bioRxiv Science⌕ Search

Biology subjects

Cui, C.

Publications and source records attributed to Cui, C..

At least 37 records · Page 2Linked to original sources

MedImg: a database for public medical image integration

The advancements of deep learning algorithms in medical image analysis has garnered tremendous attention in recent years. Several studies have reported that the models have achieved and even surpassed human performance, whereas the translation of these models into clinical practice is still accompanied by various challenges. A major challenge is the large-scale and well characterized dataset to validate the generalization of models. Therefore, we collected diverse medical image datasets from multiple public sources containing 103 datasets, 1,622,956 images. These images are derived from 14 modalities like XR, CT, MRI, OCT, ultrasound, and endoscopy, and from 9 organs such as lung, brain, eye, and heart. Subsequently, we constructed an online database, MedImg, which incorporates and hierarchically organizes medical images to facilitate data access. MedImg serves as an intuitive and open-access platform for contributing to deep learning-based medical image analysis, accessible at https://www.cuilab.cn/medimg/.

bioinformatics↗

Estimating the selection pressure and evolutionary rate of proteins on the non-neutral hypothesis of synonymous mutations

The Nonsynonymous/Synonymous substitution rate ratio (Ka/Ks) is a commonly used metric to estimate the selection pressure and evolutionary rate of proteins in comparative genomics, which plays critical roles in molecular evolution in both biology and medicine. A fundamental assumption of Ka/Ks is that synonymous mutations are evolutionarily neutral and not subject to natural selection as they do not alter protein sequences and function. However, a number of studies have demonstrated that synonymous mutations are non-neutral and may lead to diseases through a number of mechanisms, such as altering miRNA regulation. This further implies that synonymous mutations also participate in the process of natural selection and thus Ka/Ks should be redefined as well. For this purpose, here we propose an improved Ka/Ks ratio, iKa/Ks, which re-computed the neutral substitution rate by taking the altered status of miRNA binding into consideration, and thereby incorporate the impact of synonymous mutations on miRNA regulation. As a result, iKa/Ks shows better performance than Ka/Ks when comparing them using their correlation with expression distance. Moreover, case studies showed that iKa/Ks is able to identify the positive/negative selection genes that are missed by Ka/Ks. For example, TMEM72/Tmem72 is estimated to be positively selected by iKa/Ks (1.13) but negatively selected by the conventional Ka/Ks ratio (0.21). Further evidence showed its rapid evolution, which further support the power of the new algorithm.

bioinformatics↗

Comprehensive prediction and analysis of human protein essentiality based on a pre-trained protein large language model

Human essential genes and their protein products are indispensable for the viability and development of the individuals. Thus, it is quite important to decipher the essential proteins and up to now numerous computational methods have been developed for the above purpose. However, the current methods failed to comprehensively measure human protein essentiality at levels of humans, human cell lines, and mice orthologues. For doing so, here we developed Protein Importance Calculator (PIC), a sequence-based deep learning model, which was built by fine-tuning a pre-trained protein language model. As a result, PIC outperformed existing methods by increasing 5.13%-12.10% AUROC for predicting essential proteins at human cell-line level. In addition, it improved an average of 9.64% AUROC on 323 human cell lines compared to the only existing cell line-specific method, DeepCellEss. Moreover, we defined Protein Essential Score (PES) to quantify protein essentiality based on PIC and confirmed its power of measuring human protein essentiality and functional divergence across the above three levels. Finally, we successfully used PES to identify prognostic biomarkers of breast cancer and at the first time to quantify the essentiality of 617462 human microproteins. Key PointsO_LIPIC outperformed existing computational methods for predicting essential proteins. C_LIO_LIPIC could comprehensively predict human protein essentiality at levels of human, human cell lines and mice orthologues at the same time. C_LIO_LIPES could serve as a potential metric to quantify the essentiality of both human proteins and human microproteins. C_LI

bioinformatics↗

Mesenchymal stem cell-derived extracellular vesicles attenuate symptoms in dextran sodium sulfate-induced ulcerative colitis mouse model

Inflammatory bowel disease (IBD) refers to a group of multifactorial and chronic inflammation affecting intestinal tract. Based on the pathogenic mechanisms, IBD mainly comprised of two categories: ulcerative colitis (UC) and Crohns disease (CD). In this study, we established a dextran sulfate sodium (DSS)-induced colitis model to mimic UC. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as therapeutic vectors have shown regenerating effect of damaged tissues. Here, intravenous administration of MSC-EVs ameliorated IBD symptoms including gaining weight, reducing disease activity index and restoring colon length. In addition, the protective effect of MSC-EVs were demonstrated by repairing colon mucosa and reducing the infiltration of macrophages in submucosa. Collectively, MSC-EV shows a therapeutic potential for IBD.

