Biology subjects

Xiao, Y.

Publications and source records attributed to Xiao, Y..

At least 253 records · Page 14Linked to original sources

bioRxiv2022

Complex genetic architecture underlying the plasticity of maize agronomic traits

Phenotypic plasticity is the property of a given genotype to produce multiple phenotypes in response to changing environmental conditions. Understanding the genetic basis of phenotypic plasticity and establishing a predictive model is highly relevant for future agriculture under changing climate. Here, we report findings on the genetic basis of phenotypic plasticity for 23 complex traits using a maize diverse population, planted at five sites with distinct environmental conditions and genotyped with ~ 6.60 million SNPs. We found that altitude-related environmental factors were main drivers for across site variation in flowering time traits but not plant architecture and yield traits. For 23 traits, we detected 109 QTLs, of which 29 was for mean, 66 was for plasticity, and 14 for both parameters, besides, 80% of the QTLs were interreacted with the environment. The effects of several QTLs changed in magnitude or sign, driving variation in phenotype plasticity, and we further experimentally validated one plastic gene ZmTPS14.1 whose effect was likely mediated by the compensation effect of ZmSPL6 which was from the downstream pathway probably. By integrating genetic diversity, environmental variation, and their interaction in a joint model, we could provide site-specific predictions with increased accuracy by as much as 15.5%, 3.8%, and 4.4% for DTT, PH, and EW, respectively. Overall, we revealed a complex genetic architecture involving multiallelic, pleiotropy, and genotype by environment interaction underlying maize complex trait mean and plasticity variation. Our study thus provided novel insights into the dynamic genetic architectures of agronomic traits in response to changing environments, paving a practical route to precision agriculture.

genetics↗

bioRxiv2022

Task-specific neural processes underlying conflict resolution during cognitive control

Cognitive control involves flexibly combining multiple sensory inputs with task-dependent goals during decision making. Several tasks have been proposed to examine cognitive control, including Stroop, Eriksen-Flanker, and the Multi-source interference task. Because these tasks have been studied independently, it remains unclear whether the neural signatures of cognitive control reflect abstract control mechanisms or specific combinations of sensory and behavioral aspects of each task. To address this question, here we recorded invasive neurophysiological signals from 16 subjects and directly compared the three tasks against each other. Neural activity patterns in the theta and high-gamma frequency bands differed between incongruent and congruent conditions, revealing strong modulation by conflicting task demands. These neural signals were specific to each task, generalizing within a task but not across tasks. These results highlight the complex interplay between sensory inputs, motor outputs, and task demands and argue against a universal and abstract representation of conflict.

neuroscience↗

bioRxiv2022

A Computational Method to Dissect Colonization Resistance of the Gut Microbiota against Pathogens

The indigenous gut microbes have co-evolved with their hosts for millions of years. Those gut microbes play a crucial role in host health and disease. In particular, they protect the host against incursion by exogenous and often harmful microorganisms, a mechanism known as colonization resistance (CR). Yet, identifying the exact microbes responsible for the gut microbiota-mediated CR against a particular pathogen remains a fundamental challenge in microbiome research. Here, we develop a computational method --- Generalized Microbe-Phenotype Triangulation (GMPT) to systematically identify causal microbes that directly influence the microbiota-mediated CR against a pathogen. We systematically validate GMPT using a classical population dynamics model in community ecology, and then apply it to microbiome data from two mouse studies on C. difficile infection. The developed method will not only significantly advance our understanding of CR mechanisms but also pave the way for the rational design of microbiome-based therapies for preventing and treating enteric infections.

bioinformatics↗

bioRxiv2022

HMGN5 escorts oncogenic STAT3 signaling by regulating chromatin landscape in tumorigenesis of breast cancer

