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What type of conceptual information about an object do we get at a brief glance? In two experiments, we investigated the nature of conceptual tokening-the moment at which conceptual information about an object is accessed. Using a masked picture-word congruency task with dichoptic presentations at "brief" (50-60 ms) and "long" (190-200 ms) durations, participants judged the relation between a picture (e.g., a banana) and a word representing one of four property types about the object: superordinate (fruit), basic level (banana), a high-salient (yellow), or low-salient feature (peel). In Experiment 1, stimuli were presented in black-and-white; in Experiment 2, they were presented in red and blue, with participants wearing red-blue anaglyph glasses. This manipulation allowed for the independent projection of stimuli to the left- and right-hemisphere visual areas, aiming to probe the early effects of these projections in conceptual tokening. Results showed that superordinate and basic-level properties elicited faster and more accurate responses than high- and low-salient features at both presentation times. This advantage persisted even when the objects were divided into categories (e.g., animals, vegetables, vehicles, tools), and when objects contained high-salient visual features. However, contrasts between categories show that animals, fruits, and vegetables tend to be categorized at the superordinate level, while vehicles tend to be categorized at the basic level. Also, for a restricted class of objects, high-salient features representing diagnostic color information (yellow for the picture of a banana) facilitated congruency judgments to the same extent as that of superordinate and basic-level labels. We suggest that early access to object concepts yields superordinate and basic-level information, with features only yielding effects at a later stage of processing, unless they represent diagnostic color information. We discuss these results advancing a unified theory of conceptual representation, integrating key postulates of atomism and feature-based theories., (© 2024 The Author(s). Cognitive Science published by Wiley Periodicals LLC on behalf of Cognitive Science Society (CSS).)

The regioselective synthesis of functionalized naphthoquinones via the formation and capture of naphthoquinonynes has been used to prepare trypanocidal compounds. The target compounds are functionalized on the aromatic ring, leaving the quinoidal ring intact. Using this technique, eighteen functionalized naphthoquinones were succesfull obtained, divided in two main groups: the first scope using N -nucleophiles, and the second scope using pyridine N -oxides, with yields up to 74%. Evaluation against bloodstream trypomastigotes of T. cruzi has identified fourteen compounds that are more potent than benznidazole (Bz); for instance, compounds 29b-I and 30b, with IC 50 /24 h values of 10.5 and 10.1 μM, respectively, are approximately 10-fold more active than Bz. This study provides the first examples of the application of naphthoquinonyne chemistry for the synthesis of new compounds with potent trypanocidal activities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

An eco-friendly electrochemical halogenation of 2-amino-1,4-naphthoquinones has been developed. The new mild and energy efficient methodology comprises sustainable features like oxidant free and double role of the halogen source as electrolyte, originating twenty-six amino-halogenated naphthoquinoidal derivatives in good yields under mild conditions. This novel methodology permitted access to new potent trypanocidal prototypes, where six compounds were more active than benznidazole, the current market drug used in the treatment of Chagas Disease., (© 2024 Wiley‐VCH GmbH.)

Myelination of axons is a key determinant of fast action potential propagation, axonal health and circuit function. Previously considered a static structure, it is now clear that myelin is dynamically regulated in response to neuronal activity in the central nervous system (CNS). However, how activity-dependent signals are conveyed to oligodendrocytes remains unclear. Here, we review the potential mechanisms by which neurons could communicate changing activity levels to myelin, with a focus on the accumulating body of evidence to support activity-dependent vesicular signalling directly onto myelin sheaths. We discuss recent in vivo findings of activity-dependent fusion of neurotransmitter vesicles from non-synaptic axonal sites, and how modulation of this vesicular fusion regulates the stability and growth of myelin sheaths. We also consider the potential mechanisms by which myelin could sense and respond to axon-derived signals to initiate remodelling, and the relevance of these adaptations for circuit function. We propose that axonal vesicular signalling represents an important and underappreciated mode of communication by which neurons can transmit activity-regulated signals to myelinating oligodendrocytes and, potentially, more broadly to other cell types in the CNS., (© 2024 The Author(s).)

How does the language comprehension system identify and interpret word constituents-or morphemes-during sentence reading? We investigated this question by employing words containing semantically ambiguous roots (e.g., bark , with meanings related to both "dog" and "tree") which are disambiguated when affixed by - ing (e.g., barking ; related to "dog" only). We aimed to understand whether higher-level access to the meaning of the root bark would be constrained by lower-level morphological affixation. In Experiment 1, using eye-tracking, participants read sentences containing words with semantically ambiguous roots, such as barking (a prime), combined with targets that were either related to two meanings of the root ( dog , tree ) or they were cloze and unrelated controls. All five eye-tracking measures we employed (first fixation duration, gaze duration, go-past time, total reading time, and regressions to target) showed no difference between the two root-related targets, which were slower than cloze, but faster than unrelated. Results show that even in cases where a meaning is inconsistent with the full word form (barking-tree ), both meanings of the ambiguous root are activated. These results were supported by Experiment 2, employing a maze task in which the time to select the cloze ( night ) continuation for the sentence He heard loud barking during the … was disrupted by the presence of distractors related to both meanings of bark. We discuss the implications of these findings for the nature of morphological parsing and lexical ambiguity resolution in sentence contexts. We suggest that word recognition and lexical access processes involve separating roots from affixes, yielding independent and exhaustive access to root meanings-even when they are ruled out by affixation and context. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Brazil is the second largest beef producer and a leading exporter, contributing to some 3000 t CWE in global markets (27.7% of market share). The sector has experienced substantial development, but yields remain far below potential, and there are growing concerns regarding land use change and greenhouse gas emissions. The need for sustainable technologies, such as sound pasture management and integrated farming systems, is evident, but adoption may be low amongst farmers unable to keep up with technological advances. This article describes the historical developments of Brazilian beef farming towards sustainability and discusses possible socioenvironmental outcomes. We combined an extensive literature review, public data, and our own insights as senior researchers to achieve that. The trajectory shown here evidenced the technological intensification of Brazilian beef farming, with strong support of public policies for decarbonizing agriculture. Nonetheless, the pace of this transition may affect small to medium farmers with limited access to information, technologies, and credit. Our recommendations involve a broad program of technical assistance and training on sustainable technologies, including financial and digital literacy. A novel approach to financing farmers is suggested to support a sustainable and inclusive transition in beef farming in Brazil.

