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Biology subjects

Shi, L.

Publications and source records attributed to Shi, L..

At least 19 recordsLinked to original sources

Measurement-Dependent Parameter Recoverability in Neural Cardiovascular LPN Inference

Estimating cardiovascular lumped-parameter network (LPN) parameters from limited hemodynamic observations is a potentially non-unique inverse problem in cardiovascular model personalization. We investigated how parameter recoverability depends on measurement availability and noise, and whether poor recovery reflects limitations of neural inference or insufficient observational information. We developed Mada (measurement-availability and difficulty-aware), a probabilistic neural framework that provides parameter estimates and predictive uncertainty under incomplete observations. Using a closed-loop, four-chamber cardiovascular LPN with time-varying elastance, we generated a synthetic population of 650,000 cases comprising 20 chamber-mechanics and vascular parameters and up to 30 hemodynamic and timing observations. Under complete observations, Mada achieved macro R2 = 0.862, maintaining competitive accuracy across neural baselines while providing parameter-specific uncertainty. Recoverability varied substantially across parameters, with atrial active elastances remaining particularly difficult. For mask-aware Mada, macro R2 ranged from 0.066 with basic clinical measurements to 0.751 with a rich clinical set and 0.842 with all measurements, while uncertainty generally increased as informative measurements were removed. Bounded direct optimization achieved substantially smaller hemodynamic residuals but did not consistently recover the generating parameters. Complementary profile and local-sensitivity analyses revealed case-specific parameter compensation and weak observational directions, while target-specific fine-tuning offered little improvement for difficult atrial parameters. Increasing measurement noise degraded both parameter recovery and predictive-interval coverage, and similar trends were observed with a simpler probabilistic ResMLP. These findings demonstrate that accurate reconstruction of observed hemodynamics does not necessarily imply accurate recovery of the underlying LPN parameters, highlighting the importance of assessing parameter recoverability and predictive uncertainty when physiologically meaningful parameter estimates are sought.

bioengineering↗

Development of CYP8B1-specific inhibitors for metabolic diseases

Changes in bile acids (BAs) balance lead to various metabolic diseases, yet current treatment options targeting these changes remain severely limited. CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) is a liver-exclusive enzyme that controls the synthesis of 12-hydroxylated (12-OH) BAs. Inhibiting CYP8B1 is an attractive therapeutic strategy for attenuating 12-OH BA levels, remodeling the gut microbiota and thereby ameliorating metabolic diseases. CYP8B1-specific inhibitors are currently lacking due to structural similarities between the active site of CYP8B1 and other CYPs, and the lack of suitable high-throughput screening (HTS) assays. Herein, we developed a highly sensitive, and specific enzyme-coupled fluorescence assay to detect CYP8B1 activity, making it ideal for HTS. Employing this assay, structure-based drug design by protein X-ray crystallography, structure-activity relationship (SAR) analyses, and in vitro and in vivo validation, we developed novel CYP8B1-specific small molecule inhibitors. The lead candidate alters BA composition, favorably remodels the gut microbiota, and corrects metabolic disease in a metabolic dysfunction-associated steatotic liver disease (MASLD) mouse model. These findings reveal that pharmacologically inhibiting CYP8B1 is able to reshape the BA and gut microbiota profiles and effectively ameliorates metabolic diseases. Overall, CYP8B1-specific inhibitors represent a first-in-class promising, safe and effective therapeutic strategy against metabolic disorders.

pharmacology and toxicology↗

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.

neuroscience↗

Immune Reconstitution and Antigenic Exposure History Shape Virus-Specific Humoral Immunity in People with HIV

