Context-dependent Manner Research Articles

NMDA receptor blockade attenuates Japanese encephalitis virus infection-induced microglia activation

Neurodegeneration and neuroinflammation are key components in the pathogenesis of Japanese Encephalitis caused by Japanese Encephalitis Virus (JEV) infection. The N-methyl-D-aspartate (NMDA)-type glutamate receptor displays excitatory neurotoxic and pro-inflammatory properties in a cell context-dependent manner. Herein, potential roles of the NMDA receptor in excitatory neurotoxicity and neuroinflammation and effects of NMDA receptor blockade against JEV pathogenesis were investigated in rat microglia, neuron/glia, neuron cultures, and C57BL/6 mice. In microglia, JEV infection induced glutamate release and activated post-receptor NMDA signaling, leading to activation of Ca2+ mobilization and Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), accompanied by pro-inflammatory NF-κB and AP-1 activation and cytokine expression. Additionally, increased Dynamin-Related Protein-1 protein phosphorylation, NAPDH Oxidase-2/4 expression, free radical generation, and Endoplasmic Reticulum stress paralleled with the reactive changes of microglia after JEV infection. JEV infection-induced biochemical and molecular changes contributed to microglia reactivity and pro-inflammatory cytokine expression. NMDA receptor antagonists MK801 and memantine alleviated intracellular signaling and pro-inflammatory cytokine expression in JEV-infected microglia. JEV infection induced neuronal cell death in neuron/glia culture associated with the concurrent production of pro-inflammatory cytokines. Conditioned media of JEV-infected microglia compromised neuron viability in neuron culture. JEV infection-associated neuronal cell death was alleviated by MK801 and memantine. Activation of NMDA receptor-related inflammatory changes, microglia activation, and neurodegeneration as well as reversal effects of memantine were revealed in the brains of JEV-infected mice. The current findings highlight a crucial role of the glutamate/NMDA receptor axis in linking excitotoxicity and neuroinflammation during the course of JEV pathogenesis, and proposes the anti-inflammatory and neuroprotective potential of NMDA receptor blockade.

DPP an extracellular matrix molecule induces Wnt5a mediated signaling to promote the differentiation of adult stem cells into odontogenic lineage

Dentin phosphophoryn (DPP) an extracellular matrix protein activates Wnt signaling in DPSCs (dental pulp stem cells). Wnt/β catenin signaling is essential for tooth development but the role of DPP-mediated Wnt5a signaling in odontogenesis is not well understood. Wnt5a is typically considered as a non-canonical Wnt ligand that elicits intracellular signals through association with a specific cohort of receptors and co-receptors in a cell and context–dependent manner. In this study, DPP facilitated the interaction of Wnt5a with Frizzled 5 and LRP6 to induce nuclear translocation of β-catenin. β-catenin has several nuclear binding partners that promote the activation of Wnt target genes responsible for odontogenic differentiation. Interestingly, steady increase in the expression of Vangl2 receptor suggest planar cell polarity signaling during odontogenic differentiation. In vitro observations were further strengthened by the low expression levels of Wnt5a and β-catenin in the teeth of DSPP KO mice which exhibit impaired odontoblast differentiation and defective dentin mineralization. Together, this study suggests that the DPP-mediated Wnt5a signaling could be exploited as a therapeutic approach for the differentiation of dental pulp stem cells into functional odontoblasts and dentin regeneration.

Structure of METTL3-METTL14 with an m6A nucleotide reveals insights into m6A conversion and sensing.

The nuclear METTL3-METTL14 transfers a methyl group from SAM to convert the N 6 of adenosine (A) in RNA to m 6 A and in ssDNA to 6mA. m 6 A marks are prevalent in eukaryotic mRNAs and lncRNAs and modulate their stability and fate in a context-dependent manner. The cytoplasmic METTL3 can act as a m 6 A reader. However, the precise mechanism during m6A writing, reading, or sensing is unclear. Here, we present a ~2.5 Å structure of the methyltransferase core of human METTL3-METTL14 in complex with the reaction product mimic, N 6 -methyladenosine monophosphate (m 6 A), representing a state post-catalysis but before the release of m 6 A. m 6 A occupies an evolutionarily conserved RNA-binding pocket ~16 Å away from the SAM pocket that also frequently mutates in cancer. We propose a two-step model of swiveling of target A upon conversion to m 6 A and sensing its methylation status by this pocket, enabling it to actuate enzymes' switch from writer to an m 6 A-sensor. Cancer-associated mutations show impaired RNA binding dynamics, de-stacking, and defective m 6 A writing and sensing.

