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Eating onion ice cream is improbable, and levitating ice cream is impossible. But scooping ice cream using sadness is not just impossible: it is inconceivable. While prior work has examined the distinction between improbable and impossible events, there has been little empirical research on inconceivability. Here, we report a behavioral and computational study of inconceivability in three parts. First, we find that humans reliably categorize events as inconceivable, separate from probable, improbable, and impossible. Second, we find that we can decode the modal category of a sentence using language-model-derived estimates of subjective event probabilities. Third, we reproduce a recent finding that improbable events yield slowest response times in a possibility judgment task, and show that inconceivable events are faster to judge than impossible and improbable events. Overall, our results suggest that people distinguish the impossible from the inconceivable, and such distinctions may be based on graded rather than discrete judgments.

Machine creativity is on the rise. Recent studies find that large language models achieve human performance on common psychological tests of creativity, which often pose a given problem and ask for novel or unusual solutions. But can AI go beyond producing solutions for given problems, to creatively propose new problems? We present the Task Task, a novel test that asks participants to come up with creative problems. In this test, we assess the ability of humans and GPT-4 to design challenge tasks for a game show. We evaluated proposed tasks using crowdsourced subjective creativity ratings, as well as computational measures of linguistic complexity and semantic content. We found that GPT-4 achieves similar scores as humans on creativity, originality, and judgments of how fun or difficult the tasks are. However, model-generated output tends to be shorter and connect more semantically distant concepts. We discuss implications and future directions for the psychology of creativity.

Tissues comprise ordered arrangements of cells that can be surprisingly disordered in their details. How the properties of single cells and their microenvironment contribute to the balance between order and disorder at the tissue-scale remains poorly understood. Here, we address this question using the self-organization of human mammary organoids as a model. We find that organoids behave like a dynamic structural ensemble at the steady state. We apply a maximum entropy formalism to derive the ensemble distribution from three measurable parameters - the degeneracy of structural states, interfacial energy, and tissue activity (the energy associated with positional fluctuations). We link these parameters with the molecular and microenvironmental factors that control them to precisely engineer the ensemble across multiple conditions. Our analysis reveals that the entropy associated with structural degeneracy sets a theoretical limit to tissue order and provides new insight for tissue engineering, development, and our understanding of disease progression.

INTRODUCTION: Smoking during breast radiotherapy (RT) may be associated with radiation-induced skin injury (RISI). We aimed to determine if a urinary biomarker of tobacco smoke exposure is associated with increased rates of RISI during and after breast RT. PATIENTS AND METHODS: Women with Stage 0-IIIA breast cancer treated with breast-conserving surgery or mastectomy followed by RT to the breast or chest wall with or without regional nodal irradiation were prospectively enrolled on a multicenter study assessing acute/late RISI. 980 patients with urinary cotinine (UCot) measurements (baseline and end-RT) were categorized into three groups. Acute and late RISI was assessed using the ONS Acute Skin Reaction scale and the LENT-SOMA Criteria. RESULTS: Late Grade 2+ and Grade 3+ RISI occurred in 18.2% and 1.9% of patients, respectively-primarily fibrosis, pain, edema, and hyperpigmentation. Grade 2+ late RISI was associated with UCot group (P= 006). Multivariable analysis identified UCot-based light smoker/secondhand smoke exposure (HR 1.79, P= .10) and smoking (HR 1.60, p = .06) as non-significantly associated with an increased risk of late RISI. Hypofractionated breast RT was associated with decreased risk of late RISI (HR 0.51, P=.03). UCot was not associated with acute RISI, multivariable analysis identified race, obesity, RT site/fractionation, and bra size to be associated with acute RISI. CONCLUSIONS: Tobacco exposure during breast RT may be associated with an increased risk of late RISI without an effect on acute toxicity. Smoking cessation should be encouraged prior to radiotherapy to minimize these and other ill effects of smoking.

BackgroundProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionsWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

How do humans produce and comprehend language in pragmatic ways? A variety of models of pragmatic inferences have been proposed, and these models are typically evaluated on their ability to account for human inferences in reference game experiments. However, these experiments are not tailored to target theoretical differences between models or clearly tease apart model predictions. We propose an optimal experiment design approach to systematically construct reference games that can optimally differentiate between models of human pragmatic reasoning. We demonstrate this approach and apply it to four models that have been debated in the literature: Grammar-based, Iterated Best Response (IBR), Rational Speech Act (RSA), and a recent variant of RSA grounded in rate-distortion theory (RD-RSA). Using these optimal reference game experiments, we find empirical evidence favoring iterated rationality models over the grammar-based model, as well as support for the relevance of rate-distortion theory to human pragmatic inferences. These results suggest that our optimal reference game design framework may help adjudicate between computational theories of pragmatic reasoning.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

Iterated models of pragmatic reasoning, such as the Rational Speech Act model (RSA; Frank & Goodman, 2012), aim to explain how meaning is understood in context. We propose an optimal experiment design approach for teasing apart such models, in which contexts are optimized for differentiating model predictions in reference games. We use this approach to compare RSA with RD-RSA (Zaslavsky et al., 2020), a recent variant of RSA grounded in Rate-Distortion theory. First, we show that our optimal experiment design approach finds cases in which the two models yield qualitatively different predictions, in contrast to previous experimental settings for which these models generate similar predictions. Next, we test the models on newly collected experimental data using our optimal design. Our results show that in this experimental setting RD-RSA robustly outperforms the standard RSA model. This finding supports the idea that Rate-Distortion theory may characterize human pragmatic reasoning.

