Biology subjects

Zheng, X.

Publications and source records attributed to Zheng, X..

At least 199 records · Page 11Linked to original sources

bioRxiv2022

Following cell type transitions in space and time by combining live-cell tracking and endpoint cell identity in intestinal organoids

Elucidating the dynamics of cellular differentiation in space and time is key to advancing organoid biology and technology. Direct visualization of differentiation patterns is challenging, however, in part because of the difficulty of simultaneously detecting all relevant cell types by fluorescence imaging. Here we present TypeTracker, which determines the differentiation trajectories of all cells within a region of interest, including their type transitions, growth, divisions, and changes in spatial organization. We show how the lineage tree topology, as determined by automated cell tracking, allows for the retrospective identification of cell types across multiple generations. The data revealed various surprising aspects of intestinal organoid differentiation, including symmetric fate adoption by sister cells, cell type abundance regulated by division, and type commitment of cells occurring prior to their spatial reorganization. Our method can be applied broadly to study other organoid systems and to screen for compounds that affect differentiation programs.

biophysics↗

bioRxiv2022

The Arabidopsis D27like1 is a novel Isomerase that Contributes to SL Biosynthesis and Negatively Impacts ABA Level

The enzyme DWARF27 (D27) catalyzes the reversible isomerization of all-trans- into 9-cis-{beta}-carotene, initiating strigolactone (SL) biosynthesis. Genomes of higher plants encode two D27-homologs, D27-like1 and -like2, with unknown functions. Here, we investigated the enzymatic activity and biological function of the Arabidopsis D27-like1. In vitro enzymatic assays and Expression in Synechocystis sp. PCC6803 revealed a yet not reported 13-cis/15-cis/9-cis- and a 9-cis/all-trans-{beta}-carotene isomerization. Although disruption of AtD27-like1 did not cause SL deficiency phenotypes, overexpression of AtD27-like1 in the Atd27 mutant restored the more-branching phenotype, indicating a contribution of AtD27-like1 to SL biosynthesis. Accordingly, generated Atd27 Atd27like1 double mutants showed more pronounced branching phenotype, compared to Atd27. The contribution of AtD27-like1 to SL biosynthesis is likely due to its formation of 9-cis-{beta}-carotene that was present at higher levels in AtD27-like1 overexpressing lines. In contrast, AtD27-like1 expression correlated negatively with the content of 9-cis-violaxanthin, a precursor of abscisic acid (ABA), in shoots. Consistently, ABA levels were higher in shoots and also in dry seeds of the Atd27like1 and Atd27 Atd27like1 mutants. Transgenic lines expressing {beta}-glucuronidase (GUS) driven by the AtD27LIKE1 promoter and transcript analysis performed with hormone-treated Arabidopsis seedlings unraveled that AtD27LIKE1 is expressed in different tissues and regulated ABA and auxin. Taken together, our work revealed a cis/cis-{beta}-carotene isomerase activity that affects the content of both cis-carotenoid derived plant hormones ABA and SLs.

plant biology↗

bioRxiv2022

Development and application of an uncapped mRNA platform

A novel uncapped mRNA platform was developed. Five lipid nanoparticle (LNP)-encapsulated mRNA constructs were made to evaluate several aspects of our platform, including transfection efficiency and durability in vitro and in vivo and the activation of humoral and cellular immunity in several animal models. The constructs were eGFP-mRNA-LNP (for enhanced green fluorescence mRNA), Fluc-mRNA-LNP (for firefly luciferase mRNA), S{delta}T-mRNA-LNP (for Delta strain SARS-CoV-2 spike protein trimer mRNA), gDED-mRNA-LNP (for truncated glycoprotein D mRNA coding ectodomain from herpes simplex virus type 2 (HSV2)) and gDFR-mRNA-LNP (for truncated HSV2 glycoprotein D mRNA coding amino acids 1[~]400). Quantifiable target protein expression was achieved in vitro and in vivo with eGFP-and Fluc-mRNA-LNP. S{delta}T-mRNA-LNP, gDED-mRNA-LNP and gDFR-mRNA-LNP induced both humoral and cellular immune responses comparable to those obtained by previously reported capped mRNA-LNP constructs. Notably, S{delta}T-mRNA-LNP elicited neutralizing antibodies in hamsters against the Omicron and Delta strains. Additionally, gDED-mRNA-LNP and gDFR-mRNA-LNP induced potent neutralizing antibodies in rabbits and mice. The mRNA constructs with uridine triphosphate (UTP) outperformed those with N1-methylpseudouridine triphosphate (N1m{psi}TP) in the induction of antibodies via S{delta}T-mRNA-LNP. Our uncapped, process-simplified, and economical mRNA platform may have broad utility in vaccines and protein replacement drugs.