physiology↗

A Specialized Epithelial Cell Type Regulating Mucosal Immunity and Driving Human Crohn's Disease

Crohns disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression of LCN2, NOS2, and DUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohns ileitis and Crohns colitis and identify novel biomarkers associated with disease activity and treatment response.

bioinformatics↗

GENOMES UNCOUPLED1: an RNA-binding protein required for early PSII biogenesis

Genomes Uncoupled1 (GUN1), a nuclear-encoded chloroplast pentatricopeptide repeat (PPR) protein, serves as a master integrator of diverse retrograde signals, mediating chloroplast-to-nucleus retrograde signaling. Although PPR proteins primarily function in organelle RNA metabolism, a target RNA of GUN1 remained unknown. This study reveals that GUN1 recognizes psbD transcripts derived from a blue light-responsive promoter (BLRP), transcripts referred to as psbD BLRP. Overexpression of GUN1 significantly reduces the levels of psbD BLRP, whereas the loss of GUN1 leads to the accumulation of the putative target RNA. The in vitro RNA and in vivo genetic studies further demonstrate the critical role of the C-terminal small MutS-related (SMR) domain in stimulating psbD BLRP processing and PsbD (D2, a PSII core protein) synthesis. The GUN1-dependent psbD BLRP processing promotes PSII biogenesis during the early seedling development and de-etiolation phase. This finding underscores the role of GUN1 as an RNA-binding protein, highlighting the essential function of the SMR domain in processing the target RNA. SignificanceBiogenic retrograde signaling is essential in regulating chloroplast biogenesis, and it entails a nuclear-encoded chloroplast protein, Genomes Uncoupled1 (GUN1). Since its initial discovery in 1993, the gun1 mutant has been widely used to reveal the precise function of GUN1 in plastids as well as its downstream signaling components. Although GUN1 contains pentatricopeptide repeat motifs, it has been considered a non-canonical PPR protein because no one could demonstrate GUN1-RNA interaction in planta. However, through our computational analysis of PPR codes and subsequent biochemical studies, we were able to unravel its putative target RNA, namely psbD BLRP. Therefore, our finding may lead to a reevaluation of GUN1 research in the context of RNA metabolism and a revision of our current understanding of GUN1.

plant biology↗

Harnessing extracellular vesicles for efficient siRNA delivery in vitro and in vivo

To fulfill the potential of small interference RNA (siRNA) therapeutics, diverse and efficient delivery platforms for siRNA are urgently needed. Extracellular vesicles (EVs) are endogenous, cell secreted nano-vehicles which have been explored for functional siRNA delivery, yet impurities in EVs preparation and lack of efficient siRNA loading method have been limiting its further development into clinical applications. In this work, we have achieved high quality EVs production and an siRNA loading system via EVs. The prepared EV-siRNA system was able to deliver siRNA cargo to model cell lines to silence the expression of targeted genes with high potency. Furthermore, EV-siRNA administration in a tumor xenograft model significantly inhibited tumor growth. Therefore, this study establishes an innovative and efficient EV-siRNA platform for siRNA delivery in vitro and in vivo.

cancer biology↗

Defining the single base importance of human mRNAs and lncRNAs

As the fundamental unit of a gene and its transcripts, nucleotides have enormous impacts on molecular function and evolution, and thus on phenotypes and diseases. Given that different nucleotides on one gene often exhibit diverse levels of effects, it is quite crucial to comprehensively and quantitatively measure the importance of each base on a gene transcript, however, tools are still not available. Here we proposed Base Importance Calculator (BIC), an algorithm to calculate the importance score of single bases based on sequence information of human mRNAs and long noncoding RNAs (lncRNAs). We then confirmed its power by applying BIC to three different tasks. Firstly, we revealed that BIC can effectively evaluate the pathogenicity of both genes and single bases by analyzing the BIC scores and the pathogenicity of single nucleotide variations (SNVs). Moreover, the BIC score in the Cancer Genome Atlas (TCGA) somatic mutations is able to predict the prognosis of some cancers. Finally, we show that BIC can also precisely predict the transmissibility of SARS-CoV-2. The above results indicate that BIC is a useful tool for evaluating the single base important of human mRNAs and lncRNAs. Key PointsO_LIBIC could measure the single base importance of human mRNAs and lncRNAs. C_LIO_LIBIC could be applied to many aspects including measuring the pathogenicity of SNVs and enhancing the ability of predicting cancer survival. C_LIO_LIBIC could predict the transmissibility of SARS-CoV-2 C_LI

bioinformatics↗

Autonomous and non-cell autonomous etiology of ciliopathy associated structural birth defects