Epigenetic alterations are widely linked with carcinogenesis, therefore becoming emerging therapeutic targets in the treatment of cancers, including breast cancer. HMGNs are nucleosome binding proteins, which regulate chromatin structures in a cell type- and disease-specific manner. However, the roles of HMGNs in the tumorigenesis of breast cancer are less known. In this study, we report that HMGNs are highly expressed in 3D-cultured breast cancer cells. HMGN5, a member of HMGNs, controls the proliferation, invasion and metastasis of breast cancer cells in vitro and in vivo. Clinically, HMGN5 is an unfavorable prognostic marker in patients. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape oncogenic chromatin landscape and transcriptional program. Lastly, we provide evidence that interference of HMGN5 by nanoparticle-packaged siRNA is potentially an effective approach in breast cancer treatment. Taken together, our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic-target in STAT3- hyperactive breast cancer.

cancer biology↗

bioRxiv2021

Nucleocapsid 203 mutations enhance SARS-CoV-2 immune evasion

Previous work indicated that the nucleocapsid 203 mutation increase the virulence and transmission of the SARS-CoV-2 Alpha variant. However, Delta later outcompeted Alpha and other lineages, promoting a new wave of infections. Delta also possesses a nucleocapsid 203 mutation, R203M. Large-scale epidemiological analyses suggest a synergistic effect of the 203 mutation and the spike L452R mutation, associated with Delta expansion. Viral competition experiments demonstrate the synergistic effect in fitness and infectivity. More importantly, we found that the combination of R203M and L452R brings in a 3.2-fold decrease in neutralizing titers to the neutralizing serum relative to L452R-only virus. R203M/L452R show an increased fitness after the initiation of global vaccination programmes, possibly associated with the enhanced immune evasion. Another rapidly emerging variant Omicron also bears the 203 mutation. Thus, we proposed that nucleocapsid mutations play an essential role for the rise and predominance of variants in concern.

microbiology↗

bioRxiv2021

Reciprocity between retrograde signal and putative metalloprotease reconfigures plastidial metabolism and structure

Reconfiguration of the plastidial proteome in response to environmental inputs is central to readjustment of its metabolic and structural states. This is necessary for the functionality of this metabolic hub, and the maintenance of organismal integrity. This report establishes the role of the plastidial retrograde signaling metabolite, MEcPP, in increasing the abundance of the putative plastidial metalloprotease (VIR3), and the ensuing decline of VIR3 target enzymes, ascorbate peroxidase and glyceraldehyde 3-phophate dehydrogenase B. The decreased abundance of these enzymes is linked to increased levels of their substrates: H2O2, an elicitor of salicylic acid production and stromule formation; and G3P the substrate for MEcPP synthesis. High-light treatment of wild type plants recapitulated the VIR3-associated reconfiguration of the plastidial metabolic and structural states. These results identify a previously unrecognized link between the stress-induced plastidial retrograde signaling metabolite and a putative zinc-binding metalloprotease. Moreover, the data reveal that the reciprocity between these two components, results in the reconfiguration of the metabolic and structural states of the plastid, deemed necessary to maintain cellular integrity and to shape adaptive responses.

plant biology↗

bioRxiv2021

CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis

Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-{kappa}B pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose-dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.

cancer biology↗

bioRxiv2021

Improving Lab Culture Through Self-Assessment: A Case Study

PurposeMotivated by perceived dissatisfaction within our labs changed working environment brought about by the COVID-19 pandemic, we performed a self-assessment of our lab culture through anonymous surveys and live sessions. MethodsIn Survey 1, we asked each lab member to identify and rank up to 10 values that are important for a healthy lab environment. They were then asked to rate how well the lab embodied those values at two time points: before the COVID-19 pandemic while working onsite, and at the time of the survey while working remotely (10 months into the pandemic). In a series of live group sessions, we reviewed relevant literature and the survey results to finalize ten themes. We then reflected on each theme and proposed action items to address any deficiencies. Finally, we conducted Survey 2 after the self-assessment to judge the groups finalized themes, implemented changes, and overall satisfaction with the assessment process. ResultsThemes identified were attitude, accountability, teamwork/collaboration, communication, diversity/inclusion, emotional intelligence, integrity, training, well-being, and adaptability in crisis-management. All lab members liked the self-assessment process and felt their voices were heard. On average, there was a 12% increase in satisfaction across all themes from the start to end of the lab assessment. ConclusionWe successfully assessed the culture of our lab and subsequently improved lab member satisfaction. The success of this team project suggests that other scientific labs could benefit from similar interactive self-assessments.

