Biology subjects

Ge, S.

Publications and source records attributed to Ge, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Macrophages heterogeneity and significance during human fetal pancreatic development

Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and intrinsic factors specific to the tissue. For the endocrine cells of the islet of Langerhans, the local microenvironment consists of various cell types including pancreatic acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Interestingly, hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks (PCW)1,2, but whether they play a role during islet formation in humans remains largely unknown. To shed light on this question, we performed single nuclei RNA sequencing of the human fetal pancreas during the early weeks of the second trimester, specifically focusing on the molecular interaction between the hematopoietic niche and the pancreatic epithelium. Our analysis identified a wide range of hematopoietic cells as well as two distinct subsets of macrophages that are unique to the fetal pancreas and absent in neonatal or adult pancreatic tissues. Leveraging this discovery, we developed a co-culture system of hESC-derived endocrine-macrophage organoids to model their interaction in vitro. Remarkably, we found that macrophages promoted the differentiation and viability of developing endocrine cells in vitro and enhanced tissue engraftment in immunocompromised mice, supporting a role for these cells in future tissue engineering strategies for diabetes.

developmental biology↗

bioRxiv2022

Forces driving transposable element load variation during Arabidopsis range expansion

Genetic load refers to the accumulated and potentially life-threatening deleterious mutations in populations. Understanding the mechanisms underlying genetic load variation of transposable elements (TEs), one major large-effect mutations, during range expansion is an intriguing question in biology. Here, we used 1,115 globally natural accessions of Arabidopsis thaliana, to study the driving forces of TE load variation during its range expansion. The TE load increased with range expansion, especially in the recently established Yangtze River basin population. The effective population size explained 62.0% of the variance in TE load, and high transposition rate and positive selection or hitch-hiking effect contributed to the accumulation of TEs in the expanded populations. We genetically mapped the candidate causal genes or TEs and revealed the genetic architecture of TE load. Overall, this study reveals the variation in the genetic load of TEs during Arabidopsis expansion and highlights the causes of TE load variation.

evolutionary biology↗

bioRxiv2022

A comprehensive view of cell-type-specific temporal dynamics in human and mouse brains

Progenitor cells play fundamental roles in preserving optimal organismal functions under normal, aging, and disease conditions. However, progenitor cells are incompletely characterized, especially in the brain, partly because conventional methods are restricted by inadequate throughput and resolution for deciphering cell-type-specific proliferation and differentiation dynamics in vivo. Here, we developed TrackerSci, a new technique that combines in vivo labeling of newborn cells with single-cell combinatorial indexing to profile the single-cell chromatin landscape and transcriptome of rare progenitor cells and track cellular differentiation trajectories in vivo. We applied TrackerSci to analyze the epigenetic and gene expression dynamics of newborn cells across entire mouse brains spanning three age stages and in a mouse model of Alzheimers disease. Leveraging the dataset, we identified diverse progenitor cell types less-characterized in conventional single cell analysis, and recovered their unique epigenetic signatures. We further quantified the cell-type-specific proliferation and differentiation potentials of progenitor cells, and identified the molecular programs underlying their aging-associated changes (e.g., reduced neurogenesis/oligodendrogenesis). Finally, we expanded our analysis to study progenitor cells in the aged human brain through profiling [~]800,000 single-cell transcriptomes across five anatomical regions from six aged human brains. We further explored the transcriptome signatures that are shared or divergent between human and mouse oligodendrogenesis, as well as the region-specific down-regulation of oligodendrogenesis in the human cerebellum. Together, the data provide an in-depth view of rare progenitor cells in mammalian brains. We anticipate TrackerSci will be broadly applicable to characterize cell-type-specific temporal dynamics in diverse systems.

genomics↗

bioRxiv2022

Intranasal delivery of NS1-deleted influenza virus vectored COVID-19 vaccine restrains the SARS-CoV-2 inflammatory response

