Tracing the interplay between syntactic and lexical features: fMRI evidence from agreement comprehension.

The current fMRI study was designed to investigate whether the processing of different gender-related cues embedded in nouns affects the computation of agreement dependencies and, if so, where this possible interaction is mapped in the brain. We used the Spanish gender agreement system, which makes it possible to manipulate two different factors: the agreement between different sentence constituents (i.e., by contrasting congruent versus incongruent determiner-noun pairs) and the formal (i.e., orthographical/morphological) and/or lexical information embedded in the noun -i.e., by contrasting transparent (e.g., libromasc. [book]; lunafem. [moon]) and opaque nouns (e.g., lápizmasc. [pencil]; vejezfem. [old age]). Crucially, these data illustrated, for the first time, how the network underlying agreement is sensitive to different gender-to-ending cues: different sources of gender information associated with nouns affect the neural circuits involved in the computation of local agreement dependencies. When the gender marking is informative (as in the case of transparent nouns), both formal and lexical information is used to establish grammatical relations. In contrast, when no formal cues are available (as in the case of opaque nouns), gender information is retrieved from the lexicon. We demonstrated the involvement of the posterior MTG/STG, pars triangularis within the IFG, and parietal regions during gender agreement computation. Critically, in order to integrate the different available information sources, the dynamics of this fronto-temporal loop change and additional regions, such as the hippocampus, the angular and the supramarginal gyri are recruited. These results underpin previous neuroanatomical models proposed in the context of both gender processing and sentence comprehension. But, more importantly, they provide valuable information regarding how and where the brain's language system dynamically integrates all the available form-based and lexical cues during comprehension.

A phenomenological model of cell-cell adhesion mediated by cadherins.

We present a phenomenological model intended to describe at the protein population level the formation of cell-cell junctions by the local recruitment of homophilic cadherin adhesion receptors. This modeling may have a much wider implication in biological processes since many adhesion receptors, channel proteins and other membrane-born proteins associate in clusters or oligomers at the cell surface. Mathematically, it consists in a degenerate reaction-diffusion system of two partial differential equations modeling the time-space evolution of two cadherin populations over a surface: the first one represents the diffusing cadherins and the second one concerns the fixed ones. After discussing the stability of the solutions of the model, we perform numerical simulations and show relevant analogies with experimental results. In particular, we show patterns or aggregates formation for a certain set of parameters. Moreover, perturbing the stationary solution, both density populations converge in large times to some saturation level. Finally, an exponential rate of convergence is numerically obtained and is shown to be in agreement, for a suitable set of parameters, with the one obtained in some in vitro experiments.

Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aß peptide.

Aggregation of amyloid-ß peptide (Aß) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH2) on the aggregation and toxicity of Aß. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aß oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aß. PINPs also bound to Aß with high affinity (Kd=13.2-50 nM), rescued SHSY-5Y cells from the toxic effect of pre-aggregated Aß, crossed an in vitro blood-brain barrier model (hCMEC/D3 cell monolayer), entered the brains of C57 BL/6 mice, and protected against memory loss in APPSWE transgenic mice in a novel object recognition test. As the most potent aggregation inhibitor that we have tested so far, we propose to develop PINPs as a potential disease-modifying treatment for AD.

The cell-permeable Aß1-6A2VTAT(D) peptide reverts synaptopathy induced by Aß1-42wt.

Alzheimer disease (AD) is the most prevalent form of dementia. Loss of hippocampal synapses is the first neurodegenerative event in AD. Synaptic loss has been associated with the accumulation in the brain parenchyma of soluble oligomeric forms of amyloid ß peptide (Aß1-42wt). Clinical observations have shown that a mutation in the APP protein (A673V) causes an early onset AD-type dementia in homozygous carriers while heterozygous carriers are unaffected. This mutation leads to the formation of mutated Aß peptides (Aß1-42A2V) in homozygous patients, while in heterozygous subjects both Aß1-42wt and Aß1-42A2V are present. To better understand the impact of the A673V mutation in AD, we analyzed the synaptotoxic effect of oligomers formed by aggregation of different Aß peptides (Aß1-42wt or Aß1-42A2V) and the combination of the two Aß1-42MIX (Aß1-42wt and Aß1-42A2V) in an in vitro model of synaptic injury. We showed that Aß1-42A2V oligomers are more toxic than Aß1-42wt oligomers in hippocampal neurons, confirming the results previously obtained in cell lines. Furthermore, we reported that oligomers obtained by the combination of both wild type and mutated peptides (Aß1-42MIX) did not exert synaptic toxicity. We concluded that the combination of Aß1-42wt and Aß1-42A2V peptides hinders the toxicity of Aß1-42A2V and counteracts the manifestation of synaptopathy in vitro. Finally we took advantage of this finding to generate a cell-permeable peptide for clinical application, by fusing the first six residues of the Aß1-42A2V to the TAT cargo sequence (Aß1-6A2VTAT(D)). Noteworthy, the treatment with Aß1-6A2VTAT(D) confers neuroprotection against both in vitro and in vivo synaptopathy models. Therefore Aß1-6A2VTAT(D) may represent an innovative therapeutic tool to prevent synaptic degeneration in AD.

