Extracellular vesicle miRNAs drive aberrant macrophage responses in NSAID-exacerbated respiratory disease.

BACKGROUND: Extracellular vesicles (EVs) have been implicated in the pathogenesis of asthma, however, how EVs contribute to immune dysfunction and type 2 airway inflammation remains incompletely understood. We aimed to elucidate roles of airway EVs and their miRNA cargo in the pathogenesis of NSAID-exacerbated respiratory disease (N-ERD), a severe type 2 inflammatory condition. METHODS: EVs were isolated from induced sputum or supernatants of cultured nasal polyp or turbinate tissues of N-ERD patients or healthy controls by size-exclusion chromatography and characterized by particle tracking, electron microscopy and miRNA sequencing. Functional effects of EV miRNAs on gene expression and mediator release by human macrophages or normal human bronchial epithelial cells (NHBEs) were studied by RNA sequencing, LC-MS/MS and multiplex cytokine assays. RESULTS: EVs were highly abundant in secretions from the upper and lower airways of N-ERD patients. N-ERD airway EVs displayed profoundly altered immunostimulatory capacities and miRNA profiles compared to airway EVs of healthy individuals. Airway EVs of N-ERD patients, but not of healthy individuals induced inflammatory cytokine (GM-CSF and IL-8) production by NHBEs. In macrophages, N-ERD airway EVs exhibited an impaired potential to induce cytokine and prostanoid production, while enhancing M2 macrophage activation. Let-7 family miRNAs were highly enriched in sputum EVs from N-ERD patients and mimicked suppressive effects of N-ERD EVs on macrophage activation. CONCLUSION: Aberrant airway EV miRNA profiles may contribute to immune dysfunction and chronic type 2 inflammation in N-ERD. Let-7 family miRNAs represent targets for correcting aberrant macrophage activation and mediator responses in N-ERD.

Human interleukin-12α and EBI3 are cytokines with anti-inflammatory functions.

Interleukins are secreted proteins that regulate immune responses. Among these, the interleukin 12 (IL-12) family holds a central position in inflammatory and infectious diseases. Each family member consists of an α and a ß subunit that together form a composite cytokine. Within the IL-12 family, IL-35 remains particularly ill-characterized on a molecular level despite its key role in autoimmune diseases and cancer. Here we show that both IL-35 subunits, IL-12α and EBI3, mutually promote their secretion from cells but are not necessarily secreted as a heterodimer. Our data demonstrate that IL-12α and EBI3 are stable proteins in isolation that act as anti-inflammatory molecules. Both reduce secretion of proinflammatory cytokines and induce the development of regulatory T cells. Together, our study reveals IL-12α and EBI3, the subunits of IL-35, to be functionally active anti-inflammatory immune molecules on their own. This extends our understanding of the human cytokine repertoire as a basis for immunotherapeutic approaches.

Do we need to reconceptualize emotions?

Over the past decades, the emerging and ever-growing body of studies in empirical aesthetics has made one thing abundantly clear: our current models and conceptualizations of emotional experiences have outlived their usefulness. How do we go from here?

Trained immunity in type 2 immune responses.

Immunological memory of innate immune cells, also termed "trained immunity", allows for cross-protection against distinct pathogens, but may also drive chronic inflammation. Recent studies have shown that memory responses associated with type 2 immunity do not solely rely on adaptive immune cells, such as T- and B cells, but also involve the innate immune system and epithelial cells. Memory responses have been described for monocytes, macrophages and airway epithelial cells of asthmatic patients as well as for macrophages and group 2 innate lymphoid cells (ILC2) from allergen-sensitized or helminth-infected mice. The metabolic and epigenetic mechanisms that mediate allergen- or helminth-induced reprogramming of innate immune cells are only beginning to be uncovered. Trained immunity has been implicated in helminth-driven immune regulation and allergen-specific immunotherapy, suggesting its exploitation in future therapies. Here, we discuss recent advances and key remaining questions regarding the mechanisms and functions of trained type 2 immunity in infection and inflammation.

Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.

BACKGROUND: Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type 2 inflammatory conditions such as allergic asthma was not known. OBJECTIVE: We sought to decipher macrophage-trained immunity in allergic asthma. METHODS: We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation in mice, and an in vitro training setup to analyze persistent changes in macrophage eicosanoid, cytokine, and chemokine production as well as the underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or metabolic flux analysis and liquid chromatography-tandem mass spectrometry analysis, respectively. RESULTS: We found that macrophages differentiated from bone marrow or blood monocyte progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE2, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type 2 imprint, which shifted toward a classical inflammatory training over time. HDM-induced allergic airway inflammation elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl peptide receptor 2-TNF-2-HG-PGE2/PGE2 receptor 2 axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice. CONCLUSION: Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type 2 airway inflammation and thus represents a target for asthma therapy.

