Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch.

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

Acute Promyelocytic Leukemia With Torque Teno Mini Virus::RARA Fusion: An Approach to Screening and Diagnosis.

Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing 6 cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely underrecognized due to the lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide the necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA- or RNA-based NGS assays, which led to the identification of 4 cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and 3 retrospectively, including 2 from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including 1 with multiple relapses after acute myeloid leukemia-type chemotherapy and hematopoietic stem cell transplant. Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon reinduction (including all-trans retinoic acid in 1 case) and subsequent hematopoietic stem cell transplant. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or fluorescent in situ hybridization. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements and, in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of all-trans retinoic acid may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL.

Event-related potential studies of cross-situational word learning in four-year-old children.

Young children learn word-referent links in cross-situational learning paradigms despite uncertainty as to a given word's correct referent on individual exposures. However, the semantic status of these word-referent links is unknown. Here, we used a novel event-related potential (ERP) testing approach to investigate whether children showed electrophysiological signatures of semantic representations following a typical cross-situational learning paradigm. In Study 1, 20 4-year-old children (mean age: 51.35 months) learned eight new word-object pairs in a cross-situational learning task which included familiar object labeling before training. Then, they completed an ERP task which involved seeing pictures of the novel objects and then hearing words that were either congruent or incongruent with the word-referent association that was trained. Results showed a robust N400 ERP effect, thereby providing evidence for having acquired a semantic representation during the cross-situational learning paradigm. Children also showed good performance on a comprehension test approximately 20 min after training. In a second study, a different sample of 20 4-year-old children (mean age: 52 months) completed the same cross-situational task but without the initial familiar word pretraining. Here, we did not see the N400 effect we saw in Study 1, but children still showed good performance on the delayed comprehension test. We conclude that rapid semantic encoding can occur during cross-situational learning, but that pretraining on the structure of the paradigm may be critical for facilitating that encoding. We speculate on the mechanisms by which pretraining might have effects and discuss the implications of these findings for early word learning.

Multidimensional Reasoning Can Promote 3-Year-Old Children's Performance on the Dimensional Change Card Sort Task.

An important aspect of executive functioning is the ability to flexibly switch between behavioral rules. This study explored how considering the multidimensionality of objects affects behavioral rule switching in 3-year-old children. In Study 1 (N = 40), children who participated in a brief game separating and aggregating an object's dimensions (i.e., color and shape) showed improved performance on the Dimensional Change Card Sort (DCCS), a measure of behavioral rule switching, relative to controls. In Study 2 (N = 80) DCCS performance improved even when the initial practice involved a different dimension (pattern and shape). Thus, practice thinking about multidimensionality can affect 3-year-olds' DCCS performance and therefore may play an important role in the development of flexible thinking.

Inhibitory Control and Preschoolers' Use of Irregular Past Tense Verbs.

We investigated whether children's inhibitory control (IC) is associated with their ability to produce irregular past tense verb forms as well as learn from corrective feedback following overregularization errors. Forty-eight 3;6 to 4;5 year old children were tested on the irregular past tense and provided with adult corrective input via models of correct use or recasts of errors following ungrammatical responses. IC was assessed with a three-item battery of tasks that required suppressing a prepotent response in favor of a non-canonical one. Results showed that IC was associated with children's initial production of irregular forms, but not associated with their post-feedback production. Findings are discussed in terms of current theories of past tense use and acquisition.

Children remember words from ignorant speakers but do not attach meaning: evidence from event-related potentials.

Although we know much about the conditions under which children demonstrate selective social learning, we have a limited understanding of the cognitive mechanisms by which children's selectivity manifests. Here, we report findings from a brain electrophysiological (ERP) study designed to determine the extent to which words presented by ignorant speakers were later both familiar to children and associated with semantic meaning. Forty-eight children (mean age = 6.5 years) first experienced novel word training from either a knowledgeable or an ignorant speaker. Children's ERPs were subsequently recorded as they heard a recording of the speaker using the novel word, followed by a picture of either the object the word was paired with during training (congruent) or a distractor object that was also present during training (incongruent). Children trained by a knowledgeable speaker showed both N200 and N400 effects to the incongruent word-referent pairings, thereby suggesting that the novel words were both familiar and bore a semantic association. In contrast, children trained by an ignorant speaker demonstrated only the N200 effect, thereby suggesting that the word-referent links were familiar, but not associated with semantic meaning. These findings provide evidence that selective word learning involves the disruption of processes specifically associated with semantic consolidation of word learning events.

Conceptual constraints and mechanisms in children's selective learning.

Although we can support Heyes' call for more research on mechanisms, we disagree that the problem has been ignored as Heyes suggests. We also doubt that basic learning mechanisms are alone sufficient to account for the broad range of findings in the selective social learning literature. Although phylogenetically shared learning mechanisms must support selective social learning, we believe that they must also be guided by top-down conceptual considerations that may be special to humans. Research to date has been focused on establishing the boundary conditions on selective social learning, with the goal of making generalizations that will constrain theorizing about the character of that special knowledge. This is critical to our understanding of both why and how selective social learning manifests in children.

Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.

OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion. All mutations were protein-truncating or splicing mutations. We identified 2 recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, 7 of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical, and behavioral symptoms. All CS participants were nonverbal and had intellectual disability, epilepsy, and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%), and magnetic resonance imaging evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%), and a majority exhibited high pain threshold. INTERPRETATION: This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy, and regression.

The Student Curriculum Review Team: How we catalyze curricular changes through a student-centered approach.

Student feedback is a valuable asset in curriculum evaluation and improvement, but many institutions have faced challenges implementing it in a meaningful way. In this article, we report the rationale, process and impact of the Student Curriculum Review Team (SCRT), a student-led and faculty-supported organization at the Johns Hopkins University School of Medicine. SCRT's evaluation of each pre-clinical course is composed of a comprehensive three-step process: a review of course evaluation data, a Town Hall Meeting and online survey to generate and assess potential solutions, and a thoughtful discussion with course directors. Over the past two years, SCRT has demonstrated the strength of its approach by playing a substantial role in improving medical education, as reported by students and faculty. Furthermore, SCRT's uniquely student-centered, collaborative model has strengthened relationships between students and faculty and is one that could be readily adapted to other medical schools or academic institutions.

How theory of mind leads to positive first impressions.

A common conjecture is that social success relies on "theory of mind"-the everyday skill of imputing mental states to others. We test the hypothesis that individuals with stronger theory of mind skills and motivation garner more positive first impressions because of how they interact with others. Participants included 334 young adults who were paired with a peer for a first-time meeting. Dyads completed a cooperative Lego-building task, which was videotaped and later coded for behavioral manifestations of theory of mind by independent raters. Theory of mind accuracy and motivation were assessed with validated laboratory tasks and a self-report questionnaire, respectively. First impressions were assessed based on partner's ratings of participant likeability, enjoyment of the interaction, and changes in positive affect. Results of actor-partner interdependence mediation models revealed that the associations between theory of mind and first impressions are indirect and mediated through behaviors. Specifically, participants with stronger theory of mind demonstrated greater cognitive sensitivity and pragmatic conversational skills. However, only cognitive sensitivity subsequently predicted more favorable first impressions. This research shows that social-cognitive skills can affect others' social impressions through their behavioral manifestations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

FGFR Alterations in Thyroid Carcinoma: A Novel Class of Primary Drivers with Significant Therapeutic Implications and Secondary Molecular Events Potentially Mediating Resistance in Thyroid Malignancy.

Background: Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods: We completed a multicenter retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results: Overall, 5030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2:VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions: This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.

Collagen type I PET/MRI enables evaluation of treatment response in pancreatic cancer in pre-clinical and first-in-human translational studies.

Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, 68Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. Methods: We evaluated the specificity of 68Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of 68Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic 68Ga-CBP8 PET/MRI, and five underwent follow up 68Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. Results: 68Ga-CBP8 showed specific binding to PDAC compared to non-binding 68Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). 68Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. 68Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher 68Ga-CBP8 uptake in tumor compared to pancreas (SUVmean: 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUVmean: 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUVmean (R2 = 0.54, P = 0.0007). Conclusions: This study demonstrates the specificity of 68Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.

ERP responses to sexual cues among young women attracted to men.

Previous event-related potential (ERP) studies reported larger N170, P3, and late positive potential (LPP) amplitudes to sexual than nonsexual stimuli. These ERPs may not be specifically sensitive to processing sexual cues, however, because the sexual stimuli included information beyond sexual cues (e.g., faces, bodies, social interaction) to a greater extent than comparison stimuli. We investigated ERPs to stimuli that focused on sexual and nonsexual body regions, in different states of readiness for activity, to elucidate neural responses involved in processing sexual cues. Forty cisgender, primarily white, undergraduate women who were attracted to men (Mage  = 18.6, SD = 0.9) viewed images that varied by male body part (penis, arm) and activity state (rest, poised for activity). Participants viewed 40 images per category (flaccid penises, erect penises, outstretched arms, bent arms). Electroencephalography (EEG) was recorded using a 128-channel net, time-locked to the onset of each image. Using a whole-head cluster-mass approach, we found that the P3 was sensitive to sexual readiness-P3 amplitudes were larger to erect than flaccid penises, but not to bent than outstretched arms. The N170 and LPP components did not show evidence of similarly specific responses to sexual readiness, revealing potential dissociation of different neural processes commonly elicited in response to more complex sexual stimuli. An additional novel finding was that an anterior N270-400 was sensitive to sexual readiness. Findings clarify the brain's rapid responses to sexual stimuli, setting the stage for future research aimed at better understanding the neurocognitive processes that contribute to the coordination of sexual arousal.

Dopamine receptor D4 gene variation predicts preschoolers' developing theory of mind.

