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At least 19 recordsLinked to original sources

Learning neural dynamics through instructive signals.

Rapid learning is essential for flexible behavior, but its basis in the brain remains unknown. Here we introduce the PRISM plasticity rule, a unifying mechanistic model of three well-established, fast-acting synaptic plasticity rules-in hippocampus, cerebellum and mushroom body-which relies exclusively on pre-synaptic activity and an "instructive signal" from another brain area. Using a multi-region network model we show that guiding PRISM plasticity with instructive signals enables the network to quickly learn extremely flexible nonlinear dynamics underlying behaviorally relevant computations, as well as to emulate unknown external system dynamics from real-time error signals, which we demonstrate with comprehensive simulations supported by exact mathematical theory. Thus, PRISM plasticity guided by instructive signals is well-suited to rapidly learn general-purpose neural computations-in contrast to canonical Hebbian rules. Finally, we show how including this plasticity rule in artificial learning algorithms can solve long-range temporal credit assignment, a long-standing challenge in machine learning.

cerebellum

Object sorting by chimpanzees and monkeys.

Chimpanzees and two species of monkey were compared on sorting tasks. When the sets of objects differed in multiple ways, most chimpanzees learnt to sort whereas only a few monkeys performed better than chance (and then inconsistently). When the objects within a set differed in one or two respects, so that sorting by one principle entailed "unsorting" by one or more alternative principles, chimpanzees had greater difficulty. Two young animals did rapidly learn to sort by color and size ("unsorting" by size and shape or by color and shape). They did not sort pictorial material and had difficulty in sorting by shape if "unsorting" by both color and size. The sorting task differentiated between the cognitive capacities of chimpanzees and monkeys whereas other tasks did not.

Animals

The monkey's prefrontal cortex functions in motor programming.

A new experimental approach is presented which resulted in clarification of the specific functions of the monkey’s prefrontal cortex. Monkeys with chronically implanted transcortical nonpolarizable electrodes were trained on delayed response (DR) and visual delayed matching-to-sample (DMS) tasks. The onset of the trial for each group depended upon on-line computer detection of one of the specified events: FN – surface-negative steady potential shifts (SPS) from principalis cortex; MN – a similar SPS from precentral cortex; FB – near baseline SP from principalis cortex; LEM – rightward eye deviations; and YC – controls, with intertrial intervals yoked to those of other monkeys. Monkeys were trained with 1-s cue presentations. on successive delays of 2 to 12 s. The DR acquisition rate by the FN group was substantially faster than that of any other group, as indicated by its mean error that was only 17.24 percent the YC group’s error. The MN and LEM monkeys acquired the task at the same rates as the YCs, while the FB monkeys were the slowest learners. The correct DR performance transferred to testing with constant intertrial intervals (without preconditions). Subsequent on-line tests with brief (0.1 s) cue duration showed high DR performance by the FN, but not by other groups. No similar rapid learning was found with the DMS task. The findings from this, and other experiments, suggest that the major function of principalis cortex is the selection, or programming of delayed spatial choice responses. The view seems consonant with interpretations for the role of the human prefrontal cortex.

Animals

The genetics of learning disabilities.

Rapid progress in the study of learning disabilities requires a common context within which investigators and professionals with very diverse backgrounds can work towards common goals. Much evidence points to the heterogeneity of origin and clinical expression of learning disabilities as well as to many other ways in which they resemble such multifactorial conditions as mental retardation, gout and hypertension. In these conditions, genetic and epidemiological methods have been used to sort out the constitutional and environmental factors which precipitate disease in susceptible persons. Such an approach to learning disabilities can be expected to be rewarding.

Dyslexia

[The methodological position of frontal feedbacks during work with large groups of dental students].

Single-channel feedback installations without revertive communication to the single work place and without possibility for evaluating the student's performance may be used with success in lectures and diagnostic exercises for large groups of dental students. Dispensing deliberately with the evaluation of performance permits to carry on a dialogue with the student, which offers the possibility of acting rapidly on the learning process during the very same teaching event. This control procedure allows to activate and motivate the students considerably. The methodical approach is explained.

Computers

Rapid assessment of clinical severity for salmonellosis cases via protein family domain analysis and machine learning.

