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Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 559 records · Page 31Linked to original sources

GP-ML-DC: An Ensemble Machine Learning-Based Genomic Prediction Approach with Automated Two-Phase Dimensionality Reduction via Divide-and-Conquer Techniques

Traditional machine learning (ML) and deep learning (DL) methods for genome prediction often face challenges due to the imbalance between the limited number of samples (n) and the large number of single nucleotide polymorphisms (SNPs) (p), where n is much smaller than p. To address this, we propose GP-ML-DC, an innovative genome predictor that combines traditional ML and DL models with a unique two-phase, parameter-free dimensionality reduction technique. Initially, GP-ML-DC reduces feature dimensionality by characterizing genes as features. Building on big data methodologies, it employs a divide-and-conquer approach to segment gene regions into multiple haplotypes, further decreasing dimensionality. Each haplotype segment is processed by a sub-task based on traditional ML, followed by integration via a neural network that synthesizes the results of all sub-tasks. Our experiments, conducted on four cattle milk-related traits using ten-fold cross-validation and independent testing, show that GP-ML-DC significantly surpasses current state-of-the-art genome predictors in prediction performance.

bioinformatics↗

Systematic Benchmarking of High-Throughput Subcellular Spatial Transcriptomics Platforms

Recent advancements in spatial transcriptomics technologies have significantly enhanced resolution and throughput, underscoring an urgent need for systematic benchmarking. To address this, we collected clinical samples from three cancer types - colon adenocarcinoma, hepatocellular carcinoma, and ovarian cancer - and generated serial tissue sections for systematic evaluation. Using these uniformly processed samples, we generated spatial transcriptomics data across five high-throughput platforms with subcellular resolution: Stereo-seq v1.3, Visium HD FFPE, Visium HD FF, CosMx 6K, and Xenium 5K. To establish ground truth datasets, we profiled proteins from adjacent tissue sections corresponding to all five platforms using CODEX and performed single-cell RNA sequencing on the same samples. Leveraging manual cell segmentation and detailed annotations, we systematically assessed each platforms performance across key metrics, including capture sensitivity, specificity, diffusion control, cell segmentation, cell annotation, spatial clustering, and transcript-protein alignment with adjacent CODEX. The uniformly generated, processed, and annotated multi-omics dataset is valuable for advancing computational method development and biological discoveries. The dataset is accessible via SPATCH, a user-friendly web server for visualization and download (http://spatch.pku-genomics.org/).

genomics↗

Comprehensive analysis of macrophages infected with avirulent and virulent Mycobacterium tuberculosis uncovers distinct immune mechanisms and anti-TB effect of treated exosomes

Tuberculosis (TB) is now the worlds second deadliest infectious killer after COVID-19. Human-macrophages and their secreted exosomes play important roles in combating invading Mtb. However, the panoramic analysis of the underlying immune mechanism for the infected macrophages, package or secretion mechanism, and anti-TB effect of Mtb treated exosomes remain poorly understood. Here we conducted comprehensive analyses of the macrophages infected with avirulent and virulent Mtb (H37Ra & H37Rv) and their secreted exosomes, collected cells and corresponding exosomes for omics and phenotypic analysis. The results showed that avirulent Mtb stimulated robust immune-responses and apoptosis in macrophages to eliminate the invading Mtb; virulent Mtb induced severe necrosis and immune-escape for survival. The HMGB1 signaling pathway and TNFRSF1B plays important roles in the immune escape of virulent Mtb. Interestingly, our results suggest that macrophages kill Mtb in an IFN-{gamma} independent but simulative way, highlighting the central role of IFN signaling pathway in anti-TB immune response. Moreover, we observed selective transport of host and Mtb RNAs from macrophages to exosomes. Notably, "H37Ra-treated exosomes" displayed a higher anti-TB effect than "H37Rv-treated exosomes" due to some enriched pro-inflammation and immune-escape related Mtb proteins in these two exosomes, respectively. Conclusively, our findings shed new light on the immune mechanism of macrophages in response to Mtb infection, offering a new TB-treatment strategy and some promising vaccine candidates.

bioinformatics↗

Morphological Plasticity and Reproductive Strategies of Kalanchoe Species in Invasive Spread