The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) variants and "anatomical escape" characteristics threaten the effectiveness of current coronavirus disease (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines development. In this study, we investigated immune responses induced by an NS1-deleted influenza virus vectored intranasal COVID-19 vaccine (dNS1-RBD) which provides broad-spectrum protection against SARS-CoV-2 variants. Intranasal delivery of dNS1-RBD induced innate immunity, trained immunity and tissue-resident memory T cells covering the upper and lower respiratory tract. It restrained the inflammatory response by suppressing early phase viral load post SARS-CoV-2 challenge and attenuating pro-inflammatory cytokine (IL-6, IL-1B, and IFN-{gamma}) levels, thereby reducing excess immune-induced tissue injury compared with the control group. By inducing local cellular immunity and trained immunity, intranasal delivery of NS1-deleted influenza virus vectored vaccine represents a broad-spectrum COVID-19 vaccine strategy to reduce disease burden.

immunology↗

bioRxiv2022

Boreal Forest Height Mapping using Sentinel-1 Time Series and improved LSTM model

Here, a novel semi-supervised Long Short-Term Memory (LSTM) model is developed and demonstrated for predicting forest tree height using time series of Sentinel-1 images. The model uses a Helix-Elapse (HE) projection approach to capture relationship between forest temporal patterns and Sentinel-1 time series, when the acquisition time intervals are irregular. A skip-link based LSTM block is introduced and a novel backbone network, Helix-LSTM, is proposed to retrieve temporal features at different receptive scales. Additionally, a novel semi-supervised strategy, Cross-Pseudo Regression, is employed to achieve better model performance. The developed model is compared versus basic LSTM model, attention-based bidirectional LSTM and several other established regression approaches used in forest variable mapping, demonstrating consistent improvement of forest height prediction accuracy. The study site is located in Central Finland and represents boreal forestland. At best, the achieved accuracy of forest height mapping was 28.3% rRMSE for pixel-level predictions, and 18.0% rRMSE on stand level. We expect that the developed model can also be used for modeling relationships between other forest variables and satellite image time series.

ecology↗

bioRxiv2022

Harringtonine has the effects of double blocking SARS-CoV-2 membrane fusion

Fusion with host cell membrane is the main mechanism of infection of SARS-CoV-2. Here, we propose a new strategy to double block SARS-CoV-2 membrane fusion by using Harringtonine (HT), a small-molecule antagonist. By using cell membrane chromatography (CMC), we found that HT specifically targeted the SARS-CoV-2 S protein and host cell TMPRSS2, and then confirmed that HT can inhibit pseudotyped virus membrane fusion. Furthermore, HT successfully blocked SARS-CoV-2 infection, especially in the delta and Omicron mutant. Since HT is a small-molecule antagonist, it is minimally affected by the continuous variation of SARS-CoV-2. Our findings show that HT is a potential small-molecule antagonist with a new mechanism of action against SARS-CoV-2 infection, and thus HT mainly targets the S protein, and thus, greatly reduces the damage of the S proteins autotoxicity to the organ system, has promising advantages in the clinical treatment of COVID-19.

pharmacology and toxicology↗

bioRxiv2021

In situ control of root-bacteria interactions using optical trapping in transparent soil

Bacterial attachment on root surfaces is an important step preceding the colonisation or internalisation and subsequent infection of plants by pathogens. Unfortunately, bacterial attachment is not well understood because the phenomenon is difficult to observe. Here we assessed whether this limitation could be overcome using optical trapping approaches. We have developed a system based on counter-propagating beams and studied its ability to guide Pectobacterium atrosepticum (Pba) cells to different root cell types within the interstices of transparent soils. Bacterial cells were successfully trapped and guided to root hair cells, epidermis cells, border cells and tissues damaged by laser ablation. Finally, we used the system to quantify the bacterial cell detachment rate of Pba cells on root surfaces following reversible attachment. Optical trapping techniques could greatly enhance our ability to deterministically characterise mechanisms linked to attachment and formation of biofilms in the rhizosphere.

