Biology subjects

Liu, M.

Publications and source records attributed to Liu, M..

At least 271 records · Page 15Linked to original sources

bioRxiv2023

AraENCODE: a comprehensive epigenomic database of Arabidopsis Thaliana

Arabidopsis (Arabidopsis thaliana) is a vital model organism in plant biology and genetics. In the last two decades, researchers have made significant progresses in characterizing the chromatin conformation and epigenomic information within the Arabidopsis genome. This information includes but is not limited to the higher structure of chromosomes, histone modification, DNA methylation, and chromatin accessibility. The results of these studies have provided an additional layer of information that complements the DNA sequence data. However, utilizing such knowledge poses a challenge for certain groups that lack bioinformatics analysts or adequate computing resources. A user-friendly and reproducible platform for accessing this information is urgently needed. In this study, we have developed a comprehensive epigenomic database for Arabidopsis (AraENCODE http://glab.hzau.edu.cn/AraENCODE), which comprises a total of 4,511 data libraries, including published chromatin conformation capture datasets (Hi-C, HiChIP), epigenomic datasets (ChIP-Seq, ATAC-Seq, FAIRE-Seq, MNase-Seq, DNase-Seq, BS-seq), and transcriptome data (RNA-Seq, miRNA-Seq). Furthermore, we have incorporated various existing resources, such as single nucleotide polymorphisms (SNPs), cis-regulatory modules, and multi-omics associations. We aim to provide a novel platform for investigating the regulation of epigenetic and chromatin interactions in Arabidopsis in relation to biological processes.

bioinformatics↗

bioRxiv2023

Effect of Aging, Sex, and Gene (Fbln5) on Arterial Stiffness of Mice: 20 Weeks Adult Fbln5-knockout Mice Have Older Arteries than 100 Weeks Wild-Type Mice

The arterial stiffening is a strong independent predictor of cardiovascular risk and has been used to characterize the biological age of arteries ( arterial age). Here we revealed that the Fbln5 gene knockout (Fbln5-/-) significantly increases the arterial stiffening for both male and female mice. We also showed that the arterial stiffening increases with natural aging, but the stiffening effect of Fbln5-/- is much more severe than aging. The arterial stiffening of 20 weeks old mice with Fbln5-/- is much higher than that at 100 weeks in wild-type (Fbln5+/+) mice, which indicates that 20 weeks mice (equivalent to [~]26 years old humans) with Fbln5-/- have older arteries than 100 weeks wild-type mice (equivalent to [~]77 years humans). Histological microstructure changes of elastic fibers in the arterial tissue elucidate the underlying mechanism of the increase of arterial stiffening due to Fbln5-knockout and aging. These findings provide new insights to reverse arterial age due to abnormal mutations of Fbln5 gene and natural aging. This work is based on a total of 128 biaxial testing samples of mouse arteries and our recently developed unified-fiber-distribution (UFD) model. The UFD model considers the fibers in the arterial tissue as a unified distribution, which is more physically consistent with the real fiber distribution of arterial tissues than the popular fiber-family-based models (e.g., the well-know Gasser-Ogden-Holzapfel [GOH] model) that separate the fiber distribution into several fiber families. Thus, the UFD model achieves better accuracies with less material parameters. To our best knowledge, the UFD model is the only existing accurate model that could capture the property/stiffness differences between different groups of the experimental data discussed here.

bioengineering↗

bioRxiv2023

Ferroptosis induced by phenolic compound-iron complex

Phenolic compounds are the most ubiquitously distributed pollutants, and are highly toxic to living organisms, however the detailed mechanism how phenols exert toxic effects remains elusive. Here,Escherichia coli and phloroglucinol are adapted as proxy to elucidate the molecular mechanism of phenols toxicity. We demonstrated that phloroglucinol complexed with iron and promoted the generation of hydroxyl radicals in Fenton reaction, leading to reducing power depletion and lipid peroxidation, and further leading to ferroptosis-like cell death ofE. coli. This ferroptotic death can be triggered by various phenols in diverse organisms, from bacteria to mammalian cells. Furthermore, we demonstrated that phloroglucinol-induced ferroptosis suppressed tumor growth in mice effectively, indicating phloroglucinol as promising drug for therapy-resistant cancers. Its also discovered that repression of this ferroptosis-like cell death benefited microbial degradation or production of desired phenolic compounds, showing great application potential in biotechnology field.

