Biology subjects

Wei, X.

Publications and source records attributed to Wei, X..

At least 181 records · Page 10Linked to original sources

bioRxiv2022

Spateo: multidimensional spatiotemporal modeling of single-cell spatial transcriptomics

Cells do not live in a vacuum, but in a milieu defined by cell-cell communication that can be measured via emerging high-resolution spatial transcriptomics approaches. However, analytical tools that fully leverage such data for kinetic modeling remain lacking. Here we present Spateo (aristoteleo/spateo-release), a general framework for quantitative spatiotemporal modeling of single-cell resolution spatial transcriptomics. Spateo delivers novel methods for digitizing spatial layers/columns to identify spatially-polar genes, and develops a comprehensive framework of cell-cell interaction to reveal spatial effects of niche factors and cell type-specific ligand-receptor interactions. Furthermore, Spateo reconstructs 3D models of whole embryos, and performs 3D morphometric analyses. Lastly, Spateo introduces the concept of "morphometric vector field" of cell migrations, and integrates spatial differential geometry to unveil regulatory programs underlying various organogenesis patterns of Drosophila. Thus, Spateo enables the study of the ecology of organs at a molecular level in 3D space, beyond isolated single cells.

systems biology↗

bioRxiv2022

Centromere-associated retroelement evolution in Drosophila melanogaster reveals an underlying conflict

Centromeres are chromosomal regions essential for coordinating chromosome segregation during cell division. While centromeres are defined by the presence of a centromere-specific histone H3 variant rather than a particular DNA sequence, they are typically embedded in repeat-dense chromosomal genome regions. In many species, centromeres are associated with transposable elements, but it is unclear if these elements are selfish or if they play a role in centromere specification or function. Here we use Drosophila melanogaster as a model to understand the evolution of centromere-associated transposable elements. G2/Jockey-3 is a non-LTR retroelement in the Jockey clade and the only sequence shared by all centromeres. We study the evolution of G2/Jockey-3 using short and long read population genomic data to infer insertion polymorphisms across the genome. We combine estimates of the age, frequency, and location of insertions to infer the evolutionary processes shaping G2/Jockey-3 and its association with the centromeres. We find that G2/Jockey-3 is an active retroelement targeted by the piRNA pathway that is enriched in centromeres at least in part due to an insertion bias. We do not detect signatures of positive selection on any G2/Jockey-3 insertions that would suggest than individual copies are favored by natural selection. Instead, we infer that most insertions are neutral or weakly deleterious both inside and outside of the centromeres. Therefore, G2/Jockey-3 evolution is consistent with it being a selfish genetic element that targets centromeres. We propose that targeting centromeres helps active retroelements escape host defenses, as the unique centromeric chromatin may prevent targeting by the host silencing machinery. At the same time, centromeric TEs insertions may be tolerated or even beneficial if they also contribute to the transcriptional and chromatin environment. Thus, we suspect centromere-associated retroelements like G2/Jockey-3 reflect a balance between conflict and cooperation at the centromeres.

genomics↗

bioRxiv2022

Structural basis of sRNA RsmZ regulation of Pseudomonas aeruginosa virulence

Pseudomonas aeruginosa is an opportunistic human pathogen that poses threats to hospitalized immunocompromised patients 1. A non-coding small RNA (sRNA) from the repressor of secondary metabolites (Rsm) system, RsmZ, sequesters the global repressor protein RsmA to regulate downstream gene expressions that reprogram virulence repertoires associated with acute and chronic P. aeruginosa infections 2,3. Molecular insights into the full-length RsmZ architecture remain elusive, leading to the lack of understanding of RsmZ binding to RsmA and subsequent modulations of gene expressions. Here we use cryo-electron microscopy (cryo-EM) to resolve structures of the full-length RsmZ in complexes with RsmA, in which five stem-loops (SLs) and one single-stranded junction carrying the GGA binding sites in RsmZ form three pairs of clamps, each binding to a RsmA homodimer. Disruptions of the base-pairings in all stems of RsmZ significantly reduced the binding affinity to RsmA by 17-fold, which resulted in enhanced RsmA downregulation of gene expressions and phenotypes associated to both acute and chronic virulence of P. aeruginosa. Double mutations that rescued these stems of RsmZ restored the binding to RsmA by more than 5-fold, and recovered the corresponding phenotypes. Our results reveal the molecular mechanism of RsmZ regulation of P. aeruginosa virulence and suggest RsmZ as a potential target for the development of new antimicrobial agents.