CD4+ T-cell recovery is widely used to assess immune reconstitution in people with HIV, but its relationship to virus-specific humoral immunity across pathogens remains unclear. We characterized neutralizing activity against SARS-CoV-2, HIV-1, and influenza viruses in ART-treated, virologically suppressed individuals spanning distinct CD4+ T-cell levels. BA.5 was the dominant SARS-CoV-2 neutralization target across CD4 strata, whereas D614G neutralization increased with greater immune reconstitution. This gradient was largely absent for the antigenically divergent NB.1.8.1 and XFG variants. HIV-1 neutralization was inversely associated with CD4+ T-cell count, while influenza showed strain-dependent patterns. Neutralization-to-protection bridging preserved a CD4-associated gradient for D614G but not for highly immune-evasive variants. These findings show that immune reconstitution does not translate uniformly into antiviral humoral function. Instead, antibody profiles reflect host immune status, prior antigenic exposure, and viral antigenic evolution, supporting pathogen-specific functional assessment alongside conventional immune monitoring.

immunology↗

SHERLOCK: Structured representation learning and causal inference of downstream perturbation effects

Understanding the effects of genetic, molecular, and experimental perturbations is essential for decoding cellular mechanisms and guiding biomedical interventions. Existing computational approaches are typically designed for individual tasks, such as predicting perturbation responses, characterizing downstream transcriptional effects, or modeling perturbation combinations, and therefore do not provide a unified framework for learning interpretable perturbation representations while enabling causal analysis of downstream effects and characterization of condition-dependent responses. We present SHERLOCK, an interpretable deep generative framework for single-cell perturbation analysis that represents perturbation effects as structured interventions on a latent baseline cellular state. SHERLOCK learns correlated and sparse perturbation representations that organize genetic and pharmacological perturbations according to shared transcriptional responses. % By formulating perturbations as interventions within a structural causal model, it enables counterfactual estimation of their downstream transcriptional effects under explicit identifiability assumptions. The same framework quantifies how perturbation responses vary across conditions and compositionally models combinatorial perturbations, enabling prediction of held-out combinations and classification of genetic interactions. Across genome-scale CRISPR, chemical, and spatial perturbation datasets, SHERLOCK recovers perturbation relationships concordant with known biological pathways and pharmacological properties, identifies condition-dependent responses, and predicts combinatorial perturbation effects. Together, SHERLOCK provides a unified framework for interpretable and causal analysis of perturbation effects across diverse single-cell perturbation experiments.

genomics↗

sfate: Schur-free, target-conditioned absorption probabilities for scalable single-cell fate analysis

Motivation: Single-cell fate mapping at atlas scale is constrained by memory: in the tested CellRank 2.3.2 pip environment without the optional PETSc/SLEPc stack, the GPCCA estimator fell back--after a warning--to a dense Brandts Schur routine. Across three measured sizes, its peak memory was consistent with ~72 n^2 bytes, a model that back-calculates to ~405 GB [BACK-CALCULATED] for the 74,984-cell dataset studied here--beyond any consumer workstation. Results: We present scalable-fate (sfate), which computes absorption probabilities to annotation-defined target states--where 'fate probability' denotes absorption probability toward user-defined target states on a latent-space transition graph, conceptually related to Palantir-style diffusion-based Markov-chain fate modeling rather than a velocity-derived lineage probability--from latent-space kNN graphs via column-wise GMRES solves, without any Schur decomposition. Memory scaled linearly with cell number over four measured graph-construction tiers (R^2 = 0.9985; 4.03 GiB at 500,000 synthetic cells in 66.2 s); the 500k absorption solve did not converge under the default configuration, so the largest measured full-pipeline scale is the 75k real-data run (1.76 GiB). Solutions agree with float64 direct references within the prespecified 1e-5 tolerance at every tested configuration (production default L-inf = 1.74e-06; best tested configuration 3.21e-07, 31x below the threshold), and reproduce CellRank's fate probabilities when the transition kernel and terminal representative cells are held identical. On 75k mouse 5xFAD/Cd28-cKO microglia (Ayata et al., 2025; GEO: GSE296768), the full analysis ran at 1.76 GiB peak memory, returning a six-state annotation-defined absorption landscape where the archived CellRank analysis returned three comparable arms; a controlled 2x2 comparison identifies terminal-state selection as an important contributor to the cross-tool discrepancy. Availability: sfate is available at https://github.com/Ericleo-zeng/sfate (release v1.0.0, commit 5472f62; MIT license) and is archived at Zenodo (DOI: 10.5281/zenodo.22851715). The repository includes the source code, the validation suite (32 unit tests, deterministic under fixed seed), all benchmark and figure-generation scripts, the synthetic fixtures, and the records underlying every figure and table. Contact: Wei Zeng (ericleo_zeng@hotmail.com)

