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Tang, H.

Publications and source records attributed to Tang, H..

At least 37 records · Page 2Linked to original sources

Brain-like dynamics in speech representations can emerge through self-supervised learning

Speech representations in the human brain do not simply mirror the instantaneous speech signal; rather, they display several properties that are hypothesized to facilitate the integration of speech sounds into words. In particular, neural encodings of speech maintain information that has dissipated from the acoustics, and have also been argued to abstract over variability in how individual speech sounds are produced. Here, we investigate how such characteristics could arise. We introduce a computational framework that uses modern neural network models from speech technology to examine two factors in particular: the learning mechanism and the learning input. We find that self-supervised models trained without lexical or semantic feedback developed temporal dynamics similar to brain representations, regardless of whether they were trained on speech or non-speech audio. In contrast, only models trained on speech learn to abstract over variability due to word position and phonetic context. Overall, our results suggest that domain-general learning mechanisms can lead to several important properties of speech representations, but in some cases require domain-specific input in order to do so. Significance StatementUnderstanding speech often feels effortless, but in fact mapping speech sounds into words involves complex computation. Experimental neuroscience has identified key properties in brain signals that may support this computation, but why and how these properties arise is still unclear. We examined these properties in computational models and found that they occurred in models that werent given lexical or semantic feedback, but were trained to predict the acoustics of the speech signal. This suggests such properties can develop from domain-general learning combined with domain-specific input. Moreover, some properties even arose in models that were trained on non-speech audio. Overall, our work illustrates how computational modeling can help reveal the conditions under which neural properties emerge.

neuroscience↗

Closing the Sim-to-Real Gap: An End-to-End Robotic Ultrasound System Leveraging In Vivo Reinforcement Learning and 3D-Prior Guided Hybrid Control

Abdominal ultrasound is a crucial first-line diagnostic tool, yet its efficacy is inherently constrained by a strong dependency on operator skill, leading to significant inter-operator variability and limiting its widespread adoption. While robotic ultrasound systems with artificial intelligence have emerged to mitigate this, current approaches face critical limitations: they often rely on simulated or phantom data for training, which hampers generalizability, and employ control strategies that lack the flexibility to adapt to complex human anatomy. To address these challenges, this paper introduces a novel, end-to-end robotic system for autonomous abdominal scanning. Our methodology is systematic: it begins with coarse scan planning via RGB and 3D point cloud-based localization of key anatomical landmarks (e.g., xiphoid process). The core of our approach involves training a reinforcement learning scanning policy directly on live human volunteers, enabling the development of a strategy that is robust to anatomical diversity. This high-level policy is executed by a sophisticated hybrid force-position controller, enhanced with real-time normal vector calibration and 3D point cloud-based respiratory phase detection to dynamically adjust contact force, particularly during inspiration. This innovation proves critical for improving scan quality in subjects with higher Body Mass Index (BMI). Extensive validation against expert sonographers demonstrates that our system achieves high precision in standard plane recognition and superior scanning efficiency. Furthermore, to holistically assess performance where standard planes are difficult to acquire, we introduce a 3D reconstruction-based coverage metric. Results confirm that our system delivers strong adaptability and significantly improved consistency, marking a substantial step toward clinically viable, operator-independent ultrasound robotics.

bioengineering↗

Licoisoflavone A improves adipose tissue dysfunction in response to diet induced obesity by promoting METTL3 expression

