Biology subjects

Luo, A.

Publications and source records attributed to Luo, A..

28 records · Page 2Linked to original sources

bioRxiv2023

Generalizable links between symptoms of borderline personality disorder and functional connectivity

BackgroundSymptoms of borderline personality disorder (BPD) often manifest in adolescence, yet the underlying relationship between these debilitating symptoms and the development of functional brain networks is not well understood. Here we aimed to investigate how multivariate patterns of functional connectivity are associated with symptoms of BPD in a large sample of young adults and adolescents. MethodsWe used high-quality functional Magnetic Resonance Imaging (fMRI) data from young adults from the Human Connectome Project: Young Adults (HCP-YA; N = 870, ages 22-37 years, 457 female) and youth from the Human Connectome Project: Development (HCP-D; N = 223, age range 16-21 years, 121 female). A previously validated BPD proxy score was derived from the NEO Five Factor Inventory (NEO-FFI). A ridge regression model with 10-fold cross-validation and nested hyperparameter tuning was trained and tested in HCP-YA to predict BPD scores in unseen data from regional functional connectivity, while controlling for in-scanner motion, age, and sex. The trained model was further tested on data from HCP-D without further tuning. Finally, we tested how the connectivity patterns associated with BPD aligned with agerelated changes in connectivity. ResultsMultivariate functional connectivity patterns significantly predicted out-of-sample BPD proxy scores in unseen data in both young adults (HCP-YA; pperm = 0.001) and older adolescents (HCP-D; pperm = 0.001). Predictive capacity of regions was heterogeneous; the most predictive regions were found in functional systems relevant for emotion regulation and executive function, including the ventral attention network. Finally, regional functional connectivity patterns that predicted BPD proxy scores aligned with those associated with development in youth. ConclusionIndividual differences in functional connectivity in developmentally-sensitive regions are associated with the symptoms of BPD.

neuroscience↗

bioRxiv2023

Functional Connectivity Development along the Sensorimotor-Association Axis Enhances the Cortical Hierarchy

Human cortical maturation has been posited to be organized along the sensorimotor-association (S-A) axis, a hierarchical axis of brain organization that spans from unimodal sensorimotor cortices to transmodal association cortices. Here, we investigate the hypothesis that the development of functional connectivity during childhood through adolescence conforms to the cortical hierarchy defined by the S-A axis. We tested this pre-registered hypothesis in four large-scale, independent datasets (total n = 3,355; ages 5-23 years): the Philadelphia Neurodevelopmental Cohort (n = 1,207), Nathan Kline Institute-Rockland Sample (n = 397), Human Connectome Project: Development (n = 625), and Healthy Brain Network (n = 1,126). In each dataset, the development of functional connectivity systematically varied along the S-A axis. Connectivity in sensorimotor regions increased, whereas connectivity in association cortices declined, refining and reinforcing the cortical hierarchy. These robust and generalizable results establish that the sensorimotor-association axis of cortical organization encodes the dominant pattern of functional connectivity development.

neuroscience↗

bioRxiv2023

Neural Selectivity for Real-World Object Size In Natural Images

1Real-world size is a functionally important high-level visual property of objects that supports interactions with our physical environment. Critically, real-world-size is robust over changes in visual appearance as projected onto our retinae such that large and small objects are correctly perceived to have different real-world sizes. To better understand the neural basis of this phenomenon, we examined whether the neural coding of real-world size holds for objects embedded in complex natural scene images, as well as whether real-world size effects are present for both inanimate and animate objects, whether low- and mid-level visual features can account for size selectivity, and whether neural size tuning is best described by a linear, logarithmic, or exponential neural coding function. To address these questions, we used a large-scale dataset of fMRI responses to natural images combined with per-voxel regression and contrasts. Importantly, the resultant pattern of size selectivity for objects embedded in natural scenes was aligned with prior results using isolated objects. Extending this finding, we also found that size coding exists for both animate and inanimate objects, that low-level visual features cannot account for neural size preferences, and size tuning functions have different shapes for large versus small preferring voxels. Together, these results indicate that real-world size is an ecologically significant dimension in the larger space of behaviorally-relevant cortical representations that support interactions with the world around us.

neuroscience↗

bioRxiv2023

Ulinastatin Ameliorates Cardiac Ischemia/Reperfusion Injury via Inhibiting the tissue kallikrein-kinin system