microbiology↗

bioRxiv2021

Using hypertemporal Sentinel-1 data to predict forest growing stock volume

In this study, we assess the potential of long time series of Sentinel-1 SAR data to predict forest growing stock volume and evaluate the temporal dynamics of the predictions. The boreal coniferous forests study site is located near the Hyytiala forest station in central Finland and covers an area of 2,500 km2 with nearly 17,000 stands. We considered several prediction approaches (linear, support vector and random forests regression) and fine-tuned them to predict growing stock volume in several evaluation scenarios. The analyses used 96 Sentinel-1 images acquired over three years. Different approaches for aggregating SAR images and choosing feature (predictor) variables were evaluated. Our results demonstrate considerable decrease in RMSEs of growing stock volume as the number of images increases. While prediction accuracy using individual Sentinel-1 images varied from 85 to 91 m3/ha RMSE (relative RMSE 50-53%), RMSE with combined images decreased to 75.6 m3/ha (relative RMSE 44%). Feature extraction and dimension reduction techniques facilitated achieving the near-optimal prediction accuracy using only 8-10 images. When using assemblages of eight consecutive images, the GSV was predicted with the greatest accuracy when initial acquisitions started between September and January. HighlightsO_LITime series of 96 Sentinel-1 images is analysed over study area with 17,762 forest stands. C_LIO_LIRigorous evaluation of tools for SAR feature selection and GSV prediction. C_LIO_LIImproved periodic seasonality using assemblages of consecutive Sentinel-1 images. C_LIO_LIAnalysis of combining images acquired in "frozen" and "dry summer" conditions. C_LIO_LICompetitive estimates using calculation of prediction errors with stand-area weighting. C_LI

ecology↗

bioRxiv2020

Pancreatic Ductal Adenocarcinoma Comprises Coexisting Regulatory States with both Common and Distinct Dependencies

Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of regulatory protein activity in single cells identified three PDA Developmental Lineages (PDLs), coexisting in virtually all tumors, whose transcriptional states are mechanistically driven by aberrant activation of Master Regulator (MR) proteins associated with gastrointestinal lineages (GLS state), morphogen and EMT pathways (MOS state), and acinar-to-ductal metaplasia (ALS state), respectively. Each PDL is further subdivided into sub-states characterized by low vs. high MAPK pathway activity. This taxonomy was remarkably conserved across multiple cohorts, cell lines, and PDX models, and harmonized with bulk profile analyses. Cross-state plasticity and MR essentiality was confirmed by barcode-based lineage tracing and CRISPR/Cas9 assays, respectively, while MR ectopic expression induced PDL transdifferentiation. Together these data provide a mechanistic foundation for PDA heterogeneity and a roadmap for targeting PDA cellular subtypes.

cancer biology↗

bioRxiv2020

Estimating Genetic Similarity Matrices using Phylogenies

Genetic similarity is a measure of the genetic relatedness among individuals. The standard method for computing these matrices involves the inner product of observed genetic variants. Such an approach is inaccurate or impossible if genotypes are not available, or not densely sampled, or of poor quality (for example, genetic analysis of extinct species). We provide a new method for computing genetic similarities among individuals using phylogenetic trees. Our method can supplement (or stand in for) computations based on genotypes. We provide simulations suggesting that the genetic similarity matrices computed from trees are consistent with those computed from genotypes. With our methods, quantitative analysis on genetic traits and analysis of heritability and co-heritability can be conducted directly using genetic similarity matrices and so in the absence of genotype data, or under uncertainty in the phylogenetic tree. We use simulation studies to demonstrate the advantages of our method, and we provide applications to data.

genetics↗

bioRxiv2020

Virus-free and live-cell visualizing SARS-CoV-2 cell entry for studies of neutralizing antibodies and compound inhibitors

The ongoing COVID-19 pandemic, caused by SARS-CoV-2 infection, has resulted in hundreds of thousands of deaths. Cellular entry of SARS-CoV-2, which is mediated by the viral spike protein and host ACE2 receptor, is an essential target for the development of vaccines, therapeutic antibodies, and drugs. Using a mammalian cell expression system, we generated a recombinant fluorescent protein (Gamillus)-fused SARS-CoV-2 spike trimer (STG) to probe the viral entry process. In ACE2-expressing cells, we found that the STG probe has excellent performance in the live-cell visualization of receptor binding, cellular uptake, and intracellular trafficking of SARS-CoV-2 under virus-free conditions. The new system allows quantitative analyses of the inhibition potentials and detailed influence of COVID-19-convalescent human plasmas, neutralizing antibodies and compounds, providing a versatile tool for high-throughput screening and phenotypic characterization of SARS-CoV-2 entry inhibitors. This approach may also be adapted to develop a viral entry visualization system for other viruses.

microbiology↗

bioRxiv2020

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of COVID-19 Spike psedotype virus