As developing obese adipose tissue, adipocytes suffer pathological changes from inert energy storage to excessive and active endocrine organ in association with disease hazard. METTL3, as an RNA methyltransferase of key importance in adipose tissue development, functional preservation and metabolic homeostasis, is remarkably complex. Licoisoflavone A (LIC-A) is a prenylated flavonoid compound of licorice that has been suggested to display antiinflammatory, -hypertrophic, and -proliferative activities; it remains unknown whether it can directly modulate expression of METTL3 and impact functions of adipose tissue in obesity. Here in our study, 16 candidates in the top ranking molecules were screened out in the process of the molecular docking between our TCM formula Fangjihuangqin Decoction and protein METTL3 (PDB: 5TEY). Among them, LIC-A was considered as a potential upstream regulatory molecule of METTL3 and obviously promote the expression of METTL3. The effects of TNF- and LPS treatments on the inhibition of adipogenesis were successfully recovered by LIC-A treatment in the adipogenic 3T3-L1 cells, via the regulation of adipogenic cytokines, as well as the expression of inflammatory factors. These protective effects were similarly abolished with METTL3 knockdown, suggesting the role of LIC-A relies on METTL3. Moreover, in vivo data demonstrated that administration of LIC-A could significantly recover the body weight lipid metabolism, insulin resistance and gluconeogenesis in mice with reduced adipose depostion as well as abated systemic inflammation. In conclusion, our study suggested that LIC-A could be the key component in preserving the homeostasis of adipose tissues through regulating METTL3 expression, indicating LIC-As promising treatment potential for obesity-related metabolic diseases.

pharmacology and toxicology↗

A high-throughput methods SNIPR-Nm reveals small RNA methylation ratio

Small RNAs regulate gene expression and genome stability, and their functions are shaped by 3'-terminal 2'-O-methylation (Nm). Although Nm is universal in plants and mainly marks animal piRNAs, recent evidence reveals Nm on mammalian miRNAs, highlighting broader regulatory roles. However, current sequencing underestimates Nm-modified RNAs due to ligation bias, and existing qPCR-based methods cannot simultaneously quantify abundance and modification, leaving Nm dynamics largely unexplored. We developed a unified enzymatic strategy that integrates poly(A) polymerase and a thermostable ligase to measure both small RNA abundance and 3'-end Nm status. Applied to mouse testis, it enables robust quantification of Nm ratios for piRNAs and miRNAs. Our method offers a versatile tool for dissecting small RNA methylation in development and disease.

genetics↗

Cross-chemical and cross-species toxicity prediction: benchmarkingand a novel 3D-structure-based deep learning model

Prediction of a compounds toxicity is a key step toward realizing animal-free testing of chemical compounds. Recent advances have yielded significant progress in computational toxicity prediction, including machine learning methods that utilize chemical fingerprints and deep learning-based latent representations. However, challenges remain, primarily due to the lack of clean training datasets and the inconsistent model performance. To address these challenges, we curated a comprehensive dataset of aquatic toxicity from seven data sources, which contains 50,603 records for 5,889 compounds across 2,285 different species, much larger than similar datasets used in previous studies. We also developed tox-learn, a Python library featuring tools for automated dataset cleaning, machine learning methods and performance evaluation. The library places special emphasis on avoiding overestimation of prediction accuracy caused by improper train-test data splitting. Based on this toolbox, we benchmarked various predictive models using different train-test splitting strategies on the curated dataset. Our results showed that the choice of machine learning method, molecular fingerprint, and train-test splitting strategy all significantly affect performance. We demonstrated that incorporating species information generally improved predictions, although the degree of improvement depended on how this information was represented. In addition, we developed a new 3D structure-based deep-learning model, 3DMol-Tox, which achieves regression accuracy comparable to the best 2D-structure based model (GPBoost) while exhibiting consistently higher within-one-bin (W1B) classification accuracy. Finally, we analyzed the impact of different train-test splitting strategies and provide recommendations based on our benchmarking, such as using structure-aware splitting to mitigate information leakage, a common issue that inflates reported model performance.