The hunt for brain Aß oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease.

We previously showed the ability of liposomes bi-functionalized with phosphatidic acid and an ApoE-derived peptide (mApoE-PA-LIP) to reduce brain Aß in transgenic Alzheimer mice. Herein we investigated the efficacy of mApoE-PA-LIP to withdraw Aß peptide in different aggregation forms from the brain, using a transwell cellular model of the blood-brain barrier and APP/PS1 mice. The spontaneous efflux of Aß oligomers (Aßo), but not of Aß fibrils, from the 'brain' side of the transwell was strongly enhanced (5-fold) in presence of mApoE-PA-LIP in the 'blood' compartment. This effect is due to a withdrawal of Aßo exerted by peripheral mApoE-PA-LIP by sink effect, because, when present in the brain side, they did not act as Aßo carrier and limit the oligomer efflux. In vivo peripheral administration of mApoE-PA-LIP significantly increased the plasma Aß level, suggesting that Aß-binding particles exploiting the sink effect can be used as a therapeutic strategy for Alzheimer disease. From the Clinical Editor: Alzheimer disease (AD) at present is an incurable disease, which is thought to be caused by an accumulation of amyloid-ß (Aß) peptides in the brain. Many strategies in combating this disease have been focused on either the prevention or dissolving these peptides. In this article, the authors showed the ability of liposomes bi-functionalized with phosphatidic acid and with an ApoE- derived peptide to withdraw amyloid peptides from the brain. The data would help the future design of more novel treatment for Alzheimer disease.

Multifunctional liposomes reduce brain ß-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models.

Alzheimer's disease is characterized by the accumulation and deposition of plaques of ß-amyloid (Aß) peptide in the brain. Given its pivotal role, new therapies targeting Aß are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aß assemblies and evaluated their efficiency in reducing the Aß burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood-brain barrier targeting and with phosphatidic acid for Aß binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aß assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aß1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain Aß oligomers were reduced (-70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [(11)C]Pittsburgh compound B (PIB). The reduction of brain Aß was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aß aggregates and promote peptide removal across the blood-brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease.

Verbal and nominal agreement: An fMRI study.

Agreement computation is one of the pillars of language comprehension. In this fMRI study, we investigated the neuro-cognitive processes of agreement associated with number feature covariance in subject-verb agreement and determiner-noun concord in Spanish by creating mismatches (ella/*ellas corre, she/*they dances vs. el/*los anillo, thesg/*thepl ring). The results evidenced the engagement of a common bilateral fronto-parietal monitoring system, not language specific, and a left fronto-temporal system that seems to be specifically related to different aspects of phrase and sentence processing. In particular, the major difference was found in the anterior portion of the left MTG-STG, which we relate to fine-grained syntactic-combinatorial building mechanisms apparently controlled by the pars opercularis within the LIFG. These results suggest that general conflict-monitoring processes operate in parallel with language-specific mechanisms that are sensitive to the specificity of agreement type for the detection of feature covariance among sentence constituents. Specifically, the coupling between these frontal and temporal regions seems to be flexible enough to show sensitivity to the fine-grained combinatorial mechanisms that underlie nominal and subject-verb agreement.

Where agreement merges with disagreement: fMRI evidence of subject-verb integration.