Kalanchoe species, originally introduced worldwide as ornamentals, are now reported to be spreading in many regions, including China. It is hypothesized that morphological plasticity and the production of asexual plantlets contribute to their successful invasion. To address the hypothesis, four species - Kalanchoe delagoensis Eckl. & Zeyh., Kalanchoe x houghtonii D. B. Ward, Kalanchoe laetivirens Desc. and Kalanchoe daigremontiana Raym. - Hamet & H. Perrier - were cultivated under contrasting light and water conditions, and their reproductive and vegetative traits were examined. The plants subjected to high light tended to prioritize plantlet production, accompanied by a reduction in vegetative growth. Two distinct reproductive strategies were observed: K. delagoensis and K. x houghtonii significantly increased plantlet production under high light conditions, whereas K. daigremontiana and K. laetivirens enhanced the fresh weight of individual plantlets without altering the total number produced. These results highlight the high plasticity of vegetative and reproductive growth in response to light and water availability. The increased production of plantlets may contribute to the widespread occurrence of Kalanchoe species in open fields.

plant biology↗

OmiGA: A Toolkit for Ultra-efficient Molecular Trait Analysis in Complex Populations

Molecular quantitative trait loci (molQTL) mapping is one of the most popular approaches to systematically characterize functional impacts of genomic variants, leading to advanced understanding of the regulatory mechanisms underpinning complex traits and diseases. However, when applied to high-throughput molecular phenotypes, the existing molQTL mapping tools often implement simple linear models, overlooking complex inter-individual relatedness, leading to false positives and insufficient statistical power. Here, we introduce the Omics Genetic Analysis toolkit (OmiGA), an ultra-efficient linear mixed model (LMM) based toolkit, for molQTL mapping in populations with complex relatedness. Both computational simulations and real data analyses demonstrated that OmiGA outperformed the existing popular tools regarding molQTL discovery power, fine mapping of causal variants, colocalization of molQTL and trait associations, and computational efficiency. In summary, we recommend OmiGA for molQTL mapping in populations with complex relatedness, for example, those in the Farm animal Genotype-Tissue Expression (FarmGTEx) project and family-based molQTL studies in humans.

bioinformatics↗

Possible involvement of ghost introgressions in the striking diversity of V1R receptor genes in East African cichlids

Cichlids that have undergone adaptive radiation are genetically close but exhibit extreme ecological and morphological diversity, making them useful for understanding speciation mechanisms. Vomeronasal type 1 receptors (V1R) are highly conserved among teleost fish at the amino acid sequence level and believed to play a fundamental role in reproduction. We previously reported the surprisingly high sequence diversity of V1Rs among certain cichlid species, suggesting a possible role for V1Rs in their speciation. In this study, we investigated the process of evolutionary diversification of all 6 V1Rs (V1R1-6) by using the genome data of 528 cichlid species, encompassing nearly all lineages. In the case of V1R2, two highly divergent alleles (1.17%: variant sites/CDS length) without recombination were preserved and shared among cichlids found in all of the East African Great Lakes. In the case of V1R6, numerous highly variable alleles that could be derived from multiple recombination events between two highly divergent alleles (1.39%: variant sites/CDS length) were found among the Lake Victoria cichlids. Additionally, we identified highly divergent alleles of V1R1 within the tribe Tropheini, and of both V1R3 and V1R6 within Trematocarini and Ectodini. Because one of the two divergent alleles of these V1Rs emerged rapidly during cichlid evolution, they are likely to have been derived from introgression. However, despite extensive investigations, we could not identify the source lineages for these introgressions, implying that they may have become extinct. This study revealed the potential role of introgression in explaining the remarkable diversity of V1Rs in East African cichlids.

evolutionary biology↗

In silico discovery of potential inhibitors targeting the MEIG1-PACRG complex for male contraceptive development

The interaction between meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) is a critical determinant of spermiogenesis, the process by which round spermatids mature into functional spermatozoa. Disruption of the MEIG1-PACRG complex can impair sperm development, highlighting its potential as a therapeutic target for addressing male infertility or for the development of non-hormonal contraceptive methods. This study used virtual screening, molecular docking, and molecular dynamics (MD) simulations to identify small molecule inhibitors targeting the MEIG1-PACRG interface. MD simulations provided representative protein conformations, which were used to virtually screen a library of over 800,000 compounds, resulting in 48 high-ranking candidates for each protein. PACRG emerged as a favorable target due to its flexible binding pockets and better docking scores compared to MEIG1. Key binding residues with compounds included W50, Y68, N70, and E74 on MEIG1, and K93, W96, E101, and H137 on PACRG. MD simulations revealed that compound stability in MEIG1 complexes is primarily maintained by hydrogen bonding with E74 and {pi}-{pi} stacking interactions with W50 and Y68. In PACRG complexes, compound stabilization is facilitated by hydrogen bonding with E101 and {pi}-{pi} interactions involving W96 and H137. These findings highlight distinct molecular determinants of ligand binding for each protein. Our work provides mechanistic insights and identifies promising compounds for further experimental validation, establishing a foundation for developing MEIG1-PACRG interaction inhibitors as male contraceptives.