bioinformatics↗

Mechanistic Investigation of LncRNA-ZMIZ1-AS1 in the Malignant Phenotype of Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the most fatal cancers worldwide, with high recurrence and mortality rates. LncRNA-ZMIZ1-AS1 has attracted considerable attention for its role in the tumor microenvironment, particularly in the regulation of HCC cell growth, invasion, and biological behavior. However, the specific mechanisms of LncRNA-ZMIZ1-AS1 in HCC remain unclear. MethodsWe analyzed the relationship between LncRNA-ZMIZ1-AS1 and HCC clinical prognosis using bioinformatics with GEO and TCGA datasets. We also conducted molecular biology experiments, including cell culture, real-time PCR, and Western blotting, as well as cell viability and flow cytometry analyses, to investigate the effects of LncRNA-ZMIZ1-AS1 knockdown on HCC cell proliferation, migration, invasion, and apoptosis. Furthermore, we used Gene Set Enrichment Analysis (GSEA) to identify potential signaling pathways involving LncRNA-ZMIZ1-AS1. ResultsLncRNA-ZMIZ1-AS1 was highly expressed in HCC patients and significantly associated with clinical characteristics, such as gender and clinical stage. Knockdown of LncRNA-ZMIZ1-AS1 notably inhibited HCC cell proliferation, migration, and invasion while increasing apoptosis rates. Additionally, GSEA suggested a potential association between high LncRNA-ZMIZ1-AS1 expression and the NOTCH signaling pathway. ConclusionThe high expression of LncRNA-ZMIZ1-AS1 in HCC likely promotes malignant phenotypes by regulating signaling pathways such as NOTCH. This finding underscores its potential as a biomarker for HCC, providing a theoretical basis for further research on its molecular mechanisms and clinical applications in liver cancer.

molecular biology↗

Contemporary HIV-1 envelope pseudovirus panels for detecting and assessing B cell lineages with broadly neutralizing antibody potential

Although a protective HIV-1 vaccine has not yet been realized, significant progress has been made in vaccine designs that trigger B cell lineages with potential to produce broadly neutralizing antibodies (bnAbs). Advancing these strategies by optimizing vaccine boosting regimens requires early detection of maturing antibodies with neutralizing activity against native envelope glycoprotein (Env) trimers and streamlined strategies to identify antibodies as they begin to manifest desired levels of breadth and potency. Thus, we designed three types of pseudovirus screening panels based on Envs of contemporary HIV-1 isolates to facilitate detection of bnAb lineages that are on favorable trajectories during a vaccination course. The panels were selected from Tier 2 Transmitted Founder Lineage (TFL) HIV-1 Envs from placebo participants in the Antibody Mediated Prevention (AMP) efficacy trials. Using 15 bnAbs to evaluate the neutralization sensitivity of the viruses, we selected 8-member bnAb class-specific panels most sensitive to bAbs representing their class: V2-apex, V3-glycan, CD4-receptor binding site (CD4bs), Membrane-Proximal External Region (MPER), or fusion peptide (FP). Next, we combined the most sensitive viruses among the class-specific panels to create a 12-virus panel to enable optimal detection of low-titer bnAb activity across epitope specificities. Finally, as HIV-1 continues to evolve greater levels of antigenic diversity and as current global pseudoviruses bnAb panels rely on viruses collected more than twenty years ago, we showed the importance of using contemporary viral panels to assess bnAb breadth and potency and designed a 12-virus panel representative of the spectrum neutralization profiles among AMP placebo viruses. We characterized pseudoviruses bearing each selected Env using standardized human sera to confirm their Tier 2 status and biological relevance. These updated panels enable sensitive screening of neutralization activity in vaccine studies and can also provide a realistic assessment of the expected breadth and potency of maturing responses against contemporary HIV-1 Envs. AUTHOR SUMMARYA primary goal of HIV-1 vaccine research is to elicit neutralizing antibodies that can prevent infection, but HIV-1 is highly variable and so stimulating responses that can work effectively against the diverse array of HIV-1 variants remains an unsolved challenge. However, the HIV-1 vaccine field has made significant progress in terms of stimulating B cell lineages that produce antibodies known to have features able to ultimately generate potent broadly neutralizing antibodies. Inducing such precursor B cells is just the first step, as B cells need evolve in response to an antigenic stimulus through a process called affinity maturation to acquire potency and breadth against the natural diversity of circulating HIV-1 strains. The next step is to discover and optimize vaccine strategies that will selectively induce such maturation. To facilitate this work, we have designed panels of biologically relevant, contemporary HIV-1 Envelope pseudotyped viruses that will enable sensitive detection of neutralizing antibodies in human and animal vaccine studies. We also have defined a small screening panel intended to provide a quick but realistic assessment of the potential of a vaccine-stimulated antibody response or a monoclonal antibody being evaluated for clinical use to effectively counter and block currently circulating HIV-1 variants.

