Proactive reward in conflict tasks: Does it only enhance general performance or also modulate conflict effects?

In the present study, we investigated the influence of performance-contingent reward prospects on task performance across three visual conflict tasks with manual responses (Experiments 1 & 2: Simon and Stroop tasks; Experiment 3: Simon and Eriksen flanker task) using block-wise (Experiment 1) and trial-wise (Experiments 2 & 3) manipulations to signal the possibility of reward. Across all experiments, task performance (in reaction time and/or error rates) generally improved in reward compared with no-reward conditions in each conflict task. However, there was, if any, little evidence that the reward manipulation modulated the size of the mean conflict effects, and there was also no evidence for conflict-specific effects of reward when controlling for time-varying fluctuations in conflict processing via distributional analyses (delta plots). Thus, the results provide no evidence for conflict-specific accounts and instead favor performance-general accounts, where reward anticipation leads to overall performance improvements without affecting conflict effects. We discuss possible implications for how proactive control might modulate the interplay between target- and distractor-processing in conflict tasks.

Perceptual target discriminability modulates the Simon effect beyond the fading of distractor-based activation: Insights from delta plots and diffusion model analyses.

The visual Simon task is widely employed to explore the underlying mechanisms of sensorimotor processing in the presence of task-relevant (targets) and task-irrelevant (distracting) location information. Critically, the Simon effect is considered as an indicator of action-related interference resulting from distractor-based activation, which fades out over time. In this study, we tested whether attenuated Simon effects with slower task processing may be fully explained by the fading of distractor-based response activation. To that end, we selectively manipulated perceptual target discriminability by varying the ratio of differently colored dots within (Experiment 1) and between blocks (Experiment 2). According to pure fading activation accounts, the negative-going delta plots of the two discriminability conditions should overlap across the entire reaction time (RT) distribution. In contrast to this prediction, the negative-going DPs for the two discriminability conditions did not overlap in either experiment. Instead, the Simon effect was either consistently smaller (Experiment 1) or larger (Experiment 2) across the entire RT distribution in the easy condition compared to the hard condition. This result pattern indicates that perceptual target discriminability affected conflict resolution beyond the mere fading of distractor-based activation. Exploratory model-based analyses suggest a stronger processing of relevant perceptual information with more discriminable targets, which may counteract the influence of distracting location information. However, as the exact effects of discriminability on conflict processing seem to depend on variation mode (trialwise vs. blockwise), the importance of global strategic effects is also highlighted. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. RESULTS: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). CONCLUSIONS: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Seeding activity of human superoxide dismutase 1 aggregates in familial and sporadic amyotrophic lateral sclerosis postmortem neural tissues by real-time quaking-induced conversion.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report the development of a real-time quaking-induced conversion (RT-QuIC) seed amplification assay using a recombinant human SOD1 substrate to measure SOD1 seeding activity in postmortem spinal cord and motor cortex tissue from persons with different ALS etiologies. Our SOD1 RT-QuIC assay detected SOD1 seeds in motor cortex and spinal cord dilutions down to 10-5. Importantly, we detected SOD1 seeding activity in specimens from both sporadic and familial ALS cases, with the latter having mutations in either their SOD1 or C9ORF72 genes. Analyses of RT-QuIC parameters indicated similar lag phases in spinal cords of sporadic and familial ALS patients, but higher ThT fluorescence maxima by SOD1 familial ALS specimens and sporadic ALS thoracic cord specimens. For a subset of sporadic ALS patients, motor cortex and spinal cords were examined, with seeding activity in both anatomical regions. Our results suggest SOD1 seeds are in ALS patient neural tissues not linked to SOD1 mutation, suggesting that SOD1 seeding activity may be a promising biomarker, particularly in sporadic ALS cases for whom genetic testing is uninformative.

Shaping Perceptions and Inspiring Future Neurosurgeons: The Value of a Hands-On Simulated Aneurysm Clipping Workshops at a Student-Organized Neurosurgical Conference.