Scalar implicatures, one of the signatures of pragmatic reasoning, are believed to arise from competing alternative utterances, which the listener knows that the speaker could have used to express a strengthened meaning. But do scalar implicatures also arise in the presence of nonce objects, for which no alternative name is known? We conduct a series of experiments assessing the degree of scalar strengthening driven by familiar and nonce objects. We find that nonce objects can derive scalar implicatures as strongly as familiar objects in simple reference games. Our experiments also reveal an asymmetry in the relative strengths of familiar- and nonce-driven inferences: relative to the prior, participants preferentially interpret the name of a shared feature as referring to an object with an additional nonce feature over an object with an additional familiar feature, suggesting that familiar alternatives exert greater scalar pressure than nonce alternatives. We also present exploratory model simulations suggesting that our results may be explained by rationally reasoning about a high-cost description of the novel object. Our findings support the idea that novel lexical entries may be generated from one-shot encounters and spontaneously used in pragmatic inference.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Human reading behavior is tuned to the statistics of natural lan-guage: the time it takes human subjects to read a word can bepredicted from estimates of the word’s probability in context.However, it remains an open question what computational ar-chitecture best characterizes the expectations deployed in realtime by humans that determine the behavioral signatures ofreading. Here we test over two dozen models, independentlymanipulating computational architecture and training datasetsize, on how well their next-word expectations predict humanreading time behavior on naturalistic text corpora. Consistentwith previous work, we find that across model architecturesand training dataset sizes the relationship between word log-probability and reading time is (near-)linear. We next evalu-ate how features of these models determine their psychometricpredictive power, or ability to predict human reading behav-ior. In general, the better a model’s next-word expectations(as measured by the traditional language modeling perplexityobjective), the better its psychometric predictive power. How-ever, we find nontrivial differences in psychometric predictivepower across model architectures. For any given perplexity,deep Transformer models and n-gram models generally showsuperior psychometric predictive power over LSTM or struc-turally supervised neural models, especially for eye movementdata. Finally, we compare models’ psychometric predictivepower to the depth of their syntactic knowledge, as measuredby a battery of syntactic generalization tests developed usingmethods from controlled psycholinguistic experiments. Onceperplexity is controlled for, we find no significant relationshipbetween syntactic knowledge and predictive power. These re-sults suggest that, at least for the present state of natural lan-guage technology, different approaches may be required to bestmodel human real-time language comprehension behavior innaturalistic reading versus behavior for controlled linguisticmaterials designed for targeted probing of syntactic knowl-edge.

Sample multiplexing facilitates scRNA-seq by reducing costs and identifying artifacts such as cell doublets. However, universal and scalable sample barcoding strategies have not been described. We therefore developed MULTI-seq: multiplexing using lipid-tagged indices for single-cell and single-nucleus RNA sequencing. MULTI-seq reagents can barcode any cell type or nucleus from any species with an accessible plasma membrane. The method involves minimal sample processing, thereby preserving cell viability and endogenous gene expression patterns. When cells are classified into sample groups using MULTI-seq barcode abundances, data quality is improved through doublet identification and recovery of cells with low RNA content that would otherwise be discarded by standard quality-control workflows. We use MULTI-seq to track the dynamics of T-cell activation, perform a 96-plex perturbation experiment with primary human mammary epithelial cells and multiplex cryopreserved tumors and metastatic sites isolated from a patient-derived xenograft mouse model of triple-negative breast cancer.

BACKGROUND: Adjuvant radiotherapy (RT) can increase the risk of developing pain; however, the molecular mechanisms of RT-related pain remain unclear. The current study aimed to identify susceptibility loci and enriched pathways for clinically relevant acute post-RT pain, defined as having moderate to severe pain (pain score ≥ 4) at the completion of RT. METHODS: We conducted a genome-wide association study (GWAS) with 1,344,832 single-nucleotide polymorphisms (SNPs), a gene-based analysis using PLINK set-based tests of 19,621 genes, and a functional enrichment analysis of a gene list of 875 genes with p

Everyday hearing requires inferring the causal factors that produce a sound, as when we separate the acoustic effectsof the environment (reverberation) from those of sound sources. Here we consider perceptual inferences from impactsounds, in which the resonance of a struck object provides cues to its material, but via acoustic effects that might benontrivial to disentangle from reverberation. We investigated whether and how humans separate the effects of objectresonance and reverberation in a material classification task. For comparison, we implemented a Bayesian observer thatinferred material from a generative model of object sounds without reverberation. Humans were robust to reverberation,whereas the model was not. However, human robustness was specific to reverberation consistent with the statistics ofnatural environments. The results suggest that humans use internal models of room and object acoustics to determine theirrespective contributions to sound, providing an example of causal inference in audition.