Salmonella is a common pathogen, infecting more than a million people yearly. Rapid assessment of clinical case severity is essential for improving patient outcomes and optimizing healthcare resources. Advancements in genome sequencing technologies have enabled the analysis of bacterial genomes from many clinical cases, opening up new opportunities for precise and timely diagnosis. This study proposes a genome-based framework for identifying critical Salmonella cases before the onset of critical symptoms and facilitating early medical intervention. By leveraging protein family (Pfam) domains as the representation for genomic data, the complex genetic profiles of Salmonella cases are simplified into interpretable features. The severity levels of cases were investigated through rigorous data analysis, resulting in a set of 70 Pfam domains that could be potentially used as biomarkers. Machine Learning was employed to assess the predictive power of the curated Pfam biomarkers, achieving high accuracy (~93%) in sorting cases into critical, moderate, and mild categories. The results demonstrate the efficacy of the proposed approach. This framework highlights the potential of using bacterial genomic data in clinical decision-making, opening the window for timely personalized interventions for Salmonella infection management.

Domains of unknown function (DUFs)

N6-methyladenine identification using deep learning and discriminative feature integration.

N6-methyladenine (6 mA) is a pivotal DNA modification that plays a crucial role in epigenetic regulation, gene expression, and various biological processes. With advancements in sequencing technologies and computational biology, there is an increasing focus on developing accurate methods for 6 mA site identification to enhance early detection and understand its biological significance. Despite the rapid progress of machine learning in bioinformatics, accurately detecting 6 mA sites remains a challenge due to the limited generalizability and efficiency of existing approaches. In this study, we present Deep-N6mA, a novel Deep Neural Network (DNN) model incorporating optimal hybrid features for precise 6 mA site identification. The proposed framework captures complex patterns from DNA sequences through a comprehensive feature extraction process, leveraging k-mer, Dinucleotide-based Cross Covariance (DCC), Trinucleotide-based Auto Covariance (TAC), Pseudo Single Nucleotide Composition (PseSNC), Pseudo Dinucleotide Composition (PseDNC), and Pseudo Trinucleotide Composition (PseTNC). To optimize computational efficiency and eliminate irrelevant or noisy features, an unsupervised Principal Component Analysis (PCA) algorithm is employed, ensuring the selection of the most informative features. A multilayer DNN serves as the classification algorithm to identify N6-methyladenine sites accurately. The robustness and generalizability of Deep-N6mA were rigorously validated using fivefold cross-validation on two benchmark datasets. Experimental results reveal that Deep-N6mA achieves an average accuracy of 97.70% on the F. vesca dataset and 95.75% on the R. chinensis dataset, outperforming existing methods by 4.12% and 4.55%, respectively. These findings underscore the effectiveness of Deep-N6mA as a reliable tool for early 6 mA site detection, contributing to epigenetic research and advancing the field of computational biology.

Deep Learning

Smarter stomata: emergent technologies unlocking yield potential in a changing climate.

Stomata, the gatekeepers of leaf gas exchange, regulate carbon dioxide uptake and water loss, functions increasingly critical as crops face more frequent, intense heat and drought. Under dry conditions, stomatal conductance (g s) typically decreases, limiting carbon assimilation and yield. Heat stress, in contrast, elicits variable g S responses: sometimes increasing to facilitate transpirational cooling, while at other times decreasing, especially when combined with drought. Heat and drought also induce complex, context-dependent shifts in stomatal anatomy. Smaller, denser stomata improve drought resilience in some cases, while reduced density confers greater tolerance in others. The optimal stomatal ideotype remains unknown, and different or even opposing traits may confer resilience dependent on the environmental scenario. Substantial genotypic variation in g s and stomatal anatomy, high heritability and co-localized quantitative trait loci for stomatal traits and yield highlight their untapped potential as breeding targets for climate-resilient crops. However, stomatal traits remain largely absent from breeding pipelines due to challenges of phenotyping at scale. This is changing rapidly. Advances in deep learning, porometry, digital microscopy, and remote sensing now enable high-throughput measurement of stomatal physiology and anatomy. Next-generation breeding technologies including clustered regularly interspaced short palindromic repeats (CRISPR), multi-omics approaches, and artificial intelligence-driven ideotype selection models could revolutionize breeding, allowing precise engineering of stomatal traits for resilience to environmental stress. The time has come to move beyond characterizing stomatal traits and start actively incorporating them into breeding strategies. By leveraging these technologies, stomatal traits can become high value targets, unlocking their potential to enhance crop performance in a hotter, drier future.

abiotic stress

Operant conditioning of infant monkeys (Macaca fascicularis) for toxicity testing.

