Examining the cognitive costs of counterfactual language comprehension: Evidence from ERPs

Recent empirical research suggests that understanding a counterfactual event (e.g. ‘If Josie had revised, she would have passed her exams’) activates mental representations of both the factual and counterfactual versions of events. However, it remains unclear when readers switch between these models during comprehension, and whether representing multiple ‘worlds’ is cognitively effortful. This paper reports two ERP studies where participants read contexts that set up a factual or counterfactual scenario, followed by a second sentence describing a consequence of this event. Critically, this sentence included a noun that was either consistent or inconsistent with the preceding context, and either included a modal verb to indicate reference to the counterfactual-world or not (thus referring to the factual-world). Experiment 2 used adapted versions of the materials used in Experiment 1 to examine the degree to which representing multiple versions of a counterfactual situation makes heavy demands on cognitive resources by measuring individuals’ working memory capacity. Results showed that when reference to the counterfactual-world was maintained by the ongoing discourse, readers correctly interpreted events according to the counterfactual-world (i.e. showed larger N400 for inconsistent than consistent words). In contrast, when cues referred back to the factual-world, readers showed no difference between consistent and inconsistent critical words, suggesting that they simultaneously compared information against both possible worlds. These results support previous dual-representation accounts for counterfactuals, and provide new evidence that linguistic cues can guide the reader in selecting which world model to evaluate incoming information against. Crucially, we reveal evidence that maintaining and updating a hypothetical model over time relies upon the availability of cognitive resources

The dynamic relationship between pain, depression and cognitive function in a sample of newly diagnosed arthritic adults: a cross-lagged panel model

Background: Pain and depression are common in the population and co-morbid with each other. Both are also predictive of one another other, and are also associated with cognitive function; people who are in greater pain and more depressed respectively perform less well on tests of cognitive function. It has been argued that pain might cause deterioration in cognitive function, as well as better cognitive function earlier in life might be a protective factor against the emergence of disease. When looking at the dynamic relationship between these in chronic diseases, studying samples that already have advanced disease progression often confounds this relationship. Methods: Using data from waves 1 to 3 of the English Longitudinal Study of Ageing (ELSA) (n = 516), we examined the interplay between pain, cognitive function and depression in a subsample of respondents reporting their diagnosis of arthritis at Wave 2 of the ELSA using cross-lagged panel models.Results: The models showed that pain, cognitive function and depression at wave 1, prior to diagnosis, predict pain at wave 2, and that pain at wave 1 predicts depression at wave 2. Pain and depression at wave 2 predict cognitive function at wave 3. Conclusions: The results indicate that better cognitive function might be protective against the emergence of pain prior to an arthritis diagnosis, but cognitive function is subsequently impaired by pain and depression. Furthermore, higher depression predicts lower cognitive function, but not vice versa. This is discussed in the context of the emerging importance of inflammation in depression

Disease activity flares and pain flares in an early rheumatoid arthritis inception cohort; characteristics, antecedents and sequelae

© 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: RA flares are common and disabling. They are described in terms of worsening inflammation but pain and inflammation are often discordant. To inform treatment decisions, we investigated whether inflammatory and pain flares are discrete entities. Methods: People from the Early RA Network (ERAN) cohort were assessed annually up to 11 years after presentation (n = 719, 3703 person-years of follow up). Flare events were defined in 2 different ways that were analysed in parallel; DAS28 or Pain Flares. DAS28 Flares satisfied OMERACT flare criteria of increases in DAS28 since the previous assessment (≥1.2 points if active RA or ≥ 0.6 points if inactive RA). A ≥ 4.8-point worsening of SF36-Bodily Pain score defined Pain Flares. The first documented episode of each of DAS28 and Pain Flare in each person was analysed. Subgroups within DAS28 and Pain Flares were determined using Latent Class Analysis. Clinical course was compared between flare subgroups. Results: DAS28 (45%) and Pain Flares (52%) were each common but usually discordant, with 60% of participants in DAS28 Flare not concurrently in Pain Flare, and 64% of those in Pain Flare not concurrently in DAS28 Flare. Three discrete DAS28 Flare subgroups were identified. One was characterised by increases in tender/swollen joint counts (14.4%), a second by increases in symptoms (13.1%), and a third displayed lower flare severity (72.5%). Two discrete Pain Flare subgroups were identified. One occurred following low disease activity and symptoms (88.6%), and the other occurred on the background of ongoing active disease and pain (11.4%). Despite the observed differences between DAS28 and Pain Flares, each was associated with increased disability which persisted beyond the flare episode. Conclusion: Flares are both common and heterogeneous in people with RA. Furthermore our findings indicate that for some patients there is a discordance between inflammation and pain in flare events. This discrete flare subgroups might reflect different underlying inflammation and pain mechanisms. Treatments addressing different mechanisms might be required to reduce persistent disability after DAS28 and Pain Flares.Peer reviewedFinal Published versio

Linear programming can help identify practical solutions to improve the nutritional quality of food aid.

