Biology subjects

Zhang, C.

Publications and source records attributed to Zhang, C..

At least 577 records · Page 32Linked to original sources

bioRxiv2023

Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14

Chemical modification of RNAs is important for post-transcriptional gene regulation. The METTL3-METTL14 complex generates most N6-methyladenosine (m6A) modifications in mRNAs, and dysregulated methyltransferase expression has been linked to numerous cancers. Here we show that changes in m6A modification location can impact oncogenesis. A gain-of-function missense mutation found in cancer patients, METTL14R298P, promotes malignant cell growth in culture and in transgenic mice. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif and transforms gene expression without increasing global m6A levels in mRNAs. The altered substrate specificity is intrinsic to METTL3-METTL14, helping us to propose a structural model for how the METTL3-METTL14 complex selects the cognate RNA sequences for modification. Together, our work highlights that sequence-specific m6A deposition is important for proper function of the modification and that noncanonical methylation events can impact aberrant gene expression and oncogenesis.

biochemistry↗

bioRxiv2023

Evaluating performance and applications of sample-wise cell deconvolution methods on human brain transcriptomic data

Sample-wise deconvolution methods have been developed to estimate cell-type proportions and gene expressions in bulk-tissue samples. However, the performance of these methods and their biological applications has not been evaluated, particularly on human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk-tissue RNAseq, single-cell/nuclei (sc/sn) RNAseq, and immunohistochemistry. A total of 1,130,767 nuclei/cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expression. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk-tissue or single-cell eQTLs alone. Differential gene expression associated with multiple phenotypes were also examined using the deconvoluted data. Our findings, which were replicated in bulk-tissue RNAseq and sc/snRNAseq data, provided new insights into the biological applications of deconvoluted data.

genomics↗

bioRxiv2023

Spatially aware self-representation learning for tissue structure characterization and spatial functional genes identification

Spatially resolved transcriptomics (SRT) enable the comprehensive characterization of transcriptomic profiles in the context of tissue microenvironments. Unveiling spatial transcriptional heterogeneity needs to effectively incorporate spatial information accounting for the substantial spatial correlation of expression measurements. Here, we develop a computational method, SpaSRL (spatially aware self-representation learning), which flexibly enhances and decodes spatial transcriptional signals to simultaneously achieve spatial domain detection and spatial functional genes identification. This novel tunable spatially aware strategy of SpaSRL not only balances spatial and transcriptional coherence for the two tasks, but also can transfer spatial correlation constraint between them based on a unified model. Additionally, this joint analysis by SpaSRL deciphers accurate and fine-grained tissue structures and ensures the effective extraction of biologically informative genes underlying spatial architecture. We verified the superiority of SpaSRL on spatial domain detection, spatial functional genes identification and data denoising using multiple SRT datasets obtained by different platforms and tissue sections. Our results illustrate SpaSRLs utility in flexible integration of spatial information and novel discovery of biological insights from spatial transcriptomic datasets.

bioinformatics↗

bioRxiv2023

An open-source photogrammetry workflow for reconstructing 3D models

Acquiring accurate 3D biological models efficiently and economically is important for morphological data collection and analysis in organismal biology. In recent years, structure-from-motion (SFM) photogrammetry has become increasingly popular in biological research due to its flexibility and being relatively low cost. SFM photogrammetry registers 2D images for reconstructing camera positions as the basis for 3D modeling and texturing. However, most studies of organismal biology still rely on commercial software to reconstruct the 3D model from photographs, which impedes the adoption of this workflow in our field due the blocking issues such as cost and affordability. Also, prior investigations in photogrammetry did not sufficiently assess the geometric accuracy of the models reconstructed. Consequently, this study has two goals. First, we present an affordable and highly flexible structure-from-motion photogrammetry pipeline based on the open-source package OpenDroneMap (ODM) and its user interface WebODM. Second, we assess the geometric accuracy of the photogrammetric models acquired from the ODM pipeline by comparing them to the models acquired via microCT scanning, the de facto method to image skeleton. Our sample comprises fifteen Aplodontia rufa (mountain beaver) skulls. Using models derived from microCT scans of the samples as reference, our results show that the geometry of the models derived from ODM is sufficiently accurate for gross metric and morphometric analysis as the measurement errors are usually around or below 2%, and morphometric analysis captures consistent patterns of shape variations in both modalities. However, subtle but distinct differences between the photogrammetric and microCT-derived 3D models can affect the landmark placement, which in return affect the downstream shape analysis, especially when the variance within a sample is relatively small. At the minimum, we strongly advise not combining 3D models derived from these two modalities for geometric morphometric analysis. Our findings can be indictive of similar issues in other SFM photogrammetry tools since the underlying pipelines are similar. We recommend that users run a pilot test of geometric accuracy before using photogrammetric models for morphometric analysis. For the research community, we provide detailed guidance on using our pipeline for building 3D models from photographs.