bioinformatics↗

Low-dose radiopharmaceutical therapy enhances the efficacy of B7-H3 CAR T cells in murine metastatic neuroblastoma

Background: Chimeric antigen receptor (CAR) T cell therapy has had clinical success in hematologic malignancies, but limited efficacy is seen in solid tumors. In this study, we investigated whether systemic CAR T cell therapy could be enhanced in metastatic models of neuroblastoma when combined with radiopharmaceutical therapy (RPT). Methods: Non-irradiated or irradiated tumor cells were co-cultured with CAR T cells (1:1) in vitro and supernatant media was subsequently collected for cytokines analyses. CAR T cell phenotypes were characterized by flow cytometry including checkpoint marker expression. Xenograft models of metastatic neuroblastoma were generated in NOD-Rag1nullIL2rgnull (NRG) mice. Tumor-bearing mice received 1.8 Gy of radiation delivered by 177Lu-NM600 RPT five days after tumor implantation. Nine days after RPT, CAR T cells were administered intravenously. To evaluate tumor burden, mice were imaged weekly for 4 weeks. Results: In models of metastatic neuroblastoma, 177Lu-NM600 RPT significantly increased overall survival when combined with CAR T cell therapy in vivo. Pre-treatment of tumor cells with 177Lu also significantly increased CAR T cell cytotoxicity while decreasing production of IL-4 and IL-10 in vitro. Co-culture of CAR T cells with irradiated tumors led to increases in PD-1+TIM3+LAG3+ T cells, suggesting that further combination with immune checkpoint inhibitors may enhance clinical efficacy. Conclusions: Our findings demonstrate that low-dose RPT can potentiate the anti-tumor efficacy of CAR T cells in metastatic neuroblastoma. To our knowledge, this is the first report of dosimetry-based RPT being combined with CAR T cells in a metastatic solid tumor setting. These findings underscore the potential of combining RPT and CAR T cells to overcome the unique challenges of solid tumors, particularly when treating metastatic disease.

cancer biology↗

Multimodal optical imaging reveals spatial metabolic heterogeneity in the aging retina

Understanding how aging reshapes retinal metabolism requires methods that can resolve molecular and structural changes across the retinas highly organized cellular layers. Here, we applied a nonlinear multimodal imaging platform that integrates fluorescence lifetime imaging microscopy (FLIM), second-harmonic generation (SHG), hyperspectral stimulated Raman scattering (HS-SRS), and deuterium oxide-based stimulated Raman scattering (DO-SRS) to map age-associated metabolic and compositional alterations in young and aged mouse retinas. FLIM analysis of the outer nuclear layer (ONL) revealed increased free NADH and NADPH fractions in aged retinas, consistent with reduced oxidative phosphorylation and enhanced lipid anabolic activity. SHG imaging of the sclera showed pronounced age-related remodeling of collagen organization, including increased fiber density, elevated anisotropy, and the emergence of densely crosslinked bundles in the central sclera. DO-SRS further demonstrated elevated lipid turnover in rod photoreceptor outer segments and the retinal pigment epithelium (RPE) with aging which was confirmed by lipidomic analysis. Complementary HS-SRS analysis revealed reduced triacylglycerol and cholesterol content together with localized sphingosine accumulation in the RPE. Together, these findings provide a spatially resolved view of metabolic remodeling in the aging retina and establish multimodal optical imaging as a powerful framework for studying alterations associated with age-related retinal disease.

