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The organization of abstract concepts reflects different dimensions, grounded in the brain regions coding for the corresponding experience. Normative measures of linguistic stimuli offer noteworthy insights into the organization of conceptual knowledge, but studies differ in the dimensions and classes of concepts considered. Additionally, most of the available information has been collected in English, without considering possible linguistic and cultural differences. Here, we aimed to create a comprehensive Turkish database for abstract concepts (TACO), including rarely investigated classes such as political concepts. We included 503 words-78 concrete (fruits, animals, tools) and 425 abstract (emotions, social, mental states, theoretical, quantity, space, political)-rated by 134 Turkish speakers for familiarity, imageability, age of acquisition, valence, arousal, quantity, space, theoretical, social, mental state, and political dimensions. We calculated dominance and exclusivity, indicating the dimension receiving the highest mean score for each word, and the position of the word along the unidimensional-multidimensional continuum, respectively. A principal component analysis (PCA) was conducted on the semantic dimensions. The results showed that mental state was the dominant dimension for most concepts. Moderate to low levels of exclusivity indicated that the concepts were multidimensional. PCA revealed three components: Component 1 captured the juxtaposition between social/mental state and magnitude polarities, Component 2 highlighted affective components, and Component 3 grouped together political and theoretical dimensions. The introduction of political concepts provided insights into the multidimensional nature of this unexplored class, closely intertwined with the theoretical dimension. TACO constitutes the first comprehensive Turkish database covering several abstract dimensions, paving the way for cross-linguistic and cross-cultural studies of semantic representations., (© 2024. The Psychonomic Society, Inc.)

Lysosomal Ca 2+ signaling is emerging as a crucial regulator of endothelial Ca 2+ dynamics. Ca 2+ release from the acidic vesicles in response to extracellular stimulation is usually promoted via Two Pore Channels (TPCs) and is amplified by endoplasmic reticulum (ER)-embedded inositol-1,3,4-trisphosphate (InsP 3 ) receptors and ryanodine receptors. Emerging evidence suggests that sub-cellular Ca 2+ signals in vascular endothelial cells can also be generated by the Transient Receptor Potential Mucolipin 1 channel (TRPML1) channel, which controls vesicle trafficking, autophagy and gene expression. Herein, we adopted a multidisciplinary approach, including live cell imaging, pharmacological manipulation, and gene targeting, revealing that TRPML1 protein is expressed and triggers global Ca 2+ signals in the human brain microvascular endothelial cell line, hCMEC/D3. The direct stimulation of TRPML1 with both the synthetic agonist, ML-SA1, and the endogenous ligand phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ) induced a significant increase in [Ca 2+ ] i, that was reduced by pharmacological blockade and genetic silencing of TRPML1. In addition, TRPML1-mediated lysosomal Ca 2+ release was sustained both by lysosomal Ca 2+ release and ER Ca 2+ - release through inositol-1,4,5-trisphophate receptors and store-operated Ca 2+ entry. Notably, interfering with TRPML1-mediated lysosomal Ca 2+ mobilization led to a decrease in the free ER Ca 2+ concentration. Imaging of DAF-FM fluorescence revealed that TRPML1 stimulation could also induce a significant Ca 2+ -dependent increase in nitric oxide concentration. Finally, the pharmacological and genetic blockade of TRPML1 impaired ATP-induced intracellular Ca 2+ release and NO production. These findings, therefore, shed novel light on the mechanisms whereby the lysosomal Ca 2+ store can shape endothelial Ca 2+ signaling and Ca 2+ -dependent functions in vascular endothelial cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Brunetti, Berra-Romani, Conca, Soda, Biella, Gerbino, Moccia and Scarpellino.)