pharmacology and toxicology↗

A Large Language Model Guides the Affinity Maturation of Variant Antibodies Generated by Combinatorial Optimization

The ability of an antibody to bind an antigen with high specificity and strength (i.e., its binding affinity) are critical properties in the design of neutralizing antibodies. Recent technical advances in AI and a surge of experimental data on antigen-antibody interaction are driving innovations in the design and optimization of antibodies via affinity maturation. Here we introduce Ab-Affinity, a novel large language model which can accurately predict the binding affinity of specific antibodies against a target peptide within the SARS-CoV-2 spike protein. When used in conjunction with a genetic algorithm and simulated annealing, Ab-Affinity can generate novel antibodies with more than a 160-fold increase in predicted binding affinity compared to those obtained experimentally. Our experimental results show that the synthetic antibodies produced by Ab-Affinity have strong predicted biophysical properties. Molecular docking and molecular dynamics simulation of binding interactions of the best synthetic antibodies show enhanced interactions and stability on the target peptide epitope. In general, antibodies generated by Ab-Affinity are superior to those obtained with other existing computational methods.

molecular biology↗

Dopaminergic responses to identity prediction errors depend differently on the orbitofrontal cortex and hippocampus

Adaptive behavior depends on the ability to predict specific events, particularly those related to rewards. Armed with such associative information, we can infer the current value of predicted rewards based on changing circumstances and desires. To support this ability, neural systems must represent both the value and identity of predicted rewards, and these representations must be updated when they change. Here we tested whether prediction error signaling of dopamine neurons depends on two areas known to represent the specifics of rewarding events, the HC and OFC. We monitored the spiking activity of dopamine neurons in rat VTA during changes in the number or flavor of expected rewards designed to induce errors in the prediction of reward value or reward identity, respectively. In control animals, dopamine neurons registered both error types, transiently increasing firing to additional drops of reward or changes in reward flavor. These canonical firing signatures of value and identity prediction errors were significantly disrupted in rats with ipsilateral neurotoxic lesions of either HC or OFC. Specifically, HC lesions caused a failure to register either type of prediction error, whereas OFC lesions caused persistent signaling of identity prediction errors and much more subtle effects on signaling of value errors. These results demonstrate that HC and OFC contribute distinct types of information to the computation of prediction errors signaled by dopaminergic neurons.

neuroscience↗

Deficiency of DDI2 suppresses liver cancer progression byworsening cell survival conditions

The levels of reactive oxygen species (ROS) and the extent of ensuing DNA damage significantly influence cancer initiation and progression. Of crucial importance, the aspartate protease DDI2 has been proposed to play a pivotal role in monitoring intracellular ROS levels (to trigger oxidative eustress or distress), as well as in the oxidative DNA damage repair, through redox homeostasis-determining factor Nrf1 (encoded by NFE2L1). However, the specific role of DDI2 in the multi-step process resulting in the development and progression of liver cancer remains elusive to date. In the present study, we employed the CRISPR/Cas9 gene editing system to create two nuanced lines of DDI2 knockout (i.e., DDI2-/- and DDI2insG/-) from liver cancer cells. Subsequent experiments indicate that the knockout of DDI2 leads to increased ROS levels in hepatoma cells by downregulating two major antioxidant transcription factors Nrf1 and Nrf2 (encoded by NFE2L2), exacerbating endogenous DNA damages caused by ROS and not-yet-identified factors, thereby inhibiting cell proliferation and promoting apoptosis, and ultimately hindering in vivo malignant growth of xenograft tumor cells. Conversely, the restoration of DDI2 expression reverses the accumulation of ROS and associated DNA damage caused by DDI2 knockout, eliminating the subsequent inhibitory effects of DDI2 deficiency on both in vitro and in vivo growth of liver cancer cells. Collectively, these findings demonstrate that DDI2 deficiency impedes liver tumor growth by disrupting its survival environment, suggesting that DDI2 may serve as a novel therapeutic target for anti-cancer strategies aimed at modulating ROS or DNA damage processes.