evolutionary biology↗

bioRxiv2023

Viruses in deep-sea cold seep sediments harbor diverse survival mechanisms and remain genetically conserved within species

Deep sea cold seep sediments have been discovered to harbor novel, abundant, and diverse bacterial and archaeal viruses. However, little is known about viral genetic features and evolutionary patterns in these environments. Here, we examined the evolutionary ecology of viruses across active and extinct seep stages in the area of Haima cold seeps in the South China Sea. Diverse antiviral defense systems in 487 microbial genomes spanning 43 families inform the dynamics of host-virus interactions. Accordingly, a total of 338 viral operational taxonomic units are identified and linked to 36 bacterial and archaeal phyla. Cold seep viruses are predicted to harbor diverse adaptive strategies to persist in this environment, including counter-defense systems, reverse transcriptases, auxiliary metabolic genes, and alternative genetic code assignments. Extremely low nucleotide diversity is observed in cold seep viral populations, being influenced by factors including microbial host, sediment depth and cold seep stage. Most cold seep viral genes are under strong purifying selection with trajectories that differ depending on whether cold seeps are active or extinct. This work sheds light on the understanding of environmental adaptation mechanisms and evolutionary patterns of viruses in the sub-seafloor biosphere.

microbiology↗

bioRxiv2023

Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.

cell biology↗

bioRxiv2023

Cryo-EM-guided engineering of T-box-tRNA modules with enhanced selectivity and sensitivity in translational regulation

Riboswitches are non-coding RNA elements that play vital roles in regulating gene expression. Their specific ligand-dependent structural reorganization facilitates their use as templates for design of engineered RNA switches for therapeutics, nanotechnology and synthetic biology. T-box riboswitches bind tRNAs to sense aminoacylation and control gene expression via transcription attenuation or translation inhibition. Here we determine the cryo-EM structure of the wild-type Mycobacterium smegmatis ileS T-box in complex with its cognate tRNAIle. This structure shows a very flexible antisequestrator region that tolerates both 3-OH and 2,3-cyclic phosphate modification at the 3 end of tRNAIle. Elongation of one helical turn (11-base pair) in both the tRNA acceptor arm and T-box Stem III maintains T-box-tRNA complex formation and increases the selectivity for tRNA 3 end modification. Moreover, elongation of Stem III results in [~]6-fold tighter binding to tRNA, which leads to increased sensitivity of downstream translational regulation indicated by precedent translation. Our results demonstrate that cryo-EM can guide RNA engineering to design improved riboswitch modules for translational regulation, and potentially a variety of additional functions.

synthetic biology↗

bioRxiv2023

NuSAP participates in metaphase spindle length control in mammalians

Precise chromosome congression and segregation require proper assembly of a steady-state metaphase spindle, which is dynamic and maintained by continuous microtubule flux. NuSAP is a microtubule-stabilizing and -bundling protein that promotes chromosomedependent spindle assembly. However, its function in spindle dynamics remains unclear. Here, we demonstrate that NuSAP regulates the dynamics and length control of the metaphase spindle. Mechanistically, NuSAP facilitates kinetochore capture and spindle assembly via promoting Eg5 binding with microtubules. It also prevents excessive microtubule depolymerization through interacting with Kif2A and reduces its spindle-pole localization. NuSAP is phosphorylated by Aurora A at Ser-240 during mitosis, and this phosphorylation promotes its interaction with Kif2A on the spindle body and reduces its localization to the spindle poles, thus maintaining the proper spindle microtubule flux. NuSAP knockout resulted in shorter spindle formation with faster microtubule flux and chromosome misalignment. Taken together, we uncover that NuSAP participates in spindle assembly, dynamics, and metaphase spindle length control via affecting microtubule flux and Kif2A localization.

cell biology↗

bioRxiv2023

Design, evaluation and implementation of synthetic isopentyldiol pathways in Escherichia coli

