Biology subjects

Jiang, L.

Publications and source records attributed to Jiang, L..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease

To understand dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune and clinical markers of microbiomes from four body sites in 86 participants over six years. We found that microbiome stability and individuality are body-site-specific and heavily influenced by the host. The stool and oral microbiome were more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. Also, we identified individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlated across body sites, suggesting systemic coordination influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals showed altered microbial stability and associations between microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease. Study HighlightsO_LIThe stability of the human microbiome varies among individuals and body sites. C_LIO_LIHighly individualized microbial genera are more stable over time. C_LIO_LIAt each of the four body sites, systematic interactions between the environment, the host and bacteria can be detected. C_LIO_LIIndividuals with insulin resistance have lower microbiome stability, a more diversified skin microbiome, and significantly altered host-microbiome interactions. C_LI

microbiology↗

bioRxiv2024

Systematic reconstruction of molecular pathway signatures using scalable single-cell perturbation screens

Recent advancements in functional genomics have provided an unprecedented ability to measure diverse molecular modalities, but learning causal regulatory relationships from observational data remains challenging. Here, we leverage pooled genetic screens and single cell sequencing (i.e. Perturb-seq) to systematically identify the targets of signaling regulators in diverse biological contexts. We demonstrate how Perturb-seq is compatible with recent and commercially available advances in combinatorial indexing and next-generation sequencing, and perform more than 1,500 perturbations split across six cell lines and five biological signaling contexts. We introduce an improved computational framework (Mixscale) to address cellular variation in perturbation efficiency, alongside optimized statistical methods to learn differentially expressed gene lists and conserved molecular signatures. Finally, we demonstrate how our Perturb-seq derived gene lists can be used to precisely infer changes in signaling pathway activation for in-vivo and in-situ samples. Our work enhances our understanding of signaling regulators and their targets, and lays a computational framework towards the data-driven inference of an atlas of perturbation signatures.

genomics↗

bioRxiv2023

Inhibition of KLK8 promotes pulmonary endothelial repair by restoring VE-cadherin/Akt/FOXM1 pathway

The tissue kallikrein-related peptidases (KLKs) are secreted serine proteases deeply involved in angiogenesis. However, whether KLKs are involved in the regulation of endothelial regeneration during sepsis remains unknown. By comparing the mRNA levels of 15 KLKs, we found that KLK8 was the highest induced KLK member in lung tissues or primary isolated mouse lung vascular endothelial cells (MLVECs) exposed to lipopolysaccharide (LPS). Adenovirus-mediated overexpression of KLK8 caused endothelial hyperpermeability both in vitro and in vivo. Inhibition of KLK8, by either gene knockout or KLK8 neutralizing antibodies, alleviated sepsis-induced endothelial hyperpermeability, acute lung injury and mortality. Mechanistically, transcription profiling of KLK8-overexpressed endothelial cells revealed a central role of forkhead box M1 (FOXM1) downregulation in mediating the pro-injury and anti-proliferation effects of KLK8. KLK8 cleaved VE-cadherin and consequently suppressed FOXM1 expression by inactivation of the VE-cadherin/Akt pathway. KLK8 deficiency or blockade rescued VE-cadherin/Akt/FOXM1 pathway, thus promoting endothelium regeneration. This study reveals a critical role for KLK8-induced inactivation of VE-cadherin/Akt/FOXM1 pathway in mediating the impairment of endothelial regeneration and the consequent lung vascular leakiness in response to sepsis. HighlightsO_LIUpregulated KLK8 mediates lung endothelial barrier dysfunction during sepsis C_LIO_LIKLK8 inactivates VE-cadherin/Akt/FOXM1, thus impairing endothelium regeneration C_LIO_LIKLK8 deficiency or blockade rescues VE-cadherin/Akt/FOXM1 signaling pathway C_LIO_LIKLK8 deficiency or blockade promotes endothelium regeneration during sepsis C_LIO_LIKLK8 deficiency or blockade attenuates sepsis-induced acute lung injury and mortality C_LI

physiology↗

bioRxiv2023

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

cancer biology↗

bioRxiv2023

Regulated Cleavage and Relocation of FERONIA Control Immunity in Arabidopsis Roots