cancer biology↗

Modulating Prestimulus Alpha and Beta Power with tRNS Establishes Their Causal Role in Visual Perception

Variability in visual perception in response to consistent stimuli is a fundamental phenomenon linked to fluctuations in prestimulus low-frequency neural oscillations--particularly in the alpha (8-13 Hz) and beta (13-30 Hz) bands--typically measured by their power in electroencephalography (EEG) signals. However, the causal role of these prestimulus alpha and beta power fluctuations in visual perception remains unestablished. In this study, we investigated whether prestimulus alpha and beta power causally affect visual perception using transcranial random noise stimulation (tRNS). In a sham-controlled, single-blind, within-subject design, 29 participants performed a visual detection task while receiving occipital tRNS. Online functional near-infrared spectroscopy (fNIRS) was used to measure cortical excitability during stimulation, and offline EEG signals were collected after stimulation. Mental fatigue was incorporated as a state-dependent factor influencing tRNS effects. Our findings demonstrate that, primarily under low fatigue states, tRNS increased cortical excitability during stimulation (indicated by increased fNIRS oxyhemoglobin amplitude), decreased subsequent prestimulus EEG alpha and beta power, and consequently reduced the visual contrast threshold (VCT), indicating enhanced visual perception. Sensitivity analysis revealed that alpha oscillations contributed more significantly to visual perception than beta oscillations under low fatigue. Additionally, the state-dependent effects of tRNS may result from different sensitivities of VCT to neural oscillations across fatigue states. These results provide causal evidence linking prestimulus alpha and beta power to visual perception and underscore the importance of considering brain states in neuromodulation research. Our study advances the understanding of the neural mechanisms underlying visual perception and suggests potential therapeutic applications targeting neural oscillations. Significance statementUnderstanding why we perceive identical visual stimuli differently is a fundamental question in neuroscience. This study provides causal evidence that prestimulus alpha and beta neural oscillations directly influence visual perception, particularly under low mental fatigue state. By using tRNS alongside fNIRS and EEG recordings, we demonstrate that modulating neural excitability can alter perceptual outcomes. Our findings highlight the importance of considering brain state--such as fatigue levels--in neuromodulation research. This work advances our understanding of the neural mechanisms underlying visual perception and opens avenues for developing targeted interventions to enhance sensory processing and cognitive functions, potentially benefiting individuals with perceptual or attentional disorders.

neuroscience↗

EnzymeCAGE: A Geometric Foundation Model for Enzyme Retrieval with Evolutionary Insights

Enzyme catalysis is fundamental to life, driving the chemical transformations that sustain biological processes and support industrial applications. However, unraveling the intertwined relationships between enzymes and their catalytic reactions remains a significant challenge. Here, we present EnzymeCAGE, a catalytic-specific geometric foundation model trained on approximately 1 million structure-informed enzyme-reaction pairs, spanning over 2,000 species and encompassing an extensive diversity of genomic and metabolic information. EnzymeCAGE features a geometry-aware multi-modal architecture coupled with an evolutionary information integration module, enabling it to effectively model the nuanced relationships between enzyme structure, catalytic function, and reaction specificity. EnzymeCAGE supports both experimental and predicted enzyme structures and is applicable across diverse enzyme families, accommodating a broad range of metabolites and reaction types. Extensive evaluations demonstrate EnzymeCAGEs state-of-the-art performance in enzyme function prediction, reaction de-orphaning, catalytic site identification, and biosynthetic pathway reconstruction. These results highlight its potential as a transformative foundation model for understanding enzyme catalysis and accelerating the discovery of novel biocatalysts.

synthetic biology↗

Inbreeding and demography interact to impact population recovery from bottlenecks

Biodiversity loss driven by climate change and human activities poses a critical global challenge. Population restoration and reintroduction programs are essential for mitigating this threat, yet their outcomes are often unpredictable due to poorly understood success factors. The conservation program of the crested ibis (Nipponia nippon) marks a successful example where the population rose from seven survivors to over 9,000 in the past four decades. To learn whether this successful restoration was due to chance or largely repeatable, we developed an individual-based model that simulates the restoration process by incorporating life-history parameters from empirical data. Our simulation results closely mirror empirical findings, including the time taken to reach the current population size and population-level inbreeding coefficients. We further analyzed the model to compare the effectiveness of two reintroduction strategies and analyzed how inbreeding depression interacts with demography to influence the chance of recovery from bottlenecks. The reintroduction simulations reveal that the firework approach (one-source translocations) outperforms the stepping-stone (serial translocations) approach in restoration effectiveness. Our simulations over broad demographic parameters demonstrate that the net effect of inbreeding varies with species-specific demography, and highlight the importance of considering this interaction when interpreting conservation outcomes and designing future reintroduction programs.