How to drug a cloud? Targeting intrinsically disordered proteins.

Biologically active proteins/regions without stable structure (i.e., intrinsically disordered proteins and regions (IDPs and IDRs)) are commonly found in all proteomes. They have a unique functional repertoire that complements the functionalities of ordered proteins and domains. IDPs/IDRs are multifunctional promiscuous binders capable of folding at interaction with specific binding partners on a template- or context-dependent manner, many of which undergo liquid-liquid phase separation, leading to the formation of membrane-less organelles and biomolecular condensates. Many of them are frequently related to the pathogenesis of various human diseases. All this defines IDPs/IDRs as attractive targets for the development of novel drugs. However, their lack of unique structures, multifunctionality, binding promiscuity, and involvement in unusual modes of action preclude direct use of traditional structure-based drug design approaches for targeting IDPs/IDRs, and make disorder-based drug discovery for these "protein clouds" challenging. Despite all these complexities there is continuing progress in the design of small molecules affecting IDPs/IDRs. This article describes the major structural features of IDPs/IDRs and the peculiarities of the disorder-based functionality. It also discusses the roles of IDPs/IDRs in various pathologies, and shows why the approaches elaborated for finding drugs targeting ordered proteins cannot be directly used for the intrinsic disorder-based drug design, and introduces some novel methodologies suitable for these purposes. Finally, it emphasizes that regardless of their multifunctionality, binding promiscuity, lack of unique structures, and highly dynamic nature, "protein clouds" are principally druggable. Significance Statement Intrinsically disordered proteins and regions are highly abundant in nature, have multiple important biological functions, are commonly involved in the pathogenesis of a multitude of human diseases, and are therefore considered as very attractive drug targets. Although dealing with these unstructured multifunctional protein/regions is a challenging task, multiple innovative approaches have been designed to target them by small molecules.

A lineage-specific nascent RNA assay unveils principles of gene regulation in tissue biology.

Gene regulatory mechanisms that modulate RNA Polymerase II activity are difficult to access in mammalian tissues composed of multiple cell lineages. Here, we develop a nascent RNA assay (PReCIS-seq) that measures lineage-specific transcriptionally-engaged Pol II on genes and DNA enhancer elements in intact mouse tissue. By employing keratinocytes as a prototype lineage, we unearth Pol II promoter-recruitment versus pause-release mechanisms operating in adult skin homeostasis. Moreover, we relate active enhancer proximity and transcription factor binding motifs on promoters to Pol II activity and promoter-proximal pausing level. Finally, we find Pol II firing rapidly into elongation on lineage identity genes and highly paused on cellular safeguarding genes in a context-dependent manner. Our work provides a basic platform to investigate mechanistic principles of gene regulation in individual lineages of complex mammalian tissues.

A Cortical Site that Encodes Vocal Expression and Reception.

Socially effective vocal communication requires brain regions that encode expressive and receptive aspects of vocal communication in a social context-dependent manner. Here, we combined a novel behavioral assay with microendoscopy to interrogate neuronal activity in the posterior insula (pIns) in socially interacting mice as they switched rapidly between states of vocal expression and reception. We found that distinct but spatially intermingled subsets of pIns neurons were active during vocal expression and reception. Notably, pIns activity during vocal expression increased prior to vocal onset and was also detected in congenitally deaf mice, pointing to a motor signal. Furthermore, receptive pIns activity depended strongly on social cues, including female odorants. Lastly, tracing experiments reveal that deep layer neurons in the pIns directly bridge the auditory thalamus to a midbrain vocal gating region. Therefore, the pIns is a site that encodes vocal expression and reception in a manner that depends on social context.