immunology↗

Mapping brain volume changes in the zQ175DN mouse model of Huntington's disease: a longitudinal MRI study

Huntingtons disease (HD) is a progressive neurodegenerative disease affecting motor and cognitive abilities, as well as exhibiting psychiatric manifestations. Studies in people with HD (PwHD) consistently report atrophy of the caudate and putamen as an early pathological event and is therefore considered an early biomarker. Investigating whether similar phenotypic features are apparent in rodent HD models is important since it could have translational potential in evaluating the efficacy of novel therapeutic strategies. We used high-resolution anatomical images to longitudinally investigate brain morphology in the zQ175DN heterozygous mouse model (HET) and wildtype littermates (WT) at 3, 6, and 10 months of age (M), which reflect different stages of phenotypic progression. We investigated volumetric alterations using semi-automatic segmentations of HD on relevant regions-of-interest (striatum, cerebellum, corpus callosum, cerebral cortex, ventricles, and total brain volume) and whole brain voxel-wise Tensor Based Morphometry (TBM) analysis. The striatum showed the earliest progressive lower absolute volume in HET mice compared to WT, starting from 3M, followed by lower absolute volume of cortex and corpus callosum concomitantly at 6 and 10M. TBM highlighted lower relative local volume in the rostral-medial striatum at all ages, and in cerebral cortex in HET mice at 6 and 10M. A bigger relative local volume in the cerebellum was observed at all ages in HET mice, and in the globus pallidus, substantia nigra, at 6 and 10M. Overall, this study revealed key structural abnormalities that resemble the natural history of PwHD. Hence, analysis of brain structure through MRI in the zQ175DN heterozygous mouse model holds potential for testing disease-modifying treatments expected to slow down or prevent structural degeneration. HighlightsO_LIThe striatum of zQ175DN heterozygous mice shows volume decrease at 3 months compared to WT mice C_LIO_LIWidespread volume reductions are observed from 6 months in zQ175DN heterozygous mice C_LIO_LITensor Based Morphometry highlights vulnerability of the dorsomedial striatum in the zQ175DN heterozygous mouse model C_LI

neuroscience↗

Lipid Metabolism Remodeling in Human Cardiomyocyte Differentiation and Maturation

During cardiac development, metabolic remodeling is characterized by a transition from glycolysis-dependent energy production to reliance on fatty acid oxidation. Lipids function as essential energy substrates and structural components throughout cardiac formation and maturation. However, the dynamic changes in endogenous lipid species during human cardiac development remain incompletely elucidated. In this study, we delineated distinct lipidomic profiles of human embryonic stem cells (ESCs), mesoderm (MES), cardiac progenitors (CPCs), immature cardiomyocytes (CMs), and mature CMs derived from ESCs using high-performance liquid chromatography (HPLC). Notably, ceramide concentrations peaked at the CPC stage, suggesting a pivotal role in mediating the MES-to-CPCs transition. Concurrently, lipid metabolites including GM3, phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA) were significantly upregulated in mature CMs. Integrative transcriptomic and chromatin accessibility analyses further refined the landscape of lipid remodeling during CM differentiation. Functional assays demonstrated that LPA enhances the stability of the beating rhythm in CPCs, while both PC and LPA facilitate CM maturation. Collectively, our findings establish a comprehensive and dynamic lipidomic atlas of human cardiogenesis, providing a novel framework to advance the understanding of lipid-mediated regulatory mechanisms in human heart development.

developmental biology↗

Human Organoids Reveal PTEN-driven Mesendoderm Specification via Retinoic Acid Signaling Suppression