Isopentyldiol (IPDO) is an important raw material in cosmetic industry. So far IPDO is exclusively produced through chemical synthesis. Growing interest in natural personal care products has inspired the quest to develop a bio-based process. We previously reported a biosynthetic route that produces IPDO via extending leucine catabolism (route A), the efficiency of which, however, is not satisfactory. To address this issue, we computational designed a novel non-natural IPDO synthesis pathway (Route B) using RetroPath RL, the state of art tool for bio-retrosynthesis based on Artificial Intelligence methods. We compared this new pathway with route A and another two intuitively designed routes for IPDO biosynthesis from various aspects. Route B, which exhibits the highest thermodynamic driving force, least non-native reaction steps and lowest energy requirements appeared to hold the greatest potential for IPDO production. All three newly designed routes were then implemented in E. coli BL21(DE3) strain. Results show that the computationally designed route B can produce 2.2 mg/L IPDO from glucose, whereas no IPDO production from routes C and D. These results highlight the importance and usefulness of in silico design and comprehensive evaluation of the potential efficiencies of candidate pathways in constructing novel non-natural pathways for the production of biochemicals.

bioengineering↗

bioRxiv2023

Lower shear stress exacerbates atherosclerosis by inducing the generation of neutrophil extracellular traps via Piezo1-mediated mechanosensation

BACKGROUNDAtherosclerosis is a chronic lipid-driven inflammatory disease, largely influenced by hemodynamics. Neutrophil extracellular traps (NETs)-mediated inflammation plays an important role in atherosclerosis. However, little is known about the mechanism of the generation of NETs under different shear stress and subsequent damage to endothelial cells. We sought to identify a novel mechanical signal provokes NETs generation and to investigate its potential role in atherosclerosis. METHODSApoE-/- mice were fed with high-fat diet (HFD) to induce atherosclerosis. The model of lower shear stress (LSS) with a partial ligation of the left carotid artery was established to assess the role of LSS in NETs generation and atherosclerotic lesions development. Furthermore, the underlying mechanism of LSS promoting NETs generation and injuring endothelial cells was deciphered in neutrophil-like human promyelocytic leukemia (HL-60) cells in parallel-plate flow chamber. RESULTSWe found that LSS correlated spatially with both NETs and atherosclerosis, while inhibition of NETosis could significantly reduce plaque formation in ApoE-/- mice. In vitro, LSS could promote NETs generation directly through down-regulation of Piezo1, a mechanosensitive ion channel. downexpression of Piezol could activate neutrophils and promote NETosis in static. Conversely, Yoda1-evoked activation of Piezo1 attenuated LSS-induced NETosis. Mechanistically, the downexpression of Piezo1 resulted in decreased Ca2+ influx and increased histone deacetylase 2 (HDAC2), which increase reactive oxygen species levels, then led to NETosis. LSS-induced NETs generation promoted the apoptosis and adherence of endothelial cells. CONCLUSIONSLSS directly promotes NETosis through piezo1-HDAC2 axis in atherosclerosis progression. This study uncovers the essential role of Piezo1-mediated mechanical signaling in NETs generation and plaque formation, which provides a promising therapeutic strategy for atherosclerosis. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/529165v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@583911org.highwire.dtl.DTLVardef@aa3e2org.highwire.dtl.DTLVardef@8d83e5org.highwire.dtl.DTLVardef@ce55a0_HPS_FORMAT_FIGEXP M_FIG C_FIG Proposed mechanism for lower shear stress LSS exacerbating atherosclerosis. LSS stimuli decrease Piezo1 expression in the neutrophils, resulting in decreased intracellular Ca2+ concentration, as well as the higher expression level of HDAC2, which could activate oxidative stress and promote intracellular reactive oxygen species formation, and ultimately lead to NETs generation. NETs could aggravate endothelial cells injury and exasperate atherosclerosis. Highlights{blacksquare} Lower shear stress (LSS) promotes Neutrophil extracellular traps (NETs) formation, which is critical for lipid deposits and plaque formation in Atherosclerosis. {blacksquare}Atherosclerotic plaque formation was significantly reduced in the aorta of high fat diet fed ApoE-/- mice intraperitoneal injected with NETs inhibitor, GSK484, especially in the lower shear stress regions. {blacksquare}Piezo1 is a key molecule in the process of neutrophils sense lower shear stress. {blacksquare}lower shear stress inhibits the activation of Piezo1 and promotes NETosis through piezo1-HDAC2 axis. {blacksquare}LSS-induced NETs promote the apoptosis and adhesion of endothelial cells.