Language comprehension is incremental, involving the integration of information from different words together with the need to resolve conflicting cues when unexpected information occurs. The present fMRI design seeks to segregate the neuro-anatomical substrates of these two processes by comparing well-formed and ill-formed sentences during subject-verb agreement computation. Our experiment takes advantage of a particular Spanish feature, the Unagreement phenomenon: a subject-verb agreement mismatch that results in a grammatical sentence ("Los pintores trajimos…" [The painters3.pl (we)brought1.pl…]). Comprehension of this construction implies a shift in the semantic interpretation of the subject from 3rd-person to 1st-person, enabling the phrase "The painters" to be re-interpreted as "We painters". Our results include firstly a functional dissociation between well-formed and ill-formed sentences with Person Mismatches: while Person Mismatches recruited a fronto-parietal network associated to monitoring operations, grammatical sentences (both Unagreement and Default Agreement) recruited a fronto-temporal network related to syntactic-semantic integration. Secondly, there was activation in the posterior part of the left middle frontal gyrus for both Person Mismatches and Unagreement, reflecting the evaluation of the morpho-syntactic match between agreeing constituents. Thirdly, the left angular gyrus showed increased activation only for Unagreement, highlighting its crucial role in the comprehension of semantically complex but non-anomalous constructions. These findings point to a central role of the classic fronto-temporal network, plus two additional nodes: the posterior part of the left middle frontal gyrus and the left angular gyrus; opening new windows to the study of agreement computation and language comprehension.

A Review on the Applications of Natural Biodegradable Nano Polymers in Cardiac Tissue Engineering.

As cardiac diseases, which mostly result in heart failure, are increasing rapidly worldwide, heart transplantation seems the only solution for saving lives. However, this practice is not always possible due to several reasons, such as scarcity of donors, rejection of organs from recipient bodies, or costly medical procedures. In the framework of nanotechnology, nanomaterials greatly contribute to the development of these cardiovascular scaffolds as they provide an easy regeneration of the tissues. Currently, functional nanofibers can be used in the production of stem cells and in the regeneration of cells and tissues. The small size of nanomaterials, however, leads to changes in their chemical and physical characteristics that could alter their interaction and exposure to stem cells with cells and tissues. This article aims to review the naturally occurring biodegradable nanomaterials that are used in cardiovascular tissue engineering for the development of cardiac patches, vessels, and tissues. Moreover, this article also provides an overview of cell sources used for cardiac tissue engineering, explains the anatomy and physiology of the human heart, and explores the regeneration of cardiac cells and the nanofabrication approaches used in cardiac tissue engineering as well as scaffolds.

Correction: Mancini et al. A Novel Strategy for the Assessment of Radon Risk Based on Indicators. Int. J. Environ. Res. Public Health 2021, 18, 8089.

In the original publication [...].

Yesterday is history, tomorrow is a mystery: An eye-tracking investigation of the processing of past and future time reference during sentence reading.

The ability to think about nonpresent time is a crucial aspect of human cognition. Both the past and future imply a temporal displacement of an event outside the "now." They also intrinsically differ: The past refers to inalterable events; the future to alterable events, to possible worlds. Are the past and future processed similarly or differently? In this study, we addressed this question by investigating how Spanish speakers process past/future time reference violations during sentence processing, while recording eye movements. We also investigated the role of verbs (in isolation; within sentences) and adverbs (deictic; nondeictic) during time processing. Existing accounts propose that past processing, which requires a link to discourse, is more complex than future processing, which-like the present-is locally bound. Our findings show that past and future processing differs, especially at early stages of verb processing, but this difference is not limited to the presence/absence of discourse linking. We found earlier mismatch effects for past compared to future time reference in incongruous sentences, in line with previous studies. Interestingly, it took longer to categorize the past than the future tense when verbs were presented in isolation. However, it took longer to categorize the future than the past when verbs were presented in congruous sentences, arguably because the future implies alterable worlds. Finally, temporal adverbs were found to play an important role in reinspection and reanalysis triggered by the presence of undefined time frames (nondeictic adverbs) or incongruences (mismatching verbs). (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Maintenance cost in the processing of subject-verb dependencies.

Although research in sentence comprehension has suggested that processing long-distance dependencies involves maintenance between the elements that form the dependency, studies on maintenance of long-distance subject-verb (SV) dependencies are scarce. The few relevant studies have delivered mixed results using self-paced reading or phoneme-monitoring tasks. In the current study, we used eye tracking during reading to test whether maintaining a long-distance SV dependency results in a processing cost on an intervening adverbial clause. In Experiment 1, we studied this question in Spanish and found that both go-past reading times and regressions out of an adverbial clause to the previous regions were significantly increased when the clause interrupts a SV dependency compared to when the same clause doesn't interrupt this dependency. We then replicated these findings in English (Experiment 2), observing significantly increased go-past reading times on a clause interrupting a SV dependency. The current study provides the first eye-tracking data showing a maintenance cost in the processing of SV dependencies cross-linguistically. Sentence comprehension models should account for the maintenance cost generated by SV dependency processing, and future research should focus on the nature of the maintained representation. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Experimental Studies to Test a Predictive Indoor Radon Model.