A pre-registered, multi-lab non-replication of the action-sentence compatibility effect (ACE).

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero.

Aesthetic appraisals of literary style and emotional intensity in narrative engagement are neurally dissociable.

Humans are deeply affected by stories, yet it is unclear how. In this study, we explored two aspects of aesthetic experiences during narrative engagement - literariness and narrative fluctuations in appraised emotional intensity. Independent ratings of literariness and emotional intensity of two literary stories were used to predict blood-oxygen-level-dependent signal changes in 52 listeners from an existing fMRI dataset. Literariness was associated with increased activation in brain areas linked to semantic integration (left angular gyrus, supramarginal gyrus, and precuneus), and decreased activation in bilateral middle temporal cortices, associated with semantic representations and word memory. Emotional intensity correlated with decreased activation in a bilateral frontoparietal network that is often associated with controlled attention. Our results confirm a neural dissociation in processing literary form and emotional content in stories and generate new questions about the function of and interaction between attention, social cognition, and semantic systems during literary engagement and aesthetic experiences.

Sensitive Measures of Cognition in Mild Cognitive Impairment.

BACKGROUND: Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer's disease (AD) to track cognitive change and evaluate potential interventions. Neurofibrillary tangle pathology in AD is first observed in Brodmann Area 35 (BA35), the medial portion of the perirhinal cortex. The importance of the perirhinal cortex for semantic memory may explain early impairments of semantics in preclinical AD. Additionally, our research has tied figurative language impairment to neurodegenerative disease. OBJECTIVE: We aim to identify tasks that are sensitive to cognitive impairment in individuals with mild cognitive impairment (MCI), and that are sensitive to atrophy in BA35. METHODS: Individuals with MCI and cognitively normal participants (CN) were tested on productive and receptive experimental measures of semantic memory and experimental tests of figurative language comprehension (including metaphor and verbal analogy). Performance was related to structural imaging and standard neuropsychological assessment. RESULTS: On the experimental tests of semantics and figurative language, people with MCI performed worse than CN participants. The experimental semantic memory tasks are sensitive and specific; performance on the experimental semantic memory tasks related to medial temporal lobe structural integrity, including BA35, while standard neuropsychological assessments of semantic memory did not, demonstrating the sensitivity of these experimental measures. A visuo-spatial analogy task did not differentiate groups, confirming the specificity of semantic and figurative language tasks. CONCLUSION: These experimental measures appear sensitive to cognitive change and neurodegeneration early in the AD trajectory and may prove useful in tracking cognitive change in clinical trials aimed at early intervention.

Morality is in the eye of the beholder: the neurocognitive basis of the "anomalous-is-bad" stereotype.

Are people with flawed faces regarded as having flawed moral characters? An "anomalous-is-bad" stereotype is hypothesized to facilitate negative biases against people with facial anomalies (e.g., scars), but whether and how these biases affect behavior and brain functioning remain open questions. We examined responses to anomalous faces in the brain (using a visual oddball paradigm), behavior (in economic games), and attitudes. At the level of the brain, the amygdala demonstrated a specific neural response to anomalous faces-sensitive to disgust and a lack of beauty but independent of responses to salience or arousal. At the level of behavior, people with anomalous faces were subjected to less prosociality from participants highest in socioeconomic status. At the level of attitudes, we replicated previously reported negative character evaluations made about individuals with facial anomalies, and further identified explicit biases directed against them as a group. Across these levels of organization, the specific amygdala response to facial anomalies correlated with stronger just-world beliefs (i.e., people get what they deserve), less dispositional empathic concern, and less prosociality toward people with facial anomalies. Characterizing the "anomalous-is-bad" stereotype at multiple levels of organization can reveal underappreciated psychological burdens shouldered by people who look different.

A Novel Anti-Kv10.1 Nanobody Fused to Single-Chain TRAIL Enhances Apoptosis Induction in Cancer Cells.