Plant roots exhibit localized immunity (LI) specifically in the root cap and transition/elongation zone (TZ/EZ). Such immunity relies on receptor-like kinases localized at the plasma membrane (PM), which are essential for plant response to bacteria in the rhizosphere. Here, we identified a new mechanism of action for receptor kinase FERONIA (FER) in LI. In the absence of bacterial stimuli, FER is localized to the PM, maintaining plant growth. When confronted with bacterial colonization, RALF23 peptide hyper-accumulates in TZ/EZ cells and activates a metalloproteinase that cleaves FER and transfer the cytosolic kinase domain into the nucleus. The nucleus-localized kinase domain of FER contributes to LI by reducing bacterial abundance at TZ/EZ. Thus, this work uncovered a unique mechanism by which a single receptor kinase acts in two molecular forms and two distinct subcellular locations to balance growth and immunity. One Sentence SummaryBacteria induces the cleavage of FER via At2-MMP to trigger a localized immunity around TZ and EZ of Arabidopsis roots.

plant biology↗

bioRxiv2023

Population genetic analyses of longitudinal vaginal microbiome reveal racioethnic evolutionary dynamics and prevailing positive selection of Lactobacillus adhesins

The vaginal microbiome is important for reproductive health and should constantly evolve in response to dynamic host-microbe interactions. The composition of the vaginal microbiome is associated with ethnicity; however, the evolutionary landscape of the vaginal microbiome, especially in the multi-ethnic context, remains under-studied. In this study, we performed a longitudinal evolutionary vaginal microbiome analysis of 351 samples from 35 pregnant women with diverse ethnic backgrounds and validated the main findings in two cohorts totaling 462 samples from 90 multi-ethnic women. Microbiome alpha diversity and community states showed strong ethnic signatures. Lactobacillaceae species had a significantly higher nonsynonymous/synonymous mutation ratio (pN/pS) than non-Lactobacillaceae species in all ethnicities. In addition, non-Lactobacillaceae anaerobic bacteria were enriched in Black and Latino women, with significantly elevated nucleotide diversity and lower pN/pS in Black women. Intriguingly, the Lactobacillaceae species had a large repertoire of positively selected genes, including the human mucin-binding and bacterial cell wall anchor genes, which showed independent, recurrent signatures of positive selection across multiple strains, indicating that the host-microbiome interactions directly drive microbial evolution at the molecular interface. Finally, we propose that the evolutionary metrics reflect the environmental niches of adapting microbes. Our study revealed the extensive ethnic signatures in vaginal microbial diversity, composition, community state, and evolutionary dynamics at species and gene levels, highlighting the importance of studying the host-microbiome ecosystem from an evolutionary perspective. HighlightsO_LIExtensive ethnic signatures in the vaginal microbial diversity, composition, community state, and evolutionary dynamics were demonstrated. C_LIO_LIHealthy Lactobacillaceae species showed lower nucleotide diversity but much more relaxed or even positive selection of genes than non-Lactobacillaceae species. C_LIO_LIIn Black women, non-Lactobacillaceae species displayed higher nucleotide diversity and more stringent negative selection. C_LIO_LILactobacillus mucin-binding and cell wall anchor genes showed convergent signatures of positive selection across vaginal microbiomes. C_LI