microbiology↗

bioRxiv2022

Electro-acupuncture alleviates ACE-increased anxiety-like behaviors in mice of adulthood by targeting claustrum D1R CaMKII

Adolescent cocaine exposure (ACE) increases risk of developing psychiatric problems such as anxiety, which may drive relapse in later life, however, its underlying molecular mechanism remains poorly understood. Methods: ACE male mice model were established by exposing to cocaine during adolescent period. Elevated plus maze (EPM) were used to assess anxiety-like behaviors in mice. Within claustrum, local injection of SCH-23390, a specific antagonist for dopamine receptor 1 (D1R), or D1R knocking-down virus were used to regulate D1R function or expression on CaMKII-positive neurons (D1RCaMKII) in vivo. Electro-acupuncture (EA) treatment was performed at acupoints of Baihui and Yintang during withdrawal period. Results: We found that ACE mice exhibited anxiety-like behaviors, along with more activated CaMKII-positive neurons and increased D1RCaMKII levels in claustrum during adulthood. Inhibiting D1R function or knocking-down D1RCaMKII levels in claustrum efficiently reduced claustrum activation, and ultimately suppressed anxiety-like behaviors in ACE mice during adulthood. EA treatment alleviated ACE-evoked claustrum activation and anxiety-like behaviors by suppressing claustrum D1RCaMKII. Conclusion: Our findings identified a novel role of claustrum in ACE-induced anxiety-like behaviors, and put new insight into the D1RCaMKII in the claustrum. The claustrum D1RCaMKII might be a promising pharmacological target, such as EA treatment, to treat drugs-induced anxiety-like behaviors. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/512685v5_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b22744org.highwire.dtl.DTLVardef@12fed83org.highwire.dtl.DTLVardef@1924caforg.highwire.dtl.DTLVardef@1e896ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Identification of a self-renewing muscle satellite cell state by single-cell chromatin accessibility profiling

A balance between self-renewal and differentiation is critical for the regenerative capacity of tissue-resident stem cells. In skeletal muscle, successful regeneration requires the orchestrated activation, proliferation, and differentiation of muscle satellite cells (MuSCs) that are normally quiescent. A subset of MuSCs undergoes self-renewal to replenish the stem cell pool, but the features that identify and define self-renewing MuSCs remain to be elucidate. Here, through single-cell chromatin accessibility analysis, we reveal the self-renewal versus differentiation trajectories of MuSCs over the course of regeneration in vivo. We identify TGFBR3 as a unique marker of self-renewing MuSCs that can be purified and efficiently contribute to regeneration after transplantation; and we show that SMAD4 and its downstream genes are genetically required for self-renewal in vivo by restricting differentiation. Our study unveils the identity and mechanisms of self-renewing MuSCs, while providing a key resource for comprehensive analysis of muscle regeneration.

cell biology↗

bioRxiv2022

Role of mPFC DUSP1 in regulating the sensitivity to cocaine in adolescent cocaine-exposed mice of adulthood