Ciliopathies are associated with wide spectrum of structural birth defects (SBD), indicating important roles for cilia in development. Here we provide novel insights into the temporospatial requirement for cilia in SBDs arising from deficiency in Ift140, an intraflagellar transport protein regulating ciliogenesis. Ift140 deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula, randomized heart looping, congenital heart defects (CHD), lung hypoplasia, renal anomalies, and polydactyly. Tamoxifen inducible CAG-Cre deletion of a floxed Ift140 allele between E5.5 to 9.5 revealed early requirement for Ift140 in left-right heart looping regulation, mid to late requirement for cardiac outflow septation and alignment, and late requirement for craniofacial development and body wall closure. Surprisingly, CHD was not observed with four Cre drivers targeting different lineages essential for heart development, but craniofacial defects and omphalocele were observed with Wnt1-Cre targeting neural crest and Tbx18-Cre targeting epicardial lineage and rostral sclerotome through which trunk neural crest cells migrate. These findings revealed cell autonomous role of cilia in cranial/trunk neural crest mediated craniofacial and body wall closure defects, while non-cell autonomous multi-lineage interactions underlie CHD pathogenesis, revealing unexpected developmental complexity for CHD associated with ciliopathy.

developmental biology↗

Spatial transcriptome profiling uncovers metabolic regulation of left-right patterning

Left-right patterning disturbance can cause severe birth defects, but it remains least understood of the three body axes. We uncovered an unexpected role for metabolic regulation in left-right patterning. Analysis of the first spatial transcriptome profile of left-right patterning revealed global activation of glycolysis, accompanied by right-sided expression of Bmp7 and genes regulating insulin growth factor signaling. Cardiomyocyte differentiation was left-biased, which may underlie the specification of heart looping orientation. This is consistent with known Bmp7 stimulation of glycolysis and glycolysis suppression of cardiomyocyte differentiation. Liver/lung laterality may be specified via similar metabolic regulation of endoderm differentiation. Myo1d, found to be left-sided, was shown to regulate gut looping in mice, zebrafish, and human. Together these findings indicate metabolic regulation of left-right patterning. This could underlie high incidence of heterotaxy-related birth defects in maternal diabetes, and the association of PFKP, allosteric enzyme regulating glycolysis, with heterotaxy. This transcriptome dataset will be invaluable for interrogating birth defects involving laterality disturbance.

developmental biology↗

Effect and mechanism of black soybean peptides alleviating oxidative damage in the celiac disease cell model

Alpha gliadin peptide induces damage and apoptosis of intestinal cells and aggravates pathology of celiac disease (CD) by inducing oxidative stress. Therefore, inhibition or alleviation of oxidative stress in CD may be an effective approach to the adjunctive treatment of CD. Black soybean peptides (BSPs) have been shown to inhibit oxidative stress and inflammation. The effect of BSPs on CD remains unknown. In this paper, the effect and mechanism of BSPs on the -gliadin peptide (p31-43)-induced Caco-2 cytotoxicity were studied. We identified BSPs that alleviated the cytotoxicity of p31-43 in the CD cell model: Caco-2 cells were pre-treated with bioactive peptides for 3 hours before the addition of p31-43 for treatment for 24 hours, and then cells were collected for subsequent experiments. Our results show that p31-43 can significantly increase the ROS and MDA levels of Caco-2 cells, disrupt the glutathione redox cycle, reduce the activity of the antioxidant enzyme, and inhibit the activation of antioxidant signaling pathways. BSPs pretreatment can inhibit the increase of Keap1 protein induced by p31-43, activate antioxidant genes through Nrf2 protein, improve the activity of the antioxidant enzyme, alleviates glutathione redox cycle imbalance, promote the expression of GCLC or GCLM, and reduce oxidative damage. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/508472v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@b0b8c3org.highwire.dtl.DTLVardef@322434org.highwire.dtl.DTLVardef@1e70b77org.highwire.dtl.DTLVardef@1a1e8f9_HPS_FORMAT_FIGEXP M_FIG Pattern of BSPs against oxidative damage in CD cell mode. C_FIG

cell biology↗

Creating an atlas of the bone microenvironment during oral inflammatory-related bone disease using single-cell profiling