Antibody-based therapies hold promise for a safe and efficient treatment of cancer. The identification of target tumor cells through a specific antigen enriched on their surface and the subsequent delivery of the therapeutic agent only to those cells requires, besides the efficacy of the therapeutic agent itself, the identification of an antigen enriched on the surface of tumor cells, the generation of high affinity antibodies against that antigen. We have generated single-domain antibodies (nanobodies) against the voltage-gated potassium channel Kv10.1, which outside of the brain is detectable almost exclusively in tumor cells. The nanobody with highest affinity was fused to an improved form of the tumor necrosis factor-related apoptosis inducing ligand TRAIL, to target this cytokine to the surface of tumor cells. The resulting construct, VHH-D9-scTRAIL, shows rapid and strong apoptosis induction in different tumor models in cell culture. The construct combines two sources of specificity, the expression of the antigen restricted to tumor cells and the tumor selectivity of TRAIL. Such specificity combined with the high affinity obtained through nanobodies make the novel agent a promising concept for cancer therapy.

Psychological and neural responses to architectural interiors.

People spend considerable time within built environments. In this study, we tested two hypotheses about the relationship between people and built environments. First, aesthetic responses to architectural interiors reduce to a few key psychological dimensions that are sensitive to design features. Second, these psychological dimensions evoke specific neural signatures. In Experiment 1, participants (n = 798) rated 200 images of architectural interiors on 16 aesthetic response measures. Using Psychometric Network Analysis (PNA) and Principal Components Analysis (PCA), we identified three components that explained 90% of the variance in ratings: coherence (ease with which one organizes and comprehends a scene), fascination (a scene's informational richness and generated interest), and hominess (extent to which a scene reflects a personal space). Whereas coherence and fascination are well-established dimensions in response to natural scenes and visual art, hominess emerged as a new dimension related to architectural interiors. In Experiment 2 (n = 614), the PCA results were replicated in an independent sample, indicating the robustness of these three dimensions. In Experiment 3, we reanalyzed data from an fMRI study in which participants (n = 18) made beauty judgments and approach-avoidance decisions when viewing the same images. Parametric analyses demonstrated that, regardless of task, the degree of fascination covaried with neural activity in the right lingual gyrus. In contrast, coherence covaried with neural activity in the left inferior occipital gyrus only when participants judged beauty, whereas hominess covaried with neural activity in the left cuneus only when they made approach-avoidance decisions. Importantly, this neural activation did not covary in relation to global image properties including self-similarity and complexity scores. These results suggest that the visual brain harbors sensitivities to psychological dimensions of coherence, fascination, and hominess in the context of architectural interiors. Furthermore, valuation of architectural processing in visual cortices varies by dimension and task.

Context matters: Novel metaphors in supportive and non-supportive contexts.

Creative language is defined as linguistic output that is both novel and appropriate. Metaphors are one such example of creative language in which one concept is used to express another by highlighting relevant semantic features. While novelty is an inherent property of unfamiliar metaphors, appropriateness depends on the context. The current study tests the hypothesis that the context in which metaphors are encountered affects their processing. We examined the neural effects of comprehending metaphors in context by comparing neural activations in response to novel metaphors and literal sentences that were either embedded in a meaningful narrative or in matched jabberwocky contexts. We found that the neural correlates of processing metaphoric sentences and their literal counterparts are indistinguishable when embedded in a narrative: both conditions activate bilateral areas along the anterior temporal poles, middle temporal gyri, superior temporal sulci, and the angular gyri. Metaphors embedded in a narrative as compared to their identical counterparts embedded in jabberwocky show increased responses in sensorimotor areas that correspond to the modality of the literal meaning of the target word, perhaps reflecting deeper semantic processing. Our results confirm that context affects neural mechanisms for understanding creative ideas.

Behavioural and Neural Responses to Facial Disfigurement.

Faces are among the most salient and relevant visual and social stimuli that humans encounter. Attractive faces are associated with positive character traits and social skills and automatically evoke larger neural responses than faces of average attractiveness in ventral occipito-temporal cortical areas. Little is known about the behavioral and neural responses to disfigured faces. In two experiments, we tested the hypotheses that people harbor a disfigured is bad bias and that ventral visual neural responses, known to be amplified to attractive faces, represent an attentional effect to facial salience rather than to their rewarding properties. In our behavioral study (N = 79), we confirmed the existence of an implicit 'disfigured is bad' bias. In our functional MRI experiment (N = 31), neural responses to photographs of disfigured faces before treatment evoked greater neural responses within ventral occipito-temporal cortex and diminished responses within anterior cingulate cortex. The occipito-temporal activity supports the hypothesis that these areas are sensitive to attentional, rather than reward properties of faces. The relative deactivation in anterior cingulate cortex, informed by our behavioral study, may reflect suppressed empathy and social cognition and indicate evidence of a possible neural mechanism underlying dehumanization.

Antibodies Targeting KV Potassium Channels: A Promising Treatment for Cancer.