Adolescent cocaine abuse increases the risk for developing addiction in later life, which remains a big public health concern, but the underlying molecular mechanism is poorly understood. Here, adolescent cocaine-exposed (ACE) male mice models were established by administrating cocaine during adolescent period. When growing to adult age, mice were subjected to conditioned place preference (CPP) to evaluate the sensitivity to cocaine, then potential molecule of dual specificity phosphatase 1 (DUSP1) were screened out by transcriptomic sequencing. Subthreshold dose of cocaine (sdC), that is insufficient to produce CPP, was used to induce CPP in adulthood. The sdC treatment effectively induced CPP in ACE mice during adulthood, accompanied with the more triggered CaMKII-positive neurons, and induced higher Dusp1 gene, lower DUSP1 protein, lower DUSP1 activity and lower DUSP1 expression on CaMKII-positive neurons (DUSP1CaMKII) in medial prefrontal cortex (mPFC). Overexpressing DUSP1CaMKII suppressed CaMKII-positive neuronal activation, and ultimately blocked sdC-induced CPP in ACE mice during adulthood. While, knocking-down DUSP1CaMKII activated more CaMKII-positive neurons, and aggravated sdC-preferred behavior in ACE mice during adulthood. ERK1/2 might be potential subsequent signal for DUSP1 in the process. Collectively, our findings reveal a novel molecular mechanism underlying adolescent drug abuse-induced susceptibility to addiction during adulthood, and mPFC DUSP1CaMKII is a promising pharmacological target to predict or treat addiction, especially caused by adolescent substance use. SummaryAdolescent cocaine exposure causes higher cocaine-preferred behaviors during adulthood, along with evoked mPFC activity in response to cocaine challenge. Locally overexpressing but not knocking-down the dual specificity phosphatase 1 (DUSP1) on CaMKII-positive neurons (DUSP1CaMKII) suppresses mPFC activation, and ultimately rescues the higher sensitivity to cocaine during adulthood.

neuroscience↗

bioRxiv2022

Identification of divergent botulinum neurotoxin homologs in Paeniclostridium ghonii

Botulinum neurotoxins (BoNTs) are the most potent family of toxins known to science. Bioinformatic studies in recent years have revealed that they are members of a broader toxin family, with an increasing number of divergent homologs identified in genomes of organisms outside of the Clostridium genus. Here, we report the identification of two putative divergent BoNT-like homologs in the genomes of two strains of Paeniclostridium ghonii. We designated them PG-toxin 1 (PGT1) and PG-toxin 2 (PGT2), which share ~54% protein sequence identity. Unlike any other known BoNT homologs, PGT1 and PGT2 are composed of two separate subunits encoded on two neighboring genes: one encoding the protease domain (light chain, LC) with a conserved HExxH motif, and the second encoding the heavy-chain (HC) containing the putative translocation domain and receptor-binding domain. Phylogenetic analysis of both the LC and HC reveal that it is a divergent member of the lineage of BoNT that also includes BoNT/X, BoNT/En and the insecticidal PMP1. The gene clusters harboring PGT1 and PGT2 also include a putative insecticidal delta-endotoxin, Cry8Ea1, as well as putative endolysin and bacteriocin genes that may facilitate lytic toxin secretion, suggesting a possibility that this gene cluster might serve an insecticidal purpose.

bioinformatics↗

bioRxiv2022

ZmEREB57 regulates OPDA synthesis and enhances salt stress tolerance through two distinct signal pathways in Zea mays

In plants, APETALA2/Ethylene-Responsive Factor (AP2/ERF)-domain transcription factors play important roles in regulating responses to biotic and abiotic types of stress. In this study, a novel AP2/ERF gene in maize, ethylene responsive element binding factor 57 (ZmEREB57), was identified by comparative transcriptomics, which was significantly upregulated under salt treatment; however, its function remained unclear. Our findings revealed that ZmEREB57 is a nuclear protein with transactivation activity, induced by a number of abiotic types of stress. Whats more, two CRISPR/Cas9 knockout lines of ZmEREB57 conferred sensitivity to saline conditions. DNA affinity purification sequencing (DAP-Seq) analysis revealed that ZmEREB57 mainly binds to promoters containing the O-box like motif (CCGGCC) to regulate the expression of its target genes. Further experiments validated that ZmEREB57 directly bind to the promoter of ZmAOC2 involved in the synthesis of 12-oxo-phytodienoic acid (OPDA) and JA. Besides, transcriptome analysis identified a number of genes responded to both OPDA and JA treatment, while a different set of genes specifically responded specifically to OPDA, but not JA. Analysis of mutants deficient in the biosynthesis of OPDA and JA revealed that OPDA functions as a signaling molecule in the salt response. Our results provide evidence for ZmEREB57s involvement in salt tolerance by regulating OPDA and JA signaling, and confirm early observations that OPDA signaling can function independently of JA signaling in maize.