bioengineering↗

FP8 Inference in Genomic Foundation Models: Theoretical vs. Realized Speedups on GenomeOcean

Genomic Foundation Models (GFMs) are increasingly used for large-scale sequence analysis and generation. Compared with frontier language models, GFMs are typically smaller and frequently operate on long genomic sequences, with evaluation often requiring preservation of biologically meaningful structure and sequence-level relationships. Although low-precision post-training quantization (PTQ) has shown substantial memory and throughput benefits for general-purpose language models, it remains unclear whether these benefits transfer to GFMs given their distinct model scales, sequence characteristics, and evaluation requirements. We present an empirical case study of FP8 post-training quantization applied to GenomeOcean, a computationally efficient genomic foundation model with strong reported performance across diverse genomics tasks [Zhou et al., 2025]. Its range of model scales, from 100M to 4B parameters, provides a useful setting for examining how quantization effects vary with model size. We evaluate FP8 across two primary GFM inference regimes--embedding extraction and autoregressive generation--and assess its impact along two dimensions: biological fidelity relative to BF16 baselines and system-level efficiency in terms of throughput, memory usage, and energy efficiency. We find that FP8 largely preserves biological fidelity across the evaluated scales and inference regimes, while reducing GPU memory footprint at 4B scale and improving energy efficiency during autoregressive generation. However, realized throughput gains remain substantially below FP8s theoretical 2x hardware ceiling, with a best-case improvement of 19.3% in autoregressive generation and benefits varying strongly by model scale and workload. Autoregressive generation shows the clearest gains, driven largely by KV-cache compression, whereas embedding extraction provides limited or negative throughput benefits at smaller model scales. We attribute this theory-practice gap to the interaction of model-scale effects, memory-system bottlenecks, and software-stack limitations. These findings highlight the need for workload-specific empirical evaluation before adopting low-precision inference in scientific foundation models. Code availabilityhttps://github.com/jgi-genomeocean/genomeocean_efficiency

bioinformatics↗

Plasma titration provides a physical ruler for cross-platform proteomics

Plasma proteomics is expanding across platforms and cohorts, and integrating these data for AI demands comparability at the protein level, not merely concordant associations1,2. Affinity and MS platforms use distinct probes (antibodies, aptamers, or peptides) and signal readouts, yielding contradictory cross-platform results3,4. Without a known quantitative truth, we cannot distinguish biology from measurement distortion, leaving no gold standard for integration. Here we introduce Plasmix--a plasma reference suite with predefined male:female ratios (M, 1:0; Y, 3:1; P, 1:1; X, 1:3; F, 0:1)--and show that preserving this quantitative titration gradient, not just technical repeatability, predicts cross-platform concordance and identifies protein measurements suitable for integration. Profiling Plasmix across five platforms (Olink, SomaScan, NULISA, AAgAtlas, and MS-DIA) and 12 protocols across 17 batches, we found discordance is dominated by signal generation, not sample identity, and platforms distort signals in a protein-specific manner. Crucially, proteins retaining the titration response showed stronger agreement in an independent cohort; anchoring to the Plasmix midpoint (P) via sample-to-reference ratios reduced distortions, extending harmonizable coverage by 10-20%. Plasmix thus provides a physical ruler to benchmark accuracy, identifying genuinely integrable measurements before pooling datasets or training AI models--a critical bottleneck for plasma proteomics.

molecular biology↗

Drosophila co-insulator proteins Pzg and Chro but not CP190 interact with promoter-proximal insulator-binding protein BEAF from a distance