BackgroundEndothelial cells (ECs) are considered more sensitive to cardiac ischemia/reperfusion (I/R) injury compared to cardiomyocytes. However, current research is mainly focused on molecular mechanisms and preventive strategies targeting cardiomyocyte I/R injury, whereas insufficient attention is placed on protecting endothelial function. Methods and ResultsIn this study, we established an interlink among ulinastatin (UIT; a serine protease inhibitor), the kallikrein-kinin system (KKS), and EC injury in response to cardiac reperfusion for the first time, using in vitro and in vivo experiments, and bioinformatic analysis. Our data indicated that UTI affected I/R by inhibiting the activation of KKS and simultaneously down-regulating both bradykinin receptor 1 (Bdkrb1) and bradykinin receptor 2 (Bdkrb2) related signaling such as extracellularsignal-regulated kinase (ERK)/inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS), thereby reducing infarct size, attenuating inflammation and edema, and improving cardiac function and mortality. Interestingly, UIT significantly suppressed KLK1 activity but did not down-regulate the KKS in normal conditions, suggesting inhibition of KLK1 might be the crucial mechanism for UIT-induced cardioprotection in reperfusion injury. Moreover, knockdown of Bdkrb1 in reperfusion-induced cardiac endothelial cells (MCECs) injury significantly prevented ERK translocation into the nucleus, reducing apoptosis, junction disruption, and expression levels of cytokines, whereas Bdkrb2 deletion could not protect MCECs against I/R injury. ConclusionsOur findings imply that inhibition of KLK1/Bdkrb1 is a critical target for UIT in the treatment of reperfusion-induced cardiac endothelial inflammation, apoptosis, and leakage and might be a potential therapeutic strategy for cardiac reperfusion injury.

cell biology↗

bioRxiv2022

Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

Proline hydroxylation (Hyp) regulates protein structure, stability and protein-protein interaction and is widely involved in diverse metabolic and physiological pathways in cells and diseases. To reveal functional features of the proline hydroxylation proteome, we integrated various data sources for deep proteome profiling of proline hydroxylation proteome in human and developed HypDB (https://www.HypDB.site), an annotated database and web server for proline hydroxylation proteome. HypDB provides site-specific evidence of modification based on extensive LC-MS analysis and literature mining with 15319 non-redundant Hyp sites and 8226 sites with high confidence on human proteins. Annotation analysis revealed significant enrichment of proline hydroxylation on key functional domains and tissue-specific distribution of Hyp abundance across 26 types of human organs and fluids and 6 cell lines. The network connectivity analysis further revealed a critical role of proline hydroxylation in mediating protein-protein interactions. Moreover, the spectral library generated by HypDB enabled data-independent analysis (DIA) of clinical tissues and the identification of novel Hyp biomarkers in lung cancer and kidney cancer. Taken together, our integrated analysis of human proteome with publicly accessible HypDB revealed functional diversity of Hyp substrates and provides a quantitative data source to characterize proline hydroxylation in pathways and diseases.

biochemistry↗

bioRxiv2021

Impacts of Taxon-Sampling Schemes on Bayesian Molecular Dating under the Unresolved Fossilized Birth-Death Process

Evolutionary timescales can be estimated using a combination of genetic data and fossil evidence based on the molecular clock. Bayesian phylogenetic methods such as tip dating and total-evidence dating provide a powerful framework for inferring evolutionary timescales, but the most widely used priors for tree topologies and node times often assume that present-day taxa have been sampled randomly or exhaustively. In practice, taxon sampling is often carried out so as to include representatives of major lineages, such as orders or families. We examined the impacts of these diversified sampling schemes on Bayesian molecular dating under the unresolved fossilized birth-death (FBD) process, in which fossil taxa are topologically constrained but their exact placements are not inferred. We used synthetic data generated by simulation of nucleotide sequence evolution, fossil occurrences, and diversified taxon sampling. Our analyses show that increasing sampling density does not substantially improve divergence-time estimates under benign conditions. However, when the tree topologies were fixed to those used for simulation or when evolutionary rates varied among lineages, the performance of Bayesian tip dating improves with sampling density. By exploring three situations of model mismatches, we find that including all relevant fossils without pruning off those inappropriate for the FBD process can lead to underestimation of divergence times. Our reanalysis of a eutherian mammal data set confirms some of the findings from our simulation study, and reveals the complexity of diversified taxon sampling in phylogenomic data sets. In highlighting the interplay of taxon-sampling density and other factors, the results of our study have useful implications for Bayesian molecular dating in the era of phylogenomics.

evolutionary biology↗

bioRxiv2021

T Cell Predominant Response to AAV-Spike Protects hACE2 Mice from SARS-CoV-2 Pneumonia

