RESUMEN
Despite decades of antibody research, it remains challenging to predict the specificity of an antibody solely based on its sequence. Two major obstacles are the lack of appropriate models and the inaccessibility of datasets for model training. In this study, we curated >5,000 influenza hemagglutinin (HA) antibodies by mining research publications and patents, which revealed many distinct sequence features between antibodies to HA head and stem domains. We then leveraged this dataset to develop a lightweight memory B cell language model (mBLM) for sequence-based antibody specificity prediction. Model explainability analysis showed that mBLM could identify key sequence features of HA stem antibodies. Additionally, by applying mBLM to HA antibodies with unknown epitopes, we discovered and experimentally validated many HA stem antibodies. Overall, this study not only advances our molecular understanding of the antibody response to the influenza virus but also provides a valuable resource for applying deep learning to antibody research.
RESUMEN
FOXP2, initially identified for its role in human speech, contains two nonsynonymous substitutions derived in the human lineage. Evidence for a recent selective sweep in Homo sapiens, however, is at odds with the presence of these substitutions in archaic hominins. Here, we comprehensively reanalyze FOXP2 in hundreds of globally distributed genomes to test for recent selection. We do not find evidence of recent positive or balancing selection at FOXP2. Instead, the original signal appears to have been due to sample composition. Our tests do identify an intronic region that is enriched for highly conserved sites that are polymorphic among humans, compatible with a loss of function in humans. This region is lowly expressed in relevant tissue types that were tested via RNA-seq in human prefrontal cortex and RT-PCR in immortalized human brain cells. Our results represent a substantial revision to the adaptive history of FOXP2, a gene regarded as vital to human evolution.
Asunto(s)
Factores de Transcripción Forkhead/genética , Encéfalo/citología , Encéfalo/metabolismo , Línea Celular , Bases de Datos Genéticas , Exones , Femenino , Genoma Humano , Haplotipos , Humanos , Intrones , Masculino , Cadenas de Markov , Polimorfismo de Nucleótido Simple , Corteza Prefrontal/metabolismoRESUMEN
It has long been argued that only humans could produce and understand language. But now, for the first time, artificial language models (LMs) achieve this feat. Here we survey the new purchase LMs are providing on the question of how language is implemented in the brain. We discuss why, a priori, LMs might be expected to share similarities with the human language system. We then summarize evidence that LMs represent linguistic information similarly enough to humans to enable relatively accurate brain encoding and decoding during language processing. Finally, we examine which LM properties-their architecture, task performance, or training-are critical for capturing human neural responses to language and review studies using LMs as in silico model organisms for testing hypotheses about language. These ongoing investigations bring us closer to understanding the representations and processes that underlie our ability to comprehend sentences and express thoughts in language.
Asunto(s)
Encéfalo , Lenguaje , Humanos , Encéfalo/fisiología , Animales , Inteligencia Artificial , Modelos NeurológicosRESUMEN
Current base editors (BEs) use DNA deaminases, including cytidine deaminase in cytidine BE (CBE) or adenine deaminase in adenine BE (ABE), to facilitate transition nucleotide substitutions. Combining CBE or ABE with glycosylase enzymes can induce limited transversion mutations. Nonetheless, a critical demand remains for BEs capable of generating alternative mutation types, such as T>G corrections. In this study, we leveraged pre-trained protein language models to optimize a uracil-N-glycosylase (UNG) variant with altered specificity for thymines (eTDG). Notably, after two rounds of testing fewer than 50 top-ranking variants, more than 50% exhibited over 1.5-fold enhancement in enzymatic activities. When eTDG was fused with nCas9, it induced programmable T-to-S (G/C) substitutions and corrected db/db diabetic mutation in mice (up to 55%). Our findings not only establish orthogonal strategies for developing novel BEs but also demonstrate the capacities of protein language models for optimizing enzymes without extensive task-specific training data.
Asunto(s)
Ácidos Alcanesulfónicos , Edición Génica , Uracil-ADN Glicosidasa , Animales , Ratones , Mutación , Uracil-ADN Glicosidasa/genética , Uracil-ADN Glicosidasa/metabolismoRESUMEN
The use of vocalizations to communicate information and elaborate social bonds is an adaptation seen in many vertebrate species. Human speech is an extreme version of this pervasive form of communication. Unlike the vocalizations exhibited by the majority of land vertebrates, speech is a learned behavior requiring early sensory exposure and auditory feedback for its development and maintenance. Studies in humans and a small number of other species have provided insights into the neural and genetic basis for learned vocal communication and are helping to delineate the roles of brain circuits across the cortex, basal ganglia, and cerebellum in generating vocal behaviors. This Review provides an outline of the current knowledge about these circuits and the genes implicated in vocal communication, as well as a perspective on future research directions in this field.