bioengineering↗

bioRxiv2022

The right inferior frontal gyrus as pivotal node and effective regulator of the basal ganglia-thalamocortical response inhibition circuit in humans

The involvement of specific basal ganglia-thalamocortical circuits in response inhibition has been extensively mapped in the last few decades. However, the pivotal brain nodes and directed casual regulation within this inhibitory circuit in humans remains controversial. Here, we capitalize on recent progress in robust and biologically plausible directed causal modelling (DCM-PEB) and a large fMRI response inhibition dataset (n=218) to determine key nodes, their causal regulation and modulation via biological variables (sex) and inhibitory performance in the inhibitory control circuit encompassing the right inferior frontal gyrus (rIFG), caudate nucleus (rCau), globus pallidum (rGP) and thalamus (rThal).The entire neural circuit exhibited high intrinsic connectivity and an increasing rIFG inflow and its causal regulation over the rCau and rThal during response inhibition. In addition, sex and behavioral performance influenced the architecture of the regulatory circuits such that women displayed increased rThal self-inhibition and decreased rThal to GP modulation, while better inhibitory performance was associated with stronger rThal to rIFG communication. Furthermore, control analyses did not reveal a similar key communication in a left lateralized model. Together these findings indicate a pivotal role of the rIFG as input and causal regulator of subcortical response inhibition nodes.

neuroscience↗

bioRxiv2022

Opposing associations of Internet Use Disorder symptom domains with structural and functional organization of the striatum: a dimensional neuroimaging approach

BackgroundAccumulating evidence suggests brain structural and functional alterations in Internet Use Disorder (IUD). However, conclusions are strongly limited due to the retrospective case-control design of the studies, small samples, and the focus on general rather than symptom-specific approaches. MethodsWe here employed a dimensional multi-methodical MRI-neuroimaging design in a final sample of n = 203 subjects to examine associations between levels of IUD and its symptom-dimensions (loss of control/time management, craving/social problems) with brain structure, resting state and task-based (pain empathy, affective go/no-go) brain function. ResultsAlthough the present sample covered the entire range of IUD, including normal, problematic as well as pathological levels, general IUD symptom load was not associated with brain structural or functional alterations. However, the symptom-dimensions exhibited opposing associations with the intrinsic and structural organization of the brain, such that loss of control/time management exhibited negative associations with intrinsic striatal networks and hippocampal volume, while craving/social problems exhibited a positive association with intrinsic striatal networks and caudate volume. ConclusionsOur findings provided the first evidence for IUD symptom-domain specific associations with progressive alterations in the intrinsic structural and functional organization of the brain, particularly of striatal systems involved in reward, habitual and cognitive control processes.