ecology↗

Lineage-associated Human Divergently-Paired Genes (DPGs) Exhibit Regulatory Characteristics and Evolutionary Trends

Divergently-paired genes (DPGs) represent one of the minimal co-transcriptional units (the rest include tandemly- and convergently-paired genes) of clustered genes; the former and the latter constitute greater than 10% and 75% of the total human genes, respectively. Our previous studies have shown that vertebrate DPGs are more conserved, both organizationally and functionally than invertebrates. Three critical questions remain to be addressed: (1) what are the conserved DPGs over vertebrate lineages, especially among mammals and primates? (2) being bidirectionally transcribed, to what extent do DPGs share their promoter sequences and how mechanistically and stringently are their co-expression regulated within the shared inter-TSS (transcription start site) sequence space? and (3) based on the recently released high-quality human genome assemblies, how do human-associated DPGs distribute over selected primate lineages and what are their possible functional consequences biologically? Our study begins by identifying 1399 human DPGs (12% of all human protein-coding genes), and presents findings from this analysis. First, 1136, 1118, 925, and 830 human DPGs are shared genetically with primates, mammals, avians, and fish, respectively. DPGs are not only functionally enriched toward direct protein-DNA interactions and cell cycle synchronization but also exhibit obvious lineage association, narrow in principle toward synchronization of certain core molecular mechanisms and cellular processes. Second, their inter-TSS distances and expression variables affect both co-expression strength and disparity between the two genes. Finally, our results based on a comparison among the primate DPGs reveal that the human-associated DPGs exhibit intensive diversification in co-expression, duplication, and definite involvement in neural development. Within humans, 55 and 357 DPGs are associated to the Chinese (YAO) and the European (CHM13) assemblies, respectively. Our results offer novel insights into comprehending the structure-function selection of gene clusters over evolutionary time scales, as well as a deeper understanding of the regulatory characteristics of co-expressed neighboring genes.

genomics↗

Single-cell analysis reveals multi-faceted features of B cell development together with age-associated B cell subpopulations

The development and maturation of B lymphocytes involve intricate orchestrated processes, where dedicated gene regulations (GR) take place within specific microenvironments shaped by both extracellular matrix and neighboring cells. Despite extensive investigations aimed at deepening our comprehension of these mechanisms, there remains a dearth of high-dimensional and integrated analysis concerning B cell heterogeneity, gene regulation, and external factors implicated in B cell development. In this study, we scrutinized single-cell transcriptomic data and B cell receptor (BCR) sequencing data obtained from B cells and their surrounding counterparts in the bone marrow, tonsil, and peripheral blood. A full picture of the GR dynamics, the heterogeneity of conventional B cells and cell-cell interactions (CCIs) along B cell development axis was depicted. We found immature B cells represent the most quiescent stage characterized by the least number of expressed genes and low RNA velocity. The homeostatic proliferation and activation of naive B cells is niche-confined and individualized, respectively. Two development models for memory B cell subpopulations seem not mutually exclusive and warrant in-depth investigation. Moreover, CCI analysis reveals a pivotal role of myeloid cells and two dominant and stage-dependent CCI categories, TNF and adhesion signaling, in B cell development. Besides, we unexpectedly identified two age-associated B cell subpopulations that respectively express S100A8/S100A9 and C1q and experimentally confirmed the secretion of S100A8/A9 from human B cells in vitro, suggesting a senescence-associated secretion phenotype. Our integrated analysis provides valuable insights into GR dynamics, the evolution of B cells, and potential intercellular communication networks involved in B cell development and revealed novel phenotypes of age-associated B cell aberrance. This study serves as a valuable resource for in-depth exploration of the intricacies of B cell biology.

cell biology↗

ARBEL: A Machine Learning Tool with Light-Based Image Analysis for Automatic Classification of 3D Pain Behaviors