scientific communication and education↗

bioRxiv2021

Genome Assembly and Population Resequencing Reveal the Geographical Divergence of 'Shanmei'(Rubus corchorifolius)

Rubus corchorifolius ( Shanmei or mountain berry, 2n =14) is widely distributed in China, and its fruit has high nutritional and medicinal values. Here, we report a high-quality chromosome-scale genome assembly of Shanmei, with a size of 215.69 Mb and encompassing 26,696 genes. Genome comparisons among Rosaceae species show that Shanmei and Fupenzi (Rubus chingii Hu) are most closely related, and then is blackberry (Rubus occidentalis). Further resequencing of 101 samples of Shanmei collected from four regions in provinces of Yunnan, Hunan, Jiangxi, and Sichuan in South China reveals that the Hunan population of Shanmei possesses the highest diversity and may represent the relatively more ancestral population. Moreover, the Yunnan population undergoes strong selection based on nucleotide diversity, linkage disequilibrium, and the historical effective population size analyses. Furthermore, genes from candidate genomic regions that show strong divergence are significantly enriched in flavonoid biosynthesis and plant hormone signal transduction, indicating the genetic basis of adaptation of Shanmei to the local environments. The high-quality genome sequences and the variome dataset of Shanmei provide valuable resources for breeding applications and for elucidating the genome evolution and ecological adaptation of Rubus species.

genomics↗

bioRxiv2021

Mapping morphological malformation to genetic dysfunction in blood vessel organoids with 22q11.2 Deletion Syndrome

DiGeorge Syndrome, or 22q11.2 deletion syndrome (22q11.2 DS), is a genetic disorder caused by microdeletions in chromosome 22, impairing the function of endothelial cells (EC) and/or mural cells and leading to deficits in blood vessel development such as abnormal aortic arch morphology, tortuous retinal vessels, and tetralogy of Fallot. The mechanism by which dysfunctional endothelial cells and pericytes contribute to the vasculopathy, however, remains unknown. In this study, we used human blood vessel organoids (VOs) generated from iPSC of 22q11.2 DS patients to model the vascular malformations and genetic dysfunctions. We combined high-resolution lightsheet imaging and single-cell transcriptome analysis to link the genetic profile and vascular phenotype at the single-cell level. We developed a comprehensive analytical methodology by integrating deep learning-mediated blood vessel segmentation, network graph construction, and tessellation analysis for automated morphology characterization. We report that 22q11.2DS VOs demonstrate a smaller size with increased angiogenesis/sprouting, suggesting a less stable vascular network. Overall, clinical presentations of smaller vascular diameter, less connected vasculature, and increased branch points were recapitulated in 22q11.2DS VOs. Single-cell transcriptome profiling showed heterogeneity in both 22q11.2DS and control VOs, but the former demonstrated alterations in endothelial characteristics that are organ-specific and suggest a perturbation in the vascular developmental process. Intercellular communication analysis indicated that the vascular dysfunctions in 22q11.2 deletion were due to a lower cell-cell contact and upregulated extracellular matrix organization involving collagen and fibronectin. Voronoi diagram-based tessellation analysis also indicated that the colocalization of endothelial tubes and mural cells was different between control and 22q11.2 VOs, indicating that alterations in EC and mural interactions might contribute to the deficits in vascular network formation. This study illustrates the utility of VO in revealing the pathogenesis of 22q11.2DS vasculopathy.

bioengineering↗

bioRxiv2021

The overlapping modular organization of human brain functional networks across the adult lifespan