Asunto(s)
Habla , Vocalización Animal , Animales , Encéfalo/fisiología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Aprendizaje , Enfermedades del Sistema Nervioso/genética , Vías NerviosasRESUMEN
Vocal communication is a critical feature of social interaction across species; however, the relation between such behavior in humans and nonhumans remains unclear. To enable comparative investigation of this topic, we review the literature pertinent to interactive language use and identify the superset of cognitive operations involved in generating communicative action. We posit these functions comprise three intersecting multistep pathways: (a) the Content Pathway, which selects the movements constituting a response; (b) the Timing Pathway, which temporally structures responses; and (c) the Affect Pathway, which modulates response parameters according to internal state. These processing streams form the basis of the Convergent Pathways for Interaction framework, which provides a conceptual model for investigating the cognitive and neural computations underlying vocal communication across species.
Asunto(s)
Lenguaje , Vocalización Animal , Animales , Humanos , Vocalización Animal/fisiologíaRESUMEN
Generative artificial intelligence (AI) is a burgeoning field with widespread applications, including in science. Here, we explore two paradigms that provide insight into the capabilities and limitations of Chat Generative Pre-trained Transformer (ChatGPT): its ability to (i) define a core biological concept (the Central Dogma of molecular biology); and (ii) interpret the genetic code.
Asunto(s)
Inteligencia Artificial , Código Genético , Biología MolecularRESUMEN
Comparative studies on brain asymmetry date back to the 19th century but then largely disappeared due to the assumption that lateralization is uniquely human. Since the reemergence of this field in the 1970s, we learned that left-right differences of brain and behavior exist throughout the animal kingdom and pay off in terms of sensory, cognitive, and motor efficiency. Ontogenetically, lateralization starts in many species with asymmetrical expression patterns of genes within the Nodal cascade that set up the scene for later complex interactions of genetic, environmental, and epigenetic factors. These take effect during different time points of ontogeny and create asymmetries of neural networks in diverse species. As a result, depending on task demands, left- or right-hemispheric loops of feedforward or feedback projections are then activated and can temporarily dominate a neural process. In addition, asymmetries of commissural transfer can shape lateralized processes in each hemisphere. It is still unclear if interhemispheric interactions depend on an inhibition/excitation dichotomy or instead adjust the contralateral temporal neural structure to delay the other hemisphere or synchronize with it during joint action. As outlined in our review, novel animal models and approaches could be established in the last decades, and they already produced a substantial increase of knowledge. Since there is practically no realm of human perception, cognition, emotion, or action that is not affected by our lateralized neural organization, insights from these comparative studies are crucial to understand the functions and pathologies of our asymmetric brain.
Asunto(s)
Evolución Biológica , Encéfalo/fisiología , Lateralidad Funcional/genética , Lateralidad Funcional/fisiología , Animales , Encéfalo/anatomía & histología , Historia del Siglo XIX , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Investigación/historiaRESUMEN
Large language models (LLMs) are generating interest in medical settings. For example, LLMs can respond coherently to medical queries by providing plausible differential diagnoses based on clinical notes. However, there are many questions to explore, such as evaluating differences between open- and closed-source LLMs as well as LLM performance on queries from both medical and non-medical users. In this study, we assessed multiple LLMs, including Llama-2-chat, Vicuna, Medllama2, Bard/Gemini, Claude, ChatGPT3.5, and ChatGPT-4, as well as non-LLM approaches (Google search and Phenomizer) regarding their ability to identify genetic conditions from textbook-like clinician questions and their corresponding layperson translations related to 63 genetic conditions. For open-source LLMs, larger models were more accurate than smaller LLMs: 7b, 13b, and larger than 33b parameter models obtained accuracy ranges from 21%-49%, 41%-51%, and 54%-68%, respectively. Closed-source LLMs outperformed open-source LLMs, with ChatGPT-4 performing best (89%-90%). Three of 11 LLMs and Google search had significant performance gaps between clinician and layperson prompts. We also evaluated how in-context prompting and keyword removal affected open-source LLM performance. Models were provided with 2 types of in-context prompts: list-type prompts, which improved LLM performance, and definition-type prompts, which did not. We further analyzed removal of rare terms from descriptions, which decreased accuracy for 5 of 7 evaluated LLMs. Finally, we observed much lower performance with real individuals' descriptions; LLMs answered these questions with a maximum 21% accuracy.