A detailed analysis of pain-related behaviors in rodents is essential for exploring both the mechanisms of pain and evaluating analgesic efficacy. With the advancement of pose-estimation tools, automatic single-camera video animal behavior pipelines are growing and integrating rapidly into quantitative behavioral research. However, current existing algorithms do not consider an animals body-part contact intensity with- and distance from- the surface, a critical nuance for measuring certain pain-related responses like paw withdrawals ( flinching) with high accuracy and interpretability. Quantifying these bouts demands a high degree of attention to body part movement and currently relies on laborious and subjective human visual assessment. Here, we introduce a supervised machine learning algorithm, ARBEL: Automated Recognition of Behavior Enhanced with Light, that utilizes a combination of pose estimation together with a novel light-based analysis of body part pressure and distance from the surface, to automatically score pain-related behaviors in freely moving mice in three dimensions. We show the utility and accuracy of this algorithm for capturing a range of pain-related behavioral bouts using a bottom-up animal behavior platform, and its application for robust drug-screening. It allows for rapid objective pain behavior scoring over extended periods with high precision. This open-source algorithm is adaptable for detecting diverse behaviors across species and experimental platforms.

neuroscience↗

UniSPAC: A Unified Segmentation Framework for Proofreading and Annotation in Connectomics

Reconstructing dense neuronal connections from volume electron microscopy (vEM) images is a critical challenge in neuroscience, driving the development of various automatic neuron segmentation methods1. Although current state-of-the-art automated segmentation methods can achieve high segmentation accuracy, they still require substantial manual proofreading and rely heavily on labeled datasets, which are often scarce, particularly for non-model organisms. Here, we introduce a Unified Segmentation framework for Proofreading and Annotation in Connectomics (UniSPAC) by providing the interactive segmentation model in 2D-level and the neuron tracing model in 3D-level. UniSPAC-2D allows users to correct its segmentation errors through point-based prompts, combining segmentation and proofreading in a single framework. UniSPAC-3D automatically traces neurons segmented by UniSPAC-2D across image slices, significantly reducing human involvement. Furthermore, UniSPAC-2D and UniSPAC-3D models can facilitate the semi-automatic generation of labeled data for new species, eliminating the need for external annotation tools. The fresh annotated data generated during proofreading in turn optimizes the interactive model through an online learning strategy, reducing the labeling effort for novel species over time. UniSPAC outperforms the start-of-the-art Segment Anything Model (SAM) in Drosophila segmentation, achieving 47x higher efficiency, and surpasses ACRLSD in cross-species segmentation on zebra finch data.

neuroscience↗

Elucidating the dynamics of Integrin αIIb3 from native platelet membranes by cryo-EM with build and retrieve method

Platelets fulfill their essential physiological roles sensing the extracellular environment through their membrane proteins. The native membrane environment provides essential regulatory cues that impact the protein structure and mechanism of action. Single-particle cryogenic electron microscopy (cryo-EM) has transformed structural biology by allowing high-resolution structures of membrane proteins to be solved from homogeneous samples. Our recent breakthroughs in data processing now make it feasible to obtain atomic-level-resolution protein structures from crude preparations in their native environments by integrating cryo-EM with the "Build-and-Retrieve" (BaR) data processing methodology. We applied this iterative bottom-up methodology on resting human platelet membranes for an in-depth systems biology approach to uncover how lipids, metal binding, post-translational modifications, and co-factor associations in the native environment regulate platelet function at the molecular level. Here, we report using cryo-EM followed by the BaR method to solve the unmodified integrin IIb{beta}3 structure directly from resting human platelet membranes in its inactivated and intermediate states at 2.75[A] and 2.67[A], respectively. Further, we also solved a novel dimer conformation of IIb{beta}3 at 2.85[A] formed by two intermediate-states of IIb{beta}3. This may indicate a previously unknown self-regulatory mechanism of IIb{beta}3 in its native environment. In conclusion, our data show the power of using cryo-EM with the BaR method to determine three distinct structures including a novel dimer directly from natural sources. This approach allows us to identify unrecognized regulation mechanisms for proteins without artifacts due to purification processes. These data have the potential to enrich our understanding of platelet signaling circuitry. Key pointsO_LIWe report the first structural analysis of platelet membrane proteins extracted directly from human platelet membranes. C_LIO_LIOur novel structural-omics approach allowed us to solve integrin IIb{beta}3 structures in two distinct states from resting human platelets. C_LIO_LIRegulatory cues of integrin IIb{beta}3 were preserved from the native resource and revealed on the models with atomic resolutions. C_LIO_LIThis study opens the potential to build the platelet membrane protein atlas to understand platelet physiology. C_LI

biochemistry↗