Herein, we describe the Ru-catalyzed C-H alkenylation of 1,4-naphthoquinones (1,4-NQs), resulting in 1,4-naphthoquinoidal/SuFEx hybrids with moderate to good yields. This method provides a novel route for direct access to ethenesulfonyl-fluorinated quinone structures. We conducted mechanistic studies to gain an in-depth understanding of the elementary steps of the reaction. Additionally, we evaluated the prototypes against trypomastigote forms of T. cruzi, leading to the identification of compounds with potent trypanocidal activity., (© 2024 Wiley-VCH GmbH.)

Optical recording of intricate molecular dynamics is becoming an indispensable technique for biological studies, accelerated by the development of new or improved biosensors and microscopy technology. This creates major computational challenges to extract and quantify biologically meaningful spatiotemporal patterns embedded within complex and rich data sources, many of which cannot be captured with existing methods. Here, we introduce Activity Quantification and Analysis (AQuA2), a fast, accurate, and versatile data analysis platform built upon advanced machine learning techniques. It decomposes complex live imaging-based datasets into elementary signaling events, allowing accurate and unbiased quantification of molecular activities and identification of consensus functional units. We demonstrate applications across a wide range of biosensors, cell types, organs, animal models, and imaging modalities. As exemplar findings, we show how AQuA2 identified drug-dependent interactions between neurons and astroglia, and distinct sensorimotor signal propagation patterns in the mouse spinal cord., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

The first systematic exploration of the synthesis and reactivity of naphthoquinonynes is described. Routes to two regioisomeric Kobayashi-type naphthoquinonyne precursors have been developed, and the reactivity of the ensuing 6,7- and 5,6-aryne intermediates has been investigated. Remarkably, these studies have revealed that a broad range of cycloadditions, nucleophile additions and difunctionalizations can be achieved while maintaining the integrity of the highly sensitive quinone unit. The methodologies offer a powerful diversity oriented approach to C6 and C7 functionalized naphthoquinones, which are typically challenging to access. From a reactivity viewpoint, the study is significant because it demonstrates that aryne-based functionalizations can be utilized strategically in the presence of highly reactive and directly competing functionality., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality., (© 2024. The Author(s).)

Environmental conditions and available forage on pastures greatly differ between different farming systems, which can affect the behaviour of grazing cattle. The interplay between environment-, forage-, and animal-related variables may affect the use of feed and water resources in grazing-based systems. Hence, our objectives were (i) to study the differences between grazing-based systems and seasons in environment- and pasture-related variables as well as the behaviour, feed intake, performance, and water productivity of Nellore heifers, and (ii) to understand the interrelationships between these variables. The measurements were performed in a conventional grazing system (CON), an integrated crop-livestock (ICL), and a crop-livestock-forestry (ICLF) systems in the Brazilian Cerrado during the rainy and dry seasons. Ambient temperature and relative air humidity were hourly measured in both seasons. Forage biomass and sward height were determined every month. Forage samples were taken to determine the proportions of alive leaves, alive stems, and dead plant material and to analyse their nutritive value. Forage intake, drinking water intake, and liveweight changes were quantified in 12 Nellore heifers per system and season. Feeding behaviour was recorded by chewing sensors on nine continuous days in each season. Drinking water intake was measured by water meters attached to drinking water troughs, whereby trial cameras at the troughs recorded the frequency of drinking events of individual animals. Feed conversion efficiency and water productivity were estimated. The ICLF reduced the exposure time to high ambient temperatures so that heifers even grazed during the hottest hours. Forage biomass in ICL and CON had greater proportions of stem and dead plant material than in ICLF. Forage intake rate was greater and grazing events were longer for animals in ICLF than those in CON, whereas the daily number of grazing events was greater in CON. Feed conversion efficiency and water productivity were greater in integrated systems than in CON. Amongst studied variables, thermal environment and forage canopy structure with its proportions of dead plant material are the main driving factors for animal behaviour, forage intake rate, and animal performance. These variables reduce feed conversion efficiency and water productivity in grazing cattle. Further research should analyse strategies for promoting thermal comfort for the animals, increasing the proportions of alive biomass, and enhancing the nutritional value of pastures for more efficient use of forage and water resources in grazing-based systems., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains, and greater morphological diversity. Here, we report that RNA-level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination. We show that RNLTR12-int-encoded RNA binds to the transcription factor SOX10 to regulate transcription of myelin basic protein (Mbp, the major constituent of myelin) in rodents. RNLTR12-int-like sequences (which we name RetroMyelin) are found in all jawed vertebrates, and we further demonstrate their function in regulating myelination in two different vertebrate classes (zebrafish and frogs). Our study therefore suggests that retroviral endogenization played a prominent role in the emergence of vertebrate myelin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Targeted knock-in of fluorescent reporters enables powerful gene and protein analyses in a physiological context. However, precise integration of long sequences remains challenging in vivo. Here, we demonstrate cloning-free and precise reporter knock-in into zebrafish genes, using PCR-generated templates for homology-directed repair with short homology arms (PCR tagging). Our novel knock-in reporter lines of vesicle-associated membrane protein (vamp) zebrafish homologues reveal subcellular complexity in this protein family. Our approach enables fast and efficient reporter integration in the zebrafish genome (in 10-40% of injected embryos) and rapid generation of stable germline-transmitting lines., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (M pro ) and papain-like protease (PL pro ) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against M pro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against M pro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PL pro . Four compounds inhibited M pro with half-maximal inhibitory concentration (IC 50 ) values between 0.41 μM and 9.0 μM. In addition, three compounds inhibited PL pro with IC 50 ranging from 1.9 μM to 3.3 μM. To verify the specificity of M pro and PL pro inhibitors, our experiments included an assessment of common causes of false positives such as aggregation, high compound fluorescence, and inhibition by enzyme oxidation. Altogether, we confirmed novel classes of specific M pro and PL pro inhibitors. Molecular dynamics simulations suggest stable binding modes for M pro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PL pro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.

Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease., (© 2022. The Author(s).)

The spacing of nodes of Ranvier crucially affects conduction properties along myelinated axons. It is assumed that node position is primarily driven by growing myelin sheaths. Here, we reveal an additional mechanism of node positioning that is driven by the axon. Through longitudinal live imaging of node formation dynamics in the zebrafish central nervous system, we show that stable clusters of the cell adhesion molecule neurofascin a can accumulate at specific sites along axons prior to myelination. While some of these clusters are pushed into future node position by extending myelin sheaths, others are not and thus prefigure the position of where a mature node forms. Animals that lack full-length neurofascin a show increased internodal distances and less regular nodal spacing along single axons. Together, our data reveal the existence of an axonal mechanism to position nodes of Ranvier that does not depend on regulation by myelin sheath growth., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Conventional metaphors such as broken heart are interpreted rather fast and efficiently. This is because they might be stored as lexicalized, noncompositional expressions. If so, they require sense retrieval rather than sense creation. But can their literal meanings be recovered or "awakened"? We examined whether the literal meaning of a conventional metaphor could be triggered by a later cue. In a maze task, participants (N = 40) read sentences word by word (e.g., John is an early bird so he can . . .) and were presented with a two-word choice. Participants took longer and were less accurate when the correct word (attend) was paired with a literally-related distractor (fly) rather than an unrelated one (cry). This suggests that the literal meaning of a conventional metaphor is not circumvented, nor that metaphors simply involve sense retrieval. The metaphor awakening effect suggests that the mechanisms employed to process conventional metaphors are dynamic with both metaphorical sense and literal meaning being available., (© 2021. The Psychonomic Society, Inc.)

This work reports a classification analysis method based on the vibrational Raman spectra of 38 quinones and related structures, spectrally ordering and classifying the compounds. The molecular systems are relevant for chemical and biological processes, with applications in pharmacology, toxicology and medicine. The classification strategy uses a combination of principal component analysis with K-means clustering methods. Both theoretical simulations and experimental data are analysed, thus establishing their spectral characteristics, as related to their chemical structures and properties. The protocol introduced here should be broadly applicable in other molecular and solid state systems.

We investigated how the potential distribution of Histiotus velatus is affected by the addition of new records over decades (decade effect). Assuming that (1: hypothesis of the effect of the decade) the addition of new occurrence records over time increases the potential size of the species distribution; and (2: Wallacean distance hypothesis) over the years, the new points added are increasingly distant from the research centers. Considering the geographic knowledge gap of this species, our objective is to report a new record of this species and estimate its potential distribution in South America through environment niche models (ENMs). For this, we compiled records of occurrence of species, selected from 1900 to 2015. We used 19 bioclimatic variables available in the WorldClim database to estimate the potential distribution of the species, and we used three modeling algorithms: Maximum Entropy (MXT), Random Forest (RDF), and Support Vector Machine. To test the Wallacean distance hypothesis, we calculated the Euclidian distance from occurrences to bat research centers in Brazil, located using a national researchers' information dataset ("Plataforma Lattes"). To test the hypothesis of the decade effect, we used the beta regression analysis, taking conservative and non-conservative approaches. The results showed that the predicted area expanded and retracted with the addition of new occurrences over the decades, with an improvement in the accuracy of models. Most records are located in the southeastern region of Brazil, but algorithms predicted areas in regions where there are no records. Only the conservative approach has had a positive relationship over the decades. The distance from new points does not increase over the years of research centers., Competing Interests: There are no conflicts of interest., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

