusion, intense exercise impacts cognitive functioning in children with CP, both by increasing processing speed and decreasing executive function.

Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation.

The aim of the present review is to unravel the mechanisms of action of the soluble form of the neurotensin (NT) receptor-3 (NTSR3), also called Sortilin, in numerous physiopathological processes including cancer development, cardiovascular diseases and depression. Sortilin/NTSR3 is a transmembrane protein thought to exert multiple functions both intracellularly and at the level of the plasma membrane. The Sortilin/NTSR3 extracellular domain is released by shedding from all the cells expressing the protein. Although the existence of the soluble form of Sortilin/NTSR3 (sSortilin/NTSR3) has been evidenced for more than 10 years, the studies focusing on the role of this soluble protein at the mechanistic level remain rare. Numerous cancer cells, including colonic cancer cells, express the receptor family of neurotensin (NT), and particularly Sortilin/NTSR3. This review aims to summarize the functional role of sSortilin/NTSR3 characterized in the colonic cancer cell line HT29. This includes mechanisms involving signaling cascades through focal adhesion kinase (FAK), a key pathway leading to the weakening of cell-cell and cell-extracellular matrix adhesions, a series of events which could be responsible for cancer metastasis. Finally, some future approaches targeting the release of sNTSR3 through the inhibition of matrix metalloproteases (MMPs) are suggested.

The Effects of Acute Intense Physical Exercise on Postural Stability in Children With Cerebral Palsy.

This study evaluated the effects of intense physical exercise on postural stability of children with cerebral palsy (CP). Center of pressure (CoP) was measured in 9 typically developing (TD) children and 8 with CP before and after a maximal aerobic shuttle-run test (SRT) using a single force plate. Anteroposterior and mediolateral sway velocities, sway area, and sway regularity were calculated from the CoP data and compared between pre- and postexercise levels and between groups. Children with CP demonstrated significantly higher pre-SRT CoP velocities than TD children in the sagittal (18.6 ± 7.6 vs. 6.75 1.78 m/s) and frontal planes (15.4 ± 5.3 vs. 8.04 ± 1.51 m/s). Post-SRT, CoP velocities significantly increased for children with CP in the sagittal plane (27.0 ± 1.2 m/s), with near-significant increases in the frontal plane (25.0 ± 1.5m/s). Similarly, children with CP evidenced larger sway areas than the TD children both pre- and postexercise. The diminished postural stability in children with CP after short but intense physical exercise may have important implications including increased risk of falls and injury.

On the perception of stress position by French listeners: An EEG investigation.

In this EEG study, we examined the ability of French listeners to perceive and use the position of stress in a discrimination task. Event-Related-Potentials (ERPs) were recorded while participants performed a same-different task. Different stimuli diverged either in one phoneme (e.g., /ʒy'ʁi/-/ʒy'ʁɔ̃/) or in stress position (e.g., /ʒy'ʁi/-/'ʒyʁi/). Although participants reached 93% of correct responses, ERP results indicated that a change in stress position was not detected while a change in one phoneme elicited a MisMatchNegativity (MMN) response. It results that in the early moments of speech processing, stimuli that are phonemically identical but that differ in stress position are perceived as being strictly similar. We concluded that the good performance observed in behavioral responses on stress position contrasts are due to attentional/decisional processes linked to discrimination tasks, and not to automatic and unconscious processes involved in stress position processing.

Phonological neighbors cooperate during spoken-sentence processing: Evidence from a nonword detection task.

We used a novel nonword detection task to examine the lexical competition principle postulated in most models of spoken word recognition. To do so, in Experiment 1 we presented sequences of spoken words with half of the sequences containing a nonword, and the target nonword (i.e., press a response key whenever you detect a nonword in the sequence) could either be phonologically related (a phonological neighbor) or unrelated to the immediately preceding word. We reasoned that the reactivation of a phonological neighbor during target nonword processing should delay the moment at which a nonword decision can be made. Contrary to our hypothesis, participants were faster at detecting nonwords when they were preceded by a phonological neighbor compared with an unrelated word. In Experiment 2, an inhibitory effect of phonological relatedness on nonword decisions was observed in a classic priming situation using the same set of related and unrelated word-nonword pairs. We discuss the implications of these findings in regard to the main models of spoken word recognition, and conclude that our specific experimental set-up with phonological neighbors embedded in spoken sentences is more sensitive to cooperative interactions between co-activated sublexical representations than lexical competition between co-activated lexical representations, with the latter being modulated by whether or not the words compete for the same slot in time.

Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.

Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression.

To what extent do we hear phonemic contrasts in a non-native regional variety? Tracking the dynamics of perceptual processing with EEG.

This combined ERP and behavioral experiment explores the dynamics of processing during the discrimination of vowels in a non-native regional variety. Southern listeners were presented with three word forms, two of which are encountered in both Standard and Southern French ([kot] and [kut]), whereas the third one exists in Standard but not Southern French ([kot]). EEG recordings suggest that all of the word pairs were discriminated by the listeners, although discrimination arose about 100ms later for the pairs which included the non-native word form than for those which contained word forms common to both French varieties. Behavioral data provide evidence that vowel discrimination is sensitive to the influence of the listeners' native phonemic inventory at a late decisional stage of processing.