During early embryogenesis, epiblast cells ingress through the primitive streak (PS) and commit to a mesendoderm (MES) fate, giving rise to both mesodermal and endodermal lineages. Despite advancements in human organoid technology for modeling pre-implantation blastocyst stage, robust systems that accurately recapitulate MES specification and PS formation during the post-implantation stage remain limited. Here, we show that human induced pluripotent stem cells can be used to generate three-dimensional MES organoids that faithfully mimic in vivo human MES specification, particularly from the anterior PS. We demonstrate that MES organoid formation is dependent on PTEN expression and that loss of PTEN severely impairs the formation of mesoderm and definitive endoderm derivatives arising from MES organoids. To elucidate the molecular mechanisms underlying these defects, we conducted an integrative multi-omics analysis, including transcriptome, chromatin accessibility profiling, metabolism, and phosphoproteomics, on wild-type and PTEN-/-MES cells. These analyses revealed that PTEN suppresses retinoic acid (RA) signaling during MES lineage commitment. Furthermore, we identified the RA-degrading enzyme CYP26A1 as a downstream effector of PTEN. Notably, while excessive RA induced by PTEN ablation is detrimental to MES cell generation, physiological levels of RA are necessary. Collectively, our human MES organoids offer a valuable model for dissecting early human development, and our findings identify PTEN as a key regulator of MES fate commitment through inhibition of RA signaling.

developmental biology↗

Age- and Sex- Driven Transcriptional and Metabolic Diversity in Myeloid-Derived Suppressor Cells After Mouse Sepsis

Sepsis induces profound immune dysregulation, often resulting in chronic critical illness characterized by persistent immunosuppression and poor outcomes. Myeloid-derived suppressor cells (MDSCs) are central mediators of this immunosuppressive phenotype, yet the influence of age and sex on their transcriptional and metabolic states remain poorly understood. Here, we employed single-cell RNA sequencing of splenic leukocytes from young (3-4 months) and older (18-24 months) adult male and female mice subjected to a clinically relevant murine sepsis model to define age- and sex-specific MDSC phenotypes. We identified significant differences regarding age and sex in MDSC expansion, transcriptome, canonical pathway activation, RNA velocity, mitochondrial metabolism, and predicted cell-cell communication after sepsis. Using drug2cell analysis of total leukocytes we also identified cohort-specific drug target profiles. These findings underscore the importance of age and sex in shaping sepsis-induced MDSC biology and suggest that personalized immunomodulatory strategies targeting MDSCs could improve sepsis outcomes.

immunology↗

Microbes suppress genetic disorders of hyper-activated Ras by inhibiting iron-mediated growth factor modulation in C. elegans

Gut bacteria play crucial roles in promoting host health, but their ability to suppress the effects of genetic defects remains unclear. Ras(gain-of-function, gf) mutations are involved in various developmental disorders, thus identifying bacterial-activity changes capable of repressing the effects of hyper-activated Ras is important. Here, we screened mutations of all non-essential E. coli genes and identified 151 E. coli mutants that mitigate let-60/Ras(gf)-induced vulval developmental abnormalities in C. elegans. Interestingly, bacteria with mutations in genes involved in iron acquisition suppress host Ras(gf)-induced vulval defects through elevating 2,3-dihydroxybenzoic acid, a bacterial siderophore that sequesters iron. Consequently, host mitochondrial iron availability is decreased, which prompts the nuclear accumulation of the chromatin modifier LIN-65 and then downregulates lin-3/EGF transcription to repress Ras(gf)-induced vulval defects. Our findings identify a mechanism for coordinating Ras growth signaling with iron availability, through which gut bacteria suppress host Ras(gf)-induced defects and exemplify the potential of modifying gut bacterial activity to improve genetic diseases.

developmental biology↗

S3R: Spatially Smooth and Sparse Regression Reveals High-Dimensional Regulatory Networks in Spatial Transcriptomics