Chromosomes in Drosophila melanogaster are organized into distinct topologically associated domains delimited by boundaries bound by insulator proteins. The insulator protein BEAF (Boundary Element-Associated Factor of 32kDa) plays roles in both chromatin organization and transcriptional regulation, yet its precise molecular mechanisms remain elusive. To examine the role of BEAF in insulator function we used yeast 2-hybrid assays, pull-down assays with bacterially expressed proteins, and bimolecular fluorescence complementation assays in S2 cells to characterize interactions between BEAF and three co-insulator proteins: CP190, Pzg, and Chro. Our studies pinpoint minimal regions of CP190, Pzg, and Chro that directly interact with BEAF, as well as parts of BEAF that are crucial for its interactions with these co-insulator proteins. Functional analyses in transfected S2 cells revealed distinct regulatory roles for BEAF in association with CP190, Pzg, and Chro. CP190 showed a weak interaction with BEAF, and CP190 bound 2.3 kb upstream of promoter-proximal BEAF could not loop out the intervening DNA to effectively communicate with BEAF for luciferase reporter gene activation. In contrast, more robust interactions were observed between BEAF and both Pzg and Chro. Both could also effectively interact with BEAF from a distance to activate the reporter gene. It is likely that the role of CP190 in long-range insulator interactions is mediated by insulator proteins other than BEAF, although BEAF could help stabilize interactions. On the other hand, we propose that BEAF can directly collaborate with Pzg and Chro to mediate long-range chromatin interactions.

molecular biology↗

A Method for Image-Based Modeling of Uterine Passive Mechanics During Late Pregnancy

PurposeComputational models of the uterus during pregnancy enable analysis of electro-chemo-mechanical pathways to predict labor timing and guide treatment planning. We aim to develop a robust image-based modeling pipeline to investigate uterine passive mechanics during late pregnancy. MethodsA parametric model of the uterus and cervix was created using a patients MRI measurements at 38 weeks of gestation. Inspired by advances in cardiac mechanics models, we created Laplace-Dirichlet solutions to inform tissue domains, fiber structure within the uterus and cervix, and spatially varying Robin boundary conditions. Prior imaging and mechanical testing data were used to fit material parameters. Boundary condition parameters were tuned to match the displacements of a previously established approach that employed contact with surrounding tissue. The tissue mechanical response to a physiologic load was assessed across varying material properties and fiber architectures. ResultsDiscrepancies in nodal displacements between the current approach and the contact-based model were limited to 3.4 {+/-} 1.8 mm, yielding nearly 90 % computational savings. Uterine tensile strains were more sensitive to ground substance elastic modulus (E) compared to fiber properties. Reduced E and fiber stiffness increased cervical strains and compression. Fiber dispersion and architecture modulated the opening of the cervical internal ostium but had a reduced impact on compression. ConclusionWe developed a novel workflow for modeling passive uterine mechanics, informed by patient-specific measurements and in vitro mechanical tests. The robust workflow may prove useful for studying labor progression and conducting longitudinal studies to enhance our understanding of normal and pathological pregnancies.

bioengineering↗

A Donor T-Cell Receptor Structural Signature Determines Alloreactive Potential and Predicts Acute Graft-Versus-Host Disease

Acute graft-versus-host disease (GVHD) remains a lethal barrier to successful allogeneic hematopoietic cell transplantation, yet pre-transplant donor selection entirely ignores hypervariable T-cell receptor (TCR) architecture. Here, by characterizing over 64,000 alloreactive clonotypes, we demonstrate that human alloreactivity is dictated by a constrained, predictable baseline structural signature. Pathogenic, tissue-infiltrating alloreactive T cells exhibit significantly shortened CDR3{beta} regions, altered antigen-facing biophysical features, biased VJ gene usage and extensive inter-donor sharing originating from public anti-pathogen memory reservoirs. These potent clones natively cluster within the high-frequency fraction of the unstimulated baseline donor repertoire. We introduce R50, an assay-independent metric quantifying this clonal dominance, which independently predicted a six-fold increased risk of acute GVHD in a cross-institutional cohort. This scalable in silico platform shifts pre-transplant risk stratification from HLA typing and demographic surrogates to precision immune-receptor modeling.