A technique has been developed that allows infant monkeys to perform on an operant schedule as soon as they are able to self-feed. Behavior is shaped in small increments through a series of operants; sensory and motor systems as well as performance on schedules using intermittent reinforcement may be tested as early as 3-4 weeks of age. This is accomplished by exposing the infant to the operant situation almost continuously, and allowing the infant to feed only by operantly responding. Infants exposed to lead post-natally differed from controls in pattern of fixed ratio responding, "activity" as measured by pattern of responding over the course of the session, and on a two-choice form discrimination reversal learning set paradigm. This technique allows rapid accumulation of large amounts of data without experimenter intervention.

Animals

Artificial Intelligence in Predicting Systemic Complications From Retinal Findings: A New Frontier in Precision Medicine.

Innovations in retinal imaging technologies and growing evidence from retinal imaging of systemic and neurodegenerative diseases have begun to explore the utility of retinal imaging in diagnosing these conditions. Since the retina shares embryological origins with the central nervous system and reflects systemic microvascular characteristics, it is well positioned for noninvasive observation of patients' systemic and neural health. Moreover, accessibility of retinal imaging has improved with the increasing number of ophthalmology clinics. Rapid improvements in various deep learning (DL) tools have also catalyzed the automation of retinal imaging analysis. Systems that utilize DL for retinal imaging are being developed to assist with disease recognition, clinical judgment, and prognostic assessment of systemic health. Various imaging modalities are being integrated with existing genomic and clinical data to estimate an individual's predisposition to certain conditions. Contrary to many existing reviews, the objective of this review is to synthesize the most recent clinical and technological evidence on DL-based diagnostic systems for retinal imaging, with a focus on how different network architectures and their combinations have been developed, validated, and applied across systemic disease detection and prediction. Specifically, this review examines the datasets, model validation approaches, and automated diagnostic systems reported in recent literature. It discusses the extent to which these advancements address existing barriers toward real-time diagnostic application across clinical disciplines. Integrating retinal imaging with DL is an innovative and promising approach to precision medicine and health risk reduction.

artificial intelligence

A voyage of reprogrammable metabolic bioengineering reshapes plant defense: from editing tools to synthetic systems.

Metabolic bioengineering has emerged as a transformative approach for reshaping plant defense by targeting intrinsic biosynthetic pathways to enhance immunity in modern agriculture. Moving beyond proof-of-concept metabolomics to broad-spectrum programmable pathway engineering addresses gaps in plant rational design and optimizes resilience in response to diverse environmental cues. This review aims to comprehensively highlight the transition of innovative approaches to phenolics, alkaloids, flavonoids, terpenoids, and benzoxazinoids, inferring adaptive reprogramming that mediates the growth-defense balance and functions as molecular sentinels in plants. Furthermore, decoding the volatile metabolome reveals a dynamic signaling interface that influences defense responses and stress-induced plant-microbe interactions, with the shikimate, jasmonate, and salicylate pathways functioning as central hubs for microbial deterrence and priming immune memory. Recent developments in multi-scalar genome-editing strategies, including CRISPR-driven combinatorial edits, enzyme orthogonalization, fluxomics, and spatially resolved multi-omics, reconfigure central and specialized metabolic fluxes toward improved defense function and regulation. Additionally, emerging tools, such as WUSCHEL2 and BABY BOOM transcriptional modules, and artificial engineering strategies integrating deep learning model-driven predictions facilitate rapid development of synthetic genetic circuits and support a predictive engineering of plants. Moreover, Mass spectrometry imaging (MSI) in spatial metabolomics enables to obtain structures and locations of unidentified endogenous metabolites within cells and tissues. Overall, this review emphasizes a diverse array of primary and secondary metabolites, spanning molecular concepts to recent advances in plant immune mechanisms. It also illustrates new frontiers in programmable metabolic engineering that accelerate the understanding of plant-microbe-metabolite cross-talks, offering strategies to improve plant resistance and advance sustainable agricultural solutions.

metabolic bioengineering

WilsonGenAI a deep learning approach to classify pathogenic variants in Wilson Disease.