Spatial transcriptomics (ST) data demands models that recover how associations among molecular and cellular features change across tissue while contending with noise, collinearity, cell mixing, and thousands of predictors. We present Spatially Smooth Sparse Regression (S3R), a general statistical framework that estimates location-specific coefficients linking a response feature to high-dimensional spatial predictors. S3R unites structured sparsity with a minimum-spanning-tree-guided smoothness penalty, yielding coefficient fields that are coherent within neighborhoods yet permit sharp boundaries. In synthetic data, S3R accurately recovers spatially varying effects, selects relevant predictors, and preserves known boundaries. Applied to Visium-based ST data, S3R recapitulates layer-specific target-TF associations in human dorsolateral prefrontal cortex with concordant layer-wise correlations in matched single-cell data. In acute Haemophilus ducreyi skin infection, S3R converts spot-level gene expression mixtures into cell type-attributed expression fields, revealing per-cell type spatial gradients, and improving concordance of spatially variable gene calls when tests are applied to these demixed fields. In pancreatic ductal adenocarcinoma, S3R builds cross-cell-type, cross-gene co-variation tensors that quantify cell-cell interaction strength at gene-pair resolution and nominate interacting genes whose pathway enrichments align with established stromal-epithelial and immune crosstalk. An efficient implementation scales to large assays, and on a Xenium-based breast cancer dataset, S3R delineates the contributions at gene-gene, local neighborhood, and global context-level to target gene expression. Because responses and predictors in S3R are user-defined, it could flexibly address diverse biological questions within a single, scalable, and interpretable regression framework.

bioinformatics↗

The Amplified Burden of Depression in Drug-Resistant Epilepsy: Role of Limbic Network Dynamic Reconfiguration

ObjectivesTo explore potential associations between drug resistance and limbic network (LN) dynamic functional interactions in temporal lobe epilepsy (TLE), whether these LN alterations are associated with and potentially mediate comorbid depression severity, and their potential neurochemical and transcriptomic underpinnings. MethodsThis cross-sectional study included 49 patients in the Responsive group, 33 patients in the Resistant group, and 50 healthy controls (HCs). Using resting-state fMRI, we derived LN dynamic integration coefficients and used non-negative matrix factorization (NMF) to identify coactivation patterns. Depressive symptoms (Self-Rating Depression Scale, SDS), LN integration, and NMF pattern expression were compared across groups (ANOVA) and correlated. Mediation analysis tested if LN integration mediated the relationship between drug resistance status and SDS scores. LN integration differences were spatially correlated with neurotransmitter receptor density and Allen Human Brain Atlas transcriptomic data. ResultsPatients in the Resistant group reported significantly higher SDS scores than patients in the Responsive group (p = 0.008). LN integration with the dorsal attention network (DAN) and fronto-parietal network (FPN) was significantly lower in the Resistant group compared to the Responsive group (p = 0.001; p < 0.001). NMF analysis identified key LN-DAN (p = 0.013) and LN-FPN (p < 0.001) coactivation patterns. In TLE patients, DAN-LN integration was negatively correlated with depressive symptoms (r = -0.28, p = 0.01), and lower integration levels significantly mediated the relationship between group status (Resistant vs. Responsive) and increased symptom severity (p < 0.001). These LN integration coefficient differences (Responsive group vs. Resistant group) were associated with 5-hydroxytryptamine 1B (5-HT1B; r = 0.29, p = 0.036) and dopamine D2 (D2; r = -0.29, p = 0.034) receptor densities, and linked to gene expression pathways including telomerase activity regulation (p < 0.001). InterpretationThis study identifies dynamic LN dysregulation, supported by distinct neurochemical and transcriptomic profiles, as a core bridging mechanism potentially contributing to comorbid depression linked to drug response status in TLE patients.

neuroscience↗

Breaking the Salinity-Nitrogen Fixation Trade-Off: Engineering A Synthetic Nitrogen-Fixing Vibrio natriegens Strain

Inefficient nitrogen fixation in legumes under saline stress threatens food security, while conventional symbiotic nitrogen fixation is limited by host specificity and saline stress inhibition. This study engineered Vibrio natriegens with nitrogen fixation genes, creating a saline-tolerant, broad-host-range nitrogen-fixing bacteria that enhances plant-microbe interactions through reprogrammed nitrogen metabolism. We demonstrated that engineered nitrogen-fixing V. natriegen significantly enhanced soybean growth and nodulation under saline stress. It also activated nitrogenase gene (nifHDK) expression in rhizosphere bacteria and increased the abundance of rhizosphere diazotrophs. This study presents a novel approach for developing stress-resilient crop-microbe symbioses, offering a sustainable solution to improve crop growth under saline stress.