Learning to ignore visual onset distractors hinges on a configuration-dependent coordinates system.

Decrement of attentional capture elicited by visual onset distractors, consistent with habituation, has been extensively characterized over the past several years. However, the type of spatial frame of reference according to which such decrement occurs in the brain remains unknown. Here, four related experiments are reported to shed light on this issue. Observers were asked to discriminate the orientation of a titled line while ignoring a salient but task-irrelevant visual onset that occurred on some trials. The experiments all involved an initial habituation phase, during which capture elicited by the onset distractor progressively decreased, as in prior studies. Importantly, in all experiments, the location of the target and the distractor remained fixed during this phase. After habituation was established, in a final test phase of the various experiments, the spatial arrangement of the target and the distractor was changed to test for the relative contribution to habituation of retinotopic, spatiotopic, and configuration-dependent visual representations. Experiment 1 indicated that spatiotopic representations contribute little, if at all, to the observed decrement in attentional capture. The results from Experiment 2 were compatible with the notion that such capture reduction occurs in either retinotopic- or configuration-specific representations. However, Experiment 3 ruled out the contribution of retinotopic representations, leaving configuration-specific representation as the sole viable interpretation. This conclusion was confirmed by the results of Experiments 4 and 5. In conclusion, visual onset distractors appear to be rejected at a level of the visual hierarchy where visual events are encoded in a configuration-specific or context-dependent manner. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Potentiation of active locomotor state by spinal-projecting serotonergic neurons.

Animals produce diverse motor actions that enable expression of context-appropriate behaviors. Neuromodulators facilitate behavioral flexibility by altering the temporal dynamics and output of neural circuits. Discrete populations of serotonergic (5-HT) neurons target circuits in the brainstem and spinal cord, but their role in the control of motor behavior is unclear. Here we define the pre- and post-synaptic organization of the spinal-projecting serotonergic system and define a role in locomotor control. We show that while forebrain-targeting 5-HT neurons decrease their activity during locomotion, subpopulations of spinal projecting neurons increase their activity in a context-dependent manner. Optogenetic activation of ventrally projecting 5-HT neurons does not trigger initiation of movement, but rather enhances the speed and duration of ongoing locomotion over extended time scales. These findings indicate that the descending serotonergic system potentiates locomotor output and demonstrate a role for serotonergic neurons in modulating the temporal dynamics of motor circuits.

Collapsed State Mediates the Low Fidelity of the DNA Polymerase β I260 Mutant.

DNA polymerase β (Pol β) fills single nucleotide gaps during base excision repair. Deficiencies in Pol β can lead to increased mutagenesis and genomic instability in the cell, resulting in cancer. Our laboratory has previously shown that the I260 M somatic mutation of Pol β, which was first identified in prostate cancer, has reduced nucleotide discrimination in a sequence context-dependent manner. I260 M incorporates the incorrect G opposite A in this context more readily than WT. To identify the molecular mechanism of the reduced fidelity of I260M, we studied incorporation using single turnover kinetics and the nature and rates of conformational changes using steady-state fluorescence and Förster resonance energy transfer (FRET). Our data indicate that the I260 M mutation affects the fingers region of rat Pol β by creating a "collapsed" state in both the open (in the absence of nucleotide) and closed (prior to chemistry) states. I260 M is a temperature-sensitive mutator and binds nucleotides tighter than the WT protein, resulting in reduced fidelity compared to the WT. Additionally, we have generated a kinetic model of WT and I260 M using FRET and single turnover data, which demonstrates that I260 M precatalytic conformation changes differ compared to the WT as it is missing a precatalytic noncovalent step. Taken together, these results suggest that the collapsed state of I260 M may decrease its ability for nucleotide discrimination, illustrating the importance of the "fingers closing" conformational change for polymerase fidelity and accurate DNA synthesis.

Growth pattern of de novo small clusters of colorectal cancer is regulated by Notch signaling at detachment.

