Biology subjects

Cui, S.

Publications and source records attributed to Cui, S..

45 records · Page 3Linked to original sources

bioRxiv2021

Whole-cell segmentation of tissue images with human-level performance using large-scale data annotation and deep learning

Understanding the spatial organization of tissues is of critical importance for both basic and translational research. While recent advances in tissue imaging are opening an exciting new window into the biology of human tissues, interpreting the data that they create is a significant computational challenge. Cell segmentation, the task of uniquely identifying each cell in an image, remains a substantial barrier for tissue imaging, as existing approaches are inaccurate or require a substantial amount of manual curation to yield useful results. Here, we addressed the problem of cell segmentation in tissue imaging data through large-scale data annotation and deep learning. We constructed TissueNet, an image dataset containing >1 million paired whole-cell and nuclear annotations for tissue images from nine organs and six imaging platforms. We created Mesmer, a deep learning-enabled segmentation algorithm trained on TissueNet that performs nuclear and whole-cell segmentation in tissue imaging data. We demonstrated that Mesmer has better speed and accuracy than previous methods, generalizes to the full diversity of tissue types and imaging platforms in TissueNet, and achieves human-level performance for whole-cell segmentation. Mesmer enabled the automated extraction of key cellular features, such as subcellular localization of protein signal, which was challenging with previous approaches. We further showed that Mesmer could be adapted to harness cell lineage information present in highly multiplexed datasets. We used this enhanced version to quantify cell morphology changes during human gestation. All underlying code and models are released with permissive licenses as a community resource.

bioinformatics↗

bioRxiv2021

3D Mapping of Neurofibrillary Tangle Burden in the Human Medial Temporal Lobe

Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimers disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.

neuroscience↗

bioRxiv2020

Acrylamide Fragment Inhibitors that Induce Unprecedented Conformational Distortions in Enterovirus 71 3C and SARS-CoV-2 Main Protease

RNA viruses are critically dependent upon virally encoded proteases that cleave the viral polyproteins into functional mature proteins. Many of these proteases are structurally conserved with an essential catalytic cysteine and this offers the opportunity to irreversibly inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that selectively target the active site cysteine of the 3C protease (3Cpro) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we effectively re-purpose these hits towards the main protease (Mpro) of SARS-CoV-2 which shares the 3C-like fold as well as similar catalytic-triad. We demonstrate that the hit fragments covalently link to the catalytic cysteine of Mpro to inhibit its activity. In addition, we provide the first demonstration that targeting the active site cysteine of Mpro can also have profound allosteric effects, distorting secondary structures required for formation of the active dimeric unit of Mpro. These new data provide novel mechanistic insights into the design of EV71 3Cpro and SARS-CoV-2 Mpro inhibitors and identify acrylamide-tagged pharmacophores for elaboration into more selective agents of therapeutic potential.

biochemistry↗

bioRxiv2020

Comprehensive genome sequencing analysis as a promising option in the prenatal diagnosis of fetal structural anomalies: a prospective study.

PurposeGenome sequencing (GS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are few. We aimed to evaluate the feasibility of GS as a first-line approach in prenatal diagnosis and compare its clinical value with the chromosomal microarray analysis (CMA) plus exome sequencing (ES) sequential testing. MethodsWe applied trio GS ([~]40-fold) in parallel with CMA plus ES to investigate the genetic basis for structural or growth anomalies in 111 fetuses and compared their results. ResultsGS covered all genetic variants in 22 diagnosed cases detected by CMA plus ES, yielding a diagnostic rate of 19.8% (22/110). Moreover, GS provided more comprehensive and precise genetic information than CMA plus ES, revealing twin fetuses with an imbalanced translocation arising from a balanced paternal translocation and one fetus with an extra pathogenic variant in the GJA8 gene, and incidentally identified intrauterine CMV infection in a growth-restricted fetus. ConclusionCompared with CMA plus ES, GS offers a more comprehensive view of the genetic etiology of fetal anomalies and provides clues for nongenetic factors such as intrauterine infection. Our study demonstrates the feasibility of GS as a promising first-line test in prenatal diagnosis.

genomics↗

bioRxiv2020

Mechanism of duplex unwinding by coronavirus nsp13 helicases

The current COVID-19 pandemic urges in-depth investigation into proteins encoded with coronavirus (CoV), especially conserved CoV replicases. The nsp13 of highly pathogenic MERS-CoV, SARS-CoV-2, and SARS-CoV exhibit the most conserved CoV replicases. Using single-molecule FRET, we observed that MERS-CoV nsp13 unwound DNA in discrete steps of approximately 9 bp when ATP was used. If another NTP was used, then the steps were only 4 to 5 bp. In dwell time analysis, we detected 3 or 4 hidden steps in each unwinding process, which indicated the hydrolysis of 3 or 4 dTTP. Based on crystallographic and biochemical studies of CoV nsp13 helicases, we modeled an unwinding mechanism similar to the spring-loaded mechanism of HCV NS3 helicase, although our model proposes that flexible 1B and stalk domains, by allowing a lag greater than 4 bp during unwinding, cause the accumulated tension on the nsp13-DNA complex. The hinge region between two RecA-like domains in SARS-CoV-2 nsp13 is intrinsically more flexible than in MERS-CoV nsp13 due to the difference of a single amino acid, which causes the former to induce significantly greater NTP hydrolysis. Our findings thus establish a blueprint for determining the unwinding mechanism of a unique helicase family. O_LIWhen dTTP was used as the energy source, 4 hidden steps in each individual unwinding step after 3 - 4 NTP hydrolysis were observed. C_LIO_LIAn unwinding model of MERS-CoV-nsp13 which is similar to the spring-loaded mechanism of HCV NS3 helicase, except the accumulation of tension on nsp13/DNA complex is caused by the flexible 1B and stalk domains that allow a lag of 4-bp in unwinding. C_LIO_LIComparing to MERS-CoV nsp13, the hinge region between two RecA-like domains in SARS-CoV-2 nsp13 is intrinsically more flexible due to a single amino acid difference, which contributes to the significantly higher NTP hydrolysis by SARS-CoV-2 nsp13. C_LI