Objective Early exposure to niche specialities, like neurosurgery, is essential to inform decisions about future training in these specialities. This study assesses the impact of a hands-on simulated aneurysm clipping workshop on medical students' and junior doctors' perceptions of neurosurgery at a student-organized neurosurgical conference. Methods Ninety-six delegates were sampled from a hands-on workshop involving hydrogel three-dimensional printed aneurysms clipping using surgical microscopes. Consultant neurosurgeons facilitated the workshop. Changes in delegates' perceptions of neurosurgery were collected using Likert scale and free-text responses postconference. Results Postworkshop, 82% of participants reported a positive impact on their perception of neurosurgery. Thematic analysis revealed that delegates valued the hands-on experience, exposure to microsurgery, and interactions with consultant neurosurgeons. Thirty-six of the 96 delegates (37.5%) expressed that the workshop dispelled preconceived fears surrounding neurosurgery and improved understanding of a neurosurgeon's day-to-day tasks. Several delegates initially apprehensive about neurosurgery were now considering it as a career. Conclusion Hands-on simulated workshops can effectively influence medical students' and junior doctors' perceptions of neurosurgery, providing valuable exposure to the specialty. By providing a valuable and immersive introduction to the specialty, these workshops can help to dispel misconceptions, fears, and apprehensions associated with neurosurgery, allowing them to consider the specialty to a greater degree than before. This study of a one-time workshop cannot effectively establish its long-term impact on said perceptions, however.

Taboo language across the globe: A multi-lab study.

The use of taboo words represents one of the most common and arguably universal linguistic behaviors, fulfilling a wide range of psychological and social functions. However, in the scientific literature, taboo language is poorly characterized, and how it is realized in different languages and populations remains largely unexplored. Here we provide a database of taboo words, collected from different linguistic communities (Study 1, N = 1046), along with their speaker-centered semantic characterization (Study 2, N = 455 for each of six rating dimensions), covering 13 languages and 17 countries from all five permanently inhabited continents. Our results show that, in all languages, taboo words are mainly characterized by extremely low valence and high arousal, and very low written frequency. However, a significant amount of cross-country variability in words' tabooness and offensiveness proves the importance of community-specific sociocultural knowledge in the study of taboo language.

The temporal dynamics of task processing and choice in a novel multitasking paradigm.

This study investigated the temporal dynamics of task performance and voluntary task choice within a multitasking paradigm in which the task-related processing outcomes themselves determined the to-be-performed task. In the novel forced-no-go trials, the stimulus for one task required an overt response, but the stimulus for the other task was associated with a no-go response. Task performance results showed that participants often processed the no-go task's stimulus before switching to the go-task. Dual-task interference effects and switch costs indicated various forms of multitasking interference, with their underlying causes appearing to overlap, as engagement in parallel processing seemed to be limited by switch-related reconfiguration processes. Intermixing free-choice trials, where both stimuli were associated with overt responses, revealed costs associated with switching between processing modes, providing new evidence that the distinctions between free and forced task goals stem from differences in their internal representations rather than alterations in processing due to different presentations in the environment. Task choice results align with this perspective, demonstrating a preference for repeating a free- over a forced-choice task. Furthermore, these free-choice results illuminate the interplay of cognitive (task-repetition bias) and environmental constraints (first-task bias) in shaping task choices: It appears that task-specific information increases goal activations for both task goals concurrently, with participants favoring central processing of the second- over the first-presented task to optimize their behavior when shorter central processing is required (task repetition). Overall, this study offers new insights into the dynamics of task processing and choice in environments requiring the balance of multiple tasks.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Transfer of cognitive control adjustments within and between speakers.