Background: The identification and staging of Alzheimer's Disease (AD) represent a challenge, especially in the prodromal stage of Mild Cognitive Impairment (MCI), when cognitive changes can be subtle. Worldwide efforts were dedicated to select and harmonize available neuropsychological instruments. In Italy, the Italian Network of Neuroscience and Neuro-Rehabilitation has promoted the adaptation of the Uniform Data Set Neuropsychological Test Battery (I-UDSNB), collecting normative data from 433 healthy controls (HC). Here, we aimed to explore the ability of I-UDSNB to differentiate between a) MCI and HC, b) AD and HC, c) MCI and AD., Methods: One hundred thirty-seven patients (65 MCI, 72 AD) diagnosed after clinical-neuropsychological assessment, and 137 HC were included. We compared the I-UDSNB scores between a) MCI and HC, b) AD and HC, c) MCI and AD, with t-tests. To identify the test(s) most capable of differentiating between groups, significant scores were entered in binary logistic and in stepwise regressions, and then in Receiver Operating Characteristic curve analyses., Results: Two episodic memory tests (Craft Story and Five Words test) differentiated MCI from HC subjects; Five Words test, Semantic Fluency (vegetables), and TMT-part B differentiated AD from, respectively, HC and MCI., Conclusions: Our findings indicate that the I-UDSNB is a suitable tool for the harmonized and concise assessment of patients with cognitive decline, showing high sensitivity and specificity for the diagnosis of MCI and AD., (© 2024. The Author(s).)

Background: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce., Methods: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [ 18 F] FDG-PET. Correlations were performed between metabolic and behavioral data., Results: Patients' profiles were distributed across a continuum. All PPA, but two, presented a lexical retrieval impairment, in terms of reduced production of verbs and nouns. svPPA patients occupied a fairly clumped space along the continuum, showing a preponderant semantic deficit, which correlated to fusiform gyrus hypometabolism, while only few presented working memory deficits. Adjacently, lvPPA + presented a semantic impairment combined with phonological deficits, which correlated with metabolism in the anterior fusiform gyrus and posterior middle temporal gyrus. Starting from the shared phonological deficit side, a large portion of the space was occupied by all lvPPA, showing a combination of phonological, lexical, and working memory deficits, with the latter correlating with posterior temporo-parietal hypometabolism. Mixed PPA did not show unique profile, distributing across the space., Discussion: Different clinical PPA entities exist but overlaps are frequent. Identifying shared and unique clinical markers is critical for research and clinical practice. Further research is needed to identify the role of genetic and pathological factors in such distribution, including also higher sample size of less represented groups., (© 2024. The Author(s).)

Neuroscience research has provided evidence that semantic information is stored in a distributed brain network involved in sensorimotor and linguistic processing. More specifically, according to the embodied cognition accounts, the representation of concepts is deemed as grounded in our bodily states. For these reasons, normative measures of words should provide relevant information about the extent to which each word embeds perceptual and action properties. In the present study, we collected ratings for 959 Italian nouns and verbs from 398 volunteers, recruited via an online platform. The words were mostly taken from the Italian adaptation of the Affective Norms for English Words (ANEW). A pool of 145 verbs was added to the original set. All the words were rated on 11 sensorimotor dimensions: six perceptual modalities (vision, audition, taste, smell, touch, and interoception) and five effectors (hand-arm, foot-leg, torso, mouth, head). The new verbs were also rated on the ANEW dimensions. Results showed good reliability and consistency with previous studies. Relations between perceptual and motor dimensions are described and interpreted, along with relations between the sensorimotor and the affective dimensions. The currently developed dataset represents an important novelty, as it includes different word classes, i.e., both nouns and verbs, and integrates ratings of both sensorimotor and affective dimensions, along with other psycholinguistic parameters; all features only partially accomplished in previous studies., (© 2022. The Author(s).)

The second messenger cyclic AMP regulates many nuclear processes including transcription, pre-mRNA splicing and mitosis. While most functions are attributed to protein kinase A, accumulating evidence suggests that not all nuclear cyclic AMP-dependent effects are mediated by this kinase, implying that other effectors may be involved. Here we explore the nuclear roles of Exchange Protein Activated by cyclic AMP 1. We find that it enters the nucleus where forms reversible biomolecular condensates in response to cyclic AMP. This phenomenon depends on intrinsically disordered regions present at its amino-terminus and is independent of protein kinase A. Finally, we demonstrate that nuclear Exchange Protein Activated by cyclic AMP 1 condensates assemble at genomic loci on chromosome 6 in the proximity of Histone Locus Bodies and promote the transcription of a histone gene cluster. Collectively, our data reveal an unexpected mechanism through which cyclic AMP contributes to nuclear spatial compartmentalization and promotes the transcription of specific genes., (© 2023. Springer Nature Limited.)