microbiology↗

bioRxiv2023

An axonemal intron splicing program sustains Plasmodium male development

Differentiation of male gametocyte into flagellated fertile male gamete relies on the axoneme assembly, a major component of male development for mosquito transmission of malaria parasite. RNA-binding protein (RBP)-mediated post-transcription regulation plays important roles in eukaryotic sexual development, including the Plasmodium female development. However, the role of RBP in defining the Plasmodium male transcriptome and its function in the male gametogenesis remain elusive. Here, we screened the gender expression of the genome-wide RBPs and identified an undescribed male-specific RBP gene Rbpm1 in the Plasmodium. RBPm1 is localized in the nucleus of male gametocytes. RBPm1-deficient parasites fail to assemble the axoneme for male gametogenesis and thus mosquito transmission. RBPm1 interacts with spliceosome E complex and regulates splicing initiation of certain introns in a group of 26 axonemal genes. RBPm1 deficiency results in intron retention and protein loss of these axonemal genes. Intron deletion restores axonemal proteins expression and partially rectifies axonemal defects in RBPm1-null gametocytes. Further splicing assays in both reporter and endogenous genes exhibit stringent recognition of the axonemal introns by RBPm1. Therefore, the splicing activator RBPm1 and its target introns constitute an axonemal intron splicing program in the post-transcription regulation essential for Plasmodium male development.

microbiology↗

bioRxiv2023

From sensory to perceptual manifold: the twist of neural geometry

Classification constitutes a core cognitive challenge for both biological and artificial intelligence systems, with many tasks potentially reducible to classification problems. Here we investigated how the brain categorizes stimuli that are not linearly separable in the physical world by analyzing the geometry of neural manifolds in high-dimensional neural space, formed by macaques V2 neurons during a classification task on the orientations of motion-induced illusory contours. We identified two related but distinct neural manifolds in this high-dimensional neural space: the sensory and perceptual manifolds. The sensory manifold was embedded in a 3-D subspace defined by three stimulus features, where contour orientations remained linearly inseparable. However, through a series of geometric transformations equivalent to twist operations, this 3-D sensory manifold evolved into a 7-D perceptual manifold with four additional axes, enabling the linear separability of contour orientations. Both formal proof and computational modeling revealed that this dimension expansion was facilitated by nonlinear mixed selectivity neurons exhibiting heterogeneous response profiles. These findings provide insights into the mechanisms by which biological neural networks increase the dimensionality of representational spaces, illustrating how perception arises from sensation through the lens of neural geometry.

neuroscience↗

bioRxiv2023

A redundant chloroplast protein is co-opted by potyvirids as the scaffold protein to mediate viral intercellular movement complex assembly

For viruses in the family Potyviridae (potyvirids), three virus-encoded proteins (P3N-PIPO, CI and CP) and several host components are known to coordinately regulate viral cell-to-cell movement. Here, we found that HCPro2 encoded by areca palm necrotic ring spot virus is involved in the intercellular movement, which could be functionally complemented by its counterpart HCPro from a potyvirus. The affinity purification and mass spectrum analysis identified several viral factors (including CI and CP) and a variety of host proteins that physically associate with HCPro2. We demonstrated that HCPro2 interacts with either CI or CP in planta, and the three form plasmodesmata (PD)-localized interactive complex in viral infection. Further, we screened HCPro2-associating host proteins, and identified a common host protein RbCS that mediates the interactions of HCPro2-CI, HCPro2-CP and CI-CP among the complex. Knockdown of NbRbCS simultaneously impairs the interactions of HCPro2-CI, HCPro2-CP and CI-CP, and significantly attenuates the intercellular movement and systemic infection for ANRSV and other three tested potyvirids. This study highlights that a nucleus-encoded chloroplast-targeted protein is hijacked by potyvirids as the scaffold protein to mediate the assembly of viral intercellular movement complex to promote viral infection.

microbiology↗

bioRxiv2023

Progressive community, biogeochemical and evolutionary remodeling of the soil microbiome underpins long-term desert ecosystem restoration