Congruency effects in conflict tasks are typically larger after congruent compared to incongruent trials. This congruency sequence effect (CSE) indicates that top-down adjustments of cognitive control transfer between processing episodes, at least when controlling for bottom-up memory processes by alternating between stimulus-response (S-R) sets in confound-minimised designs. According to the control-retrieval account, cognitive control is bound to task-irrelevant context features (e.g., stimulus position or modality) and retrieved upon subsequent context feature repetitions. A confound-minimised CSE should therefore be larger when context features repeat rather than change between two trials. This study tested this prediction for a more abstract contextual stimulus feature, speaker gender. In two preregistered auditory prime-probe task experiments, participants classified colour words spoken by a female or male voice. Across both experiments, we found confound-minimised CSEs that were not reliably affected by whether the speaker gender repeated or changed. This indicates that speaker transitions have virtually no influence on the transfer of control adjustments in the absence of S-R repetitions. By contrast, when allowing for bottom-up memory processes by repeating the S-R set, CSEs were consistently larger when the speaker gender repeated compared to changed. This suggests that speaker transitions can in principle influence transfer between processing episodes. The discrepancy also held true when considering learning and test episodes separated by an intervening episode. Thus, the present findings call for a refinement of the control-retrieval account to accommodate the role of more abstract contextual stimulus features for the maintenance of memory traces in auditory conflict processing.

Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase.

Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer's disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of ß-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN-GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies.

Local structural preferences in shaping tau amyloid polymorphism.

Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.

Transfer of task-probability-induced biases in parallel dual-task processing occurs in similar, but is constraint in distinct task sets.

Although humans often multitask, little is known about how the processing of concurrent tasks is managed. The present study investigated whether adjustments in parallel processing during multitasking are local (task-specific) or global (task-unspecific). In three experiments, participants performed one of three tasks: a primary task or, if this task did not require a response, one of two background tasks (i.e., prioritized processing paradigm). To manipulate the degree of parallel processing, we presented blocks consisting mainly of primary or background task trials. In Experiment 1, the frequency manipulation was distributed equally across the two background tasks. In Experiments 2 and 3, only one background task was frequency-biased (inducer task). The other background task was presented equally often in all blocks (diagnostic task) and served to test whether processing adjustments transferred. In all experiments, blocks with frequent background tasks yielded stronger interference between primary and background tasks (primary task performance) and improved background task performance. Thus, resource sharing appeared to increase with high background task probabilities even under triple task requirements. Importantly, these adjustments generalized across the background tasks when they were conceptually and visually similar (Experiment 2). Implementing more distinct background tasks limited the transfer: Adjustments were restricted to the inducer task in background task performance and only small transfer was observed in primary task performance (Experiment 3). Overall, the results indicate that the transfer of adjustments in parallel processing is unrestricted for similar, but limited for distinct tasks, suggesting that task similarity affects the generality of resource allocation in multitasking. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exploring behavioral adjustments of proportion congruency manipulations in an Eriksen flanker task with visual and auditory distractor modalities.

The present study investigated global behavioral adaptation effects to conflict arising from different distractor modalities. Three experiments were conducted using an Eriksen flanker paradigm with constant visual targets, but randomly varying auditory or visual distractors. In Experiment 1, the proportion of congruent to incongruent trials was varied for both distractor modalities, whereas in Experiments 2A and 2B, this proportion congruency (PC) manipulation was applied to trials with one distractor modality (inducer) to test potential behavioral transfer effects to trials with the other distractor modality (diagnostic). In all experiments, mean proportion congruency effects (PCEs) were present in trials with a PC manipulation, but there was no evidence of transfer to diagnostic trials in Experiments 2A and 2B. Distributional analyses (delta plots) provided further evidence for distractor modality-specific global behavioral adaptations by showing differences in the slope of delta plots with visual but not auditory distractors when increasing the ratio of congruent trials. Thus, it is suggested that distractor modalities constrain global behavioral adaptation effects due to the learning of modality-specific memory traces (e.g., distractor-target associations) and/or the modality-specific cognitive control processes (e.g., suppression of modality-specific distractor-based activation). Moreover, additional analyses revealed partial transfer of the congruency sequence effect across trials with different distractor modalities suggesting that distractor modality may differentially affect local and global behavioral adaptations.

Truncated TDP-43 proteoforms diagnostic of frontotemporal dementia with TDP-43 pathology.