Oral inflammatory diseases such as apical periodontitis are common bacterial infectious diseases that may affect the periapical alveolar bone tissues. A protective healing process occurs simultaneously with the inflammatory tissue destruction, in which mesenchymal stem cells (MSCs) play a primary role. However, a systematic and precise description of the cellular and molecular composition of the microenvironment of bone affected by inflammation is lacking. In this study, we created a single cell atlas of cell populations that compose alveolar bone in healthy and inflammatory disease states. We investigated changes in expression frequency and patterns related to apical periodontitis, as well as the interactions between MSCs and immunocytes. Our results highlight an enhanced self-supporting network and osteogenic potential within MSCs during apical periodontitis-associated inflammation. MSCs not only differentiated towards osteoblast lineage cells, but also expressed higher levels of osteogenic related markers, including SPARC and Col11. This was confirmed by lineage tracing in transgenic mouse models and human samples from oral inflammatory-related alveolar bone lesions. In summary, the current study provides an in-depth description of the microenvironment of MSCs and immunocytes in both healthy and disease states. We also identified key apical periodontitis-associated MSC subclusters and their biomarkers, which could further our understanding of the healing process and the underlying mechanisms of oral inflammatory-related bone disease. Taken together, these results enhance our understanding of heterogeneity and cellular interactions of alveolar bone cells under pathogenic and inflammatory conditions. We provide these data as a tool for investigators not only to better appreciate the repertoire of progenitors that are stress responsive but importantly to help design new therapeutic targets to restore bone lesions caused by apical periodontitis and other inflammatory-related bone diseases.

cell biology↗

Combating pancreatic cancer with ovarian cancer cells

With overall five-year survival rate less than 10%, pancreatic cancer (PC) represents the most lethal one in all human cancers. Given that the incidence of PC is still increasing and current cancer treatment strategies are often inefficacious, its therapy is still a huge challenge. Here, we first revealed ovarian serous carcinoma is mostly anti-correlated with pancreatic cancer in gene expression signatures. Based on this observation, we proposed that ovarian cancer cells could defense PC. To confirm this strategy, we first showed that ovarian cancer cell SKOV3 can significantly inhibit the proliferation of pancreatic cancer cell SW1990 when they were co-cultured. We further validated this strategy by an animal model of pancreatic cancer xenografts. The result showed that the injection of SKOV3 significantly inhibits pancreatic cancer xenografts. Moreover, we found that SKOV3 with transgenic African elephant TP53 gene further enhances the therapeutic effect. RNA-sequencing analysis revealed that the ovarian cancer cell treatment strikingly induced changes of genes being involved in pancreas function and phenotype (e.g. enhancing pancreas function, pancreas regeneration, and cell adhesion) but not immune and inflammation related functions, suggesting that the proposed strategy is different from immunotherapy and could be a novel strategy for cancer treatment.

cancer biology↗

Animal complexity defines the functionality of synonymous mutations through mediating microRNA regulations

Most recently, Shen et al. revealed that most synonymous mutations (SMs) in yeast genes are strongly non-neutral, however, which was soon challenged by Kruglyak et al. who find no evidence for deleterious effect on fitness of SMs in yeast genes. We previously revealed that SMs in numerous human genes show functionality through changing miRNA regulations. Given that higher animals show higher complexity of miRNA regulations, here we present a hypothesis that SMs in lower animal genes show less functionality and vice versa. To confirm this, we comprehensively investigated the SMs changing miRNA regulations in yeast, C.elegans, Drosophila, mouse, and human. As expected, the result showed that the proportion of SMs affecting gene functionality through altering miRNA regulations is about 0%, 14%, 16%, 51%, and 60% in yeast, C. elegans, Drosophila, mouse, and human, respectively, suggesting that the complexity of animals indeed determines the functionality of SMs through mediating miRNA regulations. Finally, this study supports no evidence that most SMs in yeast genes are deleterious.

bioinformatics↗

Locomotion control during curb descent: Bilateral ground reaction variables covary consistently during the double support phase regardless of future foot placement constraints

During community ambulation, anticipatory adaptations in gait are key for navigating built, populated and natural environments. It has been argued that some instability in gait can be functionally beneficial in situations demanding high maneuverability, and while the mechanisms utilized to maintain locomotor balance are well understood, relatively less is known about how the control of gait stability changes to facilitate upcoming maneuvers in challenging environments. The double support phase may be important in this regard; since both feet can push off the ground simultaneously, there is greater control authority over the bodys movement during this phase. Our goal was to identify how this control authority is exploited to prepare for upcoming maneuvers in challenging environments. We used synergy indices to quantify the degree of coordination between the ground reaction forces and moments under the two feet for stabilizing the resultant force and moment on the body during the double support phase of curb descent. In contrast to our expectations, we observed that the kinetic synergy indices during curb descent were minimally influenced by expected foot targeting maneuvers for the subsequent step. Only the resultant moment in the frontal plane showed reduced stability when targeting was required, but the synergy index was still high, indicating that the resultant moment was stable. Furthermore, the synergy indices indicated that the main function of the ground reaction variables is to maintain stability of whole-body rotations during double support, and this prerogative was minimally influenced by the subsequent foot targeting tasks, likely because the cost of losing balance while descending a curb would be higher than the cost of mis-stepping on a visual target. Our work demonstrates the salience of stabilizing body rotations during curb negotiation and improves our understanding of locomotor control in challenging environments.