Voltage-gated potassium channels are transmembrane proteins that allow flow of potassium across the membrane to regulate ion homeostasis, cell proliferation, migration, cell volume, and specific processes such as muscular contraction. Aberrant function or expression of potassium channels can underlie pathologies ranging from heart arrhythmia to cancer; the expression of potassium channels is altered in many types of cancer and that alteration correlates with malignancy and poor prognosis. Targeting potassium channels therefore constitutes a promising approach for cancer therapy. In this review, we discuss strategies to target a particular family of potassium channels, the voltage-gated potassium channels (KV) where a reasonable structural understanding is available. We also discuss the possible obstacles and advantages of such a strategy.

When Fiction Is Just as Real as Fact: No Differences in Reading Behavior between Stories Believed to be Based on True or Fictional Events.

Experiments have shown that compared to fictional texts, readers read factual texts faster and have better memory for described situations. Reading fictional texts on the other hand seems to improve memory for exact wordings and expressions. Most of these studies used a "newspaper" vs. "literature" comparison. In the present study, we investigated the effect of reader's expectation to whether information is true or fictional with a subtler manipulation by labeling short stories as either based on true or fictional events. In addition, we tested whether narrative perspective or individual preference in perspective taking affects reading true or fictional stories differently. In an online experiment, participants (final N = 1,742) read one story which was introduced as based on true events or as fictional (factor fictionality). The story could be narrated in either 1st or 3rd person perspective (factor perspective). We measured immersion in and appreciation of the story, perspective taking, as well as memory for events. We found no evidence that knowing a story is fictional or based on true events influences reading behavior or experiential aspects of reading. We suggest that it is not whether a story is true or fictional, but rather expectations toward certain reading situations (e.g., reading newspaper or literature) which affect behavior by activating appropriate reading goals. Results further confirm that narrative perspective partially influences perspective taking and experiential aspects of reading.

Readers select a comprehension mode independent of pronoun: Evidence from fMRI during narrative comprehension.

Perspective is a crucial feature for communicating about events. Yet it is unclear how linguistically encoded perspective relates to cognitive perspective taking. Here, we tested the effect of perspective taking with short literary stories. Participants listened to stories with 1st or 3rd person pronouns referring to the protagonist, while undergoing fMRI. When comparing action events with 1st and 3rd person pronouns, we found no evidence for a neural dissociation depending on the pronoun. A split sample approach based on the self-reported experience of perspective taking revealed 3 comprehension preferences. One group showed a strong 1st person preference, another a strong 3rd person preference, while a third group engaged in 1st and 3rd person perspective taking simultaneously. Comparing brain activations of the groups revealed different neural networks. Our results suggest that comprehension is perspective dependent, but not on the perspective suggested by the text, but on the reader's (situational) preference.

In vivo imaging of tumour xenografts with an antibody targeting the potassium channel Kv10.1.

The Kv10.1 (Eag1) voltage-gated potassium channel represents a promising molecular target for novel cancer therapies or diagnostic purposes. Physiologically, it is only expressed in the brain, but it was found overexpressed in more than 70 % of tumours of diverse origin. Furthermore, as a plasma membrane protein, it is easily accessible to extracellular interventions. In this study we analysed the feasibility of the anti-Kv10.1 monoclonal antibody mAb62 to target tumour cells in vitro and in vivo and to deliver therapeutics to the tumour. Using time-domain near infrared fluorescence (NIRF) imaging in a subcutaneous MDA-MB-435S tumour model in nude mice, we showed that mAb62-Cy5.5 specifically accumulates at the tumour for at least 1 week in vivo with a maximum intensity at 48 h. Blocking experiments with an excess of unlabelled mAb62 and application of the free Cy5.5 fluorophore demonstrate specific binding to the tumour. Ex vivo NIRF imaging of whole tumours as well as NIRF imaging and microscopy of tumour slices confirmed the accumulation of the mAb62-Cy5.5 in tumours but not in brain tissue. Moreover, mAb62 was conjugated to the prodrug-activating enzyme ß-D-galactosidase (ß-gal; mAb62-ß-gal). The ß-gal activity of the mAb62-ß-gal conjugate was analysed in vitro on Kv10.1-expressing MDA-MB-435S cells in comparison to control AsPC-1 cells. We show that the mAb62-ß-gal conjugate possesses high ß-gal activity when bound to Kv10.1-expressing MDA-MB-435S cells. Moreover, using the ß-gal activatable NIRF probe DDAOG, we detected mAb62-ß-gal activity in vivo over the tumour area. In summary, we could show that the anti-Kv10.1 antibody is a promising tool for the development of novel concepts of targeted cancer therapy.