immunology↗

Notch Signaling Reprograms Glial Lipid Metabolism to Promote Hypoxia Resistance

Hypoxia poses a major threat to the developing nervous system, where high metabolic demand is required to support brain growth, glial and neuronal maturation, and function. Although glial cells are essential for maintaining neural homeostasis under stress, how specific glial subtypes remodel metabolism to promote hypoxia tolerance remains poorly understood. Here, we identify a Notch-dependent lipid metabolic program in excitatory amino acid transporter 1 (Eaat1)-positive glia that supports hypoxia adaptation in the developing Drosophila larval brain. Using stimulated Raman scattering (SRS) microscopy combined with deuterium-labeled metabolic probes, we visualized substrate-specific metabolic activity in vivo at subcellular resolution. In control, non-adapted flies, we found that acute hypoxia markedly increased de novo lipogenesis in Eaat1-positive glia. In flies adapted to chronic hypoxia, Eaat1-positive glia exhibited a pre-programmed metabolic shift, characterized by reduced glucose-derived lipogenesis and enhanced acetate-derived lipid synthesis. Constitutive activation of Notch signaling in Eaat1-positive glia was sufficient to phenocopy this acetate-favored lipogenic state, suggesting that Notch promotes metabolic plasticity under oxygen-limited conditions. To define the transcriptional programs associated with this response, we performed single-nucleus RNA sequencing (snRNA-seq) of the developing Drosophila central nervous system and mapped Eaat-1expressing cell populations across hypoxia and Notch activation. Notch activation reshaped hypoxia-associated transcriptional responses and counteracted metabolic suppression caused by low oxygen. Together, our findings identify Eaat1-positiveglia as a metabolically adaptive glial population and reveal a conserved Notch-regulated mechanism that rewires lipid metabolism to support hypoxia tolerance in the developing brain. These results provide insight into glial metabolic strategies that may be relevant to hypoxia-associated neurological conditions, including neonatal hypoxic-ischemic brain injury and ischemic stroke.

Cell Biology↗

A finite element model of pregnancy derived from maternal sonography: effect of uterine and cervical structural properties on cervical mechanical loading

Identification and treatment of pregnancies at risk for preterm birth is a central challenge in obstetric research. Many of the known causes of preterm birth originate from mechanical failure in reproductive tissues. To better understand the biomechanical environment of the gravid uterus and its potential contribution to preterm birth, this computational study presents a parametric method for modeling maternal reproductive anatomy during the early second trimester. A finite element modeling approach was built using existing sonographic measurements from early second-trimester maternal anatomy and material properties from published mechanical tests. We applied the same physiologically relevant intrauterine pressure to all models and quantified the resulting tissue stretch. The sensitivity of the stretch in the proximal cervix was explored by varying material properties and sonographic maternal anatomy dimensions. Cervical material properties, particularly the fiber stiffness modulus and ground substance Youngs modulus, were found to have the greatest effect on proximal cervix stretch compared to other material properties and sonographic dimensions. Among the sonographic dimension measurements, those defining the region surrounding the proximal cervix had the greatest effect on proximal cervix stretch, including the curvature of the posterior uterine wall and the thickness of the lower uterine segment. The computational modeling approach presented here enables future patient-specific studies of gravid reproductive tissues to elucidate differences between individuals who do and do not deliver preterm. Additionally, this study is foundational for building digital twins to support future virtual clinical studies on diagnostic and therapeutic device design to prevent preterm birth.

bioengineering↗

Effects of Left Atrial Wall Thickness on Myocardial Mechanics and Blood Dynamics using Multiscale Modeling