Prevention of COVID-19 is widely believed to depend on neutralization of SARS-CoV-2 by vaccine-induced humoral immunity1,2, raising concern that emerging escape variants may perpetuate the pandemic3-6. Here we show that a single intramuscular injection of Adeno-Associated Virus-6 (AAV6) or AAV9 encoding a modified, N-terminal domain deleted ({Delta}NTD) spike protein induces robust cellular immunity and provides long-term protection in k18-hACE2 transgenic mice from lethal SARS-CoV-2 challenge, associated weight loss and pneumonia independent of vaccine-induced neutralizing humoral immunity. In both mice and macaques, vaccine-induced cellular immunity results in the clearance of transduced muscle fibers coincident with macrophage and CD8+ cytotoxic T cell infiltration at the site of immunization. Additionally, mice demonstrate a strong Type-1 polarized cellular immunophenotype and equivalent ex vivo T cell reactivity to peptides of wt and alpha (B.1.1.7) variant spike. These studies demonstrate not only that AAV6 and AAV9 can function as effective vaccine platforms, but also that vaccines can provide long-term efficacy primarily through the induction of cellular immunity. The findings may provide an alternative approach to containment of the evolving COVID-19 pandemic and have broader implications for the development of variant-agnostic universal vaccines against a wider range of pathogens.

immunology↗

bioRxiv2020

A transposon surveillance mechanism that safeguards plant male fertility during stress

Although plants are able to withstand a range of environmental conditions, spikes in ambient temperature can impact plant fertility causing reductions in seed yield and significant economic losses1,2. Therefore, understanding the precise molecular mechanisms that underpin plant fertility under environmental constraints is critical to safeguard future food production3. Here, we identified two Argonaute-like proteins whose activities are required to sustain male fertility in maize plants under high temperatures. We found that MALE-ASSOCIATED ARGONAUTE 1 and 2 (MAGO1 and MAGO2) associate with temperature-induced phased secondary small RNAs in pre-meiotic anthers and are essential to control the activity of retrotransposons in male meiocyte initials. Biochemical and structural analyses revealed how MAGO2 activity and its interaction with retrotransposon RNA targets are modulated through the dynamic phosphorylation of a set of highly conserved surface-located serine residues. Our results demonstrate that an Argonaute-dependent RNA-guided surveillance mechanism is critical in plants to sustain male fertility under environmentally constrained conditions by controlling the mutagenic activity of transposons in male germ cells.

plant biology↗

bioRxiv2020

Fluorescent Detection of O-GlcNAc via Tandem Glycan Labeling

ABSTRACTO-GlcNAcylation is a reversible serine/threonine glycosylation on cytosolic and nuclear proteins that are involved in various regulatory pathways. However, the detection and quantification of O-GlcNAcylation substrates have been challenging. Here we report a highly efficient method for the identification of O-GlcNAc modification via tandem glycan labeling, in which O-GlcNAc is first galactosylated and then sialylated with a fluorophore-conjugated sialic acid residue, therefore enabling highly sensitive fluorescent detection. The method is validated on various proteins that are known to be modified by O-GlcNAcylation including CK2, NOD2, SREBP1c, AKT1, PKM and PFKFB3, and on the nuclear extract of HEK293 cells. Using this method, we then report the evidence that hypoxia-inducible factor HIF1α is a target for O-GlcNAcylation, suggesting a potential direct connection between the metabolic O-GlcNAc pathway and the hypoxia pathway.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗

bioRxiv2018

A Simulation-Based Evaluation of Total-Evidence Dating Under the Fossilized Birth-Death Process

Bayesian molecular dating is widely used to study evolutionary timescales. This procedure usually involves phylogenetic analysis of nucleotide sequence data, with fossil-based calibrations applied as age constraints on internal nodes of the tree. An alternative approach is Bayesian total-evidence dating, which involves the joint analysis of molecular data from present-day taxa and morphological data from both extant and fossil taxa. Part of its appeal stems from the fossilized birth-death process, which provides a model of lineage diversification for the prior on the tree topology and node times. However, total-evidence dating faces a number of considerable challenges, especially those associated with fossil sampling and evolutionary models for morphological characters. We conducted a simulation study to evaluate the performance of total-evidence dating with the fossilized birth-death model. We simulated fossil occurrences and the evolution of nucleotide sequences and morphological characters under a wide range of conditions. Our analyses show that fossil occurrences have a greater influence than the degree of among-lineage rate variation or the number of morphological characters on estimates of node times and the tree topology. Total-evidence dating generally performs well in recovering the relationships among extant taxa, but has difficulties in correctly placing fossil taxa in the tree and identifying the number of sampled ancestors. The method yields accurate estimates of the origin time of the fossilized birth-death process and the ages of the root and crown group, although the precision of these estimates varies with the probability of fossil occurrence. The exclusion of morphological characters results in a slight overestimation of node times, whereas the exclusion of nucleotide sequences has a negative impact on inference of the tree topology. Overall, our results provide a detailed view of the performance of total-evidence dating, which will inform further development of the method and its application to key questions in evolutionary biology.

evolutionary biology↗