Cancer cell clusters have a higher capacity for metastasis than single cells, suggesting cancer cell clusters have biological properties different from those of single cells. The nature of de novo cancer cell clusters that are newly formed from tumor masses is largely unknown. Herein, we generated small cell clusters from colorectal cancer organoids and tracked the growth patterns of the clusters up to four cells. Growth patterns were classified into actively growing and poorly growing spheroids (PG). Notch signaling was robustly activated in small clusters immediately after dissociation, and Notch signaling inhibition markedly increased the proportion of PG spheroids. Only a limited number of PG spheroids grew under growth-permissive conditions invitro, but xenograft tumors derived from Notch inhibited clusters showed growth rates comparable to those of untreated spheroids. Thus, de novo clusters are composed of cells with interchangeable growth fates, which are regulated in a context-dependent manner by Notch signaling.

Altered vocal communication in adult vasopressin-deficient Brattleboro rats

The neuropeptide, arginine vasopressin (AVP), has been implicated in social communication across a diverse array of species. Many rodents communicate basic behavioral states with negative versus positive valence through high-pitched vocalizations above the human hearing range (ultrasonic vocalizations; USVs). Previous studies have found that Brattleboro (Bratt) rats, which have a mutation in the Avp gene, exhibit deficits in their USVs from the early postnatal period through adolescence, but the magnitude of this effect appears to decrease from the juvenile to adolescent phase. The present study tested whether Bratt rats continue to exhibit USV deficits in adulthood. USVs of adult male and female Bratt and wild type (WT) rats were recorded in two contexts: a novel environment (empty arena) and a social context (arena filled with bedding soiled by same-sex conspecifics). The number, frequency, and duration of 50 kHz USVs were quantified by DeepSqueak after validation with manual scoring. Twenty-two kHz measures were quantified by manual scoring because DeepSqueak failed to accurately detect USVs in this frequency range. Adult Bratt rats did not exhibit deficits in the number of 50 kHz USVs: male Bratt rats emitted similar 50 kHz USVs as male WT rats, whereas female Bratt rats emitted more USVs than female WT rats. USV frequency and duration were altered in adult Bratt rats, but in a context-dependent manner. Twenty-two kHz USVs were less affected by the Bratt mutation. The present study demonstrates how chronic AVP deficiency impacts social communication across the lifespan. The present findings reveal a complex role for AVP in vocal communication, whereby disruption to the Avp gene leads to sex-, context-, and developmental phase-specific effects on the quantity and spectrotemporal characteristics of rat USVs.

Application of Attribute-Based Encryption in Military Internet of Things Environment.

The Military Internet of Things (MIoT) has emerged as a new research area in military intelligence. The MIoT frequently has to constitute a federation-capable IoT environment when the military needs to interact with other institutions and organizations or carry out joint missions as part of a coalition such as in NATO. One of the main challenges of deploying the MIoT in such an environment is to acquire, analyze, and merge vast amounts of data from many different IoT devices and disseminate them in a secure, reliable, and context-dependent manner. This challenge is one of the main challenges in a federated environment and forms the basis for establishing trusting relationships and secure communication between IoT devices belonging to different partners. In this work, we focus on the problem of fulfillment of the data-centric security paradigm, i.e., ensuring the secure management of data along the path from its origin to the recipients and implementing fine-grained access control mechanisms. This problem can be solved using innovative solutions such as applying attribute-based encryption (ABE). In this work, we present a comprehensive solution for secure data dissemination in a federated MIoT environment, enabling the use of distributed registry technology (Hyperledger Fabric), a message broker (Apache Kafka), and data processing microservices implemented using the Kafka Streams API library. We designed and implemented ABE cryptography data access control methods using a combination of pairings-based elliptic curve cryptography and lightweight cryptography and confirmed their suitability for the federations of military networks. Experimental studies indicate that the proposed cryptographic scheme is viable for the number of attributes typically assumed to be used in battlefield networks, offering a good trade-off between security and performance for modern cryptographic applications.

Left motor cortex contributes to auditory phonological discrimination.