synthetic biology↗

Accurate Site-specific Folding via Conditional Diffusion Based on Alphafold3

Accurate structure prediction of biomolecular complexes is crucial for understanding biological processes and enabling drug discovery. While AlphaFold3 represents a significant advancement, enhancing its accuracy for specific binding sites remains a challenge. We present SiteAF3, a novel method for accurate site-specific folding via conditional diffusion, built upon the AlphaFold3 framework. SiteAF3 refines the diffusion process by fixing the receptor structure and optionally incorporating binding pocket and hotspot residue information. Comprehensive evaluations on protein-small molecule, protein-peptide, and protein-nucleic acid datasets demonstrate that SiteAF3 consistently outperforms AlphaFold3, achieving higher accuracy in complex structure prediction especially for orphan proteins and allosteric ligands, with reduced computational cost. SiteAF3 offers a user-friendly plug-in compatible with AlphaFold3, providing a valuable tool for more accurate modeling of biomolecular interactions.

bioinformatics↗

A Task-Specific Transfer Learning Approach to Enhancing Small Molecule Retention Time Prediction with Limited Data

Liquid chromatography (LC) is an essential technique for separating and identifying compounds in complex mixtures across various scientific fields. In LC, retention time (RT) is a crucial property for identifying small molecules, and its prediction has been extensively researched over recent decades. The wide array of columns and experimental conditions necessary for effectively separating diverse compounds presents a challenge. Consequently, advanced deep learning for retention time prediction in real-world scenarios is often hampered by limited training data that spans these varied experimental setups. While transfer learning (TL) can leverage knowledge from upstream datasets, it may not always provide an optimal initial point for specific downstream tasks. We consider six challenging benchmark datasets from different LC systems and experimental conditions (100-300 compounds each) where TL from RT datasets under standard condition fails to achieve satisfactory accuracy (R2 [&ge;] 0.8), highlighting the need for more sophisticated TL strategies that can effectively adapt to the unique characteristics of target chromatographic systems under specific experimental conditions. We present a task-specific transfer learning (TSTL) strategy that pre-trains multiple models on distinct large-scale datasets, optimizing each for fine-tuned performance on the specific target task, then integrates them into a single model. Evaluated on five deep neural network architectures across these six datasets through 5-fold cross-validation, TSTL demonstrated significant performance improvements with the average R2 increasing from 0.587 to 0.825. Furthermore, TSTL consistently outperformed conventional TL across various sizes of training datasets, demonstrating superior data efficiency for RT prediction under various experimental conditions using limited training data. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/661631v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1330e45org.highwire.dtl.DTLVardef@ee1126org.highwire.dtl.DTLVardef@1a7f2fdorg.highwire.dtl.DTLVardef@141cb26_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

Uncovering Heterogeneous Effects via Localized Feature Selection

Identifying features that interact to trigger disease, while accounting for heterogeneity across diverse populations, is essential for the development of precision and targeted medicine. Despite the availability of vast and complex health-related datasets, most existing works focus on identifying disease-associated features at the population level or within a few subpopulations, often overlooking individual-level heterogeneity within these groups. To address this limitation, we propose a novel framework that utilizes localized test statistics to identify disease-associated features tailored to individual profiles. Our method leverages the recently developed knockoffs methodology to control the noise level of the selection set so that the results are replicable. Moreover, it allows for the discovery of hidden heterogeneous effects within the data, as demonstrated in an application to single-cell RNA sequencing data for Alzheimers disease. By aggregating localized feature selection results, our framework also enables powerful population-level feature selection. Our framework provides a powerful tool for exploratory studies of precision medicine, offering the potential to generate novel hypotheses for confirmatory biological experiments.

bioinformatics↗