cell biology↗

bioRxiv2023

A novel order-level lineage of ammonia-oxidizing Thaumarchaeota is widespread in marine and terrestrial environments

Ammonia-oxidizing archaea (AOA) are among the most ubiquitous and abundant groups of Archaea on Earth, widely distributed in marine, terrestrial, and geothermal ecosystems. However, the genomic diversity, biogeography, and evolutionary process of AOA populations in subsurface environments are vastly understudied compared to those of marine and soil AOA. We here report a novel AOA order Candidatus Nitrosomirales that forms a deeply branching basal sister lineage to the thermophilic Ca. Nitrosocaldales. Metagenomic and 16S rRNA gene read mapping demonstrates the dominant presence of Nitrosomirales AOA in various groundwater environments and their widespread distribution across a range of geothermal, terrestrial, and marine habitats. Notably, terrestrial Nitrosomirales AOA show the genetic capacity of using formate as an alternative source of reductant and appear to have acquired key metabolic genes and operons from other mesophilic populations via horizontal gene transfer, including the genes encoding urease, nitrite reductase, and V-type ATPase. Potential metabolic versatility and acquired functions may facilitate their radiation into a variety of subsurface, marine, and soil environments. Molecular thermometer-based evolutionary analysis suggests that Nitrosomirales originated from thermophilic environments and transitioned into temperate habitats in parallel with Nitrososphaerales and Nitrosopumilales. We also provide evidence that terrestrial-marine habitat transitions occurred within each one of the four AOA orders, which reveals a more complex evolutionary trajectory of major AOA lineages than previously proposed. Together, these findings establish a robust taxonomic and evolutionary framework of AOA and provide new insights into the ecology and evolution of this globally abundant functional guild.

microbiology↗

bioRxiv2023

DNA 5-methylcytosine regulates genome-wide formation of G-quadruplex structures

G-quadruplex structures (G4s) have been identified in genomes of multiple organisms and proven to play important epigenetic regulatory roles in various cellular functions. However, the G4 formation mechanism remains largely unknown. Here, we found a negative correlation between DNA 5mC methylation and G4 abundance. The abundance of genomic G4s significantly increased when the whole-genome methylation level was reduced in DNMT1-knockout cells. This increase was then suppressed by DNMT1 over-expression. And more G4s were detected in the hypomethylated cancer cell line HepG2 and rectal cancer tissues. Besides, 5mC modification significantly inhibited G4 formation of the potential G-quadruplex sequences (PQSs). The transcription of genes with 5mC modification sites in their promoter PQSs was affected after treatment with G4 stabilizer pyridostatin or methylation inhibitor 5-aza-dC. The global reduction of genomic methylation elevates gene transcription levels through increased G4s. Taken together, DNA 5mC methylation prevents PQSs from folding into G4s in genomes.

molecular biology↗

bioRxiv2023

High-fidelity Database-free Deep Learning Reconstruction for Real-time Cine Cardiac MRI

Real-time cine cardiac MRI provides an ECG-free free-breathing alternative to clinical gold-standard ECG-gated breath-hold segmented cine MRI for evaluation of heart function. Real-time cine MRI data acquisition during free breathing snapshot imaging enables imaging of patient cohorts that cannot be imaged with segmented or breath-hold acquisitions, but requires rapid imaging to achieve sufficient spatial-temporal resolutions. However, at high acceleration rates, conventional reconstruction techniques suffer from residual aliasing and temporal blurring, including advanced methods such as compressed sensing with radial trajectories. Recently, deep learning (DL) reconstruction has emerged as a powerful tool in MRI. However, its utility for free-breathing real-time cine MRI has been limited, as database-learning of spatio-temporal correlations with varying breathing and cardiac motion patterns across subjects has been challenging. Zero-shot self-supervised physics-guided deep learning (PG-DL) reconstruction has been proposed to overcome such challenges of database training by enabling subject-specific training. In this work, we adapt zeroshot PG-DL for real-time cine MRI with a spatio-temporal regularization. We compare our method to TGRAPPA, locally low-rank (LLR) regularized reconstruction and database-trained PG-DL reconstruction, both for retrospectively and prospectively accelerated datasets. Results on highly accelerated real-time Cartesian cine MRI show that the proposed method outperforms other reconstruction methods, both visibly in terms of noise and aliasing, and quantitatively.