plant biology↗

bioRxiv2022

Ancient Clostridium DNA and variants of tetanus neurotoxins associated with human archaeological remains

The analysis of microbial genomes from human archaeological samples offers a historic snapshot of ancient pathogens and provides insights into the origins of modern infectious diseases. Here, through a large-scale metagenomic analysis of archeological samples, we discovered bacterial species related to modern-day Clostridium tetani, which produces the tetanus neurotoxin (TeNT) and causes the disease tetanus. We assembled draft genomes from 38 distinct human archeological samples spanning five continents and dating to as early as ~4000 BCE. These genomes had varying levels of completeness and a subset of them displayed hallmarks of ancient DNA damage. While 24 fall into known C. tetani clades, phylogenetic analysis revealed novel C. tetani lineages, as well as two novel Clostridium species ("Clostridium sp. X and Y") closely related to C. tetani. Within these genomes, we found 13 TeNT variants with unique substitution profiles, including a subgroup of TeNT variants found exclusively in ancient samples from South America. We experimentally tested a TeNT variant selected from a ~6000-year-old Chilean mummy sample and found that it induced tetanus muscle paralysis in mice with potency comparable to modern TeNT. Our work identifies neurotoxigenic C. tetani in ancient DNA, new Clostridium species unique to ancient human samples, and a novel variant of TeNT that can cause disease in mammals.

genomics↗

bioRxiv2022

Identification of cancer-keeping genes as therapeutic targets by finding network control hubs

Finding cancer-driver genes - the genes whose mutations may transform normal cells into cancerous ones - remains a central theme of cancer research. We took a different perspective; instead of considering normal cells, we focused on cancerous cells and genes that maintained abnormal cell growth which we named cancer-keeping genes (CKGs). Intervention in CKGs may rectify aberrant cell growth so that they can be adopted as therapeutic targets for cancer treatment. We developed a novel approach to identifying CKGs by extending the well-established theory of network structural controllability, which aims at finding a control scheme (i.e., a minimal set of non-overlapping control paths covering all nodes) and control nodes (driver genes) that can steer the cell from any state to the designated state. Going beyond driver genes defined by one control scheme, we introduced control-hub genes located in the middle of a control path of every control scheme. Control hubs are essential for maintaining cancerous states and thus can be taken as CKGs. We applied our CKG-based approach to bladder cancer (BLCA) as a case study. All the genes on the cell cycle and p53 pathways in BLCA were identified as CKGs, showing the importance of these genes in cancer and demonstrating the power of our new method. Furthermore, sensitive CKGs that could be easily changed by structural perturbation were better suited as therapeutic targets. Six sensitive CKGs (RPS6KA3, FGFR3, N-cadherin (CDH2), EP300, caspase-1, and FN1) were subjected to small-interferencing-RNA knockdown in two BLCA cell lines to validate their cancer-suppressing effects. Knocking down RPS6KA3 in a mouse model of BLCA significantly inhibited the growth of tumor xenografts in mice. Combined, our results demonstrated the value of CKGs as therapeutic targets for cancer therapy. Key pointsO_LIFocus on genes that maintain aberrant cell growth, named cancer-keeping genes (CKGs). C_LIO_LIDevelop a novel approach for finding CKGs by extending the well-estabilished theory of network structural controllability to total network controllability. C_LIO_LIApply the new method to bladder cancer and experimentally validated the cancer-suppressing function of six CKGs in two bladder cancer cell lines and that of one CKG in bladder cancer mice. C_LI