INTRODUCTION: Biomarkers of TDP-43 pathology are needed to distinguish frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) from phenotypically related disorders. While normal physiological TDP-43 is not a promising biomarker, low-resolution techniques have suggested truncated forms of TDP-43 may be specific to TDP-43 pathology. To advance biomarker efforts for FTLD-TDP, we employed a high-resolution structural technique to characterize TDP-43 post-translational modifications in FTLD-TDP. METHODS: High-resolution mass spectrometry was used to characterize TDP-43 proteoforms in brain tissue from FTLD-TDP, non-TDP-43 dementias and neuropathologically unaffected cases. Findings were then verified in a larger cohort of FTLD-TDP and non-TDP-43 dementias via targeted quantitative mass spectrometry. RESULTS: In the discovery phase, truncated TDP-43 identified FTLD-TDP with 85% sensitivity and 100% specificity. The verification phase revealed similar findings, with 83% sensitivity and 89% specificity. DISCUSSION: The concentration of truncated TDP-43 proteoforms-in particular, in vivo generated C-terminal fragments-have high diagnostic accuracy for FTLD-TDP. HIGHLIGHTS: Discovery: Truncated TDP-43 differentiates FTLD-TDP from related dementias. Verification: Truncated TDP-43 concentration has high accuracy for FTLD-TDP. TDP-43 proteoforms <28 kDa have highest discriminatory power for TDP-43 pathology.

Reactive and proactive control processes in voluntary task choice.

Deciding which task to perform when multiple tasks are available can be influenced by external influences in the environment. In the present study, we demonstrate that such external biases on task-choice behavior reflect reactive control adjustments instead of a failure in control to internally select a task goal. Specifically, in two experiments we delayed the onset of one of two task stimuli by a short (50 ms), medium (300 ms), or long (1,000 ms) stimulus-onset asynchrony (SOA) within blocks while also varying the relative frequencies of short versus long SOAs across blocks (i.e., short SOA frequent vs. long SOA frequent). Participants' task choices were increasingly biased towards selecting the task associated with the first stimulus with increasing SOAs. Critically, both experiments also revealed that the short-to-medium SOA bias was larger in blocks with more frequent long SOAs when participants had limited time to prepare for an upcoming trial. When time to select an upcoming task was extended in Experiment 2, this interaction was not significant, suggesting that the extent to which people rely on reactive control adjustments is additionally modulated by proactive control processes. Thus, the present findings also suggest that voluntary task choices are jointly guided by both proactive and reactive processes, which are likely to adjust the relative activation of different task goals in working memory.

Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration.

TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43ΔNLS and FUSΔNLS), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43ΔNLS or FUSΔNLS and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43ΔNLS and FUSΔNLS in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43WT or hTDP-43Q331K and improved motor function of hTDP-43WT flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.

Disseminating cells in human oral tumours possess an EMT cancer stem cell marker profile that is predictive of metastasis in image-based machine learning.

Cancer stem cells (CSCs) undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. We have previously identified both EpCAM and CD24 as CSC markers that, alongside the mesenchymal marker Vimentin, identify EMT CSCs in human oral cancer cell lines. This afforded the opportunity to investigate whether the combination of these three markers can identify disseminating EMT CSCs in actual human tumours. Examining disseminating tumour cells in over 12,000 imaging fields from 74 human oral tumours, we see a significant enrichment of EpCAM, CD24 and Vimentin co-stained cells disseminating beyond the tumour body in metastatic specimens. Through training an artificial neural network, these predict metastasis with high accuracy (cross-validated accuracy of 87-89%). In this study, we have observed single disseminating EMT CSCs in human oral cancer specimens, and these are highly predictive of metastatic disease.