Previous lifespan studies have demonstrated that the brain functional modular organization would change along with the adult lifespan. Yet, they assumed mutual exclusion among functional modules, ignoring convergent evidence for the existence of modular overlap. To reveal how age affects the overlapping functional modular organization, this study applied a detection algorithm requiring no prior knowledge of the resting-state fMRI data of a healthy cohort (N = 570, 18-88 years). Age-related regression analyses found a linear decrease in the overlapping modularity and the similarity of modular structure and overlapping node (i.e., region involved in multiple modules) distribution. The number of overlapping nodes increased with age, but the increment was distributed unevenly. In addition, across the adult lifespan and within each age group, the nodal overlapping probability consistently exhibited positive correlations with both functional gradient and flexibility. Further, we showed that the influence of age on memory-related cognitive performance might be explained by the change in the overlapping functional modular organization. Together, our results revealed age-related decreased segregation from the perspective of brain functional overlapping modular organization, providing new insight into the adult lifespan change in brain function and its influence on cognitive performance.

neuroscience↗

bioRxiv2021

Emergence of an adaptive epigenetic cell state in human bladder urothelial carcinoma evolution

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

cancer biology↗

bioRxiv2021

Disrupted intrinsic connectivity links to language and social deficits in toddlers with autism

Social and language abilities are closely intertwined during early development. Yet, it is still unknown how neural features underlying early social and language deficits are linked in toddlers with autism spectrum disorders (ASD). We examined functional connectivity of left and right temporal language regions and its correlations with language and social abilities in a cohort of 1- 4 years old toddlers (52 ASD/34 non-ASD). Further, ASD toddlers were stratified into those who strongly prefer social visual stimuli (ASDSoc) vs. those who do not (ASDnonSoc) based on performance on an eye-tracking paradigm. In non-ASD toddlers, connectivity between temporal regions and other language- and social-related cortical regions was significantly correlated with language, communication, and social scores. Conversely, ASD toddlers showed atypical correlations between temporal-visual cortex (cuneus) connectivity and communication ability. This temporal-visual connectivity was also correlated with social visual attention in ASDnonSoc but not in ASDSoc toddlers. These findings suggest language- and social-related functional connectivity was not correlated with language and social functions in ASD toddlers. Abnormal engagement of temporal-visual cortex connectivity may be an early-age signature of ASD and may help explain why interventions targeting social skills and language are so challenging, particularly in those with poor social engagement.

neuroscience↗

bioRxiv2021

Boundary domain genes were recruited to suppress bract growth and promote branching in maize

Grass inflorescence development is diverse and complex and involves sophisticated but poorly understood interactions of genes regulating branch determinacy and leaf growth. Here, we use a combination of transcript profiling, genetic and phylogenetic analyses to investigate tasselsheath1 (tsh1) and tsh4, two maize genes that simultaneously suppress inflorescence leaf growth and inhibit branching. We identify a regulatory network of inflorescence leaf suppression that involves the phase change gene tsh4 upstream of tsh1 and the ligule identity gene liguleless2 (lg2). We also find that a series of duplications in the tsh1 gene lineage facilitated its shift from boundary domain in non-grasses to suppressed inflorescence leaves of grasses. Collectively, these results suggest that the boundary domain genes tsh1 and lg2 were recruited to inflorescence leaves where they suppress growth and regulate a non-autonomous signaling center that promotes inflorescence branching, an important component of yield in cereal grasses.

plant biology↗

bioRxiv2021

Reference genomes of 545 silkworms enable high-throughput exploring genotype-phenotype relationships

The silkworm Bombyx mori is a domestic insect for silk production and a lepidopteran model. The currently available genomes limit a full understanding of its genetic and phenotypic diversity. Here we assembled long-read genomes of 545 domestic and wild silkworms and constructed a high-resolution pan-genome dataset. We found that the silkworm population harbors extremely variable genomes containing 7,308 new gene families, 4,260 (22%) core gene families, and 3,432,266 non-redundant SVs. We deciphered a series of causal genes and variants associated with domestication, breeding, and ecological adaptation traits, and experimentally validated two of those genes using CRISPR-Cas9 or RNA interference. This unprecedented large-scale genomic resource allows for high-throughput screening of interesting traits for functional genomic research and breeding improvement of silkworms and may serve as a guideline for traits decoding in other species.