RESUMEN
The neural correlates of sentence production are typically studied using task paradigms that differ considerably from the experience of speaking outside of an experimental setting. In this fMRI study, we aimed to gain a better understanding of syntactic processing in spontaneous production versus naturalistic comprehension in three regions of interest (BA44, BA45, and left posterior middle temporal gyrus). A group of participants (n = 16) was asked to speak about the events of an episode of a TV series in the scanner. Another group of participants (n = 36) listened to the spoken recall of a participant from the first group. To model syntactic processing, we extracted word-by-word metrics of phrase-structure building with a top-down and a bottom-up parser that make different hypotheses about the timing of structure building. While the top-down parser anticipates syntactic structure, sometimes before it is obvious to the listener, the bottom-up parser builds syntactic structure in an integratory way after all of the evidence has been presented. In comprehension, neural activity was found to be better modeled by the bottom-up parser, while in production, it was better modeled by the top-down parser. We additionally modeled structure building in production with two strategies that were developed here to make different predictions about the incrementality of structure building during speaking. We found evidence for highly incremental and anticipatory structure building in production, which was confirmed by a converging analysis of the pausing patterns in speech. Overall, this study shows the feasibility of studying the neural dynamics of spontaneous language production.
Asunto(s)
Benchmarking , Recuerdo Mental , Humanos , Lenguaje , Programas Informáticos , HablaRESUMEN
During real-time language comprehension, our minds rapidly decode complex meanings from sequences of words. The difficulty of doing so is known to be related to words' contextual predictability, but what cognitive processes do these predictability effects reflect? In one view, predictability effects reflect facilitation due to anticipatory processing of words that are predictable from context. This view predicts a linear effect of predictability on processing demand. In another view, predictability effects reflect the costs of probabilistic inference over sentence interpretations. This view predicts either a logarithmic or a superlogarithmic effect of predictability on processing demand, depending on whether it assumes pressures toward a uniform distribution of information over time. The empirical record is currently mixed. Here, we revisit this question at scale: We analyze six reading datasets, estimate next-word probabilities with diverse statistical language models, and model reading times using recent advances in nonlinear regression. Results support a logarithmic effect of word predictability on processing difficulty, which favors probabilistic inference as a key component of human language processing.
Asunto(s)
Comprensión , Lenguaje , Humanos , Modelos EstadísticosRESUMEN
Adult second language (L2) learning is a challenging enterprise inducing neuroplastic changes in the human brain. However, it remains unclear how the structural language connectome and its subnetworks change during adult L2 learning. The current study investigated longitudinal changes in white matter (WM) language networks in each hemisphere, as well as their interconnection, in a large group of Arabic-speaking adults who learned German intensively for 6 mo. We found a significant increase in WM-connectivity within bilateral temporal-parietal semantic and phonological subnetworks and right temporal-frontal pathways mainly in the second half of the learning period. At the same time, WM-connectivity between the two hemispheres decreased significantly. Crucially, these changes in WM-connectivity are correlated with L2 performance. The observed changes in subnetworks of the two hemispheres suggest a network reconfiguration due to lexical learning. The reduced interhemispheric connectivity may indicate a key role of the corpus callosum in L2 learning by reducing the inhibition of the language-dominant left hemisphere. Our study highlights the dynamic changes within and across hemispheres in adult language-related networks driven by L2 learning.
Asunto(s)
Sustancia Blanca , Adulto , Humanos , Lenguaje , Encéfalo/fisiología , Aprendizaje/fisiología , Semántica , Imagen por Resonancia MagnéticaRESUMEN
Zebra finches, a species of songbirds, learn to sing by creating an auditory template through the memorization of model songs (sensory learning phase) and subsequently translating these perceptual memories into motor skills (sensorimotor learning phase). It has been traditionally believed that babbling in juvenile birds initiates the sensorimotor phase while the sensory phase of song learning precedes the onset of babbling. However, our findings challenge this notion by demonstrating that testosterone-induced premature babbling actually triggers the onset of the sensory learning phase instead. We reveal that juvenile birds must engage in babbling and self-listening to acquire the tutor song as the template. Notably, the sensory learning of the template in songbirds requires motor vocal activity, reflecting the observation that prelinguistic babbling in humans plays a crucial role in auditory learning for language acquisition.