The accumulation of the radioactive gas radon in closed environments, such as dwellings, is the result of a quite complex set of processes related to the contribution of different sources. As it undergoes different physical mechanisms, all occurring at the same time, models describing the general dynamic turns out to be difficult to apply because of the dependence on many parameters not easy to measure or calculate. In this context, the authors developed, in a previous work, a simplified approach based on the combination of a physics-mathematical model and on-site experimental measurements. Three experimental studies were performed in order to preliminarily test the goodness of the model to simulate indoor radon concentrations in closed environments. In this paper, an application on a new experimental site was realized in order to evaluate the adaptability of the model to different house typologies and environmental contexts. Radon activity measurements were performed using a portable radon detector and results, showing again good performance of the model. Results are discussed and future efforts are outlined for the refining and implementation of the model into software.

In Search for an Ionic Liquid with the Best Performance during 210Pb/210Bi Cherenkov Counting in Waters on an LS Counter.

The research presented in this paper aims to investigate the performance of several newly synthesized ionic liquids during 210Pb/210Bi detection in water on a liquid scintillation spectrometer Quantulus 1220 via Cherenkov counting. These experiments have been triggered by the recent reports that certain ionic liquids can act as wavelength shifters, thus significantly increasing the detection efficiency of Cherenkov radiation. The benefit of ionic liquid's addition to the analysed samples is reflected in the detection limit's decrement during 210Pb quantification, which is pertinent considering naturally low levels of 210Pb in aqueous samples. Firstly, it was discovered that ionic liquid, 1-butyl-3-methylimidazolium salicylate, is more efficient than the previously explored 2-hydroxypropylammonium salicylate. Consequently, the impact of a few other ionic liquids on Cherenkov counting efficiency with the same cation group (1-butyl-3-methylimidazolium benzoate, 1-butyl-3-methylimidazolium 3-hydroxybenzoate and 1-butyl-3-methylimidazolium 4-hydroxybenzoate) was also explored to test their potential influence. Molecular simulations have been carried out to reveal which structures of ionic liquids assure wavelength-shifting behavior. The obtained results confirmed that, among the investigated ones, only ionic liquids with the salicylate anion exhibited a wavelength shifting effect.

A decision-making Fokker-Planck model in computational neuroscience.

In computational neuroscience, decision-making may be explained analyzing models based on the evolution of the average firing rates of two interacting neuron populations, e.g., in bistable visual perception problems. These models typically lead to a multi-stable scenario for the concerned dynamical systems. Nevertheless, noise is an important feature of the model taking into account both the finite-size effects and the decision's robustness. These stochastic dynamical systems can be analyzed by studying carefully their associated Fokker-Planck partial differential equation. In particular, in the Fokker-Planck setting, we analytically discuss the asymptotic behavior for large times towards a unique probability distribution, and we propose a numerical scheme capturing this convergence. These simulations are used to validate deterministic moment methods recently applied to the stochastic differential system. Further, proving the existence, positivity and uniqueness of the probability density solution for the stationary equation, as well as for the time evolving problem, we show that this stabilization does happen. Finally, we discuss the convergence of the solution for large times to the stationary state. Our approach leads to a more detailed analytical and numerical study of decision-making models applied in computational neuroscience.

A Novel Strategy for the Assessment of Radon Risk Based on Indicators.

Among the physical pollutants affecting indoor air, the radioactive gas radon may turn out to be the most hazardous. Health effects related to radon exposure have been investigated for several decades, providing major scientific evidence to conclude that chronic exposures can cause lung cancer. Additionally, an association with other diseases, such as leukemia and cancers of the extra-thoracic airways, has been advanced. The implementation of a strategy to reduce the exposure of the population and minimize the health risk, according to the European Directive 59/2013/Euratom on ionizing radiations, is a new challenge in public health management. Starting from an understanding of the general state-of-the-art, a critical analysis of existing approaches has been conducted, identifying strengths and weaknesses. Then, a strategy for assessing the radon exposure of the general population, in a new comprehensive way, is proposed. It identifies three main areas of intervention and provides a list of hazard indicators and operative solutions to control human exposure. The strategy has been conceived to provide a supporting tool to authorities in the introduction of effective measures to assess population health risks due to radon exposure.

The Processing of Spanish Article-Noun Gender Agreement by Monolingual and Bilingual Toddlers.