A sentence such as We finished the paper is indeterminate with regards to what we finished doing with the paper. Indeterminate sentences constitute a test case for two major issues regarding language comprehension: (1) how we compose sentence meaning; and (2) what is retained in memory about what we read in context over time. In an eye-tracking experiment, participants read short stories that were unexpectedly followed by one of three recognition probes: (a) an indeterminate sentence ( Lisa began the book ), that is identical to the one in the story; (b) an enriched but false probe ( Lisa began reading the book ); and (c) a contextually unrelated probe ( Lisa began writing the book ). The probes were presented either at the offset of the original indeterminate sentence in context or following additional neutral discourse. We measured accuracy, probe recognition time, and reading times of the probe sentences. Results showed that, at the immediate time point, participants correctly accepted the identical probes with high accuracy and short recognition times, but that this effect reversed to chance-level accuracy and significantly longer recognition times at the delayed time point. We also found that participants falsely accept the enriched probe at both time points 50% of the time. There were no reading-time differences between identical and enriched probes, suggesting that enrichment might not be an early, mandatory process for indeterminate sentences. Overall, results suggest that while context produces an enriched proposition, an un enriched proposition true to the indeterminate sentence also lingers in memory., 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 © 2021 Antal and de Almeida.)

Myelination of axons by oligodendrocytes enables fast saltatory conduction. Oligodendrocytes are responsive to neuronal activity, which has been shown to induce changes to myelin sheaths, potentially to optimize conduction and neural circuit function. However, the cellular bases of activity-regulated myelination in vivo are unclear, partly due to the difficulty of analyzing individual myelinated axons over time. Activity-regulated myelination occurs in specific neuronal subtypes and can be mediated by synaptic vesicle fusion, but several questions remain: it is unclear whether vesicular fusion occurs stochastically along axons or in discrete hotspots during myelination and whether vesicular fusion regulates myelin targeting, formation, and/or growth. It is also unclear why some neurons, but not others, exhibit activity-regulated myelination. Here, we imaged synaptic vesicle fusion in individual neurons in living zebrafish and documented robust vesicular fusion along axons during myelination. Surprisingly, we found that axonal vesicular fusion increased upon and required myelination. We found that axonal vesicular fusion was enriched in hotspots, namely the heminodal non-myelinated domains into which sheaths grew. Blocking vesicular fusion reduced the stable formation and growth of myelin sheaths, and chemogenetically stimulating neuronal activity promoted sheath growth. Finally, we observed high levels of axonal vesicular fusion only in neuronal subtypes that exhibit activity-regulated myelination. Our results identify a novel "feedforward" mechanism whereby the process of myelination promotes the neuronal activity-regulated signal, vesicular fusion that, in turn, consolidates sheath growth along specific axons selected for myelination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The continuous emergence of resistant Mycobacterium tuberculosis keeps tuberculosis (TB) treatment options still insufficient, and new therapeutic alternatives are urgently needed. Considering the antimycobacterial activity of phenazine derivatives previously reported by our research group, we aimed to explore possible applications to circumvent the resistance in M. tuberculosis. Firstly, we evaluated the antimicrobial activity of seven benzo[a]phenazine derivatives against eleven M. tuberculosis strains: ten resistant and one susceptible (H 37 Rv). Then, we determined the cytotoxicity of benzo[a]phenazine derivatives and investigated the possible mechanism of action of the most promising compound. Among them, compound 10 was the only one active against all strains evaluated, with a minimum inhibitory concentration between 18.3 and 146.5 µM. For some resistant strains, this compound showed antimicrobial activity higher than rifampicin and it was also active against MDR strains, indicating an absence of cross-resistance with anti-TB drugs. Also, 10 showed a pharmacological safety for further in vivo studies and its mechanism of action seems to be related to oxidative stress. Thus, our findings indicate that benzo[a]phenazine derivatives are promising scaffolds for the development of new anti-TB drugs, mainly focusing on the treatment of resistant TB cases., (© 2021 John Wiley & Sons A/S.)

We report the synthesis of 47 new quinone-based derivatives via click chemistry and their subsequent evaluation against cancer cell lines and the control L929 murine fibroblast cell line. These compounds combine two redox centers, such as an ortho -quinone/ para -quinone or quinones/selenium with the 1,2,3-triazole nucleus. Several of these compounds present IC 50 values below 0.5 μM in cancer cell lines with significantly lower cytotoxicity in the control cell line L929 and good selectivity index. Hence, our study confirms the use of a complete and very diverse range of quinone compounds with potential application against certain cancer cell lines., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Desulfonylative alkylation of N -tosyl-1,2,3-triazoles under metal-free conditions leading to β-triazolylenones is reported here. The present study encompasses the synthesis of triazoles with a new substitution pattern in a single step from cyclic 1,3-dicarbonyl compounds and N -tosyl triazole in moderate to high yields. Our synthesis takes place with complete regioselectivity as confirmed by crystallographic analysis which is rationalized by a suitable mechanistic proposal. This method provides an efficient, versatile and straightforward strategy towards the synthesis of new functionalized 1,2,3-triazoles., (Copyright © 2021, Pati et al.)