Individual differences in preschoolers' understanding that human action is caused by internal mental states, or representational theory of mind (RTM), are heritable, as are developmental disorders such as autism in which RTM is particularly impaired. We investigated whether polymorphisms of genes affecting dopamine (DA) utilization and metabolism constitute part of the molecular basis of this heritability. Seventy-three 42- to 54-month-olds were given a battery of RTM tasks along with other task batteries that measured executive functioning and representational understanding more generally. Polymorphisms of the dopamine D4 receptor gene (DRD4) were associated with RTM performance such that preschoolers with shorter alleles outperformed those with one or more longer alleles. However, polymorphisms of the catechol-O-methyl transferase gene (COMT) and the dopamine transporter gene (DAT1) genes were not associated with children's RTM performance. Further tests showed that the association between DRD4 allele length and RTM performance was not attributable to a common association with executive functioning or representational understanding more generally. We conclude that DRD4 receptors, likely via their effects on frontal lobe development and functioning, may represent a neuromaturational constraint governing the stereotypical and universal trajectory of RTM development.

For love or money? What motivates people to know the minds of others?

Mood affects social cognition and "theory of mind", such that people in a persistent negative mood (i.e., dysphoria) have enhanced abilities at making subtle judgements about others' mental states. Theorists have argued that this hypersensitivity to subtle social cues may have adaptive significance in terms of solving interpersonal problems and/or minimising social risk. We tested whether increasing the social salience of a theory of mind task would preferentially increase dyspshoric individuals' performance on the task. Forty-four dysphoric and 51 non-dysphoric undergraduate women participated in a theory of mind decoding task following one of three motivational manipulations: (i) social motivation (ii) monetary motivation, or (iii) no motivation. Social motivation was associated with the greatest accuracy of mental state decoding for the dysphoric group, whereas the non-dysphoric group showed the highest accuracy in the monetary motivation condition. These results suggest that dysphoric individuals may be especially, and preferentially, motivated to understand the mental states of others.

Learning foreign labels from a foreign speaker: the role of (limited) exposure to a second language.

Three- and four-year-olds (N = 144) were introduced to novel labels by an English speaker and a foreign speaker (of Nordish, a made-up language), and were asked to endorse one of the speaker's labels. Monolingual English-speaking children were compared to bilingual children and English-speaking children who were regularly exposed to a language other than English. All children tended to endorse the English speaker's labels when asked 'What do you call this?', but when asked 'What do you call this in Nordish?', children with exposure to a second language were more likely to endorse the foreign label than monolingual and bilingual children. The findings suggest that, at this age, exposure to, but not necessarily immersion in, more than one language may promote the ability to learn foreign words from a foreign speaker.

Theory of mind in dysphoric and non--dysphoric adults: An ERP study of true-- and false--belief reasoning.

Theory of mind (ToM) - the understanding that others' behaviors are connected with internal mental states - is an important part of everyday social cognition. There is increasing behavioral evidence that ToM reasoning can be affected by mood. To gain insight into the ways sad mood may affect the underlying mechanisms of ToM reasoning, we recorded event-related brain potentials (ERPs) as dysphoric (N = 16) and non-dysphoric (N = 24) participants reasoned about a protagonist's true or false beliefs about an object's location. Results showed significant group effects on early components of the ERP - individuals in the dysphoric group showed greater amplitudes for the anterior N1 and N2/P2 components relative to those in the non-dysphoric group. Later in the ERP, non-dysphoric individuals showed evidence of neurocognitive dissociations between true and false belief. Dysphoric individuals, however, did not show evidence for these later dissociations. This evidence suggests that dysphoria may be associated with effortful reasoning about other's mental states, even when that effort is not necessary (i.e., when reasoning about true beliefs). We discuss the implications of these findings for understanding how mood affects ToM reasoning and for how especially deliberative ToM processing in dysphoria may lead to social difficulties.

Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain.

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Maternal history of depression is associated with enhanced theory of mind in depressed and nondepressed adult women.

Theory of mind forms the basis of social cognition and develops on a stereotyped ontogenetic timetable. Yet, there are individual differences in theory of mind that may be transmitted through genetic and/or environmental mechanisms. In the current study we examined the relation of maternal history of depression to individual differences in theory of mind in a sample of adult women. Sixty-one depressed women (23% with a positive maternal history of depression) and 30 non-depressed women (33% with a positive maternal history of depression) completed the 'Reading the Mind in the Eyes task', a test of theory of mind decoding. Women with a maternal history of depression performed better on the Eyes task than those without. Further, the younger the mother's onset of depression, the better the current probands' Eyes task performance. These results are consistent with a broader literature linking hypersensitive social cognition and depression risk. We discuss the potential clinical implications of our results.

Parents' use of conventional and unconventional labels in conversations with their preschoolers.

Parents' use of conventional versus unconventional labels with their two- (n=12), three- (n=12) and four-year-old children (n=12) was assessed as they talked about objects that were either known or unknown to them. For known objects, parents provided typical conventional labels casually during the conversation. For unknown objects, parents were less likely to use typical nouns as labels and marked their labels with additional information suggesting that the labels might be unconventional. Parents marked potentially unconventional labels by providing explicit statements of ignorance and paralinguistic cues of uncertainty. These patterns were strongest when the unknown objects were manufactured as opposed to homemade, possibly because manufactured objects are supposed to have conventional names that parents were unable to provide. Parents' marking of unconventional labels may help children recognize when new word forms should be treated with caution and guide their learning accordingly.