When oral cancers metastasise ­ that is, when tumour cells invade other parts of the body ­ they typically do so by first colonizing the lymph nodes present in the neck. As this event significantly reduces chances of survival, oral cancer patients often have their neck lymph nodes removed to prevent the spread of the disease. However, this surgery carries risks and leads to longer hospital stays, stressing the need for better ways to predict which oral tumours will metastasise. Evidence from lab-grown cells and mice studies suggest that, in oral cancer, metastasis occurs when some cells in the original tumour go through a process called the epithelial-mesenchymal transition (EMT for short). This transformation allows the cells to detach from the tumour and become invasive. However, it has so far been difficult to observe this process in actual human tumours; this is partly because cells undergoing EMT stop producing the proteins that scientists rely on to distinguish cancer and healthy cells. To address this knowledge gap, Youssef et al. focused on three proteins: two tumour markers, EpCAM and CD24; and Vimentin, which is produced in greater quantities in the invasive mesenchymal state. Previous work had shown that a specific population of oral tumour cells can continue to express all three proteins even when adopting a mesenchymal identity through EMT. Based on this knowledge, Youssef et al. hypothesised that tracking Vimentin, EpCAM and CD24 using fluorescence microscopy would allow them to identify metastasising cells in human samples. An analysis of over 12,000 images from 74 tumours obtained from surgeries revealed that, in the metastatic samples, the cells detaching from primary tumours were more likely to express these three proteins. Finally, Youssef et al. used these images to train a machine learning algorithm. When applied to data from new oral cancer patients, the programme was able to predict whether their tumours were likely to spread with 89% accuracy. If confirmed by further work, and in particular on larger samples, these findings could in the future help clinicians decide which patients with oral cancer would benefit the most from surgery to remove neck lymph nodes.

A Diffusion Model Analysis of Object-Based Selective Attention in the Eriksen Flanker Task.

Selective attention might be space-, feature-, and/or object-based. Clear support for the involvement of an object-based mechanism is rather scarce, possibly because the predictions of models from these different classes often overlap. Yet, only object-based models can account for a larger congruency effect (CE) in the Eriksen flanker task when flankers are more (vs. less) strongly grouped to the target, but spacing and other response-irrelevant features of target and flankers are held constant. Exactly this was observed by Kramer and Jacobson (1991). So far, this theoretically relevant finding has not been replicated closely. We replicated the finding in two web-based experiments. Specifically, CEs were larger when flanker lines were connected to the central target line (vs. to outer neutral lines). We also successfully fitted the Diffusion Model for Conflict tasks (DMC) to the experimental data. Critically, diffusion modeling (DMC) and distributional analyses (delta functions) revealed that object membership primarily affected target processing strength rather than strength or timing of flanker processing. This challenges the prominent attentional spreading (sensory enhancement) account of object-based selective attention and motivates an alternative target attenuation account.

Cognitive control in cross-modal contexts: Abstract feature transitions of task-related but not task-unrelated stimuli modulate the congruency sequence effect.

Context information can guide cognitive control, but both the extent and the underlying processes are poorly understood. Previous studies often found that the congruency sequence effect (CSE) is larger when perceptual context features (e.g., modality and format) of task-related distractors and targets repeat compared to change. However, it is unclear whether control adjustments can also be contextualized by more abstract stimulus features and/or by features of task-unrelated stimuli. The present study addressed this issue using a novel context manipulation in a confound-minimized prime-probe task. In Experiment (Exp.) 1, the modality (visual and auditory) of the distractor and target either repeated or changed. Critically, in Exp. 2, the distractor and target modality always switched, but the cross-modal intensity (brightness and loudness) could either repeat (e.g., bright → loud) or change (e.g., bright → soft). A larger CSE for context repeats (vs. changes) was observed in Exps. 1 and 2, indicating that both concrete (modality) and abstract stimulus features (cross-modal intensity) can contextualize control adjustments. Exps. 3 and 4 demonstrated that the CSE was not reliably affected when the context manipulation concerned a prior signal or a simultaneous background stimulus. Thus, task-related, but not task-unrelated, concrete and abstract stimulus features contextualize control adjustments. Moreover, distributional (delta plot) analyses of present and previous data revealed that the confound-minimized CSE and its contextual modulation reflect adjustments in the strength of cognitive control rather than in its timing. Overall, the present study provides new insights into how context information interacts with cognitive control to optimize decision making under conflict. (PsycInfo Database Record (c) 2023 APA, all rights reserved).