OBJECTIVES: To assess the nutritional quality of food aid delivered by food banks in France and to identify practical modifications to improve it. DESIGN: National-level data were collected for all food aid distributed by French food banks in 2004, and its nutrient content per 2000 kcal was estimated and compared with French recommendations for adults. Starting with the actual donation and allowing new foods into the food aid donation, linear programming was used to identify the minimum changes required in the actual donation to achieve the French recommendations. RESULTS: French food-bank-delivered food aid does not achieve the French recommendations for dietary fibre, ascorbic acid, vitamin D, folate, magnesium, docosahexaenoic acid, alpha-linolenic acid and the percentage of energy from saturated fatty acids. Linear programming analysis showed that these recommendations are achievable if more fruits, vegetables, legumes and fish were collected and less cheese, refined cereals and foods rich in fat, sugar and/or salt. In addition, new foods not previously collected are needed, particularly nuts, wholemeal bread and rapeseed oil. These changes increased the total edible weight (42%) and economic value (55%) of the food aid donation, with one-third of its edible weight coming from fruits and vegetables, one-third from staples, one-quarter from dairy products and approximately a tenth from meat/fish/eggs. CONCLUSIONS: Important changes in the types and amounts of food collected will improve the nutritional quality of food-bank-delivered food aid in France. Such changes are recommended to improve the diets of deprived French populations

AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity

Characterization of DNA binding, transcriptional activation, and regulated nuclear association of recombinant human NFATp

BACKGROUND: NFATp is one member of a family of transcriptional activators whose nuclear accumulation and hence transcriptional activity is regulated in mammalian cells. Human NFATp exists as a phosphoprotein in the cytoplasm of naive T cells. Upon antigen stimulation, NFATp is dephosphorylated, accumulates in nuclei, and functions to regulate transcription of genes including those encoding cytokines. While the properties of the DNA binding domain of NFATp have been investigated in detail, biochemical studies of the transcriptional activation and regulated association with nuclei have remained unexplored because of a lack of full length, purified recombinant NFATp. RESULTS: We developed methods for expressing and purifying full length recombinant human NFATp that has all of the properties known to be associated with native NFATp. The recombinant NFATp binds DNA on its own and cooperatively with AP-1 proteins, activates transcription in vitro, is phosphorylated, can be dephosphorylated by calcineurin, and exhibits regulated association with nuclei in vitro. Importantly, activation by recombinant NFATp in a reconstituted transcription system required regions of the protein outside of the central DNA binding domain. CONCLUSIONS: We conclude that NFATp is a bona fide transcriptional activator. Moreover, the reagents and methods that we developed will facilitate future studies on the mechanisms of transcriptional activation and nuclear accumulation by NFATp, a member of an important family of transcriptional regulatory proteins

Regarding Pilot Usage of Display Technologies for Improving Awareness of Aircraft System States

ed systems and the procedures for ng in complexity. This interacting trend places a larger burden on pilots to manage increasing amounts of information and to understand system interactions. The result is an increase in the likelihood of loss of airplane state awareness (ASA). One way to gain more insight into this issue is through experimentation using objective measures of visual behavior. This study summarizes an analysis of oculometer data obtained during a high-fidelity flight simulation study that included a variety of complex pilot-system interactions that occur in current flight decks, as well as several planned for the next generation air transportation system. The study was comprised of various scenarios designed to induce low and high energy aircraft states coupled with other emulated causal factors in recent accidents. Three different display technologies were evaluated in this recent pilot-in-the-loop study conducted at NASA Langley Research Center. These technologies include a stall recovery guidance algorithm and display concept, an enhanced airspeed control indication of when the automation is no longer actively controlling airspeed, and enhanced synoptic diagrams with corresponding simplified electronic interactive checklists. Multiple data analyses were performed to understand how the 26 participating airline pilots were observing ASA-related information provided during different stag specific events within these stages

Outcomes of elective induction of labour compared with expectant management: population based study

Objective To determine neonatal outcomes (perinatal mortality and special care unit admission) and maternal outcomes (mode of delivery, delivery complications) of elective induction of labour compared with expectant management

Exploiting Connections for Viral Replication.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the COVID-19 (coronavirus disease 2019) pandemic, is a positive strand RNA (+RNA) virus. Like other +RNA viruses, SARS-CoV-2 is dependent on host cell metabolic machinery to survive and replicate, remodeling cellular membranes to generate sites of viral replication. Viral RNA-containing double-membrane vesicles (DMVs) are a striking feature of +RNA viral replication and are abundant in SARS-CoV-2-infected cells. Their generation involves rewiring of host lipid metabolism, including lipid biosynthetic pathways. Viruses can also redirect lipids from host cell organelles; lipid exchange at membrane contact sites, where the membranes of adjacent organelles are in close apposition, has been implicated in the replication of several +RNA viruses. Here we review current understanding of DMV biogenesis. With a focus on the exploitation of contact site machinery by +RNA viruses to generate replication organelles, we discuss evidence that similar mechanisms support SARS-CoV-2 replication, protecting its RNA from the host cell immune response