What are the roles of semantic and pragmatic processes in the interpretation of sentences in context? And how do we attain such interpretations when sentences are deemed indeterminate? Consider a sentence such as " Lisa began the book " which does not overtly express the activity that Lisa began doing with the book. Although it is believed that individuals compute a specified event to enrich the sentential representation - yielding, e.g., " began [reading] the book " - there is no evidence that a default event meaning is attained. Moreover, if indeterminate sentences are enriched, it is not clear where the information required to generate enriched interpretations come from. Experiment 1 showed that, in isolation, there is no default interpretation for indeterminate sentences. The experiment also showed that biasing contexts constrain event interpretations and improve plausibility judgments, suggesting that event representations for indeterminate sentences are generated by context. In Experiment 2, participants heard biasing discourse contexts and later falsely recognized foil sentences containing the biased events (" Lisa began reading the book ") at the same proportion and with the same confidence as the original indeterminate sentence (" Lisa began the book "). We suggest that indeterminate sentences trigger event-enriching inferences but only in sufficiently constraining contexts. We also suggest that indeterminate sentences create two memory traces, one for the proposition consistent with the denotational, compositional meaning, and another for the proposition that is enriched pragmatically over time., 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 © 2021 Riven and de Almeida.)

We investigated the representation and breakdown of verb knowledge employing different syntactic and semantic classes of verbs in a group of individuals with probable Alzheimer's Disease (pAD). In an action naming task with coloured photographs (Fiez & Tranel, 1997. Standardized stimuli and procedures for investigating the retrieval of lexical and conceptual knowledge for action. Memory and Cognition , 25(4), 543-569. https://doi.org/10.3758/BF03201129), pAD individuals were impaired for naming actions compared to objects. Verb tense was also affected, with simple-past (e.g., chopped ) being more difficult to name than the gerundial form (e.g., chopping ). Employing action-naming with short movies depicting events and states, we contrasted three verb classes based on their hypothetical structural and semantic/conceptual properties: argument structure, thematic structure, and conceptual templates. The three classes were: causatives ( peel ), verbs of perception ( hear ), and verbs of motion ( run ) Overall, results suggest that individuals with pAD are selectively impaired for verb tense and thematic assignment, but not conceptual-template complexity. Methodologically, we also show that dynamic scenes are more ecologically valid than static scenes to probe verb knowledge in AD.

Over the past few decades, regioselective catalytic C-H functionalization has provided an attractive tool for unique retrosynthetic disconnections. The advancement of the directing group strategy in metal catalyzed synthetic transformation has contributed significantly to the incorporation of a wide range of functionalization reactions in both aromatic systems and aliphatic backbones. However, the extensive utilization of these methodologies depends on the ease of removal of the directing group to restore the free functional group. In this review, we have summarised the reported approaches for removing/modifying versatile directing groups.

Double ruthenium(II)-catalyzed alkyne annulations of quinones were accomplished. Thus, a strategy is reported that provides step-economical access to valuable quinones with a wide range of applications. C-H/N-H activations for alkyne annulations of naphthoquinones provided challenging polycyclic quinoidal compounds by forming four new bonds in one step. The singular power of the thus-obtained compounds was reflected by their antileukemic activity., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Rhodium-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulations and nitroalkene reactions have been employed for the synthesis of 56 quinone-based compounds. These were evaluated against Trypanosoma cruzi, the parasite that causes Chagas disease. The reactions described here are part of a program that aims to utilize modern, versatile and efficient synthetic methods for the one or two step preparation of trypanocidal compounds. We have identified 9 compounds with potent activity against the parasite; 3 of these were 30-fold more potent than benznidazole (Bz), a drug used for the treatment of Chagas disease. This article provides a comprehensive outline of reactions involving over 120 compounds aimed at the discovery of new quinone-based frameworks with activity against T. cruzi., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ortho -Quinones represent a special class of redox active compounds associated with a spectrum of pronounced biological activities, including selective cytotoxicity and antimicrobial actions. The modification of the quinone ring by simple nitrogen and sulphur substitutions leads to several new classes of compounds with their own, distinct redox behaviour and equally distinct activities against cancer cell lines and Trypanosoma cruzi . Some of the compounds investigated show activity against T. cruzi at concentrations of 24.3 and 65.6 μM with a selectivity index of around 1. These results demonstrate that simple chemical modifications on the ortho -quinone ring system, in particular, by heteroatoms such as nitrogen and sulphur, transform these simple redox molecules into powerful cytotoxic agents with considerable "potential", not only in synthesis and electrochemistry, but also, in a broader sense, in health sciences., (This journal is © The Royal Society of Chemistry 2020.)

Through a genetic screen in zebrafish, we identified a mutant with disruption to myelin in both the CNS and PNS caused by a mutation in a previously uncharacterized gene, slc12a2b, predicted to encode a Na+, K+, and Cl- (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited a severe and progressive pathology in the PNS, characterized by dysmyelination and swelling of the periaxonal space at the axon-myelin interface. Cell-type-specific loss of slc12a2b/NKCC1b in either neurons or myelinating Schwann cells recapitulated these pathologies. Given that NKCC1 is critical for ion homeostasis, we asked whether the disruption to myelinated axons in slc12a2b/NKCC1b mutants is affected by neuronal activity. Strikingly, we found that blocking neuronal activity completely prevented and could even rescue the pathology in slc12a2b/NKCC1b mutants. Together, our data indicate that NKCC1b is required to maintain neuronal activity-related solute homeostasis at the axon-myelin interface, and the integrity of myelinated axons., (© 2020 Marshall-Phelps et al.)