Introduction: Neural circuit alterations lay at the core of brain physiopathology, and yet are hard to unveil in living subjects. The Virtual Brain (TVB) modeling, by exploiting structural and functional magnetic resonance imaging (MRI), yields mesoscopic parameters of connectivity and synaptic transmission., Methods: We used TVB to simulate brain networks, which are key for human brain function, in Alzheimer's disease (AD) and frontotemporal dementia (FTD) patients, whose connectivity and synaptic parameters remain largely unknown; we then compared them to healthy controls, to reveal novel in vivo pathological hallmarks., Results: The pattern of simulated parameter differed between AD and FTD, shedding light on disease-specific alterations in brain networks. Individual subjects displayed subtle differences in network parameter patterns that significantly correlated with their individual neuropsychological, clinical, and pharmacological profiles., Discussion: These TVB simulations, by informing about a new personalized set of networks parameters, open new perspectives for understanding dementias mechanisms and design personalized therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Monteverdi, Palesi, Schirner, Argentino, Merante, Redolfi, Conca, Mazzocchi, Cappa, Cotta Ramusino, Costa, Pichiecchio, Farina, Jirsa, Ritter, Gandini Wheeler-Kingshott and D’Angelo.)

Primary progressive aphasia (PPA) classification relies on profile characterization of quantitatively impaired/spared performance in language tasks. In this study, we coextracted 8 qualitative types of errors in 67 PPA patients submitted to a comprehensive language assessment. Canonical correlation analysis was applied to simultaneously correlate qualitative errors and brain metabolism, collected with FDG-PET. Results showed the contribution of semantic, syntactic and working memory errors associated with specific correlates of regional metabolic changes. Reduced metabolism in the left fusiform gyrus, anterior-middle and inferior-temporal gyri and middle-temporal pole correlated with an increase of semantic errors. Hypometabolism in the left inferior, middle, and superior frontal gyri, insula and right middle-occipital gyrus was related to syntactic errors. Higher metabolism in the bilateral pallidum, putamen, and left thalamus, as well as hypometabolism in the left angular and supramarginal gyri, inferior-parietal lobule, posterior-middle and inferior-temporal gyri and posterior cingulum predicted the increase of working memory errors. A relevant role of working memory subcomponents was associated with distinct neural systems. Patients' profiles are easily represented in a qualitative multidimensional space, in which mixed PPA overlapped with different phenotypes., (Copyright © 2022. Published by Elsevier Inc.)

The linguistic and anatomical variability of the logopenic variant of Primary Progressive Aphasia (lv-PPA) as defined by current diagnostic criteria has been the topic of an intense debate. The present review and meta-analysis aims at characterizing the profile of lv-PPA, by a comprehensive analysis of the available literature on the neuropsychological, neuroimaging, electrophysiological, pathological, and genetic features of lv-PPA. We conducted a systematic bibliographic search, leading to the inclusion of 207 papers. Of them, 12 were used for the Anatomical Likelihood Estimation meta-analysis on grey matter revealed by magnetic resonance imaging data. The results suggest that the current guidelines outline a relatively consistent syndrome, characterized by a core set of linguistic and, to a lesser extent, non-linguistic deficits, mirroring the involvement of left temporal and parietal regions typically affected by Alzheimer Disease pathology. Variations of the lv-PPA profile are discussed in terms of heterogeneity of the neuropsychological instruments and the diagnostic criteria adopted., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer's disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue., Methods: Following the initiative of the University of Washington's National Alzheimer's Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms., Results: Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward., Conclusions: The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings., (© 2022. The Author(s).)