BackgroundThe novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019 and there is no sign that the epidemic is abating. The major issue for controlling the infectious is lacking efficient prevention and therapeutic approaches. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been reported to treat the disease, but the underlying mechanism remains controversial. PurposeThe objective of this study is to investigate whether CQ and HCQ could be ACE2 blockers and used to inhibit 2019-nCoV virus infection. MethodsIn our study, we used CCK-8 staining, flow cytometry and immunofluorescent staining to evaluate the toxicity and autophagy of CQ and HCQ, respectively, on ACE2 high-expressing HEK293T cells (ACE2h cells). We further analyzed the binding character of CQ and HCQ to ACE2 by molecular docking and surface plasmon resonance (SPR) assays, 2019-nCoV spike pseudotyped virus was also used to observe the viropexis effect of CQ and HCQ in ACE2h cells. ResultsResults showed that HCQ is slightly more toxic to ACE2h cells than CQ. Both CQ and HCQ could bind to ACE2 with KD =(7.31{+/-}0.62)e-7 M and (4.82{+/-}0.87)e-7 M, respectively. They exhibit equivalent suppression effect for the entrance of 2019-nCoV spike pseudotyped virus into ACE2h cells. ConclusionsCQ and HCQ both inhibit the entrance 2019-nCoV into cells by blocking the binding of the virus with ACE2. Our findings provide novel insights into the molecular mechanism of CQ and HCQ treatment effect on virus infection.

biochemistry↗

bioRxiv2020

Time-dependent roles of adolescent- and adult-born dentate granule neurons in spatial learning

The dentate gyrus presents the peculiarity to be formed after birth in rodents. Adolescence is a very sensitive period during which cognitive competences are programmed. We investigated and compared the role of dentate neurons born during adolescence or generated during adulthood. We demonstrated that the ontogenetic stage of dentate neurons in relation to when they are generated dictates their participation in memory processes.

neuroscience↗

bioRxiv2020

Room-temperature-storable PCR Mixes for SARS-CoV-2 Detection

A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) emerged in late 2019, causing an outbreak of pneumonia [coronavirus disease 2019 (COVID-19)] in Wuhan, China, which then rapidly spread globally. Although the use of ready-made reaction mixes can enable more rapid PCR-based diagnosis of COVID-19, the need to transport and store these mixes at low temperatures presents challenges to already overburdened logistics networks. Here, we present an optimized freeze-drying procedure that allows SARS-CoV-2 PCR mixes to be transported and stored at ambient temperatures, without loss of activity. Additive-supplemented PCR mixes were freeze-dried. The residual moisture of the freeze-dried PCR mixes was measured by Karl-Fischer titration. We found that freeze-dried PCR mixes with [~]1.2% residual moisture are optimal for storage, transport, and reconstitution. The sensitivity, specificity, and repeatability of the freeze-dried reagents were similar to those of freshly prepared, wet reagents. The freeze-dried mixes retained activity at room temperature (18[~]25{degrees}C) for 28 days, and for 14 and 10 days when stored at 37{degrees}C and 56{degrees}C, respectively. The uptake of this approach will ease logistical challenges faced by transport networks and make more cold storage space available at diagnosis and hospital laboratories. This method can also be applied to the generation of freeze-dried PCR mixes for the detection of other pathogens.

microbiology↗

bioRxiv2020

Robust neutralization assay based on SARS-CoV-2 S-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressed BHK21 cells

The global pandemic of Coronavirus disease 2019 (COVID-19) is a disaster for human society. A convenient and reliable in vitro neutralization assay is very important for the development of neutralizing antibodies, vaccines and other inhibitors. In this study, G protein-deficient vesicular stomatitis virus (VSVdG) bearing full-length and truncated spike (S) protein of SARS-CoV-2 were evaluated. The virus packaging efficiency of VSV-SARS-CoV-2-Sdel18 (S with C-terminal 18 amino acid truncation) is much higher than VSV-SARS-CoV-2-S. A neutralization assay for antibody screening and serum neutralizing titer quantification was established based on VSV-SARS-CoV-2-Sdel18 pseudovirus and human angiotensin-converting enzyme 2 (ACE2) overexpressed BHK21 cell (BHK21-hACE2). The experimental results can be obtained by automatically counting EGFP positive cell number at 12 hours after infection, making the assay convenient and high-throughput. The serum neutralizing titer of COVID-19 convalescent patients measured by VSV-SARS-CoV-2-Sdel18 pseudovirus assay has a good correlation with live SARS-CoV-2 assay. Seven neutralizing monoclonal antibodies targeting receptor binding domain (RBD) of SARS-CoV-2-S were obtained. This efficient and reliable pseudovirus assay model could facilitate the development of new drugs and vaccines.