Ecological restoration of degraded lands is essential to human sustainability. Yet, an in-depth community, functional, and evolutionary microbial perspective of long-term restoration of damaged ecosystems is lacking. Herein, we comprehensively assessed the impact of long-term (up to 17 years) restoration of Tengger Desert, China, by multi-omic profiling of 1,910 topsoil samples. The soil biophysiochemical properties, especially soil hydraulics, microbiome stability, and functional diversity, significantly improved during restoration. The soil microbiome transitioned from an extreme oligotrophic and autotrophic community to a diverse copiotrophic ecosystem. The soil microbiota, including fungi, could mediate the soil physicochemical changes through metabolites. Importantly, the systematic rewiring of nutrient cycles featured the multi-domain preference of an efficient carbon fixation strategy in the extreme desert environment. Finally, the microbiome was evolving via positive selections of genes of biogeochemical cycles, resistance, and motility. In summary, we present a comprehensive community, functional, biogeochemical, and evolutionary landscape of the soil microbiome during the long-term restoration of desert environments. We highlight the crucial microbial role in restoration from soil hydraulic and biogeochemical perspectives, offering promising field applications. HighlightsO_LIThe desert soil microbiome transformed from simple oligotrophic to a diverse, stable, and nutrient-rich ecosystem with expanded functional diversity. C_LIO_LIRestoration led to systematically rewired biogeochemical cycles, which are highly efficient in carbon fixation in the desert environment. C_LIO_LIThe microbiome was evolving via positive selections of genes involved in biogeochemical cycles and environmental adaptations. C_LIO_LIMicrobes and metabolites could facilitate desert restoration from hydraulic and biogeochemical aspects, offering promising field applications. C_LI

microbiology↗

bioRxiv2023

PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hy-pertension

Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. PAI1-/- male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.

cell biology↗

bioRxiv2023

Mapping the developmental potential of mouse inner ear organoids at single-cell resolution

Inner ear organoids recapitulate development and are intended to generate cell types of the otic lineage for applications such as basic science research and cell replacement strategies. Here, we use single-cell sequencing to study the cellular heterogeneity of late-stage mouse inner ear organoid sensory epithelia, which we validated by comparison with data sets of the mouse cochlea and vestibular epithelia. We resolved supporting cell sub-types, cochlear like hair cells, and vestibular Type I and Type II like hair cells. While cochlear like hair cells aligned best with an outer hair cell trajectory, vestibular like hair cells followed developmental trajectories similar to in vivo programs branching into Type II and then Type I extrastriolar hair cells. These results highlight the transcriptional accuracy of the organoid developmental program but will also inform future strategies to improve synaptic connectivity and regional specification.

developmental biology↗

bioRxiv2023

Reply to: Contribution of carbon inputs to soil carbon accumulation cannot be neglected

In the accompanying Comment1, He et al. argue that the determinant role of microbial carbon use efficiency in global soil organic carbon (SOC) storage shown in Tao et al. (2023)2 was overestimated because carbon inputs were neglected in our data analysis while they suggest that our model-based analysis could be biased and model-dependent. Their argument is based on a different choice of independent variables in the data analysis and a sensitivity analysis of two process-based models other than that used in our study. We agree that both carbon inputs and outputs (as mediated by microbial processes) matter when predicting SOC storage - the question is their relative contributions. While we encourage further studies to examine how the evaluation of the relative importance of CUE to global SOC storage may vary with different model structures, He et al.s claims about Tao et al. (2023) need to be taken as an alternative, unproven hypothesis until empirical data support their specific parameterization. Here we show that an additional literature assessment of global data does not support He et al.s argument, in contrast to our study, and that further study on this topic is essential.