bioinformatics↗

bioRxiv2022

The lingering effects of Neanderthal introgression on human complex traits

The mutations introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed mutations. We developed rigorous methods to assess the contribution of introgressed Neanderthal mutations to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal mutations and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal mutations have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.1% of heritable variation averaged across phenotypes; p = 9.59x10-9). However, the contribution of introgressed mutations tends to be significantly depleted relative to modern human mutations matched for allele frequency and linkage disequilibrium (about 57% depletion on average), consistent with purifying selection on introgressed mutations. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal mutations with 64 phenotypes (p < 1 x10-10). Previous work (Skov 2021) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed mutations that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed mutations are highly likely to have a phenotypic effect. Examination of these mutations reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.

genetics↗

bioRxiv2022

The nanoCUT&RUN technique visualizes telomeric chromatin in Drosophila

Advances in genomic technology led to a more focused pattern for the distribution of chromosomal proteins and a better understanding of their functions. The recent development of the CUT&RUN technique marks one of the important such advances. Here we develop a modified CUT&RUN technique that we termed nanoCUT&RUN, in which a high affinity nanobody to GFP is used to bring micrococcal nuclease to the binding sites of GFP-tagged chromatin proteins. Subsequent activation of the nuclease cleaves the chromatin, and sequencing of released DNA identifies binding sites. We show that nanoCUT&RUN efficiently produces high quality data for the TRL transcription factor in Drosophila embryos, and distinguishes binding sites specific between two TRL isoforms. We further show that nanoCUT&RUN dissects the distributions of the HipHop and HOAP telomere capping proteins, and uncovers unexpected binding of telomeric proteins at centromeres. nanoCUT&RUN can be readily applied to any system in which a chromatin protein of interest, or its isoforms, carries the GFP tag.

genetics↗

bioRxiv2022

mRNAid, an Open-Source Platform for Therapeutic mRNA Design and Optimization Strategies

Recent COVID-19 vaccines unleashed the potential of mRNA-based therapeutics. mRNA optimization is indispensable for reducing immunogenicity, ensuring stability, and maximizing protein output. We present mRNAid, an experimentally validated software for mRNA optimization and visualization that generates mRNA sequences with comparable if not superior characteristics to commercially optimized sequences. To encompass all aspects of mRNA design, we also interrogated the impact of uridine content, nucleoside analogs and UTRs on expression and immunogenicity.

bioinformatics↗

bioRxiv2022

STOmicsDB: a database of Spatial Transcriptomic data

Recent technological development in spatial transcriptomics allows researchers to measure gene expression of cells and their spatial locations at the almost single-cell level, which generates detailed biological insight into biological processes. However, specialized spatial transcriptomics databases are rare. Here, we present the Spatial TranscriptOmics DataBase (STOmicsDB), a user-friendly database with multifunctions including search of relevant publications and tools, public dataset visualization, customized specialized databases, new data archive, and online analysis. The current version of STOmicsDB consists of 141 curated spatial transcript datasets covering 12 species, and includes 5,618 spatial multi-omics publications and 674 tools. STOmicsDB is freely accessible at https://db.cngb.org/stomics/.

genomics↗

bioRxiv2022

Targeted degradation of PCNA outperforms stoichiometric inhibition to result in programed cell death