bioengineering↗

bioRxiv2023

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification

NAT10 is dysregulated and plays an essential role in various types of cancers. However, the exact machenism of how NAT10 regulates cancer progression remains debatable. In this report, we show that NAT10 affects tumorigeneis mainly based on its acetylation function on tRNA. In addition, we found NAT10 regulate the ac4C of tRNA in cancer via interaction with RNPS1, which in turn protect NAT10 from degradation by E3 ubiquitin ligase ZSWIM6. We developed TRMC-seq method to compreshensively profile tRNA ac4C sites and uncovered the presence of ac4C in a broader range of tRNA isoacceptors than previous studies. Multi-omics analysis identified AP-1 signaling pathway as a major downstream mediator of NAT10. Mechanistically, we found NAT10 is responsible for the translation efficiency genes which contain higher ac4C-tRNA codon. Importantly, our genetic mouse model validated our in vitro findings of NAT10 in cancer. Our study highlights a role of NAT10 in mediating tRNA ac4C to regulate the translation and tumorigenesis of cancer.

molecular biology↗

bioRxiv2023

Duck pan-genome reveals two transposon-derived structural variations caused bodyweight enlarging and white plumage phenotype formation during evolution

Structural variations (SVs) are a major source of domestication and improvement traits, however SV profiles of duck and their phenotypic impacts largely hidden. We present the first duck pan-genome constructed using five genome assemblies capturing [~]40.98 Mb new sequences. This pan-genome together with high-depth sequencing data ([~]46.5X) identified 101,041 SVs, of which substantial proportions were derived from transposable element (TE) activity. Many TE-derived SVs anchoring in a gene body or regulatory region are linked to ducks domestication and improvement. By combining quantitative genetics with molecular experiments, we dissect how TE-derived SVs change gene expression of IGF2BP1 and generate a novel transcript of MITF, shaping bodyweight and white plumage. In the IGF2BP1 locus, the TE-derived SV explains the largest effect on bodyweight among avian species (27.61% of phenotypic variation). Our findings highlight the importance of using a pan-genome as a reference in genomics studies and explore the roles of TE-derived SVs in trait formation and in livestock breeding.

genetics↗

bioRxiv2023

Single-cell transcriptomic landscape deciphers novel olfactory neuroblastoma subtypes and intratumoral heterogeneity

Olfactory neuroblastoma (ONB) is an uncommon malignant tumor known to originate from the olfactory epithelial. The complex tumor ecosystem of this pathology remained unclear. Here, we explored the cellular components with ONB tumors based on scRNA profiles of 96,325 single-cells derived from 10 tumors and 1 olfactory mucosa sample. We discovered 11 major cell types, including 6 immune cell, 3 stromal cell subtypes and epithelial cluster in the tumor microenvironment (TME), and identified 5 common expression programs from malignant epithelial cells. We analyzed subclusters of TME and the interactions among different cell types in the TME. An innovative three-classification of ONB was established via scRNA analysis. Markers for categorizing tumor samples into new subtypes were elucidated. Different responses towards certain chemotherapy regimens could be inferred according to the molecular features of three tumor types. Relative abundance of immunosuppressive TAMs indicated the benefits of immunotherapies targeting myeloid cells.

cancer biology↗

bioRxiv2023

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

Cerebral ischaemia-reperfusion injury, during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RBP interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA-miRNA-mRNA ceRNA mechanism and that 3UTR methylation of mRNAs can hinder miRNA-mRNA binding. Three methylation patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA methylation and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

neuroscience↗

bioRxiv2023

Engineering synthetic CopT/A-based genetic circuits for miRNA imaging and functional gene regulation

Synthetic genetic circuits that can operate at the transcriptional and translation levels have been widely applied in the control of cellular behaviors and functions. However, the regulation of genetic circuits is often accompanied by the introduction of exogenous substances or the endogenous generation of inhibitory products, which would bring uncontrollable hazards for biological safety and reduce the efficiency of the system. Here, we described a miRNA-responsive CopT-CopA (miCop) genetic circuit system to realize real-time monitoring the intracellular expression of miRNA-124a during neurogenesis or miRNA-122 under the stimulation of extracellular drugs in living cells and animals. Furthermore, to prove the modularity of the system, we engineered this mipCop to tune the expression of DTA (diphtheria toxin A) gene, and showed the powerful capacity of killing cancer cells by inducing apoptosis and cell cycle arrest based on miRNA response. This study provides an effective means to couple miRNA sensing with miRNA-responsive gene modulation, which may open up new diagnostic or therapeutic applications.

synthetic biology↗