Does accentual variation in the pronunciation of French words influence their recognition? It depends on the ear of presentation.

This repetition priming study examined how word accentual variation in French is represented and processed during spoken word recognition. Mismatched primes in the accentual pattern were less effective than matched primes in facilitating target word recognition when the targets were presented in the left ear but not in the right ear. This indicates that in French, the accentual pattern of words influences their recognition when processing is constrained in the right hemisphere. This study pleads in favor of two memory systems, the one retaining words in an abstract format and the other retaining words in their various forms.

When phonological neighbours cooperate during spoken sentence processing.

This study examined for the first time the impact of the presence of a phonological neighbour on word recognition when the target word and its neighbour co-occur in a spoken sentence. To do so, we developed a new task, the verb detection task, in which participants were instructed to respond as soon as they detected a verb in a sequence of words, thus allowing us to probe spoken word recognition processes in real time. We found that participants were faster at detecting a verb when it was phonologically related to the preceding noun than when it was phonologically unrelated. This effect was found with both correct sentences (Experiment 1) and with ungrammatical sequences of words (Experiment 2). The effect was also found in Experiment 3 where adjacent phonologically related words were included in the non-verb condition (i.e., word sequences not containing a verb), thus ruling out any strategic influences. These results suggest that activation persists across different words during spoken sentence processing such that processing of a word at position n + 1 benefits from the sublexical phonology activated during processing of the word at position n. We discuss how different models of spoken word recognition might be able (or not) to account for these findings.

Rime Priming Effects in Spoken Word Recognition.

In this study, we re-examined the facilitation that occurs when auditorily presented monosyllabic primes and targets share their final phonemes, and in particular the rime (e.g., /vɔʀd/-/kɔʀd/). More specifically, we asked whether this rime facilitation effect is also observed when the two last consonants of the rime are transposed (e.g., /vɔʀd/-/kɔʀd/). In comparison to a control condition in which the primes and the targets were unrelated (e.g., /pylt/-/kɔʀd/), we found significant priming effects in both the rime (/vɔdʀ/-/kɔʀd/) and the transposed-phoneme "rime" /vɔdʀ/-/kɔʀd/ conditions. We also observed a significantly greater priming effect in the former condition than in the latter condition. We use the theoretical framework of the TISK model (Hannagan et al., 2013) to propose a novel account of final overlap phonological priming in terms of activation of both position-independent phoneme representations and bi-phone representations.

Effects of consonant-vowel status on transposed-phoneme priming.

Nonwords created by transposing two phonemes of auditory words (e.g., /buʒãle/) are more effective primes for the corresponding base word target (/bulãʒe/) than nonword primes created by substituting two phonemes (e.g., /buvãʀe/). In one in-lab experiment and one online experiment using the short-term phonological priming paradigm, here, we examine the role of vowels and consonants in driving transposed-phoneme priming effects. Results showed that facilitatory transposed-phoneme priming occurs when the transposed phonemes are consonants (/buʒãle/-/bulãʒe/; /lubãʒe/-/bulãʒe/), but not when they are vowels (/bãluʒe/-/bulãʒe/; /buleʒã/-/bulãʒe/). These results add to existing findings showing differences in the processing of vowels and consonants during spoken and visual word recognition. We suggest that differences in the speed of processing of consonants and vowels combined with differences in the amount of information provided by consonants and vowels relative to the identity of the word being recognized provide a complete account of the present findings.

Unlocking Therapeutic Synergy: Tailoring Drugs for Comorbidities such as Depression and Diabetes through Identical Molecular Targets in Different Cell Types.

Research in the field of pharmacology aims to generate new treatments for pathologies. Nowadays, there are an increased number of chronic disorders that severely and durably handicap many patients. Among the most widespread pathologies, obesity, which is often associated with diabetes, is constantly increasing in incidence, and in parallel, neurodegenerative and mood disorders are increasingly affecting many people. For years, these pathologies have been so frequently observed in the population in a concomitant way that they are considered as comorbidities. In fact, common mechanisms are certainly at work in the etiology of these pathologies. The main purpose of this review is to show the value of anticipating the effect of baseline treatment of a condition on its comorbidity in order to obtain concomitant positive actions. One of the implications would be that by understanding and targeting shared molecular mechanisms underlying these conditions, it may be possible to tailor drugs that address both simultaneously. To this end, we firstly remind readers of the close link existing between depression and diabetes and secondly address the potential benefit of the pleiotropic actions of two major active molecules used to treat central and peripheral disorders, first a serotonin reuptake inhibitor (Prozac ®) and then GLP-1R agonists. In the second part, by discussing the therapeutic potential of new experimental antidepressant molecules, we will support the concept that a better understanding of the intracellular signaling pathways targeted by pharmacological agents could lead to future synergistic treatments targeting solely positive effects for comorbidities.

When you hear /baksɛt/ do you think /baskɛt/? Evidence for transposed-phoneme effect with multisyllabic words.