We assessed monolingual Spanish and bilingual Spanish-Basque toddlers' sensitivity to gender agreement in correct vs. incorrect Spanish noun phrases (definite article + noun), using a spontaneous preference listening paradigm. Monolingual Spanish-learning toddlers exhibited a tendency to listen longer to the grammatically correct phrases (e.g., la casa; "the house"), as opposed to the incorrect ones (e.g., *el casa). This listening preference toward correct phrases is in line with earlier results obtained from French monolingual 18-month-olds (van Heugten & Christophe, 2015). Bilingual toddlers in the current study, however, tended to listen longer to the incorrect phrases. Basque was not a source of interference in the bilingual toddler's input as Basque does not instantiate grammatical gender agreement. Overall, our results suggest that both monolingual and bilingual toddlers can distinguish between the correct and incorrect phrases by 18 months of age; however, monolinguals and bilinguals allocate their attention differently when processing grammatically incorrect forms.

Who are you talking to? The role of addressee identity in utterance comprehension.

Experimental evidence suggests that speaker and addressee quickly adapt to each other from the earliest moments of sentence processing, and that interlocutor-related information is rapidly integrated with other sources of nonpragmatic information (e.g., semantic, morphosyntactic, etc.). These findings have been taken as support for one-step models of sentence comprehension. The results from the present event-related potential study challenge this theoretical framework providing a case where discourse level information is integrated only at a late stage of processing, when morphosyntactic analysis has been already initiated. We considered the case of Basque allocutive agreement, where information about addressee gender is encoded in verbal inflection. Two different types of Basque grammatical violations were presented together with the corresponding control conditions: one could be detected based on a morphosyntactic mismatch (person agreement violation), while the other could be detected only if the addressee's gender was considered (allocutive violation). Morphosyntactic violations elicited greater N400 effects followed by P600 effects, while allocutive violations elicited only P600 effects. These results provide new constraints to one-step accounts as they represent a case where speakers do not immediately adjust to the addressee's perspective. We propose that the relevance of discourse-level information might be a crucial variable to reconcile the dichotomy between one- and two-step models.

Alpha Spectrometry of Radon Short-Lived Progeny in Drinking Water and Assessment of the Public Effective Dose: Results from the Cilento Area, Province of Salerno, Southern Italy.

Radon is a naturally occurring radioactive gas present in the hydrosphere, lithosphere and atmosphere abundantly. Its ionizing radiation provides the largest human internal exposure by inhalation and ingestion to natural sources, constituting a serious health hazard. The contribution to total exposure is mainly due to inhalation, as ingestion by food or drinking water is typically very small. However, because of public health concerns, the contributions from all these sources are limited by regulations and remedial action should be taken in the event that the defined threshold values are overcome. In this paper, the first campaign of measurements to control the radon activity concentration in drinking water from public water supplies in the province of Salerno, south Italy, is described. The results represent a main reference for the area, as it was never investigated before. The purpose of this survey was to contribute to data compilation concerning the presence of radon-222 in groundwater in the Campania region and to determine the associated risk for different age groups. The maximum radon activity concentrations and the related total annual public effective dose turned out to be lower than the threshold values (100 Bq/l and 0.1 mSv/y, respectively) indicated by international guidelines and the national regulation, showing that the health risks for public consumption can be considered negligible.

Agreement and illusion of disagreement: An ERP study on Basque.

Agreement is a syntactic relation involving a controller (e.g., a noun) and a target with matching inflectional morphology (e.g., a verb). Across languages, electrophysiological studies consistently report that the presence of a mismatch yields late positive effects (P600), often preceded by early negativities. The current study focuses on person agreement in Basque to investigate whether online processing routines are modulated by the relative semantic prominence of nominal and verbal person features. In an event-related potentials experiment in Basque, we manipulated the semantic markedness of nominal and verbal person features, creating 1st (marked) and 3rd (unmarked) person correct and incorrect sentences [Japoniarrok1pleuskara ikasi dugu1pl/*dute3plgustora (We Japanese have1pl/*3pl learn Basque with pleasure); Japoniarrek3pleuskara ikasi dute3pl/*dugu1pl gustora (The Japanese have3pl/*1pl learnt Basque with pleasure)]. Both mismatches elicited an N400 effect, but only marked 1st person mismatches (Japoniarrok1pl … *dute3.pl) generated a P600, suggesting that (i) mismatches with unmarked 3rd person subjects (Japoniarrek3.pl… *dugu1.pl) are not treated as outright violations; (ii) the emergence of late positive effects is sensitive to fine-grained discourse information. Overall, these results call for a revision in the analysis of agreement relations from a theoretical and a processing perspective.