bioengineering↗

Step length and the extrapolated center of mass co-vary to stabilize the margin of stability in the anterior-posterior direction during unobstructed and obstructed walking

In human gait, the bodys mechanical energy at the end of one step is reused to achieve forward progression during the subsequent step, thereby reducing the required muscle work. During the single stance phase, humans rely on the largely uncontrolled passive inverted pendular motion of the body to perpetuate forward motion. These passive body dynamics, while improving walking efficiency, also indicate that lower passive dynamic stability in the anterior direction since the individual will be less able to withstand a forward external perturbation. Here we test the novel hypothesis that humans manipulate passive anterior-posterior (AP) stability via active selection of step length to either achieve energy-efficient gait or to improve stability when it is threatened. We computed the AP margin of stability, which quantifies the passive dynamic stability of gait, for multiple steps as healthy young adults (N=20) walked on a clear and on an obstructed walkway. Participants used passive dynamics to achieve energy-efficient gait for all but one step; when crossing the obstacle with the leading limb, AP margin of stability was increased. This increase indicated caution to offset the greater risk of falling after a potential trip. Furthermore, AP margin of stability increased while approaching the obstacle, indicating that humans proactively manipulate the passive dynamics to meet the demands of the locomotor task. Finally, the step length and the center of mass motion co-varied to maintain the AP margin of stability for all steps in both tasks at the specific values for each step. We conclude that humans actively regulate step length to maintain specific levels of passive dynamic stability for each step during unobstructed and obstructed gait.

bioengineering↗

Multiplexed imaging mass cytometry reveals distincttumor-immune microenvironments linked to immunotherapyresponses in melanoma

Single-cell technologies have enabled extensive analysis of complex immune composition, phenotype and interactions within tumor, which is crucial in understanding the mechanisms behind cancer progression and treatment resistance. Unfortunately, the knowledge on cell phenotypes and their spatial interactions at present has only limited utilization in guiding pathological stratification on patients based on their immune microenvironments for better clinical decisions. Here we used imaging mass cytometry (IMC) to simultaneously quantify 35 proteins in a spatially resolved manner on tumor tissues from melanoma patients receiving anti-programmed cell death-1 (anti-PD-1) therapy. Unbiased single-cell analysis revealed highly dynamic tumor-immune microenvironments that are characterized with variable tumor and immune cell phenotypes and their organizations across and within melanomas, and identified distinct archetypes of melanoma microenvironments that are associated with benefit from anti-PD-1 therapy based on high-dimensional multicellular features. Our results demonstrate the utility of multiplex proteomic imaging technologies in studying complex molecular events in a spatially resolved manner for the development of new strategies for patient stratification and treatment outcome prediction.

immunology↗

The PD-1 checkpoint receptor maintains tolerance of self-reactive CD8 T cell in skin

Peripheral tolerance is thought to result from anergy or deletion of self-reactive T cells shortly after antigen encounter. However, the frequent occurrences of immune-related Adverse Events (irAEs) following checkpoint inhibitor (CPI) treatment suggest a hypothesis that immunologically healthy individuals have self-reactive effector T cells that are kept in a non-pathogenic state through checkpoint receptor-mediated suppression, instead of anergy or deletion. We expressed self-antigens in healthy skin and found that antigen-specific CD8 T cells infiltrated the tissue, but remained tolerant, despite having a transcriptional program that resembled effector T cells found after CPIs. These self-reactive PD-1+ CD8 T cells drove IFN{gamma}-dependent increases in PD-L1 on skin myeloid cells. Blockade of PD-1 or PD-1/CTLA-4 led to post-transcriptional upregulation of effector proteins by antigen-specific CD8 T cells and elimination of antigen-expressing epithelial cells, resulting in localized tissue pathology with features of human cutaneous irAEs. This data supports the hypothesis that myeloid cells in healthy skin prevent pathology from self-reactive effector CD8 T cells through the PD-1/PD-L1 pathway.

immunology↗