biophysics↗

bioRxiv2020

Binding of the SARS-CoV-2 Spike Protein to Glycans

The pandemic of SARS-CoV-2 has caused a high number of deaths in the world. To combat it, it is necessary to develop a better understanding of how the virus infects host cells. Infection normally starts with the attachment of the virus to cell-surface glycans like heparan sulfate (HS) and sialic acid-containing oligosaccharides. In this study, we examined and compared the binding of the subunits and spike (S) proteins of SARS-CoV-2 and SARS-CoV, MERS-CoV to these glycans. Our results revealed that the S proteins and subunits can bind to HS in a sulfation-dependent manner, the length of HS is not a critical factor for the binding, and no binding with sialic acid residues was detected. Overall, this work suggests that HS binding may be a general mechanism for the attachment of these coronaviruses to host cells, and supports the potential importance of HS in infection and in the development of antiviral agents against these viruses.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗

bioRxiv2020

Three-dimensional reconstructions of the internal structures of haustoria in parasitic Orobanchaceae

Parasitic plants infect other plants by forming haustoria, specialized multicellular organs consisting of several cell types each of which has unique morphological features and physiological roles associated with parasitism. Understanding the spatial organization of cell types is, therefore, of great importance in elucidating the functions of haustoria. Here, we report a three-dimensional (3-D) reconstruction of haustoria from two Orobanchaceae species, the obligate parasite Striga hermonthica infecting rice and the facultative parasite Phtheirospermum japonicum infecting Arabidopsis. Our images reveal the spatial arrangements of multiple cell types inside haustoria and their interaction with host roots. The 3-D internal structures of haustoria highlight differences between the two parasites, particularly at the xylem connection site with the host. Our study provides structural insights into how organs interact between hosts and parasitic plants. One-sentence summaryThree-dimensional image reconstruction was used to visualize the spatial organization of cell types in the haustoria of parasitic plants with special reference to their interaction with host roots.

plant biology↗

bioRxiv2019

PointSite: a point cloud segmentation tool for identication of protein ligand binding atoms

Accurate identifications of ligand binding sites (LBS) on protein structure is critical for understanding protein function and designing structure-based drug. As the previous pocket-centric methods are usually based on the investigation of pseudo surface points (PSPs) outside the protein structure, thus inherently cannot incorporate the local connectivity and global 3D geometrical information of the protein structure. In this paper, we propose a novel point clouds segmentation method, PointSite, for accurate identification of protein ligand binding atoms, which performs protein LBS identification at the atom-level in a protein-centric manner. Specifically, we first transfer the original 3D protein structure to point clouds and then conduct segmentation through Submanifold Sparse Convolution (SSC) based U-Net. With the fine-grained atom-level binding atoms representation and enhanced feature learning, PointSite can outperform previous methods in atom-IoU by a large margin. Furthermore, our segmented binding atoms can work as a filter on predictions achieved by previous pocket-centric approaches, which significantly decreases the false-positive of LBS candidates. Through cascaded filter and re-ranking aided by the segmented atoms, state-of-the-art performance can be achieved over various canonical benchmarks and CAMEO hard targets in terms of the commonly used DCA criteria. Our code is publicly available through https://github.com/PointSite.

bioinformatics↗

bioRxiv2019

Residue retention promotes soil carbon accumulation in minimum tillage systems: Implications for conservation tillage

Crop residue retention and minimum tillage (including no-tillage, NT, and reduced tillage, RT) are common conservation tillage practices that have been extensively practised for improving soil health and reducing the negative environmental impact caused by intensive farming. However, the complex effect of conservation tillage practices on soil organic carbon (SOC) storage has not been systematically analyzed, and particularly, the synergistic effect of crop residue retention and minimum tillage on SOC storage remains nonexistent. We conducted a global meta-analysis using a dataset consisting of 823 pairs of data points from 164 studies. We analyzed the effect of crop residue retention and minimum tillage on SOC storage and how the above effects were influenced by various soil/environmental (soil sampling depth, soil texture, and climate) and management conditions (cropping intensity and treatment duration). We found that either residue retention or minimum tillage alone increased SOC stock, while the former increased SOC more. The NT and RT increased SOC stock by 10 and 6%, respectively, in comparison to conventional tillage (CT). The NT plus residue retention (NTS) and RT plus residue retention (RTS) resulted in 20 and 26% more increase in SOC than NT and RT, respectively. Compared with CT, NTS and RTS further increased SOC stock by 29 and 27%, respectively. The above effects were greater in the topsoil than in the subsoil. Availability of initial soil nutrient played a greater role in affecting SOC stock than climatic conditions and management practices. Both residue retention and NT increased SOC rapidly in the first 6 years regardless of soil texture or climate condition, followed by a period of slower sequestration phase before reaching a slow steady rate. Double cropping generally increased SOC stock across all conservation tillage practices as compared to single or multiple cropping. Therefore, we conclude that minimum tillage coupled with residue retention in a double cropping system is the most beneficial management system for increasing cropland SOC storage, which can inform sustainable soil management practices aimed at increasing global C sequestration.

ecology↗