neuroscience↗

bioRxiv2022

Genetic architecture of spatially complex color patterning in hybrid Mimulus

Coloration in living organisms varies in hue, saturation, and pattern. Here we use genetic mapping to investigate all three elements in monkeyflowers Mimulus luteus var. variegatus and M. cupreus, whose flower petals differ in both yellow carotenoid and magenta anthocyanin pigmentation and whose hybrids exhibit anthocyanin pattern variation not seen in either parent. We report two QTLs associated with carotenoid intensity, and show that lighter yellow petals accumulate relatively high proportions of beta-carotene at the expense of downstream carotenoids. We propose that the derived loss of carotenoid saturation in M. l. variegatus is due to a function-reducing mutation in a Beta-Carotene Hydroxylase candidate gene, coupled with a reduction in the availability of carotenoid-storing chromoplasts influenced by the ORANGE candidate gene. We next identify five QTLs associated with the spatial patterning of anthocyanin pigment. Two QTLs, 9b and 23, each contain genes in the anthocyanin-activating subgroup of the MYB family. We hypothesize that MYB5a/NEGAN, at QTL-9b, activates spot formation in hybrids as part of a Turing-type reaction-diffusion system, while a MYB at QTL-23 activates solid, unpatterned anthocyanin pigment and may also be able to activate the variegatus allele of MYB5a/NEGAN. In addition to the apparently stochastic placement of most spots (consistent with a Turing mechanism), some pattern aspects - notably spots at the petal tips - appear to conform to a positional specification model in which spot location is predetermined. Collectively, this work begins to identify how combinations of yellow and red hues, shifts in carotenoid intensity, and two cryptic patterning systems all contribute to the complexity of color divergence between two close relatives.

genetics↗

bioRxiv2022

Sweet taste receptor cells may participate in mucosal immune surveillance

The oral microbiome is second only to its intestinal counterpart in diversity and abundance, but its effects on taste cells remains largely unexplored. Using single cell RNASeq, we found that mouse taste receptor cells (STRCs) have a gene expression signature reminiscent of Microfold (M) cells, a central player in immune surveillance in the mucosa associated lymphoid tissue (MALT) such as those in the Peyers patch and tonsils. Administration of Tumor Necrosis Factor Ligand Superfamily Member 11 (TNFSF11, also known as RANKL), a growth factor required for differentiation of M cells dramatically increased M cell proliferation and marker gene expression in the taste papillae and in cultured taste organoids from wild type (WT) mice. Taste papillae and organoids from knockout mice lacking Spib (SpibKO), a RANKL-regulated transcription factor required for M cell development and regeneration on the other hand, failed to respond to RANKL. Taste papillae from SpibKO mice also showed reduced expression of NF-{kappa}B signaling pathway components and proinflammatory cytokines and attracted fewer immune cells. However, lipopolysaccharide-induced expression of cytokines was strongly upregulated in SpibKO mice compared to their WT counterparts. Like M cells, STRCs from WT but not SpibKO mice readily took up fluorescently labeled microbeads, a proxy for microbial transcytosis. The proportion of STRCs and other taste cell subtypes are unaltered in SpibKO mice; however, they displayed increased attraction to sweet and umami taste stimuli. We propose that STRCs are involved in immune surveillance at the taste papillae and tune their taste responses to microbial signaling and infection.

neuroscience↗

bioRxiv2022

Study on the interference of DicdsVg4 and DicdsVgR in egg formation in the ovary of Diaphorina citri (Kuwayama)

The ovary is the key organ in insect female oviposition. For the continuation of populations in nature, the whole life cycle of female adults is centred on reproduction. Vg and VgR genes are important in determining the synthesis and transport of vitellogenin. Therefore, Vg and VgR gene expression in insect females affects the formation of mature eggs in the ovary, which is very important. RNAi interference of Vg and VgR genes may become an important means to control D. citri populations. A study found that the expression of the DicVg4 and DicVgR genes was significantly affected by DicdsVg4 and DicdsVgR. DicVg4 and DicVgR gene expression interference could prevent the accumulation of vitellogenin in the ovaries of females, rendering ovaries unable to form mature eggs normally and leading to the production of abnormal eggs and nymphs. After knockdown of DicVg4 and DicVgR gene expression, the proportion of ovarian mature eggs was only 8.33 {+/-} 1.67% and 7.75 {+/-} 0.5% in the 10-d developmental stage, the proportion of negative control group ovarian mature eggs was 13.19 {+/-} 0.14% in the 10-d developmental stage, and the proportion of ovarian mature eggs in the interference group was 0.00 {+/-} 0.00% in the 5, 15, 20, 25, and 30-d developmental stages. These results provide a theoretical basis for the use of mixed polygene interference technology to control damage from D. citri populations.