BACKGROUND: Advances in Next Generation Sequencing have made rapid variant discovery and detection widely accessible. To facilitate a better understanding of the nature of these variants, American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG-AMP) have issued a set of guidelines for variant classification. However, given the vast number of variants associated with any disorder, it is impossible to manually apply these guidelines to all known variants. Machine learning methodologies offer a rapid way to classify large numbers of variants, as well as variants of uncertain significance as either pathogenic or benign. Here we classify ATP7B genetic variants by employing ML and AI algorithms trained on our well-annotated WilsonGen dataset. METHODS: We have trained and validated two algorithms: TabNet and XGBoost on a high-confidence dataset of manually annotated, ACMG & AMP classified variants of the ATP7B gene associated with Wilson's Disease. RESULTS: Using an independent validation dataset of ACMG & AMP classified variants, as well as a patient set of functionally validated variants, we showed how both algorithms perform and can be used to classify large numbers of variants in clinical as well as research settings. CONCLUSION: We have created a ready to deploy tool, that can classify variants linked with Wilson's disease as pathogenic or benign, which can be utilized by both clinicians and researchers to better understand the disease through the nature of genetic variants associated with it.

Hepatolenticular Degeneration

DNA methylation and machine learning: challenges and perspective toward enhanced clinical diagnostics.

DNA methylation is an epigenetic modification that regulates gene expression by adding methyl groups to DNA, affecting cellular function and disease development. Machine learning, a subset of artificial intelligence, analyzes large datasets to identify patterns and make predictions. Over the past two decades, advances in bioinformatics technologies for arrays and sequencing have generated vast amounts of data, leading to the widespread adoption of machine learning methods for analyzing complex biological information for medical problems. This review explores recent advancements in DNA methylation studies that leverage emerging machine learning techniques for more precise, comprehensive, and rapid patient diagnostics based on DNA methylation markers. We present a general workflow for researchers, from clinical research questions to result interpretation and monitoring. Additionally, we showcase successful examples in diagnosing cancer, neurodevelopmental disorders, and multifactorial diseases. Some of these studies have led to the development of diagnostic platforms that have entered the global healthcare market, highlighting the promising future of this field.

Humans

ProMeta: a meta-learning framework for robust disease diagnosis and prediction from plasma proteomics.

MOTIVATION: The plasma proteome offers a dynamic window of human health, capturing the real-time intersections between genetics and physiology. However, the application of deep learning to proteomics is currently hindered by a reliance on large-scale labeled datasets, rendering standard models ineffective for rare or novel diseases where patient samples are inherently scarce. RESULTS: Here, we present ProMeta, a meta-learning framework designed to enable robust disease modeling under extreme data restrictions. By integrating knowledge-guided pathway encoding with bi-level meta-optimization, ProMeta projects unstructured proteomic profiles into biologically interpretable functional tokens. This architecture allows the model to learn a global initialization containing transferable biological priors from biobank-scale data, facilitating rapid adaptation to novel tasks. Through comprehensive benchmark experiments, ProMeta consistently outperformed transfer learning and traditional machine learning baselines in both disease diagnosis and prediction tasks. In the most challenging 4-shot scenarios (utilizing only 2 cases and 2 controls), the model achieved robust generalization with an average AUROC of ∼0.69, representing a 24.6% relative improvement over the best-performing baseline methods. Mechanistic investigation revealed that ProMeta disentangles cases from controls in the latent space prior to task-specific adaptation, confirming the acquisition of universal biological rules rather than rote memorization. Furthermore, gradient-based interpretation identified disease-specific protein biomarkers and functional pathways consistent with known pathophysiology. Collectively, ProMeta overcomes the data-scarcity bottleneck in precision medicine, providing a scalable, interpretable framework for characterizing the full spectrum of human diseases, particularly for rare conditions lacking extensive clinical cohorts. AVAILABILITY AND IMPLEMENTATION: The source code of ProMeta is available at GitHub (https://github.com/lihan97/ProMeta).

Proteomics

ALPAR: automated learning pipeline for antimicrobial resistance.