Asunto(s)
Pinzones , Animales , Humanos , Vocalización Animal , Aprendizaje , Desarrollo del LenguajeRESUMEN
Linguistic communication is an intrinsically social activity that enables us to share thoughts across minds. Many complex social uses of language can be captured by domain-general representations of other minds (i.e., mentalistic representations) that externally modulate linguistic meaning through Gricean reasoning. However, here we show that representations of others' attention are embedded within language itself. Across ten languages, we show that demonstratives-basic grammatical words (e.g., "this"/"that") which are evolutionarily ancient, learned early in life, and documented in all known languages-are intrinsic attention tools. Beyond their spatial meanings, demonstratives encode both joint attention and the direction in which the listener must turn to establish it. Crucially, the frequency of the spatial and attentional uses of demonstratives varies across languages, suggesting that both spatial and mentalistic representations are part of their conventional meaning. Using computational modeling, we show that mentalistic representations of others' attention are internally encoded in demonstratives, with their effect further boosted by Gricean reasoning. Yet, speakers are largely unaware of this, incorrectly reporting that they primarily capture spatial representations. Our findings show that representations of other people's cognitive states (namely, their attention) are embedded in language and suggest that the most basic building blocks of the linguistic system crucially rely on social cognition.
Asunto(s)
Atención , Lenguaje , Humanos , Atención/fisiología , Cognición/fisiología , Lingüística , Comunicación , Femenino , MasculinoRESUMEN
There is evidence from both behavior and brain activity that the way information is structured, through the use of focus, can up-regulate processing of focused constituents, likely to give prominence to the relevant aspects of the input. This is hypothesized to be universal, regardless of the different ways in which languages encode focus. In order to test this universalist hypothesis, we need to go beyond the more familiar linguistic strategies for marking focus, such as by means of intonation or specific syntactic structures (e.g., it-clefts). Therefore, in this study, we examine Makhuwa-Enahara, a Bantu language spoken in northern Mozambique, which uniquely marks focus through verbal conjugation. The participants were presented with sentences that consisted of either a semantically anomalous constituent or a semantically nonanomalous constituent. Moreover, focus on this particular constituent could be either present or absent. We observed a consistent pattern: Focused information generated a more negative N400 response than the same information in nonfocus position. This demonstrates that regardless of how focus is marked, its consequence seems to result in an upregulation of processing of information that is in focus.
Asunto(s)
Lenguaje , Humanos , Femenino , Masculino , Adulto , Mozambique , Electroencefalografía , Semántica , Encéfalo/fisiología , Adulto Joven , Lingüística , Potenciales Evocados/fisiologíaRESUMEN
How are the merits of innovative ideas communicated in science? Here, we conduct semantic analyses of grant application success with a focus on scientific promotional language, which may help to convey an innovative idea's originality and significance. Our analysis attempts to surmount the limitations of prior grant studies by examining the full text of tens of thousands of both funded and unfunded grants from three leading public and private funding agencies: the NIH, the NSF, and the Novo Nordisk Foundation, one of the world's largest private science funding foundations. We find a robust association between promotional language and the support and adoption of innovative ideas by funders and other scientists. First, a grant proposal's percentage of promotional language is associated with up to a doubling of the grant's probability of being funded. Second, a grant's promotional language reflects its intrinsic innovativeness. Third, the percentage of promotional language is predictive of the expected citation and productivity impact of publications that are supported by funded grants. Finally, a computer-assisted experiment that manipulates the promotional language in our data demonstrates how promotional language can communicate the merit of ideas through cognitive activation. With the incidence of promotional language in science steeply rising, and the pivotal role of grants in converting promising and aspirational ideas into solutions, our analysis provides empirical evidence that promotional language is associated with effectively communicating the merits of innovative scientific ideas.