ecology↗

bioRxiv2023

PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation

Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by herbal medicines. Previously, we found that proline-serine-threonine phosphatase interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) play important roles in kidney injury and immune defense, respectively; however, the mechanism of AAN regulation by PSTPIP2 and NETs remains unclear. We found that renal tubular epithelial cell (RTEC) apoptosis, neutrophil infiltration, and inflammatory factor and NET production were increased in a mouse model of AAN, while PSTPIP2 expression was low. Conditional knock-in of PSTPIP2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. In contrast, restoring normal PSTPIP2 expression promoted kidney injury. In vivo, the use of Ly6G-neutralizing antibody to remove neutrophils and peptidyl arginine deiminase 4 (PAD4) inhibitors to prevent NET formation reduced apoptosis, thereby alleviating kidney injury. In vitro, damaged RTECs released interleukin-19 (IL-19) via the PSTPIP2/nuclear factor (NF)-{kappa}B pathway and induced NET formation via the IL-20R{beta} receptor. Concurrently, NETs promoted the apoptosis of damaged RTECs. PSTPIP2 affected NET formation by regulating IL-19 expression via inhibition of NF-{kappa}B pathway activation in RTECs, inhibiting their apoptosis and reducing kidney damage.

pharmacology and toxicology↗

bioRxiv2023

Loss of the mitochondrial citrate carrier, SLC25A1/CIC disrupts embryogenesis via 2-Hydroxyglutarate

Germline inactivating mutations of the SLC25A1 gene contribute to various human developmental disorders, including combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic syndrome characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 deficiency leads to this disease and the role of 2HG are unclear and no therapies exist. We now show that mice lacking both Slc25a1 alleles display a spectrum of alterations that resemble human D/L-2HGA. Mechanistically, SLC25A1 loss results in a proliferation defect and activates two distinct senescence pathways, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), both involving the p53 tumor suppressor and driven by two discernible signals: the accumulation of 2HG, inducing OIS, and mitochondrial dysfunction, triggering MiDAS. Inhibiting these senescence programs or blocking p53 activity reverses the growth defect caused by SLC25A1 dysfunction and restores proliferation. These findings reveal novel pathogenic roles of senescence in human disorders and suggest potential strategies to correct the molecular alterations caused by SLC25A1 loss.

developmental biology↗

bioRxiv2023

Breakthrough infection elicits hypermutated IGHV3-53/3-66 public antibodies with broad and potent neutralizing activity against SARS-CoV-2 variants including BQ and XBB lineages

The rapid emergence of SARS-CoV-2 variants of concern (VOCs) calls for efforts to study broadly neutralizing antibodies elicited by infection or vaccination so as to inform the development of vaccines and antibody therapeutics with broad protection. Here, we identified two convalescents of breakthrough infection with relatively high neutralizing titers against all tested viruses including BQ and XBB lineages. Among 50 spike-specific monoclonal antibodies (mAbs) cloned from their B cells, the top 6 neutralizing mAbs (KXD01-06) belong to previously defined IGHV3-53/3-66 public antibodies. Although most antibodies in this class are dramatically escaped by VOCs, KXD01-06 exhibit broad neutralizing capacity with the IC50s of KXD01 ranging from 0.011[~]0.059g/ml. Deep mutational scanning reveals that KXD01-06 target highly conserved sites on RBD including D420, Y421, L455, F456, A475 and N487. Genetic and functional analysis further indicates that the extent of somatic hypermutation is critical for the breadth of IGHV3-53/3-66 public antibodies. Overall, we discovered and characterized IGHV3-53/3-66 public antibodies with broad and potent neutralizing activity against SARS-CoV-2, which provides rationale for novel vaccines and antibody therapeutics based on this class of antibodies.

immunology↗

bioRxiv2023

DNA Storage Designer: A practical and holistic design platform for storing digital information in DNA sequence