microbiology↗

bioRxiv2023

Periodic hypothalamic attractor-like dynamics during the estrus cycle

Cyclic changes in hormonal state are well-known to regulate mating behavior during the female reproductive cycle, but whether and how these changes affect the dynamics of neural activity in the female brain is largely unknown. The ventromedial hypothalamus, ventro-lateral subdivision (VMHvl) contains a subpopulation of VMHvlEsr1+,Npy2r- neurons that controls female sexual receptivity. Longitudinal single cell calcium imaging of these neurons across the estrus cycle revealed that overlapping but distinct subpopulations were active during proestrus (mating-accepting) vs. non-proestrus (rejecting) phases. Dynamical systems analysis of imaging data from proestrus females uncovered a dimension with slow ramping activity, which generated approximate line attractor-like dynamics in neural state space. During mating, the neural population vector progressed along this attractor as male mounting and intromission proceeded. Attractor-like dynamics disappeared in non-proestrus states and reappeared following re-entry into proestrus. They were also absent in ovariectomized females but were restored by hormone priming. These observations reveal that hypothalamic line attractor-like dynamics are associated with female sexual receptivity and can be reversibly regulated by sex hormones, demonstrating that attractor dynamics can be flexibly modulated by physiological state. They also suggest a potential mechanism for the neural encoding of female sexual arousal.

neuroscience↗

bioRxiv2023

Visible-Light Optical Coherence Tomography Fibergraphy of the Tree Shrew Retinal Ganglion Cell Axon Bundles

We seek to develop techniques for high-resolution imaging of the tree shrew retina for visualizing and parameterizing retinal ganglion cell (RGC) axon bundles in vivo. We applied visible-light optical coherence tomography fibergraphy (vis-OCTF) and temporal speckle averaging (TSA) to visualize individual RGC axon bundles in the tree shrew retina. For the first time, we quantified individual RGC bundle width, height, and cross-sectional area and applied vis-OCT angiography (vis-OCTA) to visualize the retinal microvasculature in tree shrews. Throughout the retina, as the distance from the optic nerve head (ONH) increased from 0.5 mm to 2.5 mm, bundle width increased by 30%, height decreased by 67%, and cross-sectional area decreased by 36%. We also showed that axon bundles become vertically elongated as they converge toward the ONH. Ex vivo confocal microscopy of retinal flat-mounts immunostained with Tuj1 confirmed our in vivo vis-OCTF findings.

bioengineering↗

bioRxiv2023

Longitudinal analysis of memory T follicular helper cells and antibody response following CoronaVac vaccination

The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by CoronaVac remains elusive compared to other vaccine platforms. Here, we recruited 88 healthy individuals that received 3 doses of CoronaVac vaccine. We longitudinally evaluated their polyclonal and antigen-specific CD4+ T cells and neutralizing antibody response after receiving each dose of vaccine for over 300 days. Both the 2nd and 3rd dose of vaccination induced robust spike-specific neutralizing antibodies, with a 3rd vaccine further increased the overall magnitude of antibody response, and neutralization against Omicron sub-lineages B.1.1.529, BA.2, BA.4/BA.5 and BA.2.75.2. Spike-specific CD4+ T cell and circulating T follicular helper (cTFH) cells were markedly increased by the 2nd and 3rd dose of CoronaVac vaccine, accompanied with altered composition of functional cTFH cell subsets with distinct effector and memory potential. Additionally, cTFH cells are positively correlated with neutralizing antibody titers. Our results suggest that CoronaVac vaccine-induced spike-specific T cells are capable of supporting humoral immunity for long-term immune protection.

immunology↗

bioRxiv2023

Remodeling the central metabolism of Escherichia coli enables a universal chassis

E. coli is the host of choice to produce a wide variety of chemicals and proteins. Overflow metabolism is considered as the widespread and major obstacle in microbial synthesis, and overcoming this common bottleneck may enable a universal chassis. Here, we constructed an E. coli universal chassis (ABKS strain) with significantly suppressed overflow metabolism, presenting similar growth rate, decreased glucose consumption, and increased production of desired chemicals and proteins when compared with wild-type BL21(DE3) strain. Furthermore, we demonstrated that metabolic flux of ABKS strain was reprogrammed from TCA cycle to glyoxylate bypass at isocitrate node via the synergistic effect of multi-layer regulation in gene transcription and protein modification. This metabolic reconfiguration alleviates overflow metabolism, avoids CO2 release in TCA cycle, finally improving the carbon atom economy in bioprocess. Our chassis has widespread and practical use for elevating the production and yield of multiple desired chemicals and proteins from different carbon source. The metabolic reconfiguration also provides theoretical basis for rational design of efficient bioproduction strains.