PurposePatient-specific models of left atrial (LA) mechanics often assume uniform left atrial wall thickness (LAWT), but the effect of LAWT on the mechanics and hemodynamics remains less quantified. MethodsFour LA myocardium models were built from gated CTA images: a baseline variable thickness (VT#0), two reduced-dilation variants, and a 2mm uniform thickness model. Multi-scale mechanics and blood flow simulations were performed across all the thickness variants using model parameters personalized on the baseline model. Predicted displacements, wall stresses and strains, and hemodynamics were compared. ResultsAcross all LAWT variants, myocardial volume spanned 14.4-19.9mL (38%), while cavity volume remained mostly within 5% of image data throughout the cardiac cycle. Circulatory system output, myocardial displacements, and strains varied by 5-6% relative to the baseline model. Instantaneous stresses increased by up to 19% in the thinner variable thickness models and decreased by up to 16% in the uniformly thick case. Globally, the area under low time-averaged wall shear stress (TAWSS) varied between 23% and 30% across all thickness variants, while LA exposed to elevated oscillatory shear index (OSI) increased from nearly 6% to 19%. Over 90% of LAA was exposed to low shear, but the high-OSI area increased from 7% in VT#0 to over 30% in Uniform. ConclusionA personalized multiscale modeling framework was leveraged to demonstrate that the left atrial myocardial stresses and oscillatory shear had a greater sensitivity to local wall thickness representation compared to cavity volumes, tissue displacements, strains, and mean blood shear.

bioengineering↗

Preconception e-nicotine impairs airway development and progenitor proliferation across generations in Drosophila Melanogaster

Electronic nicotine delivery devices are increasingly used worldwide, raising concern about the potential effects of nicotine exposure during fetal and early postnatal development. However, evidence regarding the effects of vaping during pregnancy remains limited, and the consequences of exposure before conception are largely unknown. Here, we investigated whether maternal nicotine vaping prior to conception alters airway development using the fruit fly Drosophila melanogaster. Offspring of nicotine-exposed mothers exhibited abnormal airway architecture, epithelial remodelling, and impaired terminal branching. These defects were accompanied by reduced proliferation of airway progenitor cells without increased apoptosis, resulting in decreased hypoxia tolerance, altered activity patterns, and reduced lifespan. Transcriptomic and functional analyses revealed suppression of innate immune signalling mediated by nuclear factor kappa-B (NF-{kappa}B). Notably, knockdown of its regulator Relish reproduced key phenotypes. Developmental abnormalities persisted across generations, with their severity progressively declining. Together, these findings identify maternal preconception nicotine exposure as a previously unrecognized determinant of airway development and provide insight into early origins of chronic airway disease. TeaserPreconception e-nicotine exposure shapes airway development, structural and physiological abnormalities across generations in Drosophila.

Developmental Biology↗

Transformer-based framework uncovers state-dependent modular organization and conformational landscapes of the β-arrestin 1 C-terminal tail

{beta}-arrestins ({beta}arr) regulate signaling and trafficking of G protein-coupled receptors (GPCRs) across diverse physiological and pathological processes. However, mechanistic understanding of how ligand-activated GPCRs engage and activate {beta}arr remains limited, with the conformation of the entire {beta}arr tail in the active state still unknown. Here, by comparatively analyzing temperature replica-exchange molecular dynamics simulation data of {beta}arr1 in basal and active states, we investigated the conformational landscape of the {beta}arr1 tail to elucidate its role in activation. To overcome limitation of conventional analyses in characterizing the vast conformational space sampled by the 62-residue tail, we developed a transformer-based autoencoder (TAE) framework that integrates attention-derived residue relationships and latent-space clustering to identify the tails modular organization and conformational substates, providing an interpretable description of how local residue interactions couple to large-scale conformational rearrangements. Using the conformationally constrained basal state as a control, we validated the framework by showing that it recovers interpretable conformational features. In the active state, the framework revealed a reorganized modular architecture, recovered key interactions identified through manual analysis, and uncovered segment-specific dynamics inaccessible to conventional approaches. Our findings show that, in the active state, the {beta}arr1 tail preferentially engages the back side of the main body and forms substates in which the middle segment occupies the central crest crevice, suggesting that the released tail can self-engage functionally critical surfaces and influence the balance between tail-only and core-engaged receptor complexes. Together, this work establishes a TAE framework for analyzing large-scale conformational ensembles and advances our understanding of {beta}arr1 activation.

biophysics↗