Functional Characterization of Plasmodium falciparum TATA-box binding-like Protein (PfTLP)

Plasmodium falciparum, the deadliest strain of human malaria, affected 200 million people and resulted in several hundred thousand deaths in 2017 (World Health Organization, 2018). A better understanding of the mechanisms of P. falciparum gene regulation can open novel avenues for the development of much needed new drugs. A key step in eukaryotic gene regulation is the process of transcription, which is largely uncharacterized in Plasmodium. Bioinformatic analysis identified putatuve P. falciparum orthologues of RNA polymerase II general transcription factors (Bing, 2014; Milton, 2017), including a TATA box-binding-like protein, PfTLP. Bioinformatic analysis suggested that PfTLP is a TRF2-type TBP-like protein. However, PfTLP differs in several aspects from previously characterized TRF2-type proteins. These differences are thought to be Plasmodium specific adaptations to the parasite’s intricate life cycle and AT-rich genome. This study investigates two Plasmodium-specific features of PfTLP. Firstly, DNA binding by eukaryotic TATA-box binding protein (TBP) is mediated by four evolutionary conserved phenylalanine residues, two of which intercalate into the DNA. These residues are absent in previously characterized TRF2-type TLPs, and consistent with this, these proteins lack detectable DNA binding activity (Duttke et al., 2014). In contrast, PfTLP, a TRF2-type TLP, has DNA binding activity, and all four of the DNA binding phenylalanine residues are conserved (Bing, 2014; Milton, 2017). The importance of evolutionary conserved intercalating phenylalanine residues F60 and F283 was investigated by generating mutant PfTLP proteins, carrying alanine substitutions, and analysing their DNA-binding properties. The results suggest that while both phenylalanine residues are important for PfTLP DNA-binding, only F60 is critical for stabilization of PfTLP/DNA complexes. Secondly, PfTLP possesses two low-complexity or intrinsically disordered regions (LCR1 and 2), which are absent in TLPs from model eukaryotes. These regions are located at the same positions within the two quasi-symmetrical repeats of the TLP core structure and show a non-random compositional bias towards a limited set of amino acids. A growing body of evidence supports the idea that low complexity or intrinsically disordered proteins mediate liquid-liquid phase separation (LLPS) (Alberti et al., 2019; Brangwynne et al., 2009; Elbaum-Garfinkle et al., 2015; Nott et al., 2015). Bioinformatic analysis revealed that PfTLP LCRs are enriched in asparagine and lysine, and that these regions are well conserved throughout Plasmodium TLPs. PfTLP LCRs were fused to fluorescent proteins and the fusion proteins were functionally characterized in liquid-liquid phase separating assays. The results demonstrate that PfTLP LCR1 is capable of mediating LLPS, at least under certain conditions in vitro

Does Extreme Language Control Training Improve Cognitive Control? A Comparison of Professional Interpreters, L2 Teachers and Monolinguals

There is currently a lively debate in the literature whether bilingualism leads to enhanced cognitive control or not. Recent evidence suggests that knowledge of more than one language does not always suffice for the manifestation of a bilingual cognitive control advantage. As a result, ongoing research has focused on modalities of bilingual language use that may interact with the bilingual advantage. In this study, we explored the cognitive control performance of simultaneous interpreters. These highly proficient bilinguals comprehend information in one language while producing in the other language, which is a complex skill requiring high levels of language control. In a first experiment, we compared professional interpreters to monolinguals. Data were collected on interference suppression (flanker task), prepotent response inhibition (Simon task), and short-term memory (digit span task). The results showed that the professional interpreters performed similarly to the monolinguals on all measures. In Experiment 2, we compared professional interpreters to monolinguals and second language teachers. Data were collected on interference suppression (advanced flanker task), prepotent response inhibition (advanced flanker task), attention (advanced flanker task), short-term memory (Hebb repetition paradigm), and updating (n-back task). We found converging evidence for our finding that experience in interpreting may not lead to superior interference suppression, prepotent response inhibition, and short-term memory. In fact, our results showed that the professional interpreters performed similarly to both the monolinguals and the second language teachers on all tested cognitive control measures. We did, however, find anecdotal evidence for a (small) advantage in short-term memory for interpreters relative to monolinguals when analyzing composite scores of both experiments together. Taken together, the results of the current study suggest that interpreter experience does not necessarily lead to general cognitive control advantages. However, there may be small interpreter advantages in short-term memory, suggesting that this might be an important cognitive control aspect of simultaneous interpreting. The results are discussed in the light of ongoing debates about bilingual cognitive control advantages

Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS Consortium.

BACKGROUND The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic. METHODS For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere. FINDINGS Overall, 116 841 cases were analysed: 76 481 in 2018-19, before the pandemic, and 40 360 in 2020-21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40-0·55), H influenzae (0·51; 0·40-0·66) and N meningitidis (0·26; 0·21-0·31), while no significant changes were observed for S agalactiae (1·02; 0·75-1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145-55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories. INTERPRETATION COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies. FUNDING Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization

Cognitive control of language in the bilingual brain : behavioral and brain correlates in (a)typical populations

The majority of the world’s population is bilingual nowadays, meaning that they are able to communicate in at least two languages. One of the most remarkable scientific findings in research on bilingualism is that multiple languages are simultaneously active in the bilingual brain, but that this rarely leads to cross-language intrusions during communication (e.g., saying a word in French while the target language is English). This shows that bilinguals have a very effective language control system that enables them to confine their speech to the appropriate language. But how exactly do bilinguals manage to keep their languages separated if they are continuously active in parallel in their mind? This question has intrigued many researchers. There is currently a scientific debate about whether language control is a language-specific mechanism or rather part of domain-general cognitive control, which manages non-verbal goal-directed behavior. In this dissertation, we postulate that studying the interactions between bilingualism and language pathologies that are (partially) linked to a cognitive control impairment might offer another perspective to obtain a better understanding of bilingual language control. The findings reported here support the idea that bilingual language control is achieved by a domain-general cognitive control mechanism rather than being language-specific. They also offer a promising framework to further investigate the precise nature of bilingual language control.(PSYE - Sciences psychologiques et de l'éducation) -- UCL, 201

Serial-order learning impairment and hypersensitivity-to-interference in dyscalculia

In the context of heterogeneity, the different profiles of dyscalculia are still hypothetical. This study aims to link features of mathematical difficulties to certain potential etiologies. First, we wanted to test the hypothesis of a serial-order learning deficit in adults with dyscalculia. For this purpose we used a Hebb repetition learning task. Second, we wanted to explore a recent hypothesis according to which hypersensitivity-to-interference hampers the storage of arithmetic facts and leads to a particular profile of dyscalculia. We therefore used interfering and non-interfering repeated sequences in the Hebb paradigm. A final test was used to assess the memory trace of the non-interfering sequence and the capacity to manipulate it. In line with our predictions, we observed that people with dyscalculia who show good conceptual knowledge in mathematics but impaired arithmetic fluency suffer from increased sensitivity-to-interference compared to controls. Secondly, people with dyscalculia who show a deficit in a global mathematical test suffer from a serial-order learning deficit characterized by a slow learning and a quick degradation of the memory trace of the repeated sequence. A serial-order learning impairment could be one of the explanations for a basic numerical deficit, since it is necessary for the number-word sequence acquisition. Among the different profiles of dyscalculia, this study provides new evidence and refinement for two particular profiles.publisher: Elsevier articletitle: Serial-order learning impairment and hypersensitivity-to-interference in dyscalculia journaltitle: Cognition articlelink: http://dx.doi.org/10.1016/j.cognition.2015.07.007 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe

Serial-order learning impairment and hypersensitivity-to-interference in dyscalculia