Evidence suggests that the articulatory motor system contributes to speech perception in a context-dependent manner. This study tested 2 hypotheses using magnetoencephalography: (i) the motor cortex is involved in phonological processing, and (ii) it aids in compensating for speech-in-noise challenges. A total of 32 young adults performed a phonological discrimination task under 3 noise conditions while their brain activity was recorded using magnetoencephalography. We observed simultaneous activation in the left ventral primary motor cortex and bilateral posterior-superior temporal gyrus when participants correctly identified pairs of syllables. This activation was significantly more pronounced for phonologically different than identical syllable pairs. Notably, phonological differences were resolved more quickly in the left ventral primary motor cortex than in the left posterior-superior temporal gyrus. Conversely, the noise level did not modulate the activity in frontal motor regions and the involvement of the left ventral primary motor cortex in phonological discrimination was comparable across all noise conditions. Our results show that the ventral primary motor cortex is crucial for phonological processing but not for compensation in challenging listening conditions. Simultaneous activation of left ventral primary motor cortex and bilateral posterior-superior temporal gyrus supports an interactive model of speech perception, where auditory and motor regions shape perception. The ventral primary motor cortex may be involved in a predictive coding mechanism that influences auditory-phonetic processing.

Kinematically distinct saccades are used in a context-dependent manner by larval zebrafish

Saccades are rapid eye movements that are used by all species with good vision. In this study, we set out to characterize the complete repertoire of larval zebrafish horizontal saccades to gain insight into their contributions to visually guided behavior and underlying neural control. We identified five saccade types, defined by systematic differences in kinematics and binocular coordination, which were differentially expressed across a variety of behavioral contexts. Conjugate saccades formed a large group that serves at least four functions. These include fast phases of the optokinetic nystagmus, visual scanning in stationary animals, and shifting gaze in coordination with body turns. In addition, we discovered a previously undescribed pattern of eye-body coordination in which small conjugate saccades partially oppose head rotation to maintain gaze during forward locomotion. Convergent saccades were coordinated with body movements to foveate prey targets during hunting. Detailed kinematic analysis showed that conjugate and convergent saccades differed in the millisecond coordination of the eyes and body and followed distinct velocity main sequence relationships. This challenges the prevailing view that all horizontal saccades are controlled by a common brainstem circuit and instead indicates saccade-type-specific neural control.

Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner. One such molecule is the transcription factor C/EBPδ, where we recently showed that C/EBPδ exerts tumor-suppressive effects in PDAC cells in vitro. To better understand the role of C/EBPδ in different contexts and the development of PDAC, we here build on these findings and assess the effect of C/EBPδ in a PDAC model in mice. We establish that the lack of oxygen in vivo-hypoxia-counteracts the tumor-suppressive effects of C/EBPδ, and identify a reciprocal feedback loop between C/EBPδ and HIF-1α. RNA sequencing of C/EBPδ-induced cells under hypoxia also suggests that the growth-limiting effects of C/EBPδ decrease with oxygen tension. Consequently, in vitro proliferation assays reveal that the tumor-suppressive activities of C/EBPδ are abrogated due to hypoxia. This study demonstrates the importance of considering major physiological parameters in preclinical approaches.

Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment.

Galectin-9 is a multifaceted regulator of various pathophysiological processes that exerts positive or negative effects in a context-dependent manner. Here, we elucidated the distinctive functional properties of galectin-9 on myeloid cells within the brain tumor microenvironment. Galectin-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared to the contralateral hemisphere in an intracranial mouse brain tumor model. Galectin-9 was highly expressed in microglia and macrophages in tumor-infiltrating cells. In primary glia, both the expression and secretion of galectin-9 were influenced by tumors. Analysis of a human glioblastoma bulk RNA-sequencing dataset and a single-cell RNA-sequencing dataset from a murine glioma model revealed a correlation between galectin-9 expression and glial cell activation. Notably, the galectin-9high microglial subset was functionally distinct from the galectin-9neg/low subset in the brain tumor microenvironment. Galectin-9high microglia exhibited properties of inflammatory activation and higher rates of cell death, whereas galectin-9neg/low microglia displayed a superior phagocytic ability against brain tumor cells. Blockade of galectin-9 suppressed tumor growth and altered the activity of glial and T cells in a mouse glioma model. Additionally, glial galectin-9 expression was regulated by Hif-2α in the hypoxic brain tumor microenvironment. Myeloid-specific Hif-2α deficiency led to attenuated tumor progression. Together, these findings reveal that galectin-9 on myeloid cells is an immunoregulator and putative therapeutic target in brain tumors.