bioengineering↗

bioRxiv2023

Establishment and Evaluation of Rat Models of Cervical Spondylopathy with Yin Deficiency Syndrome

ObjectiveCervical spondylosis (CS) with Yin deficiency syndrome is an important classification of traditional Chinese medicine (TCM) symptoms of CS. However, there is no animal model for studying this TCM syndrome. This study aimes to establish and evaluate rat models of cervical spondylopathy with Yin deficiency syndrome. MethodThirty-six Sprague-Dawley male rats were randomly divided into the blank control (control), CS and CS with Yin deficiency syndrome (YCS) groups (n = 12 rats/group). CS was induced using cervical static-dynamic imbalance to mimic disk degeneration (except in the control group). After 30 days of the CS rat model, rats in the YCS group were subjected to sustained sleep deprivation for 168h. After different induction times, the rats in each group were observed for behavior and weight. Pain behavior was assessed by a withdrawal response to von Frey filament application, and heart rate and blood pressure were measured using a rat noninvasive sphygmomanometer. Intervertebral disc pathology sections were observed using hematoxylin and eosin staining and an electron microscope. Western blotting was used to evaluate the protein level of collagen-II, Bcl-2, Bax and Bcl-2/Bax expression in the cervical intervertebral disc. Determination of related laboratory serum indexes, cyclic adenosine monophosphate, and cyclic guanosine phosphate were conducted using enzyme-linked immunosorbent assay. ResultsThe laboratory indexes in the YCS group were significantly different from those in the control and CS groups (P < 0.05), and indicators of 72-, 120-, and 178-h sleep deprivation showed varying degrees of difference from those of the CS group. ConclusionAfter establishing a model of CS, continuous sleep deprivation for 72 h was used to create a rat model of CS with Yin deficiency syndrome. The established rat models of CS with Yin deficiency syndrome met the clinical and Chinese medicine characteristics, and thus, they can be expected to become an ideal model for studying CS with Yin deficiency syndrome in the future.

zoology↗

bioRxiv2023

Synergistic Integration of Deep Neural Networks and Finite Element Method with Applications for Biomechanical Analysis of Human Aorta

Motivation: Patient-specific finite element analysis (FEA) has the potential to aid in the prognosis of cardiovascular diseases by providing accurate stress and deformation analysis in various scenarios. It is known that patient-specific FEA is time-consuming and unsuitable for time-sensitive clinical applications. To mitigate this challenge, machine learning (ML) techniques, including deep neural networks (DNNs), have been developed to construct fast FEA surrogates. However, due to the data-driven nature of these ML models, they may not generalize well on new data, leading to unacceptable errors. MethodsWe propose a synergistic integration of DNNs and finite element method (FEM) to overcome each others limitations. We demonstrated this novel integrative strategy in forward and inverse problems. For the forward problem, we developed DNNs using state-of-the-art architectures, and DNN outputs were then refined by FEM to ensure accuracy. For the inverse problem of heterogeneous material parameter identification, our method employs a DNN as regularization for the inverse analysis process to avoid erroneous material parameter distribution. ResultsWe tested our methods on biomechanical analysis of the human aorta. For the forward problem, the DNN-only models yielded acceptable stress errors in majority of test cases; yet, for some test cases that could be out of the training distribution (OOD), the peak stress errors were larger than 50%. The DNN-FEM integration eliminated the large errors for these OOD cases. Moreover, the DNN-FEM integration was magnitudes faster than the FEM-only approach. For the inverse problem, the FEM-only inverse method led to errors larger than 50%, and our DNN-FEM integration significantly improved performance on the inverse problem with errors less than 1%.

bioengineering↗

bioRxiv2023

PyTorch-FEA: Autograd-enabled Finite Element Analysis Methods with Applications for Biomechanical Analysis of Human Aorta