biochemistry↗

bioRxiv2022

Additive and Dominant Loci Jointly Pyramiding the Grain Quality of Hybrid Rice

Hybrid rice has an advantage in its heterosis, resulting in high yield and resistance to biotic and abiotic stress. However, genetic improvement of grain quality is more challenging in hybrid rice than in inbred rice due to additional complexity, such as the dominant effect. It is critical to identify a path to efficiently develop inbreds and identify their superior crosses for hybrid production. Here, we developed a pipeline for joint analysis of phenotypes, effects, and generations (JPEG) and analysed 113 inbred varieties as male parents, five tester varieties as female parents, and their 565 (113x5) hybrid testcrosses for 12 grain quality traits, including grain length and width, chalkiness, and amylose content. A total of 1,619,588 single nucleotide polymorphisms were obtained for the parent varieties and inferred for the hybrids using whole-genome sequencing with an average sequencing depth of 11x. Genome-wide association studies with JPEG identified 128 loci associated with at least one of the 12 traits. There were 44 and 97 loci with additive and dominant effects, respectively, including 13 overlaps. Among the 128 associated loci, 42 loci are located in or near (<200 kb) 17 known genes. Pyramiding genetic loci with additive and/or dominant effects in genomic selection dramatically improves the accuracy of predicting hybrid performances. More than 45% of genetic variation was explained by the identified markers for all traits except one (30%). These results demonstrate that pyramiding genetically identified additive and dominant loci can afford substantial power for predicting hybrid performances, presenting opportunities to identify superior crosses from existing phenotypes and genotypes of inbreds and hybrids.

plant biology↗

bioRxiv2022

Noncoding RNA's competing endogenous gene pair as motif in serous ovarian cancer

The non-coding RNA (ncRNA) regulation apprears to be associated to the diagnosis and targeted therapy of complex diseases. Motifs of non-coding RNAs and genes in the competing endogenous RNA (ceRNA) network would probably contribute to the accurate prediction of serous ovarian carcinoma (SOC). Hence, we profiled a whole transcriptome of eight human SOCs and eight controls and constructed a ceRNA network including mRNAs, long ncRNAs, and circular RNAs (circRNAs). We identified the mRNA-ncRNA-mRNA motifs in the ceRNA network named the non-coding RNAs competing endogenous gene pairs (ceGPs), through the denoised individualized pair analysis of gene expression (deiPAGE) proposed in this study. 18 cricRNAs ceGPs (cceGPs) were identified from multiple cohorts and were fused as an indicator (SOC index) for SOC discrimination, which carried a high predictive capacity in independent cohorts. It was found that the index was negatively correlated with the CD8+/CD4+ ratio in tumour-infiltration, reflecting the migration and growth of tumour cells in ovarian cancer progression.

bioinformatics↗

bioRxiv2022

Effect of TSS on anti-CVB3 through TLR3 pathway

Toll-like receptors (TLRs) can recognize molecular patterns associated with microorganisms and induce immune responses. TLR3 is responsible for recognizing viruses and making hosts resistant to Coxsackie B3 (CVB3) infection. In this study, we found that Tectorigenin Sodium Sulfonate (TSS) has a TLR3 inhibitory effect and exerts strong anti-CVB3 activity through the TLR3 pathway both in vivo and in vitro. Balb/c mice were infected by ip injection of CVB3 virus, and subcutaneously injected with TSS at 264mg{middle dot}Kg-1{middle dot}d-1 for 7 d. The life extension rate of CVB3-infected mice was up to 46.67%, and the mean time to death was prolonged from 6.00 {+/-} 0.47 d to 8.80 {+/-} 2.78 d (P < 0.01). TSS was also able to reduce the level of weight loss in mice, significantly reduce the symptoms of myocarditis caused by CVB3, reduce the virus titer in the heart, improve the spleen and thymus index, and enhance immune function. We further explored the underlying mechanism of TSS in CVB3-infected HT-29 cells and mice: TSS reduced TLR3 expression and downregulated its downstream TRIF, TRAF6, IRF3, NF-{kappa} B. MAPK, AP1 expression, reduced expression of IFN-{beta}IL-6TNF-. TSS has strong anti-CVB3 activity in vitro and in vivo and has the effect of inhibiting the activation of TLR3 pathway. IMPORTANCETSS is expected to be an antiviral drug for the treatment of CVB3 infection. Its regulatory effect on the immune system provides a new approach for antiviral research.