Previous brain functional specialization evidence has shown that both aware and unaware visual processing of manipulable objects activate left premotor, parietal, and posterior temporal cortices, which are thought to constitute object-directed action and object-function processing streams. An open question is whether, both under supraliminal and subliminal processing conditions, there is directional spread of activation along these functional streams, leading to causal inter-regional connectivity effects. In this study, we used Dynamic Causal Modelling to estimate the effective connectivity influences within the premotor-parieto-temporal network, as a function of factorial contrasts for Manipulability (manipulable vs non-manipulable objects) and Perceptual Awareness (above vs below perceptual threshold). We modeled forward and backward connections originating from visual area V4, as a region underlying object texture segregation, and spreading through the left premotor-parieto-temporal network. Both above and below perceptual threshold, the visual processing of manipulable objects was associated with a specific increase of reciprocal effective connectivity coupling among left premotor-parieto-temporal regions. Aware and unaware manipulable object processing differed from each other for their distinct patterns of top-down activation enhancement exerted, in the former case, by left premotor-parieto-temporal regions on area V4 and, in the latter case, by left premotor on temporal regions. Although it is only under aware processing conditions that effective connectivity in the action representation system may promote object visual contour segregation in area V4, our results suggest that the encoding of object-action and object-function information can occur through left-hemispheric premotor, parietal, and temporal causal interdependencies, even when the object is not consciously perceived., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

(1) Background: Store-operated Ca 2+ entry (SOCE) drives the cytotoxic activity of cytotoxic T lymphocytes (CTLs) against cancer cells. However, SOCE can be enhanced in cancer cells due to an increase in the expression and/or function of its underlying molecular components, i.e., STIM1 and Orai1. Herein, we evaluated the SOCE expression and function in tumour-infiltrating lymphocytes (TILs) from metastatic colorectal cancer (mCRC) patients. (2) Methods: Functional studies were conducted in TILs expanded ex vivo from CRC liver metastases. Peripheral blood T cells from healthy donors (hPBTs) and mCRC patients (cPBTs) were used as controls. (3) Results: SOCE amplitude is enhanced in TILs compared to hPBTs and cPBTs, but the STIM1 protein is only up-regulated in TILs. Pharmacological manipulation showed that the increase in SOCE mainly depends on tonic modulation by diacylglycerol kinase, which prevents the protein kinase C-dependent inhibition of SOCE activity. The larger SOCE caused a stronger Ca 2+ response to T-cell receptor stimulation by autologous mCRC cells. Reducing Ca 2+ influx with BTP-2 during target cell killing significantly increases cytotoxic activity at low target:effector ratios. (4) Conclusions: SOCE is enhanced in ex vivo-expanded TILs deriving from mCRC patients but decreasing Ca 2+ influx with BTP-2 increases cytotoxic activity at a low TIL density.

Concrete conceptual knowledge is supported by a distributed neural network representing different semantic features according to the neuroanatomy of sensory and motor systems. If and how this framework applies to abstract knowledge is currently debated. Here we investigated the specific brain correlates of different abstract categories. After a systematic a priori selection of brain regions involved in semantic cognition, i.e. responsible of, respectively, semantic representations and cognitive control, we used a fMRI-adaptation paradigm with a passive reading task, in order to modulate the neural response to abstract (emotions, cognitions, attitudes, human actions) and concrete (biological entities, artefacts) categories. Different portions of the left anterior temporal lobe responded selectively to abstract and concrete concepts. Emotions and attitudes adapted the left middle temporal gyrus, whereas concrete items adapted the left fusiform gyrus. Our results suggest that, similarly to concrete concepts, some categories of abstract knowledge have specific brain correlates corresponding to the prevalent semantic dimensions involved in their representation., (© 2021. The Author(s).)

The cyclic AMP (cAMP) signalling cascade is necessary for cell homeostasis and plays important roles in many processes. This is particularly relevant during ageing and age-related diseases, where drastic changes, generally decreases, in cAMP levels have been associated with the progressive decline in overall cell function and, eventually, the loss of cellular integrity. The functional relevance of reduced cAMP is clearly supported by the finding that increases in cAMP levels can reverse some of the effects of ageing. Nevertheless, despite these observations, the molecular mechanisms underlying the dysregulation of cAMP signalling in ageing are not well understood. Compartmentalization is widely accepted as the modality through which cAMP achieves its functional specificity; therefore, it is important to understand whether and how this mechanism is affected during ageing and to define which is its contribution to this process. Several animal models demonstrate the importance of specific cAMP signalling components in ageing, however, how age-related changes in each of these elements affect the compartmentalization of the cAMP pathway is largely unknown. In this review, we explore the connection of single components of the cAMP signalling cascade to ageing and age-related diseases whilst elaborating the literature in the context of cAMP signalling compartmentalization.