In the context of heterogeneity, the different profiles of dyscalculia are still hypothetical. This study aims to link features of mathematical difficulties to certain potential etiologies. First, we wanted to test the hypothesis of a serial-order learning deficit in adults with dyscalculia. For this purpose we used a Hebb repetition learning task. Second, we wanted to explore a recent hypothesis according to which hypersensitivity-to-interference hampers the storage of arithmetic facts and leads to a particular profile of dyscalculia. We therefore used interfering and non-interfering repeated sequences in the Hebb paradigm. A final test was used to assess the memory trace of the non-interfering sequence and the capacity to manipulate it. In line with our predictions, we observed that people with dyscalculia who show good conceptual knowledge in mathematics but impaired arithmetic fluency suffer from increased sensitivity-to-interference compared to controls. Secondly, people with dyscalculia who show a deficit in a global mathematical test suffer from a serial-order learning deficit characterized by a slow learning and a quick degradation of the memory trace of the repeated sequence. A serial-order learning impairment could be one of the explanations for a basic numerical deficit, since it is necessary for the number-word sequence acquisition. Among the different profiles of dyscalculia, this study provides new evidence and refinement for two particular profile

Verbal and nonverbal cognitive control in bilinguals and interpreters

The present study explored the relation between language control and nonverbal cognitive control in different bilingual populations. We compared monolinguals, Dutch-French unbalanced bilinguals, balanced bilinguals, and interpreters on the Simon task (Simon & Rudell, 1967) and the Attention Network Test (ANT; Fan, McCandliss, Sommer, Raz, & Posner, 2002). All bilingual groups showed a smaller congruency effect in the Simon task than the monolingual group. They were also faster overall in the ANT. Furthermore, interpreters outperformed unbalanced, but not balanced, bilinguals in terms of overall accuracy on both tasks. In the ANT, the error congruency effect was significantly smaller for interpreters and balanced bilinguals. Using a measure of switching fluency in language production, this study also found direct evidence for a relation between language control and executive control. This relation was only observed in balanced bilinguals, where fluent switching was correlated with the Simon effect. These findings support the existence of a bilingual advantage and also indicate that different patterns of bilingual language use modulate the nature and extent of a cognitive control advantage in multilingual populations

Does extreme language control training improve cognitive control? A comparison of professional interpreters, L2 teachers and monolinguals

There is currently a lively debate in the literature about whether bilingualism leads to enhanced cognitive control or not. Recent evidence suggests that knowledge of more than one language does not always suffice for the manifestation of a bilingual cognitive control advantage. As a result, ongoing research has focused on modalities of bilingual language use that may interact with the bilingual advantage. In this study, we explored the cognitive control performance of simultaneous interpreters. These highly proficient bilinguals comprehend information in one language while producing in the other language, which is a complex skill requiring high levels of language control. In a first experiment, we compared professional interpreters to monolinguals. Data were collected on interference suppression, prepotent response inhibition, and working memory capacity, using the flanker task, the Simon task, and a digit span task, respectively. The results showed that the professional interpreters performed similarly to the monolinguals on all measures. In Experiment 2, we compared professional interpreters to monolinguals and second language teachers. Data were collected on interference suppression, prepotent response inhibition, attention, working memory capacity, and updating. These cognitive control measures were assessed using three computerized tasks: an advanced flanker task, a Hebb repetition paradigm, and an n-back task. We found converging evidence for our finding that experience in interpreting may not lead to superior interference suppression, prepotent response inhibition, and working memory capacity. In fact, our results showed that the professional interpreters performed similarly to both the monolinguals and the second language teachers on all tested cognitive control measures. We did however find evidence for a (small) advantage in working memory capacity for interpreters relative to monolinguals when analyzing composite scores of both experiments together. Taken together, the results of the current study suggest that interpreter experience does not necessarily lead to general cognitive control advantages. However, there may be small interpreter advantages in working memory capacity, suggesting that this might be an important cognitive control aspect of simultaneous interpreting. The results are discussed in the light of ongoing debates about bilingual cognitive control advantages