pharmacology and toxicology↗

bioRxiv2022

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the inactivated vaccine BBIBP-CorV. Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

immunology↗

bioRxiv2022

The gender gap in academic career achievements and the mediation effect of work-family conflict and partner support

Parenthood has long been associated with gender disparities in academia. Yet, the underlying mechanism of how parenting is associated with career achievement gaps of academics remains unclear. Using data from a large-scale survey distributed to 7,764 scholars and their publication profiles from the Web of Science database, we analyze the gender differences in parenthood, academic achievements, and the mediation effect of work-family conflict and partner support in these gender gaps. Our results suggest that gender gaps in academic achievements are in fact "parenthood gaps". Specifically, we found significant gender gaps exist in all measures of objective and subjective career achievements of academics in the parent group but not in the non-parent group. Additionally, mothers are more likely than fathers to experience higher levels of work-family conflict, and receive lower levels of partner support, contributing significantly to the gender gaps in objective and subjective career achievements for the parent group. Findings from this study identify the forms and the impact of parenthood on gender disparities in career achievements of academics and shed light on possible interventions and actions for mitigating gender inequalities in academia.

scientific communication and education↗

bioRxiv2022

Mother cells control daughter cell proliferation in intestinal organoids to minimize proliferation fluctuations

During renewal of the intestine, cells are continuously generated by proliferation. Proliferation and differentiation must be tightly balanced, as any bias towards proliferation results in uncontrolled exponential growth. Yet, the inherently stochastic nature of cells raises the question how such fluctuations are limited. We used time-lapse microscopy to track all cells in crypts of growing mouse intestinal organoids for multiple generations, allowing full reconstruction of the underlying lineage dynamics in space and time. Proliferative behavior was highly symmetric between sister cells, with both sisters either jointly ceasing or continuing proliferation. Simulations revealed that such symmetric proliferative behavior minimizes cell number fluctuations, explaining our observation that proliferating cell number remained constant even as crypts increased in size considerably. Proliferative symmetry did not reflect positional symmetry, but rather lineage control through the mother cell. Our results indicate a concrete mechanism to balance proliferation and differentiation with minimal fluctuations, that may be broadly relevant for other tissues.

cell biology↗

bioRxiv2022

Earliest evidence for frugivory and seed dispersal by birds

The Early Cretaceous diversification of birds was a major event in the history of terrestrial ecosystems, occurring during the earliest phase of the Cretaceous Terrestrial Revolution. Frugivorous birds play an important role in seed dispersal today, and may have done so since their origins. However, evidence of this has been lacking. Jeholornis is one of the earliest-diverging birds, only slightly more derived than Archaeopteryx, but its cranial anatomy has been poorly understood, obscuring diet-related functional interpretations. Originally hypothesised to be granivorous based on seeds preserved as gut contents, this interpretation has become controversial. We conducted high-resolution synchrotron tomography on an exquisitely preserved new skull of Jeholornis, revealing remarkable cranial plesiomorphies combined with a specialised rostrum. We use this to provide a near-complete cranial reconstruction of Jeholornis, and exclude the possibility that Jeholornis was granivorous, based on morphometric analyses of the mandible (3D) and cranium (2D), and comparisons with the 3D alimentary contents of extant birds. We show that Jeholornis was at least seasonally frugivorous, providing the earliest evidence for fruit consumption in birds, and indicating that seed dispersal was present from early in the avian radiation. As highly-mobile seed dispersers, early frugivorous birds could expand the scope for biotic dispersal in plants, and may explain, in part, the subsequent evolutionary expansion of fruits, indicating a potential role of bird-plant interactions in the Cretaceous Terrestrial Revolution.

