The Na/K pump hydrolyzes ATP to export three intracellular Na (Nai) as it imports two extracellular K (Ko) across animal plasma membranes. Within the protein, two ion-binding sites (sites I and II) can reciprocally bind Na or K, but a third site (site III) exclusively binds Na in a voltage-dependent fashion. In the absence of Nao and Ko, the pump passively imports protons, generating an inward current (IH). To elucidate the mechanisms of IH, we used voltage-clamp techniques to investigate the [H]o, [Na]o, and voltage dependence of IH in Na/K pumps from ventricular myocytes and in ouabain-resistant pumps expressed in Xenopus oocytes. Lowering pHo revealed that Ho both activates IH (in a voltage-dependent manner) and inhibits it (in a voltage-independent manner) by binding to different sites. Nao effects depend on pHo; at pHo where no Ho inhibition is observed, Nao inhibits IH at all concentrations, but when applied at pHo that inhibits pump-mediated current, low [Na]o activates IH and high [Na]o inhibits it. Our results demonstrate that IH is a property inherent to Na/K pumps, not linked to the oocyte expression environment, explains differences in the characteristics of IH previously reported in the literature, and supports a model in which 1), protons leak through site III; 2), binding of two Na or two protons to sites I and II inhibits proton transport; and 3), pumps with mixed Na/proton occupancy of sites I and II remain permeable to protons.

Relative meaning frequency is a critical factor to consider in studies of semantic ambiguity. In this work, we examined how this measure may change across the European and Rioplatense dialects of Spanish, as well as how the overall distributional properties differ between Spanish and English, using a computer-assisted norming approach based on dictionary definitions (Armstrong, Tokowicz, & Plaut, 2012). The results showed that the two dialects differ considerably in terms of the relative meaning frequencies of their constituent homonyms, and that the overall distributions of relative frequencies vary considerably across languages, as well. These results highlight the need for localized norms to design powerful studies of semantic ambiguity and suggest that dialectal differences may be responsible for some discrepant effects related to homonymy. In quantifying the reliability of the norms, we also established that as few as seven ratings are needed to converge on a highly stable set of ratings. This approach is therefore a very practical means of acquiring essential data in studies of semantic ambiguity, relative to past approaches, such as those based on the classification of free associates. The norms also present new possibilities for studying semantic ambiguity effects within and between populations who speak one or more languages. The norms and associated software are available for download at

Neuroimaging has undergone enormous progress during the last two and a half decades. The combination of neuroscientific methods and educational practice has become a focus of interdisciplinary research in order to answer more applied questions. In this realm, conditions that hamper learning success and have deleterious effects in the population – such as learning disorders (LD) – could especially profit from neuroimaging findings. At the moment, however, there is an ongoing debate about how far neuroscientific research can go to inform the practical work in educational settings. Here, we put forward a theoretical translational framework as a method of conducting neuroimaging and bridging it to education, with a main focus on dyscalculia and dyslexia. Our work seeks to represent a theoretical but mainly empirical guide on the benefits of neuroimaging, which can help people working with different aspects of LD, who need to act collaboratively to reach the full potential of neuroimaging. We provide possible ideas regarding how neuroimaging can inform LD at different levels within our multidirectional framework, i.e., mechanisms, diagnosis/prognosis, training/intervention, and community/education. In addition, we discuss methodological, conceptual, and structural limitations that need to be addressed by future research.

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Large scale word association datasets are both important tools used in psycholinguistics and used as models that capture meaning when considered as semantic networks. Here we present word association norms for Rioplatense Spanish, a variant spoken in Argentina and Uruguay. The norms were derived through a large-scale crowd-sourced continued word association task in which participants give three associations to a list of cue words. Covering over 13,000 words and +3.6M responses, it is currently the most extensive dataset available for Spanish. We compare the obtained dataset with previous studies in Dutch and English to investigate the role of grammatical gender and studies that used Iberian Spanish to test generalizability to other Spanish variants. Finally, we evaluated the validity of our data in word processing (lexical decision reaction times) and semantic (similarity judgment) tasks. Our results demonstrate that network measures such as in-degree provide a good prediction of lexical decision response times. Analyzing semantic similarity judgments, showed that results replicate and extend previous findings demonstrating that semantic similarity derived using spreading activation or spectral methods outperform word embeddings trained on text corpora.

Massive and timely screening of the student population for early signs of reading difficulties is needed to implement timely effective remediation of these difficulties. However, traditional approaches are costly and hard to apply. Here we present Lexiland, a tablet-based reading assessment tool for kindergarten and primary school children developed to be applied in school settings with minimal personnel intervention. Following a story line, players help a character of the game perform several tasks that measure different predictors of reading outcomes. Most of the tasks that usually involve a verbal response were switched to receptive tasks to demand a touch-screen response only. The tablet application was administered to a sample of N=616 5-yo kindergarten children and to a sub-sample of these children twice during the following two years (First and Second Grades). Applying logistic regression and cross-validation, we selected a reduced subset of tasks that can predict with great sensitivity and specificity, whether a five-year-old child will have reading difficulties by the end of first grade (sensitivity, 90% and specificity 76%) and two years later (sensitivity 90%, specificity, 61%). Importantly, Lexiland is a scalable tool to implement universal screening, given the increasing availability of devices able to run android and iOS applications.

a protonatable side chain in E2P-like conformations might allow shuttling of protons across the membrane. We therefore evaluated the role of three key carboxylates, E336 (TM4), E788 (TM5), and D935 (TM8), by mutating C113Y Xenopus pumps. Outward Na/K-pump current was practically abolished in E336Q(C113Y) or E336C(C113Y) pumps, but nonstoichiometric inward current at zero Ko and Nao (replaced by TMAo) was little altered, and was greatly augmented in high Nao. E788C(C113Y) pumps, on the other hand, like parent C113Y pumps, generated robust stoichiometric outward Na/K transport currents (voltage dependent in Nao, but not in TMAo), and little nonstoichiometric inward current in high Nao; but nonstoichiometric current in TMAo was dimin-ished~3-fold compared to parent C113Y pumps. In contrast, D935N(C113Y) pumps generated stoichiometric outward Na/K transport currents with altered voltage dependence that was similar in Nao or in TMAo, but inward nonstoichiometric current was nearly absent both in Nao and in TMAo, and was not augmented by lowering pH to 6 either in Nao and in TMAo. The D935 carboxylate thus seems uniquely required for the nonstoichiometric inward flow of protons through the Na/K-pump. [NIH HL36783].

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