MotivationFinite-element analysis (FEA) is widely used as a standard tool for stress and deformation analysis of solid structures, including human tissues and organs. For instance, FEA can be applied at a patient-specific level to assist in medical diagnosis and treatment planning, such as risk assessment of thoracic aortic aneurysm rupture/dissection. These FEA-based biomechanical assessments often involve both forward and inverse mechanics problems. Current commercial FEA software packages (e.g., Abaqus) and inverse methods exhibit performance issues in either accuracy or speed. MethodsIn this study, we propose and develop a new library of FEA code and methods, named PyTorch-FEA, by taking advantage of autograd, an automatic differentiation mechanism in PyTorch. We develop a class of PyTorch-FEA functionalities to solve forward and inverse problems with improved loss functions, and we demonstrate the capability of PyTorch-FEA in a series of applications related to human aorta biomechanics. In one of the inverse methods, we combine PyTorch-FEA with deep neural networks (DNNs) to further improve performance. ResultsWe applied PyTorch-FEA in four fundamental applications for biomechanical analysis of human aorta. In the forward analysis, PyTorch-FEA achieved a significant reduction in computational time without compromising accuracy compared with Abaqus, a commercial FEA package. Compared to other inverse methods, inverse analysis with PyTorch-FEA achieves better performance in either accuracy or speed, or both if combined with DNNs.

bioengineering↗

bioRxiv2023

Evolving antibody evasion and receptor affinity of the Omicron BA.2.75 sublineage of SARS-CoV-2

SARS-CoV-2 Omicron BA.2.75 has diversified into multiple subvariants with additional spike mutations, and several are expanding in prevalence, particularly CH.1.1 and BN.1. Here, we investigated the viral receptor affinities and neutralization evasion properties of major BA.2.75 subvariants actively circulating in different regions worldwide. We found two distinct evolutionary pathways and three newly identified mutations that shaped the virological features of these subvariants. One phenotypic group exhibited a discernible decrease in viral receptor affinities, but a noteworthy increase in resistance to antibody neutralization, as exemplified by CH.1.1, which is apparently as resistant as XBB.1.5. In contrast, a second group demonstrated a substantial increase in viral receptor affinity but only a moderate increase in antibody evasion, as exemplified by BN.1. We also observed that all prevalent SARS-CoV-2 variants in the circulation presently, except for BN.1, exhibit profound levels of antibody evasion, suggesting this is the dominant determinant of virus transmissibility today.

microbiology↗

bioRxiv2023

A hierarchical strategy to decipher protein dynamics in vivo with chemical cross-linking mass spectrometry

Protein dynamics are essential for their various functions. Meanwhile, the intracellular environment would affect protein structural dynamics, especially for the intrinsically disordered proteins (IDPs). Chemical cross-linking mass spectrometry (CXMS) can unbiasedly capture the protein conformation information in cells and can also represent the protein dynamics. Here, we proposed a hierarchy deciphering strategy for protein dynamics in vivo. With the prior structure from AlphaFold2, the steady local conformation can be extensively evaluated. On this basis, the full-length structure of multi-domain proteins with various dynamic features can be characterized using CXMS. Furthermore, the complementary strategy with unbiased sampling and distance-constrained sampling enables an objective description of the intrinsic motion of the IDPs. Therefore, the hierarchy strategy we presented herein could help us better understand the molecular mechanisms of protein functions in cells.

cell biology↗

bioRxiv2023

Unfolded Protein Response Factor ATF6 Augments T Helper Cell Responses and Promotes Mixed Granulocytic Airway Inflammation

The unfolded protein response (UPR) is associated with the risk of asthma, including treatment- refractory severe asthma. Several recent studies demonstrated a pathogenic role of activating transcription factor 6 (ATF6 or ATF6), one of the essential arms of UPR, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by STAT6 and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specific Atf6-deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed ATF6 downstream gene expression and TH cell cytokine expression in both murine and human memory CD4+ T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responses in vivo, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.

immunology↗

bioRxiv2023

Cryo-EM of α-tubulin isotype containing microtubules revealed a contracted structure of α4A/β2A microtubules

Microtubules are hollow /{beta}-tubulin heterodimeric polymers playing critical roles in cells. In vertebrates, both - and {beta}-tubulin have multiple isotypes encoded by different genes, which are intrinsic factors in regulating microtubule functions. However, structures of microtubules composed of different tubulin isotypes, especially -tubulin isotypes, remain largely unknown. Here, we purified recombinant tubulin heterodimers composed of different mouse -tubulin isotypes, including 1A, 1C and 4A, with {beta}-tubulin isotype {beta}2A. We further assembled and determined the cryo-electron microscopy (cryo-EM) structures of 1A/{beta}2A, 1C/{beta}2A, and 4A/{beta}2A microtubules. Our structural analysis demonstrated that 4A/{beta}2A microtubules exhibit a longitudinal contraction between tubulin interdimers compared with 1A/{beta}2A and 1C/{beta}2A microtubules. Collectively, our findings reveal that -tubulin isotype composition could tune microtubule structures, and also provide evidence for the "tubulin code" hypothesis.