microbiology↗

bioRxiv2020

Supervised Adversarial Alignment of scRNA-seq Data

Dimensionality reduction is an important first step in the analysis of single cell RNA-seq (scRNA-seq) data. In addition to enabling the visualization of the profiled cells, such representations are used by many downstream analyses methods ranging from pseudo-time reconstruction to clustering to alignment of scRNA-seq data from different experiments, platforms, and labs. Both supervised and unsupervised methods have been proposed to reduce the dimension of scRNA-seq. However, all methods to date are sensitive to batch effects. When batches correlate with cell types, as is often the case, their impact can lead to representations that are batch rather than cell type specific. To overcome this we developed a domain adversarial neural network model for learning a reduced dimension representation of scRNA-seq data. The adversarial model tries to simultaneously optimize two objectives. The first is the accuracy of cell type assignment and the second is the inability to distinguish the batch (domain). We tested the method by using the resulting representation to align several different datasets. As we show, by overcoming batch effects our method was able to correctly separate cell types, improving on several prior methods suggested for this task. Analysis of the top features used by the network indicates that by taking the batch impact into account, the reduced representation is much better able to focus on key genes for each cell type.

bioinformatics↗

bioRxiv2019

MECP2 duplication causes aberrant GABA pathways, circuits and behaviors in transgenic monkeys: neural mappings to patients with autism

MECP2 gain- and loss-of-function in genetically-engineered monkeys demonstrably recapitulate typical phenotypes in patients, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remains unknown. Using expression profiles of 13,888 genes in 182 macaque neocortical samples, we first show that MECP2 coexpressed genes are enriched in GABA-related signaling pathways. We then perform analyses on multiple phenotypic levels including locomotive and cognitive behavior, resting-state electroencephalography and fMRI in MECP2 overexpressed and wild-type macaque monkeys. Behaviorally, transgenic monkeys exhibit hyperactive and repetitive locomotion, greater separation anxiety response, and less flexibility in rule switching. Moreover, decreased neural synchronization at beta frequency (12-30 Hz) is associated with greater locomotion after peer separation. Further analysis of fMRI-derived connectomics reveals widespread hyper- and hypo-connectivity, where hyper-connectivity prominently involving prefrontal and cingulate networks accounts for deficits in cognitive flexibility. To map MECP2-related aberrant circuits of monkeys to the pathological circuits of autistic patients, individuals in a large public neuroimaging database of autism were clustered using community detection on functional connectivity patterns. In a stratified cohort of 49 autisms and 72 controls, the dysfunctional connectivity profile particularly in prefrontal and temporal networks is highly correlated with that of transgenic monkeys, as is further responsible for the severity of social communicative deficits in patients. Through establishing a circuit-based construct link between transgenic animal models and stratified clinical patients, the present findings with explicable biological causes are potentially amenable to translation for accurate diagnosis and evaluation of future treatments in autism-related disorders.\n\nOne sentence summaryWe identify shared circuit-level abnormalities between MECP2 transgenic monkeys and a stratified subgroup of human autism, and demonstrate the translational need of a multimodal approach to capture multifaceted effects triggered by a single genetic event in a genetically-engineered primate model.

neuroscience↗

bioRxiv2019

Cortical ensemble activity discriminates auditory attentional states

Selective attention modulates sensory cortical activity. It remains unclear how auditory cortical activity represents stimuli that differ behaviorally. We designed a cross-modality task in which mice made decisions to obtain rewards based on attended visual or auditory stimuli. We recorded auditory cortical activity in behaving mice attending to, ignoring, or passively hearing auditory stimuli. Engaging in the task bidirectionally modulates neuronal responses to the auditory stimuli in both the attended and ignored conditions compared to passive hearing. Neuronal ensemble activity in response to stimuli under attended, ignored and passive conditions are readily distinguishable. Furthermore, ensemble activity under attended and ignored conditions are in closer states compared to passive condition, and they share a component of attentional modulation which drives them to the same direction in the population activity space. Our findings suggest that task engagement changes sensory cortical representations across modalities in the same directions, and cross-modality attention may differentially modulates attended and ignored modalities.

neuroscience↗