genomics↗

bioRxiv2021

An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets

Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics, from pandemics caused by novel virus subtypes, and from viruses adapted to a variety of animals including poultry, pigs and horses. Vaccines that broadly protect against all such IAVs, so-called "universal" influenza vaccines, do not currently exist, but are urgently needed. This study demonstrates that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, is broadly protective against challenges with multiple IAV HA/NA subtypes in both mice and ferrets, including challenges with IAV subtypes not contained in the vaccine. This vaccine approach indicates the feasibility of eliciting broad "universal" IAV protection, and identifies a promising candidate for influenza vaccine clinical development. One-Sentence SummaryAn inactivated, whole avian influenza virus vaccine delivered intramuscularly or intranasally provides extremely broad protection against antigenically divergent viral challenge and is a promising candidate for a "universal" influenza virus vaccine.

microbiology↗

bioRxiv2021

STRIDE: accurately decomposing and integrating spatial transcriptomics using single-cell RNA sequencing

The recent advances in spatial transcriptomics have brought unprecedented opportunities to understand the cellular heterogeneity in the spatial context. However, the current limitations of spatial technologies hamper the exploration of cellular localizations and interactions at single-cell level. Here, we present spatial transcriptomics deconvolution by topic modeling (STRIDE), a computational method to decompose cell types from spatial mixtures by leveraging topic profiles trained from single-cell transcriptomics. STRIDE accurately estimated the cell-type proportions and showed balanced specificity and sensitivity compared to existing methods. We demonstrate STRIDEs utility by applying it to different spatial platforms and biological systems. Deconvolution by STRIDE not only mapped rare cell types to spatial locations but also improved the identification of spatial localized genes and domains. Moreover, topics discovered by STRIDE were associated with cell-type-specific functions, and could be further used to integrate successive sections and reconstruct the three-dimensional architecture of tissues. Taken together, STRIDE is a versatile and extensible tool for integrated analysis of spatial and single-cell transcriptomics and is publicly available at https://github.com/wanglabtongji/STRIDE.

bioinformatics↗

bioRxiv2021

Recruitment of an ancient branching program to suppress carpel development in maize flowers

Floral morphology is immensely diverse. One developmental process acting to shape this diversity is growth suppression. For example, grass flowers exhibit extreme diversity in floral sexuality, arising through differential suppression of stamens or carpels. In maize, carpels undergo programmed cell death in half of the flowers initiated in ears and in all flowers in tassels. The HD-ZIP I transcription factor gene GRASSY TILLERS1 (GT1) is one of only a few genes known to regulate this process. To identify additional regulators of carpel suppression, we performed a gt1 enhancer screen, and found a genetic interaction between gt1 and ramosa3 (ra3). RA3 is a classic inflorescence meristem determinacy gene that encodes a trehalose-6-phosphate (T6P) phosphatase (TPP). Dissection of floral development revealed that ra3 single mutants have partially derepressed carpels, whereas gt1; ra3 double mutants have completely derepressed carpels. Surprisingly, gt1 suppresses ra3 inflorescence branching, revealing a role for gt1 in meristem determinacy. Supporting these genetic interactions, GT1 and RA3 proteins colocalize to carpel nuclei in developing flowers. Global expression profiling revealed common genes misregulated in single and double mutant flowers, as well as in derepressed gt1 axillary meristems. Indeed, we found that ra3 enhances gt1 vegetative branching, similar to the roles for the trehalose pathway and GT1 homologs in the eudicots. This functional conservation over ~160 million years of evolution reveals ancient roles for GT1-like genes and the trehalose pathway in regulating axillary meristem suppression, later recruited to mediate carpel suppression. Our findings expose hidden pleiotropy of classic maize genes, and show how an ancient developmental program was redeployed to sculpt floral form.

plant biology↗