Metabolic features of tumor-derived extracellular vesicles: challenges and opportunities

Tumor-derived extracellular vesicles (TDEVs) play crucial roles in intercellular communication both in the local tumor microenvironment and systemically, facilitating tumor progression and metastatic spread. They carry a variety of molecules with bioactive properties, such as nucleic acids, proteins and metabolites, that trigger different signaling processes in receptor cells and induce, among other downstream effects, metabolic reprogramming. Interestingly, the cargo of TDEVs also reflects the metabolic status of the producing cells in a time- and context-dependent manner, providing information on the functionality and state of those cells. For these reasons, together with their ability to be detected in diverse biofluids, there is increasing interest in the study of TDEVs, particularly their metabolic cargo, as diagnostic and prognostic tools in cancer management. This review presents a compilation of metabolism-related molecules (enzymes and metabolites) described in cancer extracellular vesicles (EVs) with potential use as cancer biomarkers, and discusses the challenges arising in this rapidly evolving field.

Analysis of the DNA-binding properties of TGF-β-activated Smad complexes unveils a possible molecular basis for cellular context-dependent signaling.

Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that modulates a wide variety of cellular responses by regulating target gene expression. It principally transmits signals via receptor-activated transcription factors Smad2 and Smad3, which form trimeric complexes with Smad4 upon activation and regulate gene expression by binding to genomic DNA. Here, we examined the mechanisms by which TGF-β regulates the transcription of target genes in a cell context-dependent manner by screening a double-stranded DNA oligonucleotide library for DNA sequences bound to endogenous activated Smad complexes. Screening was performed by cyclic amplification of selected targets (CASTing) using an anti-Smad2/3 antibody and nuclear extracts isolated from three cell lines (A549, HepG2, and HaCaT) stimulated with TGF-β. The preference of the activated Smad complexes for conventional Smad-binding motifs such as Smad-binding element (SBE) and CAGA motifs was different in HepG2 than in the other two cell lines, which may indicate the distinct composition of the activated Smad complexes. Several transcription factor-binding motifs other than SBE or CAGA, including the Fos/Jun-binding motifs, were detected in the enriched sequences. Reporter assays using sequences containing these transcription factor-binding motifs together with Smad-binding motifs indicated that some of the motifs may be involved in cell type-dependent transcriptional activation by TGF-β. The results suggest that the CASTing method is useful for elucidating the molecular basis of context-dependent Smad signaling.

Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.

The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.

Context effects in cognitive effort evaluation.

When given a choice, people will avoid cognitively effortful courses of action because the experience of effort is evaluated as aversive and costly. At the same time, a body of work spanning psychology, economics, and neuroscience suggests that goods, actions, and experiences are often evaluated in the context in which they are encountered, rather in absolute terms. To probe the extent to which theevaluation of cognitive effort is also context-dependent, we had participants learn associations between unique stimuli and subjective demand levels across low-demand and high-demand contexts. We probed demand preferences and subjective evaluation using a forced-choice paradigm as well by examining effort ratings, taken both on-line (during learning) and off-line (after choice). When choosing between two stimuli objectively identical in terms of demand, participants showed a clear preference for the stimulus learned in the low- versus high-demand context and rated this stimulus as more subjectively effortful than the low-demand context in on-line but not off-line ratings, suggesting an assimilation effect. Finally, we observed that the extent to which individual participants who exhibited stronger assimilation effects in off-line demand ratings were more likely to manifest an assimilation effect in demand preferences. Broadly, our findings suggest that effort evaluations occur in a context-dependent manner and are specifically assimilated to the broader context in which they occur.