SUMMARY: The field of machine learning in antimicrobial resistance (AMR) research has experienced rapid growth, fueled by advancements in high-throughput genome sequencing and the growing capacity of computational resources. However, the complexity and lack of standardized data preparation and bioinformatic analyses present significant challenges, especially for newcomers to the domain. In response to these challenges, we introduce ALPAR (Automated Learning Pipeline for Antimicrobial Resistance), a comprehensive AMR data analysis tool covering the entire process from processing of raw genomic data to training machine learning models to interpretation of results. Our method relies on a reproducible pipeline that integrates widely used bioinformatics tools, presenting a simplified, automatic workflow specifically tailored for single-reference AMR analysis. Accepting genomic data in the form of FASTA files as input, ALPAR facilitates the generation of machine learning-ready data tables and both the training of machine learning and the execution of genome-wide association studies (GWAS) experiments. Additionally, our tool offers supplementary functionalities such as phylogeny-based analysis of the distribution of mutations, enhancing its utility for researchers. The tool has also proven its performance in competitive benchmarks, winning the 2024 CAMDA Anti-Microbial Resistance Prediction Challenge and placing third in the 2025 edition. AVAILABILITY AND IMPLEMENTATION: ALPAR is open-source and freely accessible via GitHub (https://github.com/kalininalab/ALPAR). The pipeline is fully reproducible and can be easily installed as a Conda package (https://anaconda.org/kalininalab/ALPAR).

Machine Learning

Leveraging structure-informed machine learning for fast steric zipper propensity prediction across whole proteomes.

Predicting the amyloid fold and the propensity of peptide segments to adopt amyloid-like structures remain a challenge. However, recent progress has facilitated structure-based prediction of steric zipper propensity and the use of machine learning to accelerate the calculation of predictive models across many scientific areas. Leveraging these advances, we have developed a new approach for rapid proteome-wide assessment of zipper profiles that is informed by four million steric zipper predictions collected over ten years. This collection is used to build a machine learning model capable of rapidly predicting steric zipper propensity, and allowing for the assessment of zippers at both the protein and proteome level. Our predictions show enrichment for zipper forming segments in proteins involved in cell wall reorganization in yeast, highlighting a potential category of interest for experimental characterization. Overall, our predictive model allows for the exploration of amyloid formation across the tree of life and provides a tool for assessment of both novel and designed sequences for zipper density.

Machine Learning

Large language models in bioinformatics: a comprehensive survey.

The emergence of foundation models with trillion-level parameters has redefined the landscape of artificial intelligence. Various fields are developing their own large-scale models, which can solve many problems within the field and improve work efficiency. Biological large-scale models are a cross-disciplinary research field that combines mathematics, computer science, and biology, aiming to simulate and understand the structure, function, and dynamic changes of biological systems through the establishment of complex computational models. This field covers multiple levels such as biological pathways, population dynamics, protein folding, etc., providing us with tools for deep exploration of the mysteries of life and applications in medicine, ecology, and other fields. This article reviews the background and research status of biological large-scale models, and discusses future directions. Large language models (LLMs) and other large-scale foundation models have rapidly advanced in recent years, enabling powerful representation learning and generation across text, sequences, and multimodal data. In bioinformatics and biomedicine, these models are increasingly used to analyze genomic sequences, infer protein properties and structures, support drug discovery, and integrate heterogeneous biomedical evidence. This survey reviews the basic principles of LLMs and summarizes representative applications in (i) gene and genome sequence analysis, (ii) protein structure and function prediction, and (iii) drug design, including virtual screening and personalized medicine. We also discuss emerging multi-model modeling approaches, as well as key challenges such as data quality and privacy, interpretability, generalization to new organisms and tasks, and responsible deployment in health-related settings. Finally, we outline future directions for developing reliable, scalable, and explainable bioinformatics foundation models.

bioinformatics

Acceptable and controversial approaches to treating the child with learning disabilities.

There are many professionals in multiple disciplines developing approaches for helping children with learning disabilities. Much of these data and reports are published in journals normally not read by physicians. On occasion, such publications are reported in newspapers or lay magazines. Thus, parents may know of ideas and suggestions before the professional. It is understandable that the parent of a handicapped child would continually seek out improved ways of helping his or her child. The treatment of choice is basically special education. Medication will minimize the hyperactivity and distractability; psychotherapy may minimize the emotional effects. However, special educational therapy for the underlying learning disabilities is essential. No one yet has a rapid or "guaranteed" cure. Parents are often caught in the middle. They turn to their physician for guidance. It is the purpose of this paper to review the significant literature in an effort to assist the family physician in providing this guidance.

Anti-Anxiety Agents