Targeted protein degradation has emerged as a powerful technology - both as a biological tool and for broadening the therapeutic proteome. As tools to probe this approach on historically intractable targets, we have previously advanced biodegraders -- targeted degradation fusion constructs composed of mini-proteins/peptides linked to modified E3 ligase receptors. Herein, we gain deeper insights into the utility and potential of biodegraders, through a detailed study on Con1-SPOP, a biodegrader which rapidly degrades the potential cancer target, proliferating cell nuclear antigen (PCNA). In a variety of settings, the active biodegrader (Con1-SPOP) proved pharmacologically superior to its stoichiometric (non-degrading) inhibitor equivalent (Con1-SPOPmut). Specifically, in addition to more potent anti-proliferative effects in both 2D cell culture and 3D spheroids, PCNA degradation uniquely induced DNA damage, cell apoptosis and necrosis. Global proteomic profiling of a stable cell-line expressing Con1-SPOP under doxycycline (Dox) induction revealed that impaired mitotic division and mitochondria dysfunction is a direct consequence of PCNA degradation, effects not seen with the stoichiometric inhibitor protein. To evaluate the therapeutic potential of biodegraders, we showed that Dox-induced Con1-SPOP achieved complete tumor-growth inhibition in a xenograft model. To explore application of biodegraders as a novel therapeutic modality, modified mRNA encoding Con1-SPOP was synthesized and encapsulated into lipid nanoparticles (LNPs). The approach successfully delivered mRNA in vitro to deplete endogenous PCNA within hours of application and with nanomolar potency. Overall, our results demonstrate the utility of biodegraders as biological tools and highlight target-degradation as a more efficacious approach versus stoichiometric inhibition. Finally, once in vivo delivery and expression are optimized, biodegraders may be leveraged as an exciting therapeutic modality.

cell biology↗

bioRxiv2022

Collateral cleavage of 28s rRNA by RfxCas13d causes death of mice

The CRISPR-Cas13 system is an RNA-guided RNA-targeting system, and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still controversial whether Cas13 exhibits collateral activity in mammalian cells. Here, we found that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which was not resulted from the loss of target gene function or off-target effects. Mechanistically, we showed that RfxCas13d exhibited collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAK-JNK/p38-immediate early gene (IEG) pathway. These results provide new mechanistic insights into the collateral activity of RfxCas13d and warn that the biosafety of CRISPR-Cas13 system needs further evaluation before applying it to clinical treatments.

bioengineering↗

bioRxiv2022

Asymmetric wall ingrowth deposition in Arabidopsis phloem parenchyma transfer cells is tightly associated with sieve elements

In Arabidopsis, polarized deposition of wall ingrowths in phloem parenchyma (PP) transfer cells (TCs) occurs adjacent to cells of the sieve element/companion cell (SE/CC) complex. However, the spatial relationships between these different cell types in minor veins, where phloem loading occurs, are poorly understood. PP TC development and wall ingrowth localization were compared to other phloem cells in leaves of Col-0 and the transgenic lines AtSUC2::AtSTP9-GFP and AtSWEET11::AtSWEET11-GFP that identify CCs and PP respectively. The development of PP TCs in minor veins, indicated by deposition of wall ingrowths, proceeded basipetally in leaves. However, not all PP develop ingrowths and higher levels of wall ingrowth deposition occur in abaxial-compared to adaxial-positioned PP TCs. Furthermore, the deposition of wall ingrowths was exclusively initiated on and preferentially covered the PP TC/SE interface, rather than the PP TC/CC interface, and only occurred in PP cells that were adjacent to SEs. Collectively, these results demonstrate the dominant impact of SEs on wall ingrowth deposition in PP TCs and suggest the existence of two sub-types of PP cells in leaf minor veins. Compared to PP cells, PP TCs showed more abundant accumulation of AtSWEET11-GFP, indicating functional differences in phloem loading between PP and PP TCs. HighlightWall ingrowth deposition in phloem parenchyma transfer cells of Arabidopsis leaf minor veins is initiated adjacent to sieve elements, rather than companion cells, and expands to preferentially cover this interface.

plant biology↗

bioRxiv2021

Cell transcriptomic atlas of the non-human primate Macaca fascicularis

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP.

cell biology↗