Objective: To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates., Methods: The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [ 18 F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network., Results: Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors., Conclusions: Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias., (© 2020 American Academy of Neurology.)

Syntax is a species-specific component of human language combining a finite set of words in a potentially infinite number of sentences. Since words are by definition expressed by sound, factoring out syntactic information is normally impossible. Here, we circumvented this problem in a novel way by designing phrases with exactly the same acoustic content but different syntactic structures depending on the other words they occur with. In particular, we used phrases merging an article with a noun yielding a Noun Phrase (NP) or a clitic with a verb yielding a Verb Phrase (VP). We performed stereo-electroencephalographic (SEEG) recordings in epileptic patients. We measured a different electrophysiological correlates of verb phrases vs. noun phrases in multiple cortical areas in both hemispheres, including language areas and their homologous in the non-dominant hemisphere. The high gamma band activity (150-300 Hz frequency), which plays a crucial role in inter-regional cortical communications, showed a significant difference during the presentation of the homophonous phrases, depending on whether the phrase was a verb phrase or a noun phrase. Our findings contribute to the ultimate goal of a complete neural decoding of linguistic structures from the brain.

The neural representation of abstract concepts is a current matter of debate. While social concepts have been associated to superior anterior temporal lobe (sATL), the neural correlates of quantity-related concepts have seldom been investigated. The right intraparietal sulcus (IPS) is known to be involved in the processing of numerical information and of quantifiers. In the present study, we investigated the causal role of right sATL and right IPS in representing social and quantity-related concepts, using a state-dependent transcranial magnetic stimulation (TMS)-priming paradigm. We modulated the neural activation by priming to a category label (either SOCIAL or QUANTITY), before applying TMS and presenting the target (i.e., an exemplar of one of the two abstract classes). When the target word belonged to the quantity category, TMS applied over the IPS (but not sATL) abolished the expected priming effect by speeding up reaction times (RTs) in incongruent trials. For the social category, both IPS and sATL stimulation abolished the priming effect, by reducing RTs in incongruent trials. Our results suggest a specialization of distinct brain areas in processing different classes of abstract concepts. The right IPS contains neuronal representations tuned to quantity-related concepts, in line with its well-known role in numerical and magnitude representation. Social concepts, in contrast, are represented in both the right sATL and the right IPS, known to be involved in social cognition and person-related knowledge., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The hypothesis that the brain constitutively encodes observed manipulable objects for the actions they afford is still debated. Yet, crucial evidence demonstrating that, even in the absence of perceptual awareness, the mere visual appearance of a manipulable object triggers a visuomotor coding in the action representation system including the premotor cortex, has hitherto not been provided. In this fMRI study, we instantiated reliable unaware visual perception conditions by means of continuous flash suppression, and we tested in 24 healthy human participants (13 females) whether the visuomotor object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices is activated even under subliminal perceptual conditions. We found consistent activation in the target visuomotor cortices, both with and without perceptual awareness, specifically for pictures of manipulable versus non-manipulable objects. By means of a multivariate searchlight analysis, we also found that the brain activation patterns in this visuomotor network enabled the decoding of manipulable versus non-manipulable object picture processing, both with and without awareness. These findings demonstrate the intimate neural coupling between visual perception and motor representation that underlies manipulable object processing: manipulable object stimuli specifically engage the visuomotor object-directed action representation system, in a constitutive manner that is independent from perceptual awareness. This perceptuo-motor coupling endows the brain with an efficient mechanism for monitoring and planning reactions to external stimuli in the absence of awareness. SIGNIFICANCE STATEMENT Our brain constantly encodes the visual information that hits the retina, leading to a stimulus-specific activation of sensory and semantic representations, even for objects that we do not consciously perceive. Do these unconscious representations encompass the motor programming of actions that could be accomplished congruently with the objects' functions? In this fMRI study, we instantiated unaware visual perception conditions, by dynamically suppressing the visibility of manipulable object pictures with mondrian masks. Despite escaping conscious perception, manipulable objects activated an object-directed action representation system that includes left-hemispheric premotor, parietal, and posterior temporal cortices. This demonstrates that visuomotor encoding occurs independently of conscious object perception., (Copyright © 2017 the authors 0270-6474/17/3710712-13$15.00/0.)