DNA molecules, as natural information carriers, have several benefits over conventional digital storage mediums, including high information density and long-term durability. It is expected to be a promising candidate for information storage. However, despite significant research in this field, the pace of development has been slow due to the lack of complete encoding-decoding platform and simulaton-evaluation system. And the mutation in DNA sequences during synthesis and sequencing requires multiple experiments, and wet experiments can be costly. Thus, a silicon-based simulation platform is urgently needed for promoting research. Therefore, we proposed DNA Storage Designer, the first online platform to simulate the whole process of DNA storage experiments. Our platform offers classical and novel technologies and experimental settings that simulate three key processes: encoding, error simulation, and decoding for DNA storage system. Fisrt, 8 mainstream encoding methods were embedded in the encoding process to convert files to DNA sequences. Secondly, to uncover potential mutations and sequence distribution changes in actual experiments we integrate the simulation setting for five typical experiment sub-processes (synthesis, decay, PCR, sampling, and sequencing) in the error simulation stage. Finally, the corresponding decoding process realizes the conversion of DNA sequence to binary sequence. All the above simulation processes correspond to an analysis report will provide guides for better experiment design for researchers convenience. In short, DNA Storage Designer is an easy-to-use and automatic web-server for simulating DNA storage experiments, which could advance the development of DNA storage-related research. And it is freely available for all users at: https://dmci.xmu.edu.cn/dna/. Author summaryDNA storage technology is an emerging and promising storage technology. At the same time, DNA storage is an interdisciplinary technology that requires researchers to know both computer cryptography and biological experiments knowledge. However, DNA storage experiments are costly and lengthy, many studies have been prevented by the lack of a comprehensive design and evaluation platform to guide DNA storage experiments. Herein, we introduce DNA Storage Designer, the first integrated and practical web server for providing the simulation of the whole process of DNA storage application, from encoding, error simulation during preservation, to decoding. In the encoding process, we not only provided the coding DNA sequences but also analyzed the sequence stability. In the error simulation process, we simulated as many experimental situations as possible, such as different mutation probabilities of DNA sequences due to being stored in different bacteria hosts or different sequencing platforms. The platform provides high freedom in that users could not only encode their files and conduct the entire operation but also could upload FASTA files and only simulate the sustaining process of sequences and imitate the mutation errors together with distribution changes of sequences.

bioinformatics↗

bioRxiv2023

Single-cell landscape reveals NAMPT mediated macrophage polarization that regulate smooth muscle cell phenotypic switch in pulmonary arterial hypertension

RationalePulmonary arterial hypertension (PAH) is a progressive and lethal disease that leads to elevated pulmonary vascular resistance and right ventricular failure. The phenotypic switching of pulmonary arterial smooth muscle cells (SMCs) plays a crucial role in the pathological progression of PAH. However, the underlying mechanism of SMC phenotypic modulation remains unclear. ObjectivesWe aim to provide a comprehensive understanding of SMC phenotypes and regulatory networks by analyzing hypertensive and non-diseased pulmonary arteries. MethodsWe performed single-cell RNA sequencing (scRNA-seq) on pulmonary arteries obtained from patients with PAH and healthy donors. This was followed by bioinformatics analyses, mouse models, and in vitro studies to construct a normal pulmonary artery atlas, characterize SMC phenotypes, investigate intercellular communication, and explore the molecular mechanisms underlying SMC phenotypic switching. Measurements and Main ResultsOur scRNA-seq analysis identified specific activation of vascular cells, including myofibrocytes, macrophage M2 polarization, endothelial-mesenchymal transition, and chondroid-like SMCs in healthy pulmonary arteries. In PAH pathology, there was an enhanced phenotypic switch of SMCs from contractile to fibroblast-like. Intercellular communication revealed increased M1 macrophage-SMC crosstalk in PAH, which was facilitated by NAMPT. Using a cellular co-culture system, we found that NAMPT-mediated M1 macrophage polarization induced fibroblast-like phenotypic switching in SMCs via the CCR2/CCR5 axis. ConclusionsOur findings provide a comprehensive cell atlas of healthy human pulmonary arteries and demonstrate that NAMPT-driven M1 macrophage polarization plays a critical role in the fibroblast-like phenotypic switching of SMCs through CCR2/CCR5 cellular crosstalk in PAH.

molecular biology↗