Objective: This study aimed to assess the safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccination in childhood-onset systemic lupus erythematosus (cSLE) patients., Methods: Volunteer cSLE patients aged 9-20 years and healthy controls (HC) were enrolled to receive a two- or three-dose qHPV vaccination schedule from March 2014 to March 2016. Study visits were performed before the first dose, one month after the second and third doses and one year after the first dose. In each study visit, disease activity and adverse events following vaccination were analyzed, and a serum sample was collected for testing antibody concentrations. Participant recruitment was conducted in 15 Brazilian paediatric rheumatology units. Of the 256 cSLE patients included, 210 completed the two- or three-dose schedules; 15 had previously received one dose, and 18 had received two doses of the vaccine. The analysis was based on intention-to-treat so that participants who did not complete the entire study protocol were also included., Results: No severe adverse events were related to the vaccination. Disease activity was generally low and remained stable or even improved. The HC presented 100% seropositivity to HPV16 and HPV18, whereas the two- and three-dose cSLE groups presented 93% and 83% versus 97% and 91%, respectively. One year after the first dose, seropositivity of the three-dose cSLE group was 91% to HPV16 and 84% to HPV18., Conclusions: HPV vaccination in cSLE patients is safe and immunogenic. Since the seropositivity to HPV16 and HPV18 was higher for the three-dose schedule group, this regimen should be recommended for cSLE patients.

Selection of the correct targets for myelination and regulation of myelin sheath growth are essential for central nervous system (CNS) formation and function. Through a genetic screen in zebrafish and complementary analyses in mice, we find that loss of oligodendrocyte Neurofascin leads to mistargeting of myelin to cell bodies, without affecting targeting to axons. In addition, loss of Neurofascin reduces CNS myelination by impairing myelin sheath growth. Time-lapse imaging reveals that the distinct myelinating processes of individual oligodendrocytes can engage in target selection and sheath growth at the same time and that Neurofascin concomitantly regulates targeting and growth. Disruption to Caspr, the neuronal binding partner of oligodendrocyte Neurofascin, also impairs myelin sheath growth, likely reflecting its association in an adhesion complex at the axon-glial interface with Neurofascin. Caspr does not, however, affect myelin targeting, further indicating that Neurofascin independently regulates distinct aspects of CNS myelination by individual oligodendrocytes in vivo., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Two experiments evaluated the effects of injectable trace minerals (ITM) administered 11 d before artificial insemination (AI) on body weight (BW), body condition score (BCS), ovarian structures, pregnancy rate, and antioxidant response of Nellore cows. In Experiment 1, 20 multiparous cows were assigned to one of two treatments: subcutaneous injection (6 mL/cow; 11 d before AI) of saline solution or ITM (60, 10, 5, and 15 mg/mL of Zn, Mn, Se and Cu, respectively) and BW, BCS, ovarian structures and blood were evaluated. In Experiment 2, 1,144 multiparous cows were assigned to same treatments described in Experiment 1 and pregnancy rate on d 30 was evaluated. In Experiment 1, ITM did not affect (P ≥  0.23) BW, dominant follicle size, ovulation rate, and plasma concentrations of haptoglobin, ceruloplasmin and progesterone (P4). The ITM treatment tended to increase (P =  0.06) cow BCS and reduce (P ≤  0.06) corpus luteum (CL) diameter and volume. Furthermore, ITM treatment tended to increase (P =  0.06) plasma concentrations of SOD and increased (P =  0.007) GSH-Px compared with saline injection. In Experiment 2, ITM treatment tended (P =  0.06) to increase pregnancy rate of cows with BCS ≤ 5.0 but not cows with BCS > 5.0 (P =  0.99). The ITM treatment did not alter BW, plasma P4, and acute phase response, but enhanced plasma concentrations of antioxidant enzymes, and tended to enhance BCS and pregnancy rates to AI of cows with BCS ≤ 5.0, even though there was a smaller corpus luteum size., (Copyright © 2019 Elsevier B.V. All rights reserved.)

As Macnamara (1978) once asked, how can we talk about what we see? We report on a study manipulating realistic dynamic scenes and sentences aiming to understand the interaction between linguistic and visual representations in real-world situations. Specifically, we monitored participants' eye movements as they watched video clips of everyday scenes while listening to sentences describing these scenes. We manipulated two main variables. The first was the semantic class of the verb in the sentence and the second was the action/motion of the agent in the unfolding event. The sentences employed two verb classes-causatives (e.g., break ) and perception/psychological (e.g., notice )-which impose different constraints on the nouns that serve as their grammatical complements. The scenes depicted events in which agents either moved toward a target object (always the referent of the verb-complement noun), away from it, or remained neutral performing a given activity (such as cooking). Scenes and sentences were synchronized such that the verb onset corresponded to the first video frame of the agent motion toward or away from the object. Results show effects of agent motion but weak verb-semantic restrictions: causatives draw more attention to potential referents of their grammatical complements than perception verbs only when the agent moves toward the target object. Crucially, we found no anticipatory verb-driven eye movements toward the target object, contrary to studies using non-naturalistic and static scenes. We propose a model in which linguistic and visual computations in real-world situations occur largely independent of each other during the early moments of perceptual input, but rapidly interact at a central, conceptual system using a common, propositional code. Implications for language use in real world contexts are discussed., (Copyright © 2019 de Almeida, Di Nardo, Antal and von Grünau.)