biophysics↗

bioRxiv2023

Enrichment and delivery of target proteins into the cell cytosol via Outer Membrane Vesicles

Advanced intracellular delivery of proteins has profound applications in both scientific investigations and therapies. However, existing strategies relying on various chemical and physical methods, have drawbacks such as the requirement of high concentration in vitro prepared target proteins and difficulty in labeling target proteins. Developing new delivery systems integrating the enveloping and labeling of target proteins would bring great advantages for efficient protein transfections. Here, we enriched a high concentration (62 mg/ml) of several target proteins into outer membrane vesicles (OMVs) of E. coli to employ the native property of OMVs to deliver proteins into the cytosol of eukaryotic cells. The results revealed a high protein transfection efficiency arranging from 90-97% for different cell lines. Moreover, the free penetration of molecules less than 600 Dalton across the membrane of OMVs allows direct labeling of target proteins within OMVs, facilitating the visualization of target proteins. Importantly, the nanobody delivered intracellularly by OMVs retains the biological activity of binding with its target, highlighting the advantages of OMVs as an emerging tool for efficient intracellular delivery of proteins.

cell biology↗

bioRxiv2023

CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment

Germline CTLA-4 deficiency causes severe autoimmune diseases characterized by dysregulation of Foxp3+ Tregs, hyper-activation of effector memory T cells, and variable forms autoimmune cytopenia including gradual loss of B cells. Cancer patients with severe immune-related adverse events (irAE) after receiving anti-CTLA-4/PD-1 combination immunotherapy also have markedly reduced peripheral B cells. The immunological basis for B cell loss remains unexplained. Here we probe the decline of B cells in human CTLA-4 knock-in mice by using anti-human CTLA-4 antibody Ipilimumab conjugated to a drug payload emtansine (Anti-CTLA-4 ADC). The anti-CTLA-4 ADC-treated mice have T cell hyper-proliferation and their differentiation into effector cells which results in B cell depletion. B cell depletion is mediated by both CD4 and CD8 T cells and at least partially rescued by anti-TNF-alpha antibody. These data revealed an unexpected antagonism between T and B cells and the importance of regulatory T cells in preserving B cells.

immunology↗

bioRxiv2023

Spatial transcriptomic atlas of shoot organogenesis in tomato callus

Callus is a reprogrammed transitional cell mass during plant regeneration. Pluripotent callus cells develop into fertile shoots through de novo shoot organogenesis. This study represents a pioneering effort in exploring the spatial transcriptome of tomato callus during shoot regeneration, using technologies including BGI Stereo-seq, BMKMANU S1000, and 10x Visium. The results indicate that the callus comprises highly heterogeneous cells, classified into various cell types based on spatial gene expression and histological observation, including epidermis, shoot primordium, vascular tissue, inner callus, and outgrowth shoots. The developmental trajectories from shoot primordium to outgrowth shoot are traced, and vascular tissue development is characterized. The single-cell resolution spatial approach reveals the origin of shoot primordia from the sub-epidermis. The spatial full length RNA sequencing shows high incompletely spliced (IS) ratios in the shoot primordium cells. These findings enhance our knowledge of plant organogenesis and highlight the significance of spatial biology in plant research.

cell biology↗

bioRxiv2023

Cardiac Development Long non-coding RNA (CARDEL) is activated during human heart development and contributes to cardiac specification and homeostasis

Successful heart development depends on the careful orchestration of a network of transcription factors and signaling pathways. In recent years, the in vitro cardiac differentiation using human pluripotent stem cells (hPSCs) has been used to uncover the intricate gene network regulation involved in the proper formation and function of the human heart. Here, we searched for uncharacterized cardiac developmental genes by combining a temporal evaluation of the human cardiac specification in vitro with the analysis of fetal and adult heart tissue gene expression. We discovered that CARDEL (CARdiac DEvelopment Long non-coding RNA; LINC00890; SERTM2) expression coincides with the commitment to the cardiac lineage. CARDEL knockout hPSCs differentiated poorly in cardiac cells, and hPSC-derived cardiomyocytes showed faster beating rates after CARDEL controlled overexpression during differentiation. Altogether, we demonstrate physiological and molecular evidence that CARDEL expression contributes to sculpting the cardiac program during cell-fate commitment.

developmental biology↗