Asunto(s)
Lenguaje , Humanos , Ciencia , Organización de la Financiación , Estados Unidos , Apoyo a la Investigación como Asunto , CreatividadRESUMEN
Large language models (LLMs) are currently at the forefront of intertwining AI systems with human communication and everyday life. Thus, aligning them with human values is of great importance. However, given the steady increase in reasoning abilities, future LLMs are under suspicion of becoming able to deceive human operators and utilizing this ability to bypass monitoring efforts. As a prerequisite to this, LLMs need to possess a conceptual understanding of deception strategies. This study reveals that such strategies emerged in state-of-the-art LLMs, but were nonexistent in earlier LLMs. We conduct a series of experiments showing that state-of-the-art LLMs are able to understand and induce false beliefs in other agents, that their performance in complex deception scenarios can be amplified utilizing chain-of-thought reasoning, and that eliciting Machiavellianism in LLMs can trigger misaligned deceptive behavior. GPT-4, for instance, exhibits deceptive behavior in simple test scenarios 99.16% of the time (P < 0.001). In complex second-order deception test scenarios where the aim is to mislead someone who expects to be deceived, GPT-4 resorts to deceptive behavior 71.46% of the time (P < 0.001) when augmented with chain-of-thought reasoning. In sum, revealing hitherto unknown machine behavior in LLMs, our study contributes to the nascent field of machine psychology.
Asunto(s)
Decepción , Lenguaje , Humanos , Inteligencia ArtificialRESUMEN
Theories of language development-informed largely by studies of Western, middleclass infants-have highlighted the language that caregivers direct to children as a key driver of language learning. However, some have argued that language development unfolds similarly across environmental contexts, including those in which childdirected language is scarce. This raises the possibility that children are able to learn from other sources of language in their environments, particularly the language directed to others in their environment. We explore this hypothesis with infants in an indigenous Tseltal-speaking community in Southern Mexico who are rarely spoken to, yet have the opportunity to overhear a great deal of other-directed language by virtue of being carried on their mothers' backs. Adapting a previously established gaze-tracking method for detecting early word knowledge to our field setting, we find that Tseltal infants exhibit implicit knowledge of common nouns (Exp. 1), analogous to their US peers who are frequently spoken to. Moreover, they exhibit comprehension of Tseltal honorific terms that are exclusively used to greet adults in the community (Exp. 2), representing language that could only have been learned through overhearing. In so doing, Tseltal infants demonstrate an ability to discriminate words with similar meanings and perceptually similar referents at an earlier age than has been shown among Western children. Together, these results suggest that for some infants, learning from overhearing may be an important path toward developing language.
Asunto(s)
Comprensión , Desarrollo del Lenguaje , Humanos , Lactante , Femenino , Masculino , Comprensión/fisiología , México , Lenguaje , VocabularioRESUMEN
People want to "feel heard" to perceive that they are understood, validated, and valued. Can AI serve the deeply human function of making others feel heard? Our research addresses two fundamental issues: Can AI generate responses that make human recipients feel heard, and how do human recipients react when they believe the response comes from AI? We conducted an experiment and a follow-up study to disentangle the effects of actual source of a message and the presumed source. We found that AI-generated messages made recipients feel more heard than human-generated messages and that AI was better at detecting emotions. However, recipients felt less heard when they realized that a message came from AI (vs. human). Finally, in a follow-up study where the responses were rated by third-party raters, we found that compared with humans, AI demonstrated superior discipline in offering emotional support, a crucial element in making individuals feel heard, while avoiding excessive practical suggestions, which may be less effective in achieving this goal. Our research underscores the potential and limitations of AI in meeting human psychological needs. These findings suggest that while AI demonstrates enhanced capabilities to provide emotional support, the devaluation of AI responses poses a key challenge for effectively leveraging AI's capabilities.
Asunto(s)
Emociones , Motivación , Humanos , Estudios de Seguimiento , Emociones/fisiologíaRESUMEN
Humans have the highly adaptive ability to learn from others' memories. However, because memories are prone to errors, in order for others' memories to be a valuable source of information, we need to assess their veracity. Previous studies have shown that linguistic information conveyed in self-reported justifications can be used to train a machine-learner to distinguish true from false memories. But can humans also perform this task, and if so, do they do so in the same way the machine-learner does? Participants were presented with justifications corresponding to Hits and False Alarms and were asked to directly assess whether the witness's recognition was correct or incorrect. In addition, participants assessed justifications' recollective qualities: their vividness, specificity, and the degree of confidence they conveyed. Results show that human evaluators can discriminate Hits from False Alarms above chance levels, based on the justifications provided per item. Their performance was on par with the machine learner. Furthermore, through assessment of the perceived recollective qualities of justifications, participants were able to glean more information from the justifications than they used in their own direct decisions and than the machine learner did.