The objective was to evaluate vaginal temperature as a thermoregulatory response of Nellore heifers under different microclimatic conditions. The study was conducted during one year in an experimental area located at 54°37'W, 20°27'S, and 530 m of altitude in Brazil. Twenty-four Nellore females were reared in integrated crop-livestock-forestry systems with different shading patterns. The randomized complete block experimental design was utilized with a sub subdivided plots scheme, with plot corresponding to the production systems, the subplot to the season of the year, and the sub subplot, the hours of the day. To characterize the microclimate, data regarding air and black globe temperatures, and air relative humidity were collected and from them, temperature-humidity index was calculated. Vaginal temperature was obtained by using a bottom-type temperature logger (i-button) attached to an adapted intravaginal device. The black-globe temperature explained the variation on vaginal temperature. Increases on vaginal temperature were only observed, on average, two hours after the increase of black-globe temperature. The microclimatic conditions found in the systems, resulting from the various tree densities, modify the vaginal temperature in different degrees, demonstrating that the shading effect is not always accompanied by improvements in thermal comfort. The system with intermediate density showed a better microclimatic condition and, consequently, a lower increase in vaginal temperature. The interaction between air temperature, humidity and solar radiation resulted in adverse environmental conditions, however, Nellore heifers showed good adaptation to the environment. In conclusion, vaginal temperature is a good indicator to evaluate the thermoregulatory response in Nellore heifers., Competing Interests: The authors have declared that no competing interests exist.

Prehospital emergency telephone triages are mechanisms to verify the appropriate need for care in an emergency call by telephone. Considering the high rates of trauma and clinical cases that need prehospital care, the importance of knowing how the services that send rescue teams can guarantee improved care is highlighted. The objective of this study was to characterize the services that support effective telephone triage. Literature review was conducted in 6 phases to answer the following question: How can prehospital emergency telephone triage be performed? To search for primary studies, we used specific search strategies in the databases: LILaCs, PubMed, CINAHL, LISA, ISTA, and SCOPUS. The sample consisted of 23 studies whose information was extracted using a validated tool. Among the selected studies, 2 come from CINAHL, 2 from LISA, 4 from PubMed, 1 from ISTA, and 14 from SCOPUS, which were published between 2006 and 2016 in 17 different journals with varying types of scopes and originated from 13 countries on 3 distinct continents. The articles were nonexperimental and indicated the broad use of software constructed to support the telephone triage. The prehospital emergency telephone triages are frequently performed to identify the event, deduct the need for support, and prioritize those calls that require a rescue team. They should take place with the support of institutional protocols and technological support to guarantee dynamic data and constant training of the ambulance dispatchers.

Zebrafish are now well established as the preeminent vertebrate model with which to carry out gene discovery/forward genetic screens to identify the molecular genetic basis of biological processes. Gene discovery screens in zebrafish have already provided novel insight into mechanisms of glial cell development and function. The vast majority of genetic screens in zebrafish are based around a three generation screen that starts with the random induction of mutations in adult males using the chemical mutagen ENU. Here we outline the methods that underlie this type of screen, detailing each step, from ENU mutagenesis, through the breeding schemes required to recover homozygous mutant animals in subsequent generations, the screening procedure itself, with a focus on the analysis of myelinating glia, and the subsequent confirmation of mutant phenotypes.

In the central nervous system, oligodendrocyte-lineage cells and myelination can adapt to physiological brain activity. Since myelin can in turn regulate neuronal function, such "adaptive" myelination has been proposed as a form of nervous system plasticity, implicated in learning and cognition. The molecular and cellular mechanisms underlying adaptive myelination and its functional consequences remain to be fully defined, partly because it remains challenging to manipulate activity and monitor myelination over time in vivo at single-cell resolution, in a model that would also allow examination of the functional output of individual neurons and circuits. Here, we describe a workflow to manipulate neuronal activity and to assess oligodendrocyte-lineage cell dynamics and myelination in larval zebrafish, a vertebrate animal model that is ideal for live imaging and amenable to genetic discovery, and that has well-characterized neuronal circuits with myelinated axons.

The wrapping of myelin around axons is crucial for the development and function of the central nervous system (CNS) of vertebrates, greatly regulating the conduction of action potentials. Oligodendrocytes, the myelinating glia of the CNS, have an intrinsic tendency to wrap myelin around any permissive structure in vitro , but in vivo , myelin is targeted with remarkable specificity only to certain axons. Despite the importance of myelination, the mechanisms by which oligodendrocytes navigate a complex milieu that includes many types of cells and their cellular projections and select only certain axons for myelination remains incompletely understood. In this Mini-review, I highlight recent studies that shed light on the molecular and cellular rules governing CNS myelin targeting.