In this study we asked whether nonwords created by transposing two phonemes (/biksɔt/) are perceived as being more similar to their base words (/biskɔt/) than nonwords created by substituting two phonemes (/bipfɔt/). Using the short-term phonological priming and a lexical-decision task, Experiment 1 showed that transposed-phoneme nonword primes lead to shorter RTs on the target base words than substituted-phoneme nonword primes. Using a single-presentation lexical-decision task, Experiment 2 showed that transposed-phoneme nonwords lead to longer "no" decision responses than substituted-phoneme nonwords. In both Experiments 1 and 2, the transposed-phoneme effect was observed when the transposed phonemes were adjacent (/biksɔt/-/biskɔt/) but not when they were distant (/ʃoloka/-/ʃokola/). Our findings suggest that nonwords created by transposing adjacent phonemes in real words generate more activation of the lexical representations associated with the base words than do matched control nonwords. More generally, our findings present a challenge for models of spoken word recognition that code for the precise order of speech segments. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Phonological abstraction before lexical access: New evidence from rime priming.

In this study, we focused on the rime priming effect and examined whether the frequency of rimes influences the size of the effect. Using the lexical decision task, we observed that the rime priming effect interacted with rime frequency with a stronger priming effect when the target words contained low-frequency rimes, in comparison with target words containing high-frequency rimes. Moreover, for both target words with low- and high-frequency rimes, a priming effect of similar magnitude was observed whether the primes and targets were pronounced by the same speaker or by different speakers. All together, these findings provide additional support for all the studies that plead for the existence of prelexical units and, in a more general way, for phonological abstraction prior to lexical access.

Investigating the locus of transposed-phoneme effects using cross-modal priming.

In this study, we examined whether the facilitatory priming effect found when auditory primes and targets are related by a phoneme transposition (e.g., /ʀͻb/-/bͻʀ/: Dufour & Grainger, 2019, 2020) is also observed under cross-modal presentation. In two experiments using the same materials as in the previous studies, we found no evidence for a facilitatory priming effect when the targets were presented visually rather than auditorily. On the contrary, an inhibitory priming effect was found when both unrelated words (Experiment 1; e.g., /mas/-/bͻR/) and vowel overlap words (Experiment 2; e.g., /vͻl/-/bͻʀ/) were used as control conditions. In Experiment 2, this inhibitory effect was found to be equivalent in size whether the target words were of higher or lower frequency than the prime words (e.g. /ʀͻb/-/bͻʀ/ vs. /bͻʀ/-/ʀͻb/). We interpret this pattern of effects as reflecting the greater impact of word-level inhibition in cross-modal priming, and the parallel influence of prime-target relative frequency on bottom-up phoneme-to-word facilitation and word-level inhibition. Therefore, the facilitatory priming effect previously observed with auditory primes and targets would mainly reflect bottom-up activation of the target word representation during prime word processing.

Transposed-word effects in speeded grammatical decisions to sequences of spoken words.

We used the grammatical decision task (a speeded version of the grammaticality judgment task) with auditorily presented sequences of five words that could either form a grammatically correct sentence or an ungrammatical sequence. The critical ungrammatical sequences were either formed by transposing two adjacent words in a correct sentence (transposed-word sequences: e.g., "The black was dog big") or were matched ungrammatical sequences that could not be resolved into a correct sentence by transposing any two words (control sequences: e.g., "The black was dog slowly"). These were intermixed with an equal number of correct sentences for the purpose of the grammatical decision task. Transposed-word sequences were harder to reject as being ungrammatical (longer response times and more errors) relative to the ungrammatical control sequences, hence attesting for the first time that transposed-word effects can be observed in the spoken language version of the grammatical decision task. Given the relatively unambiguous nature of the speech input in terms of word order, we interpret these transposed-word effects as reflecting the constraints imposed by syntax when processing a sequence of spoken words in order to make a speeded grammatical decision.

Linotrins: Omega-3 oxylipins featuring an E,Z,E conjugated triene motif are present in the plant kingdom and alleviate inflammation in LPS-challenged microglial cells.

Alpha-linolenic acid (ALA), an essential omega-3 polyunsaturated fatty acid found in plants, exerts neuroprotection and anti-inflammatory effects in chronic and acute CNS disease models. However, the underlying mechanisms are not yet understood. Since ALA is not incorporated into the brain, the observed health benefits may result from some of its metabolites. The putative formation of dihydroxylated ALA derivatives (called linotrins) was recently shown in vitro in the presence of lipoxygenases. However, the in vitro biosynthesis of linotrins was neither stereoselective nor quantitatively efficient for studying their physiological roles as enantiomeric pure forms. Herein, we report the first stereo-controlled synthesis that features regio- and stereoselective hydrometalations of alkynes for assembling the sensitive E,Z,E-conjugated trienes, as well as LC-MS investigations that provide evidence of linotrins occurrence in plants. Moreover, strong anti-inflammatory effects on microglia highlight the potential physiological importance of linotrins and open new perspectives in search of CNS therapeutics.