paleontology↗

bioRxiv2022

Assessing base-resolution DNA mechanics on the genome scale

Intrinsic DNA properties such as bending play a crucial role in diverse biological systems. A recent advantage in the high-throughput method called loop-seq makes it possible to determine bendability of hundred thousand 50-bp DNA duplexes in one experiment. However, its still infeasible to assess whole sequence bendability in large genomes such as human, which needs thousands of loop-seq experiments. Here we introduce BendNet - a neural network to accurately predict the intrinsic DNA bending at base-resolution by only given DNA sequences. BendNet can increase the resolution of experimental results, and can predict DNA bendability for any new given sequences in high accuracy. We applied BendNet to the human genome and observed high-stiffness regions located at both transcriptional start sites and transcriptional end sites. Such stiffness patterns are different for coding and non-coding genes, which matches distinct nucleosome occupancy patterns. As expected, most transcription factors (TFs) bind in DNA of low bendability. In contrast, we observed an unusually high bendability within binding elements of specific TFs such as EBF1 and regulators of genome folding such as CTCF. These factors either co-bind or compete with nucleosomes to carry out their functions. More interestingly, CTCF binding regions exhibit the highest bendability than other DNA elements, implying their potential role in trapping and holding the CTCF in the exact locations to make sure CTCF as stable anchor in loop extrusion process. Our work provides a tool to assess DNA bendability for large-scale DNA sequences and expands our understanding on DNA mechanics in chromatin regulation and genome folding.

genomics↗

bioRxiv2022

An evolutionarily conserved mechanism for control the translation of long proteins

Plants have evolved sophisticated mechanisms to regulate gene expression to activate immune responses against pathogen infections. However, how the translation system contributes to plant immunity is largely unknown. The evolutionarily conserved thiolation modification of tRNA ensures efficient decoding during translation. Here we show that tRNA thiolation is required for plant immunity in Arabidopsis. We identify a cgb Arabidopsis mutant, which is hyper-susceptible to the pathogen Pseudomonas syringae. CGB encodes ROL5, a homolog of yeast NCS6 required for tRNA thiolation. ROL5 physically interacts with CTU2, a homolog of yeast NCS2. Mutations in either ROL5 or CTU2 result in loss of tRNA thiolation. Further analyses reveal that both transcriptional reprogramming and translational reprogramming during immune responses are compromised in cgb. Notably, the translation of the salicylic acid receptor NPR1 is reduced in cgb, resulting in reduced salicylic acid signaling. Our study not only reveals a new regulatory mechanism for plant immunity but also uncovers a new biological function of tRNA thiolation.

biochemistry↗

bioRxiv2022

Metagenomic and Metabolomic Analyses Reveal Synergistic Effects of Fecal Microbiota Transplantation and Anti-PD-1 Therapy on Treating Colorectal Cancer

Anti-PD-1 immunotherapy has saved numerous lives of cancer patients; however, it only exerts efficacy in 10-15% of patients with colorectal cancer. Fecal microbiota transplantation (FMT) is a potential approach to improving the efficacy of anti-PD-1 therapy, whereas the detailed mechanisms and the applicability of this combination therapy remain unclear. In this study, we evaluated the synergistic effect of FMT with anti-PD-1 in curing colorectal tumor-bearing mice using a multi-omics approach. Mice treated with the combination therapy showed superior survival rate and tumor control, compared to the mice received anti-PD-1 therapy or FMT alone. Metagenomic analysis showed that composition of gut microbiota in tumor-bearing mice treated with anti-PD-1 therapy was remarkably altered through receiving FMT. Particularly, Bacteroides genus, including FMT-increased B. thetaiotaomicron, B. fragilis, and FMT-decreased B. ovatus might contribute to the enhanced efficacy of anti-PD-1 therapy. Furthermore, metabolomic analysis upon mouse plasma revealed several potential metabolites that upregulated after FMT, including punicic acid and aspirin, might promote the response to anti-PD-1 therapy via their immunomodulatory functions. This work broadens our understanding of the mechanism by which FMT improves the efficacy of anti-PD-1 therapy, which may contribute to the development of novel microbiota-based anti-cancer therapies.

microbiology↗