Objective: To evaluate symptomatic polyautoimmunity (PA) at childhood-onset systemic lupus erythematosus(cSLE) diagnosis, and its association with demographic data, disease activity, clinical manifestations and laboratorial abnormalities in a large Brazilian cSLE population., Methods: A multicenter retrospective study was performed in 1463 cSLE(ACR criteria) patients from 27 Pediatric Rheumatology services. Symptomatic PA was defined according to the presence of more than one concomitant autoimmune disease(AD) and symptomatic multiple autoimmune syndrome(MAS) was defined as three or more AD. An investigator meeting was held to define the protocol. Demographic data, SLICC classification criteria and SLEDAI-2K were evaluated., Results: At cSLE diagnosis symptomatic PA was observed in 144/1463(9.8%) and symptomatic MAS occurred in solely 10/1463(0.7%). In the former group the more frequently observed associated AD were Hashimoto thyroiditis n = 42/144(29%), antiphospholipid syndrome n = 42/144(29%), autoimmune hepatitis n = 26/144(18%) and type 1 diabetes mellitus n = 23/144(15.9%). Further comparisons between cSLE patients with and without PA showed a higher median age(p = 0.016) and lower mean SLICC criteria (p = 0.039) in those with PA. Additionally, these cSLE patients had less renal involvement(35% vs. 44%, p = 0.038) and red blood cell cast(6% vs. 12%, p = 0.042) and more antiphospholipid antibodies(29% vs. 15%, p < 0.0001)., Conclusions: Approximately 10% of cSLE had symptomatic PA at diagnosis, particularly endocrine autoimmune disorders and antiphospholipid syndrome. Lupus was characterized by a mild disease onset and MAS was infrequently evidenced. Further studies are necessary to determine if this subgroup of cSLE patients have a distinct genetic background with a less severe disease and a better long-term outcome., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Morita-Baylis-Hillman acetates and α-bromonitroalkenes have been employed in cascade reactions with lawsone and 2-aminonaphthoquinone for the one-pot synthesis of heterocycle fused quinonoid compounds. The reactions reported here utilized the 1,3-binucleophilic potential of hydroxy- and aminonaphthoquinones and the 1,2/1,3-bielectrophilic potential of bromonitroalkenes and Morita-Baylis-Hillman acetates for the synthesis of pyrrole and furan fused naphthoquinones. The synthesized compounds were evaluated against HCT-116 (human colon carcinoma cells), PC3 (human prostate cancer cells), HL-60 (human promyelocytic leukemia cells), SF295 (human glioblastoma cells) and NCI-H460 (human lung cancer cells) and exhibited antitumor activity with IC 50 values as low as < 2 μM. Selected compounds were also evaluated against OVCAR-8 (ovary), MX-1 (breast) and JURKAT (leukemia) cell lines. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC) and L929 cells., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The correct targeting of myelin is essential for nervous system formation and function. Oligodendrocytes in the CNS myelinate some axons, but not others, and do not myelinate structures including cell bodies and dendrites [1]. Recent studies indicate that extrinsic signals, such as neuronal activity [2, 3] and cell adhesion molecules [4], can bias myelination toward some axons and away from cell bodies and dendrites, indicating that, in vivo, neuronal and axonal cues regulate myelin targeting. In vitro, however, oligodendrocytes have an intrinsic propensity to myelinate [5-7] and can promiscuously wrap inert synthetic structures resembling neuronal processes [8, 9] or cell bodies [4]. A current therapeutic goal for the treatment of demyelinating diseases is to greatly promote oligodendrogenesis [10-13]; thus, it is important to test how accurately extrinsic signals regulate the oligodendrocyte's intrinsic program of myelination in vivo. Here, we test the hypothesis that neurons regulate myelination with sufficient stringency to always ensure correct targeting. Surprisingly, however, we find that myelin targeting in vivo is not very stringent and that mistargeting occurs readily when oligodendrocyte and myelin supply exceed axonal demand. We find that myelin is mistargeted to neuronal cell bodies in zebrafish mutants with fewer axons and independently in drug-treated zebrafish with increased oligodendrogenesis. Additionally, by increasing myelin production of oligodendrocytes in zebrafish and mice, we find that excess myelin is also inappropriately targeted to cell bodies. Our results suggest that balancing oligodendrocyte-intrinsic programs of myelin supply with axonal demand is essential for correct myelin targeting in vivo and highlight potential liabilities of strongly promoting oligodendrogenesis., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Brazilian Portuguese language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 231 JIA patients (14.7% systemic, 43.3% oligoarticular, 22.5% RF negative polyarthritis, 19.5% other categories) and 72 healthy children, were enrolled in three centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Brazilian Portuguese version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Studies of activity-driven nervous system plasticity have primarily focused on the gray matter. However, MRI-based imaging studies have shown that white matter, primarily composed of myelinated axons, can also be dynamically regulated by activity of the healthy brain. Myelination in the CNS is an ongoing process that starts around birth and continues throughout life. Myelin in the CNS is generated by oligodendrocytes and recent evidence has shown that many aspects of oligodendrocyte development and myelination can be modulated by extrinsic signals including neuronal activity. Because modulation of myelin can, in turn, affect several aspects of conduction, the concept has emerged that activity-regulated myelination represents an important form of nervous system plasticity. Here we review our increasing understanding of how neuronal activity regulates oligodendrocytes and myelinated axons in vivo , with a focus on the timing of relevant processes. We highlight the observations that neuronal activity can rapidly tune axonal diameter, promote re-entry of oligodendrocyte progenitor cells into the cell cycle, or drive their direct differentiation into oligodendrocytes. We suggest that activity-regulated myelin formation and remodeling that significantly change axonal conduction properties are most likely to occur over timescales of days to weeks. Finally, we propose that precise fine-tuning of conduction along already-myelinated axons may also be mediated by alterations to the axon itself. We conclude that future studies need to analyze activity-driven adaptations to both axons and their myelin sheaths to fully understand how myelinated axon plasticity contributes to neuronal circuit formation and function., (Copyright © 2017 the authors 0270-6474/17/3710023-12$15.00/0.)